Prognostic Factor In Glioblastoma Patients Research Articles

STMO-08 INFLUENCE OF WIDE OPENING OF THE LATERAL VENTRICLE ON SURVIVAL FOR SUPRATENTORIAL GLIOBLASTOMA PATIENTS WITH RADIOTHERAPY AND CONCOMITANT TEMOZOLOMIDE-BASED CHEMOTHERAPY

BACKGROUNDThe prognosis for glioblastoma (GBM) varies among patients. Ventricular opening during surgery has been reported as a prognostic factor for GBM patients, but the influence of ventricular opening itself on patient prognosis remains controversial.OBJECTIVEAccumulating evidence has suggested that the subventricular zone (SVZ) harbors a neural stem cell niche and is associated with gliomagenesis. Several reports have hypothesized that aggressive characteristics of GBM in contact with the SVZ may be associated with the recruitment of neural stem cells from the SVZ that have abilities associated with invasive proliferation, leading to poor prognosis. We presumed that the degree of ventricular opening would correlate with the degree of SVZresection and with prognosis in GBM patients. This study therefore investigated whether the degree of ventricular opening correlates with prognosis in GBM patients treated with the standard protocol of chemo-radiotherapy.METHODSParticipants comprised 111 patients with newly diagnosed GBM who underwent surgery and postoperative radiotherapy and TMZ-based chemotherapy from 2005 to 2018. We classified 111 patients into “No ventricular opening” (NVO), “Ventricular opening, small” (VOS; distance < 21 mm) and “Ventricular opening, wide” (VOW; distance > 21 mm) groups. We evaluated the relationship between degree of ventricular opening and prognosis using survival analyses that included other clinicopathological factors.RESULTSLog-rank testing revealed age, KPS, extent of resection, MGMT status, IDH1 mutation, and degree of ventricular opening correlated significantly with overall survival. Multivariate analysis identified the degree of ventricular opening (small vs. wide) as the most significant prognostic factor (hazard ratio = 3.674; p < 0.0001).CONCLUSIONSWe demonstrated that wide opening of the lateral ventricle (LV) contributes to longer survival compared with small opening among GBM patients. Our results indicate that wide opening of the LV may correlate with the removal of a larger proportion of tumor stem cells from the SVZ.

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.

Influence of wide opening of the lateral ventricle on survival for supratentorial glioblastoma patients with radiotherapy and concomitant temozolomide-based chemotherapy.

The prognosis for glioblastoma (GBM) varies among patients. Ventricular opening during surgery has been reported as a prognostic factor for GBM patients, but the influence of ventricular opening itself on patient prognosis remains controversial. We presumed that the degree of ventricular opening would correlate with the degree of subventricular zone (SVZ) resection and with prognosis in GBM patients. This study therefore investigated whether the degree of ventricular opening correlates with prognosis in GBM patients treated with the standard protocol of chemo-radiotherapy. Participants comprised 111 patients with newly diagnosed GBM who underwent surgery and received postoperative radiotherapy and temozolomide-based chemotherapy from 2005 to 2018. We classified 111 patients into "No ventricular opening (NVO)", "Ventricular opening, small (VOS; distance < 23.2mm)", and "Ventricular opening, wide (VOW; distance ≥ 23.2mm)" groups. We evaluated the relationship between degree of ventricular opening and prognosis using survival analyses that included other clinicopathological factors. Log-rank testing revealed age, Karnofsky performance status (KPS), extent of resection, O6-methylguanine-DNA methyltransferase (MGMT) status, isocitrate dehydrogenase (IDH)1 mutation, and degree of ventricular opening correlated significantly with overall survival. Multivariate analysis identified the degree of ventricular opening (small vs. wide) as the most significant prognostic factor (hazard ratio = 3.674; p < 0.0001). We demonstrated that wide opening of the lateral ventricle (LV) contributes to longer survival compared with small opening among GBM patients. Our results indicate that wide opening of the LV may correlate with the removal of a larger proportion of tumor stem cells from the SVZ.

Clinical observation of lymphopenia in patients with newly diagnosed glioblastoma.

Lymphopenia in patients with glioblastoma (GBM) is related to treatment as well as disease progression. This retrospective study investigated the prevalence, influencing factors, recoverability, and clinical significance of lymphopenia in GBM patients treated with concomitant chemoradiotherapy (CCRT). A total of 219 patients with newly diagnosed GBM who had received at least 3 cycles of adjuvant temozolomide (TMZ) followed by CCRT with TMZ were enrolled. Serial data on complete blood cell counts, including differential cell counts, were collected just before a new phase and before every treatment cycle of the regimen. Relationships between white blood cell (WBC) variable changes and treatment modalities as well as survival were analyzed. Lymphopenia was classified using the definition of the Common Terminology Criteria for Adverse Events version 5.0. A total of 92 patients (42.0%) showed decreased levels of lymphocytes (< 1500/µL) at baseline. The WBC count, absolute neutrophil count, lymphocyte count, and neutrophil-to-lymphocyte ratio were all significantly decreased after RT/TMZ treatment and did not recover during the adjuvant TMZ period. However, these metrics all began to recover 3months after the last TMZ cycle, except for the lymphocyte count. The proportion of lymphopenia patients (< 1500 lymphocytes/µL) increased to 74.8% after RT/TMZ and remained steady at approximately 71.5% (range 63.7-75.3%) throughout the management period. Moreover, the number of patients with grade 3 lymphopenia (< 500 lymphocytes/µL) also increased significantly after treatment to reach 2.9% (from 0.9% at baseline). Statistically, 75.7% of lymphopenia patients were predicted to recover in a median time of 240.3days (95% confidence interval ± 104.7days) after TMZ withdrawal. There were no dose-dependent relationships between RT or TMZ and lymphopenia. Grade 3 (< 500 lymphocytes/µL) lymphopenia measured at 1month after RT/TMZ predicted significantly reduced survival (13.0months vs. 19.5months, p = 0.011). Lymphopenia is a frequent event during GBM disease progression and treatment. Treatment-related lymphopenia is profound and prolonged and can be used as a prognostic factor for GBM patients.

Transient Receptor Potential Mucolipin-1 Channels in Glioblastoma: Role in Patient's Survival.

A link between mucolipin channels and tumors has been recently suggested. Herein, we aim to investigate the transient receptor potential mucolipin (TRPML)-1 relevance in glioblastoma. The expression of this channel was evaluated via qRT-PCR and immunohistochemistry in biopsies from 66 glioblastoma patients and two human glioblastoma cell lines and compared to normal human brain, astrocytes, and epileptic tissues. The subcellular distribution of TRPML-1 was examined via confocal microscopy in the glioma cell lines. Then, to assess the role of TRPML-1, cell viability assays have been conducted in T98 and U251 cell lines treated with the specific TRPML-1 agonist, MK6-83. We found that MK6-83 reduced cell viability and induced caspase-3-dependent apoptosis. Indeed, the TRPML-1 silencing or the blockage of TRPML-1 dependent [Ca2+]i release abrogated these effects. In addition, exposure of glioma cells to the reactive oxygen species (ROS) inducer, carbonyl cyanide m-chlorophenylhydrazone (CCCP), stimulated a TRPML-1-dependent autophagic cell death, as demonstrated by the ability of the autophagic inhibitor bafilomycin A, the TRPML-1 inhibitor sphingomyelin, and the TRPML-1 silencing to completely inhibit the CCCP-mediated effects. To test a possible correlation with patient’s survival, Kaplan–Meier, univariate, and multivariate analysis have been performed. Data showed that the loss/reduction of TRPML-1 mRNA expression strongly correlates with short survival in glioblastoma (GBM) patients, suggesting that the reduction of TRPML-1 expression represents a negative prognostic factor in GBM patients.

387P - Corticosteroids administration as a prognostic factor in glioblastoma patients: An Egyptian experience

Background: Glioblastoma multiform (GBM) is the most common primary malignant brain tumors. Standard management is maximal safe resection followed by concurrent chemoradiotherapy then adjuvant chemotherapy with temozolomide TMZ. Management of GBM patients also involves medical treatment containing corticosteroids that might have direct effects on tumor cell proliferation and apoptosis. We aimed at discussing the clinical relation between corticosteroids usage in GBM patients, overall survival OS, and progression free survival PFS, according to the records from Clinical Oncology Department, Ain Shams University, Cairo, Egypt. Methods: Retrospective analysis was performed on 66 adult patients diagnosed with GBM by surgery or imaging criteria between January 2014 and December 2016. Data analysis was performed on October 2017 to assess the relation between corticosteroid dependence (defined as the failure to withdraw the corticosteroids after their initiation during the treatment with radiotherapy and TMZ) with OS and PFS. Patients were arranged in 2 arms according to steroid dependency. Arm (A) was steroid dependent (34 patients) and arm (B) was steroid non-dependent (32 patients). Results: The median age of the entire cohort was 52.8 years (Range 25-72) with male predominance (68.1%) and 72.7 % of the patients received radiotherapy as their main treatment. 59.1 % of the whole cohort were treated by standard radiotherapy regimen of 60 Gy, while 13.6 % were treated by hypo-fractionation radiotherapy with total dose of 45 Gy. 62.1 % of the patients received TMZ concurrently with radiotherapy. Corticosteroids dependency was statistically significantly correlated to both OS with a median of 2.5 months in the corticosteroids dependent group vs. 13.1 months in the corticosteroids non-dependent group (p < 0.001), and also to PFS with a median of 2.3 in the corticosteroids dependent group vs. 9.4 months in the corticosteroid non- dependent group (p = 0.035). Conclusions: This study from an Egyptian center shows that dependence on corticosteroids during the course of treatment of GBM patients may affect survival. Larger multicentric studies are needed to elaborate the influence of corticosteroids on the disease course. Legal entity responsible for the study: Clinical Oncology Department, Ain Shams University, Cairo, Egypt. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Molecular Study of Long-Term Survivors of Glioblastoma by Gene-Targeted Next-Generation Sequencing.

Glioblastoma (GBM) is the most common malignant adult primary brain tumor. Despite its high lethality, a small proportion of patients have a relatively long overall survival (OS). Here we report a study of a series of 74 GBM samples from 29 long-term survivors ([LTS] OS ≥36 months) and 45 non-LTS. Using next-generation sequencing, we analyzed genetic alterations in the genes most frequently altered in gliomas. Approximately 20% of LTS had a mutation in the IDH1 or IDH2 (IDH) genes, denoting the relevance of this molecular prognostic factor. A new molecular group of GBMs harbored alterations in ATRX or DAXX genes in the absence of driver IDH or H3F3A mutations. These patients tended to have a slightly better prognosis, to be younger at diagnosis, and to present frontal or temporal tumors, and, morphologically, to present giant tumor cells. A significant fraction of LTS GBM patients had tumors with 1 or more alterations in the relevant GBM signaling pathways (RTK/PI3K, TP53 and RB1). In these patients, the PDGFRA alteration is suggested to be a favorable molecular factor. Our findings here are relevant for developing future targeted therapies and for identifying molecular prognostic factors in GBM patients.

Decreased BRMS1L expression is correlated with glioma grade and predicts poor survival in glioblastoma via an invasive phenotype.

To evaluate the prognostic and clinicopathological features of glioma with BRMS1L expression. Total 120glioma samples were obtained as discovery cohort. CGGA, GSE and TCGA datasets were obtained as validation sets. Furthermore, Kaplan-Meier survival and multivariate Cox analysis were used to evaluate the survival distributions. Moreover, the functional role of BRMS1L was also analyzed by transwell assay. In the discovery cohort, decreased BRMS1L expression was significantly associated with high-grade glioma as well as the higher mortality in survival analysis (log-rank test, p< 0.01). And the three validation cohorts showed the similar results. Furthermore, BRMS1L act as an independent prognostic factor in glioblastoma patients. Additionally, functional assay showed that ectopic of BRMS1L suppressed glioma cells' invasion. BRMS1L plays as an anti-oncogene in GBM and indicates a new potential therapeutic target.

A large, multicenter, retrospective study to identify a cutoff of MGMT methylation status by quantitative pyrosequencing approach in patients (PTS) with glioblastoma (GBM).

2012A LARGE, MULTICENTER, RETROSPECTIVE STUDY TO IDENTIFY A CUT-OFF OF MGMT METHYLATION STATUS BY QUANTITATIVE PYROSEQUENCING APPROACH IN PATIENTS (PTS) WITH GLIOBLASTOMA (GBM). Background: MGMT pr...

Gender and MGMT methylation in glioblastoma patients: interactions in the PERNO prospective study

Background: Glioblastoma (GBM) remains an incurable disease. Radiotherapy and temozolomide are the backbone of the treatment. Clinical and molecular factors are essential to define prognosis. Methods: Data on all new cases of primary brain tumors observed from January 1, 2009, to December 31, 2010, in adults residing within the Emilia-Romagna region were recorded in a prospective registry in the Project of Emilia Romagna on Neuro-Oncology (PERNO). We perform a prospective evaluation about prognostic factors in GBM patients treated with temozolomide concurrent with and adjuvant to radiotherapy. Results: One hundred sixty-nine GBM patients (median age, 60 years; range 29 – 82) were prospectively evaluated. MGMT methylation status was available in 140 patients. Combining gender and MGMT methylation status we obtained four groups of patients: 36 male pts with methylated MGMT (25.7%), 47 male pts with unmethylated MGMT (33.6%), 32 female pts with methylated MGMT (22.9%), 25 female pts with unmethylated MGMT (17.9%). Results of univariate analysis are summarized in the table 1.Table: M1nmOS95%CImethylated male3116.39.2 -23.4unmethylated male4115.611.8 - 19.5methylated female26nrunmethylated female2117.011.8 - 22.2total11917.015.2 - 18.9 Open table in a new tab Overall survival (OS) was significantly different between methylated male and methylated female (p = 0.028), methylated male and unmethylated female (p = 0.031), unmethylated male and methylated female (p = 0.002), methylated female and unmethylated female (p < 0.001). In multivariate analysis, gender and MGMT methylation considered together (met female vs met male HR = 0.459; 95% CI 0.242 – 0.827; p = 0.017), age (HR 1.025; 95% CI 1.002 – 1.049; p = 0.032) and Karnofsky Performance Status (KPS) (HR 0.965; 95% CI 0.948 – 0.982; p < 0.001) were significantly correlated with OS. Conclusions: The median overall survival is consistently higher for female pts with methylated MGMT, treated with temozolomide concurrent with and adjuvant to radiotherapy. When considered simultaneously with MGMT methylation status, gender might impact on clinical outcome and should be considered as a prognostic factor.

Galectin-1 (Gal-1) expression as a prognostic factor in patients with newly diagnosed glioblastoma (GB) treated with Stupp regimen (GLIOCAT study).

e13526 Background: Gal-1 is a β-galactoside binding protein that plays an important role in cancer, promoting cell invasion, proliferation, migration, angiogenesis and evasion of the immune response. Gal-1 is involved in glioma progression and is related to tumor grade and poor clinical outcome. Gal-1 has been implicated in resistance to chemotherapy and as a potential mediator of resistance to anti-VEGF therapy. The aim of our study was to evaluate the prognostic significance of Gal-1 in a homogenous cohort of GB patients and to analyze its potential predictive value of response to bevacizumab at recurrence. Methods: A substudy of GLIOCAT, a multicenter study of newly diagnosed GB patients treated with standard Stupp regimen (previously reported). GLIOCAT enrolled 432 patients between 2005-2014. Tissue was available from 243 cases, from which a tissue microarray (TMA) was constructed. Gal-1 expression in tissue from initial surgery was analyzed by immunohistochemistry. Results were evaluated by three reviewers and quantified by H-score. Expression levels were correlated with clinical outcome, known GB prognostic factors and response to bevacizumab. Results: We defined a cut off for Gal-1 H-Score of &gt;60 (cytoplasm) and &gt;25 (nucleus). HighcytoplasmicGal-1 expression significantly correlated with worse OS and with a trend for shorter PFS. In the multivariate analysis KPS, age, MGMT methylation status and, extent of resection but not Gal-1 expression were independent prognostic factors for survival. Of 92 patients who received bevacizumab at recurrence, only 54 were included in the TMA, and only 1 had low Gal-1 expression. We couldn’t find any relationship with OS or PFS in this population. Conclusions: Gal-1 expression may represent a prognostic factor for GB patients treated with standard therapy. [Table: see text]

Prognostic value of CDKN2A mRNA level in glioblastoma

Objective To investigate the prognostic value of CDKN2A mRNA in glioblastoma (GBM). Methods CDKN2A gene mRNA data were obtained from three different GBM database online (TCGA, REMBARNDT and GSE16011). The correlations between overall survival (OS) and CDKN2A expression were analyzed by Kaplan-Meier method and multivariate Cox regression analysis. Results In the TCGA database (n = 358), patients with high CDKN2A mRNA level got longer OS than those with low expression level [median OS: 18.0 months (95 % CI 15.0-21.0 months) vs 13.9 months (95 % CI 12.4-15.4 months), P= 0.001]. In another two validation datasets, patients with high CDKN2A mRNA level had longer OS than those with low expression level [median OS in REMBRANT: 16.6 months (95 % CI 13.3-19.8 months) vs 11.8 months (95 % CI 7.3-16.4 months), P= 0.019; in GSE16011: 11.9 months (95 % CI 8.3-15.6 months) vs 8.4 months (95 % CI 6.2-10.5 months), P= 0.005]. CDKN2A mRNA level was an independent prognostic factor for GBM. The combination of CDKN2A mRNA expression with MGMT promoter methylation status or G-CIMP status/IDH1 mutations provided an optimized prognostic factor in GBM patients. Conclusion The CDKN2A mRNA has prognostic value in GBM patients, which provided an optimized stratification strategy based on multiple biomarkers. Key words: Glioblastoma; CDKN2A gene; Prognostic factor

PO33CORRELATION BETWEEN EXTEND OF RESECTION IN DIFFUSION TENSOR MR AND GLIOBLASTOMA PATIENT OUTCOME

INTRODUCTION: Extent of resection (EOR) based on the T1 contrast MRI had been shown as an important prognostic factor in glioblastoma patients. However, tumor can extend beyond these areas. These invasive regions can be detected using diffusion tensor imaging (DTI) due to subtle white mater change. This study is to analyze the influence of extending resection into the DTI-determined invasive region with patient outcome. METHOD: Immediate (within 72 hours) post-operative MRI were reviewed from 14 patients who had undergone 5-ALA guided resection of a glioblastoma. Post-operative images were further co-registered with pre-operative images for calculating volumetric change. DTI was split into isotropic (p) and anisotropic (q) components. Extent of resection was assessed in p map, q map, T2 Flair and T1 contrast enhanced MR images by using 3D volumetric calculator. RESULTS: The EOR of the p map showed significant correlation to both event free survival and progression free survival (PFS) (r2 = 0.3991, 0.4415; p value = 0.015, 0.0257). Further multiple regression study with age and EOR based on T1 contrast MR revealed a higher correlation between PFS and EOR (r2 = 0.632, p value =0.01). There was no correlation with overall survival or with the EOR of q map and FLAIR to any clinical outcomes. CONCLUSION: DTI can detect tumor outside T1 contrast enhanced image and extending resections beyond this region appears to be associated with a prolonged progression free survival.

R03 - Prognostic factors in glioblastoma patients treated with the nitrosourea fotemustine at first relapse after the Stupp regimen: results from the GLIOSTRY (GLIOblastoma regiSTRY) of the AINO (Italian Association of Neuro-Oncology)

R03 - Prognostic factors in glioblastoma patients treated with the nitrosourea fotemustine at first relapse after the Stupp regimen: results from the GLIOSTRY (GLIOblastoma regiSTRY) of the AINO (Italian Association of Neuro-Oncology)

High expression of CXCR3 is an independent prognostic factor in glioblastoma patients that promotes an invasive phenotype.

Chemokines are a superfamily of small heparin-binding cytokines that induce leukocytes to migrate to sites of inflammation or injury through interacting with specific transmembrane G protein-coupled receptors. Currently, attention is focused on chemokine/chemokine receptor pairs and their ability to promote tumor cell migration and angiogenesis. The chemokine receptor CXCR3 is involved in tumor metastasis and is used as a prognostic biomarker. However, its relationship with the clinicopathological features of primary glioblastoma multiforme (pGBM) and its potential prognostic value have yet to be investigated. Here, we report that high CXCR3 expression conferred poor survival in pGBM patients. Further analysis showed that CXCR3 served as an independent prognostic biomarker for pGBM patients. In addition, functional assays indicated that CXCR3 induced glioma cell invasion. Therefore, this evidence indicates CXCR3 is an independent prognostic factor for pGBM patients and promotes an invasive phenotype, which suggests a new potential biotarget for glioblastoma multiforme therapy.

O9.06 * PROGNOSTIC RELEVANCE AND ONCOGENIC CORRELATES OF EPILEPSY IN GLIOBLASTOMA PATIENTS

BACKGROUND: In 30-40% of glioblastoma patients, the disease present with an epileptic seizure. Some studies suggest that tumor-associated epilepsy influences the survival of glioblastoma patients, possibly due to early diagnosis or the tumors' biology. However, the in vivo mechanisms underlying the suggested prognostic effect of epilepsy in glioblastoma patients are still unclear. METHODS: In a retrospective cohort study, we investigated the effect of epilepsy on survival of 230 glioblastoma patients using multivariate Weibull analysis. Gene set enrichment analyses defined the transcriptional effects of epilepsy and anti-epileptic drug treatments using gene expression microarrays of 50 fresh frozen surgical specimens. Protein expression was analyzed using immunohistochemistry on tissue microarrays containing surgical specimens of 230 patients. In vitro reporter gene assays, western blotting, kinase assays and immunocytochemistry experiments were performed to confirm our findings. RESULTS: Epilepsy is an independent prognostic factor in glioblastoma patients (HR 0.71, 95%CI: 0.53 - 0.96, p = 0.024), irrespective of other clinical characteristics. The epilepsy subgroup displayed a distinct gene expression pattern, with a significant downregulation of, notably, the oncologically relevant NF-κB, C/EBPβ and STAT3, -5A and -5B transcription factor associated genes. At a protein level, a significant downregulation of phosphorylated STAT3 and C/EBPβ expression, but not of phosphorylated STAT5b or NF-κB p65, was confirmed in the surgical samples. In addition, a significant repression of NF-κB was observed in the patients who were treated with the anti-epileptic drug valproic acid (VPA) prior to their surgery. In vitro, VPA inhibited NF-κB transcriptional activity and was shown to increase acetylated histone H3 and H4 expression. CONCLUSION: Glioblastoma patients with tumor-associated epilepsy form a distinct subgroup with a favorable prognosis and a distinct gene expression pattern involving downregulation of oncologically relevant pathways. The anti-epileptic drug VPA downregulates NF-κB signaling, which might, as suggested in recent literature, contribute to a longer survival of glioblastoma patients.

Role of Cysteine-rich 61 Protein (CCN1) in Macrophage-mediated Oncolytic Herpes Simplex Virus Clearance

Glioblastoma is a devastating disease, and there is an urgent need to develop novel therapies, such as oncolytic HSV1 (OV) to effectively target tumor cells. OV therapy depends on tumor-specific replication leading to destruction of neoplastic tissues. Host responses that curtail virus replication limit its efficacy in vivo. We have previously shown that cysteine-rich 61 protein (CCN1) activates a type 1 IFN antiviral defense response in glioblastoma cells. Incorporating TCGA data, we found CCN1 expression to be a negative prognostic factor for glioblastoma patients. Based on this, we used neutralizing antibodies against CCN1 to investigate its effect on OV therapy. Use of an anti-CCN1 antibody in mice bearing glioblastomas treated with OV led to enhanced virus expression along with reduced immune cell infiltration. OV-induced CCN1 increases macrophage migration toward infected glioblastoma cells by directly binding macrophages and also by enhancing the proinflammatory activation of macrophages inducing MCP-1 expression in glioblastoma cells. Activation of macrophages by CCN1 also increases viral clearance. Neutralization of integrin αMβ2 reversed CCN1-induced macrophage activation and migration, and reduced MCP-1 expression by glioblastoma cells. Our findings reveal that CCN1 plays a novel role in pathogen clearance; increasing macrophage infiltration and activation resulting in increased virus clearance in tumors.

Preoperative prognostic neurologic index for glioblastoma patients receiving tumor resection.

Neurologic status is one of the major prognostic factors in glioblastoma patients; however, no consensus exists on a clinical index for predicting patient outcomes. The purpose of this study was to evaluate the correlation between neurologic deficits and clinical outcomes in glioblastoma patients, and to develop a prognostic neurologic index for identifying patients with poor outcomes. Patients receiving tumor resection with pathologically confirmed glioblastoma were retrospectively evaluated. The patients' preoperative neurologic deficits were categorized, and patients with poor overall survival (OS) were identified. Other common prognostic factors, including age, performance, imaging findings, and extent of resection, were analyzed. We evaluated 162 glioblastoma patients receiving tumor resection between February 2000 and December 2011, of whom 54 received adjuvant radiotherapy (RT) alone and 84 received concurrent chemo-RT with temozolomide. At a median follow-up of 57.6 (range 26.3-88.9)months, 26 patients had survived without loss to follow-up. We defined adverse neurologic status by using an index of combined increased intracranial pressure (IICP) and non-IICP signs. In univariate analysis, the median OS of patients with and without adverse neurologic status were 9.6 and 18.7months, respectively (p<0.001). In multivariate analyses, adverse neurologic status remained significantly associated with poor OS (hazard ratio 2.18, 95% confidence interval 1.54-3.10). Our proposed neurologic index enables significantly identifying glioblastoma patients receiving tumor resection with poor outcomes, independent of other common prognostic factors. Using the index provides a preoperative predictor of prognosis in glioblastoma patients receiving tumor resection.

Assessment and prognostic significance of the epidermal growth factor receptor vIII mutation in glioblastoma patients treated with concurrent and adjuvant temozolomide radiochemotherapy

The epidermal growth factor receptor vIII mutant (EGFRvIII) is found in ~50% of all EGFR-amplified glioblastomas and constitutes a tumor-specific therapeutic target. To assess molecular testing approaches and the prognostic role of EGFRvIII in patients treated according to current standards of care, we compared different EGFRvIII detection methods and correlated EGFRvIII status with outcome in a prospective patient cohort of the German Glioma Network. In total, 184 newly diagnosed glioblastoma patients were investigated for EGFR amplification and for expression of EGFR and EGFRvIII by immunohistochemistry. Further, the EGFRvIII status was additionally studied by multiplex ligation-dependent probe amplification (MLPA) analysis and reverse transcription-PCR (RT-PCR). Immunohistochemistry demonstrated EGFRvIII in 34 of 184 patients (18%). RT-PCR or MLPA analysis detected four additional EGFRvIII-positive patients. Overall, RT-PCR and immunohistochemistry were more sensitive for EGFRvIII detection than MLPA. EGFRvIII status was not associated with progression-free and overall survival. EGFRvIII also had no prognostic significance in the subgroup of patients who were free from progression after concomitant radiochemotherapy and thus would be eligible for the ongoing ACT IV EGFRvIII vaccination trial. Age, extent of resection and O⁶-methylguanine DNA methyltransferase (MGMT) promoter methylation status appeared to be less prognostic in EGFRvIII-positive patients. Thus, EGFRvIII positivity is not a major negative prognostic factor in glioblastoma patients treated according to current standards of care. Data from phase II EGFRvIII-targeted vaccination trials compare favorably with the present contemporary results, supporting the further exploration of EGVRvIII vaccination in newly diagnosed glioblastoma.

Treatment outcomes in glioblastoma patients aged 76 years or older: a multicenter retrospective cohort study

Age is one of the most important prognostic factors in glioblastoma patients, but no standard treatment has been established for elderly patients with this condition. We therefore conducted a retrospective cohort study to evaluate treatment regimens and outcomes in elderly glioblastoma patients. The study population consisted of 79 glioblastoma patients aged ≥ 76 years (median age 78.0 years; 34 men and 45 women). The median preoperative Karnofsky performance status (KPS) score was 60. Surgical procedures were classified as biopsy (31 patients, 39.2 %), <95 % resection of the tumor (21 patients, 26.9 %), and ≥ 95 % resection of the tumor (26 patients, 33.3 %). Sixty-seven patients (81.0 %) received radiotherapy and 45 patients (57.0 %) received chemotherapy. The median overall progression-free survival time was 6.8 months, and the median overall survival time was 9.8 months. Patients aged ≥ 78 years were significantly less likely to receive radiotherapy (p = 0.004). Patients with a postoperative KPS score of ≥ 60 were significantly more likely to receive maintenance chemotherapy (p = 0.008). Multivariate analyses identified two independent prognostic factors: postoperative KPS score ≥ 60 (hazard ratio [HR] = 0.531, 95 % confidence interval [CI] 0.315-0.894, p = 0.017) and temozolomide therapy (HR = 0.442, 95 % CI 0.25-0.784, p < 0.001).The findings of this study suggest that postoperative KPS score is an important prognostic factor for glioblastoma patients aged ≥ 76 years, and that these patients may benefit from temozolomide therapy.