Overall Survival In Glioblastoma Multiforme Research Articles

Glioblastoma multiforme in patients with human immunodeficiency virus: an integrated review and analysis.

As lifespans for persons living with HIV (PLWH) have improved over the last decade, there has been a simultaneous increase in non-AIDS-related cancer in that group. However, there is a paucity of data regarding the incidence of glioblastoma multiforme (GBM) in PLWH. Better understanding of the oncogenesis, natural history, and treatment outcomes of GBM in PLWH should lead to improved treatment strategies. We performed a comprehensive literature search of six electronic databases to identify eligible cases of GBM among PLWH. Kaplan-Meier estimates, Fisher's exact test, and logistic regression were used to interrogate the data. Epidemiologic data on global HIV prevalence was obtained from the 2016 UNAIDS incidence report, and CNS cancer incidence was obtained from the GDB 2016 Brain and Other CNS Cancer Collaborators. There is an inverse relationship between the incidence of HIV and CNS cancer globally. Median overall survival (OS) from GBM diagnosis was 8months. Estimates for survival at 1 and 2years were 28 and 5%, respectively. There were no statistically significant predictors of OS in this setting. There was a significant difference (p < 0.01) in OS in PLWH and GBM when compared to TCGA age matched cohorts. The diagnosis of GBM in PLWH is severely underreported in the literature. Despite maximal treatment, OS in this patient population is significantly less than in HIV-negative people. There was a poor prognosis of GBM in PLWH, which is inconsistent with previous reports. Further investigation is required for PLWH and concomitant GBM. Analyses must consider if HAART is maintained in PLWH during GBM treatment.

Prognostic value of O 6-methylguanine-DNA methyltransferase methylation in isocitrate dehydrogenase mutant gliomas.

BackgroundPatients with isocitrate dehydrogenase (IDH) mutant gliomas have been associated with longer survival time than those that are IDH wild-type. Previous studies have shown the prognostic value of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation for glioblastoma multiforme (GBM), which are predominantly IDH wild-type. Little is known of the prognostic value of MGMT methylation status for IDH mutant gliomas.MethodsWe retrospectively identified IDH mutant gliomas patients between 2011 and 2020 that were tested for MGMT promoter methylation. We generated Kaplan–Meier estimator curves and performed Cox proportional hazard models for overall survival (OS) and progression-free survival (PFS) to compare the outcomes of MGMT promoter methylated versus MGMT unmethylated patients.ResultsOf 419 IDH mutant gliomas with MGMT promoter methylation testing, we identified 54 GBMs, 223 astrocytomas, and 142 oligodendrogliomas. 62.3% patients had MGMT methylated tumors while 37.7% were MGMT unmethylated. On Kaplan–Meier analysis, median OS for all MGMT methylated patients was 17.7 years and 14.6 years for unmethylated patients. Median PFS for all MGMT methylated patients was 7.0 years and for unmethylated patients 5.2 years. After univariate subgroup analysis, MGMT methylation is only prognostic for OS and PFS in GBM, and for OS in anaplastic oligodendroglioma and anaplastic oligodendroglioma for OS. In multivariate analysis, MGMT unmethylated GBM patients carry a higher risk of death (HR 7.72, 95% CI 2.10–28.33) and recurrence (HR 3.85, 95% CI 1.35–10.96).Conclusions MGMT promoter methylation is associated with better OS and PFS for IDH mutant GBM. MGMT promoter methylation testing for other IDH mutant glioma subtypes may not provide additional information on prognostication.

Expressions and significances of CTSL, the target of COVID-19 on GBM.

IntroductionCathepsin L (CTSL) is a kind of the SARS-entry-associated CoV-2's proteases, which plays a key role in the virus's entry into the cell and subsequent infection. We investigated the association between the expression level of CTSL and overall survival in Glioblastoma multiforme (GBM) patients, to better understand the possible route and risks of new coronavirus infection for patients with GBM.MethodsThe expression level of CTSL in GBM was analyzed using TCGA and CGGA databases. The relationship between CTSL and immune infiltration levels was analyzed by means of the TIMER database. The impact of CTSL inhibitors on GBM biological activity was tested.ResultsThe findings revealed that GBM tissues had higher CTSL expression levels than that of normal brain tissues, which was associated with a significantly lower survival rate in GBM patients. Meanwhile, the expression level of CTSL negatively correlated with purity, B cell and CD8+ T cell in GBM. CTSL inhibitor significantly reduced growth and induced mitochondrial apoptosis.ConclusionAccording to the findings, CTSL acts as an independent prognostic factor and can be considered as promising therapeutic target for GBM.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00432-021-03843-9.

Transcriptional expression of ZICs as an independent indicator of survival in gliomas

The functional significance of the zinc-finger of the cerebellum (ZIC) gene family in gliomas remains to be elucidated. Clinical data from patients with gliomas, containing expression levels of ZIC genes, were extracted from CCLE, GEPIA2 and The Human Protein Atlas (HPA). Univariate survival analysis adjusted by Cox regression via OncoLnc was used to determine the prognostic significance of ZIC expression. We used cBioPortal to explore the correlation between gene mutations and overall survival (OS). ZIC expression was found to be related to immune cell infiltration in gliomas via TIMER analysis. GO term and KEGG pathway enrichment analyzes were performed with Metascape. PPI networks were constructed using STRING. The expression levels of ZIC1/3/4/5 in gliomas were significantly different from those in normal samples. High expression levels of ZIC1/5 were associated with poor OS in brain low-grade glioma (LGG) patients, while low ZIC3 expression combined was related to favorable OS in glioblastoma multiforme (GBM). ZIC alterations were associated with poor prognosis in LGG patients and related to favorable prognosis in GBM patients. We observed that the expression of ZICs was related to immune cell infiltration in glioma patients. ZICs were enriched in several pathways and biological processes involving Neuroactive ligand-receptor interaction (hsa04080). The PPI network revealed that some proteins coexpressed with ZICs played a role in the pathogenesis of gliomas. Differences in the expression levels of ZIC genes could provide a significant marker for predicting prognosis in gliomas.

Systematic Analyses Reveals the Functional Roles of Ferroptosis Across Cancers

Background: Ferroptosis is a newly discovered type of cell death that is closely related to cancer, however, the characteristics of ferroptosis and its regulators in cancers are still largely unknown. Methods: Based on the cancer omics data in The Cancer Genome Atlas, we comprehensively analyzed the alterations of ferroptosis regulator genes (FRGs) and computationally established the ferroptosis potential index (FPI) to reveal the functional roles of ferroptosis in cancer. Findings: We found that the mutation rates of FRGs were generally low, but most FRGs were differentially expressed in tumors among various cancer types. Frequent copy number alterations (CNA) and differential DNA methylation of FRGs contributed greatly to their aberrant expression. In most cancers, the FPI was higher in tumors than in the adjacent normal tissues and was associated with histological/molecular subtypes and clinical features. We observed that the FPI was negatively correlated with a number of metabolism pathways such as terpenoid backbone biosynthesis, but positively associated with metastasis-related pathways such as epithelial-mesenchymal transition (EMT), WNT beta-catenin signaling and angiogenesis. The FPI was also correlated immune microenvironment since it was positively correlated with pathways such as IL6 JAK-STAT signaling, inflammatory response, complement. Furthermore, it was observed that high FPI predicted significantly worse overall survival in glioblastoma multiforme, renal clear/papillary cell carcinoma, hepatocellular carcinoma, and lung adenocarcinoma, while FPI and FRGs were intensively correlated with cancer drug sensitivity. Interpretation: Our study presents a systematical analysis of ferroptosis and its regulatory genes across cancers, and highlights the potential of ferroptosis-based cancer therapy. Funding Statement: This work was supported by grants from National Key RD and Science and Technology Program of Guangdong (2019B020227002 to RH.X.). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: Not required.

MIR155HG is a prognostic biomarker and associated with immune infiltration and immune checkpoint molecules expression in multiple cancers.

In recent years, immune checkpoint inhibitor has achieved remarkable success in multiple cancer treatment. However, how to pre‐judge which patients are suitable for immune checkpoint inhibitor is a difficult problem. We use the existing public bioinformatics database to comprehensively analyze the relationship between clinical data of various cancers with immune checkpoint blocking molecules and long non‐coding RNAs (lncRNAs), and try to find the potential predictive value of lncRNA for immunotherapy with checkpoint inhibitors. In this study, we found that: (a) high expression of lncRNA MIR155 host gene (MIR155HG) was closely related to better overall survival (OS) in cholangiocarcinoma (CHOL), lung adenocarcinoma (LUAD), and skin cutaneous melanoma (SKCM), and have better disease‐free survival (DFS) in CHOL. Meanwhile, the high level of MIR155HG was associated with poorer OS in glioblastoma multiforme (GBM), kidney renal clear cell carcinoma (KIRC), brain lower grade glioma (LGG), and uveal melanoma (UVM). (b) The expression of MIR155HG was significantly correlated with infiltrating levels of immune cells and immune molecules, especially with immune checkpoint molecules such as programmed cell death protein 1 (PD‐1), PD‐1 ligand 1 (PD‐L1), and cytotoxic T lymphocyte‐associated antigen 4 (CTLA4) in most kinds of cancers. (c) Detection of clinical CHOL and liver hepatocellular carcinoma tissues confirmed that there was a strong positive correlation between MIR155HG expression and the levels of CTLA4 and PD‐L1. MIR155 host gene can be used as a prognostic marker in multiple cancers, and of great value in predicting the curative effect of immune checkpoint inhibitor therapy owing to it is closely related with immune cells infiltration and immune checkpoint molecules expression.

High EMP3 expression might independently predict poor overall survival in glioblastoma and its expression is related to DNA methylation.

In this study, we analyzed the prognostic value of epithelial membrane protein 3 (EMP3) in terms of overall survival (OS) in glioblastoma multiforme (GBM) and the association between its expression and DNA methylation.Bioinformatic analysis was performed by using data from the Cancer Genome Atlas (TCGA) database.EMP3 expression was markedly higher in GBM tissues than in normal brain tissues. High EMP3 expression was associated with significantly worse OS in patients with GBM. Univariate and multivariate analysis showed that EMP3 expression was an independent prognostic factor of poor OS no matter converting its expression into categorical variables (Hazard Ratio [HR] = 1.359, 95%CI: 1.118–1.652, P = .002) or setting it as a continuous variable (HR = 1.178, 95%CI: 1.101–1.260, P < .001). Among different subtypes of GBM, proneural subtype had the lowest EMP3 expression. The lowest EMP3 expression was observed in cluster 5 DNA methylation, which all belong to G-CIMP phenotype. Regression analysis confirmed a moderate negative correlation between EMP3 expression and its DNA methylation (Pearson's r = −0.61).Based on these findings, we infer that high EMP3 expression might be an independent indicator of unfavorable OS in GBM. EMP3 expression might be repressed by DNA methylation.

A systematic review of overall survival in pediatric primary glioblastoma multiforme of the spinal cord.

OBJECTIVE The incidence of primary spinal cord glioblastoma multiforme (GBM) in the pediatric age group is very rare. Only a few case series and case reports have been published in the literature; therefore, overall survival (OS) outcome and the as-yet poorly defined management options are not discussed in detail. The authors performed a cumulative survival analysis of all reported cases of pediatric spinal cord GBM to identify the predictive factors related to final survival outcome. METHODS A comprehensive search for relevant articles was performed on PubMed's electronic database MEDLINE for the period from 1950 to 2015 using the search words "malignant spinal cord tumor" and "spinal glioblastoma multiforme." This study was limited to patients younger than 18 years of age. Survival rates for children with various tumor locations and treatments were collected from the published articles and analyzed. RESULTS After an extensive literature search, 29 articles met the study inclusion criteria. From the detailed information in these articles, the authors found 53 children eligible for the survival analysis. The majority (45%) of the children were more than 12 years old. Thirty-four percent of the cases were between 7 and 12 years of age, and 21% were younger than 7 years. In the Kaplan-Meier survival analysis, children younger than 7 years of age had better survival (13 months) than the children older than 7 years (7-12 years: 10 months, > 12 years: 9 months; p = 0.01, log-rank test). Fifty-five percent of the children were female and 45% were male. A cervical tumor location (32%) was the most common, followed by thoracic (28.3%). Cervicothoracic (18.9%) and conus (18.8%) tumor locations shared the same percentage of cases. Cervical tumors had a worse outcome than tumors in other locations (p = 0.003, log-rank test). The most common presenting symptom was limb weakness (53%), followed by sensory disturbances (25%). Median OS was 10 months. The addition of adjuvant therapy (radiotherapy [RT] and/or chemotherapy [CT]) after surgery significantly improved OS (p = 0.01, log-rank test). Children who underwent gross-total resection and RT had better outcomes than those who underwent subtotal resection and RT (p = 0.04, log-rank test). Cerebrospinal fluid spread, hydrocephalus, brain metastasis, and spinal metastasis were not correlated with OS in primary spinal GBM. CONCLUSIONS Adjuvant therapy after surgery had a beneficial effect on overall outcome of spinal GBM in the pediatric age group. Gross-total resection followed by RT produced a better outcome than subtotal resection with RT. Further large-scale prospective study is required to establish the genetic and molecular factors related to OS in primary GBM of the spinal cord in pediatric patients.

Impact of Peritumoral Edema on Overall Survival in Glioblastoma Multiforme

Impact of Peritumoral Edema on Overall Survival in Glioblastoma Multiforme

P0111 Sub-ventricular zone irradiation in glioblastoma: Can it increase survival?

Background Glioblastoma multiforme are aggressive tumours with high relapse rates, which could be attributed to the neural progenitor stem cells in the sub-ventricular zone (SVZ). Irradiation of stem cell niche in the SVZ could translate into increased overall survival. We aimed to correlate the radiation dose received by the SVZ and its effect on overall survival. Methods We did a retrospective analysis of data from patients with glioblastoma multiforme (treated at our institute in 2008–10) whose treatment plans could be retrieved and for whom current clinical status was known. All adult patients who underwent maximum safe resection and concurrent chemoradiation followed by adjuvant chemotherapy, were included in the study. The planning CT were de-archived, SVZ was contoured in axial segments by taking a 3 mm and 5 mm auto-margin lateral to the lateral ventricle. Laterality of the SVZ was determined according to the tumour epicentre and was denoted as ipsilateral SVZ (IL SVZ), contralateral SVZ (CL SVZ) and combined volume of SVZ (Comb SVZ). Irradiation doses received by each structure were analysed. Findings 50 patients were included. The ratio of men to women was 66:34. Recursive partitioning analysis classified 28% of tumours as RPA class grade 3, 62% as grade 4, and 10% as grade 5. Gross total excision was done in 46%, sub-total resection was done in 54%. Median overall survival was 15.63 months (95% CI 8.83–22.43). Doses >50 Gy to IL SVZ (both 3 mm and 5 mm) were associated with a significant increase in overall survival (median OS 19.83 months versus 6.07 months; p = 0.031). Doses > 37 Gy to the CL SVZ (3 mm) were associated with a non-significant increase in overall survival (median OS 16.73 months versus 8.73 months; p = 0.305). Doses > 37 Gy to the CL SVZ (5 mm) were associated with a non-significant increase in overall survival (median 19.83 months versus 8.73 months; p = 0.118). Interpretation Irradiation of potential cancer stem cell niches in the SVZ influences overall survival in glioblastoma multiforme. Increased doses to the IL SVZ are associated with increased survival in glioblastoma multiforme. Further studies are needed to know what dose should be delivered to what portion of the SVZ to attain this survival advantage. Age, KPS, RPA, extent of surgical resection, and various other biological factors also play an important part.

The relative value of postoperative versus preoperative Karnofsky Performance Scale scores as a predictor of survival after surgical resection of glioblastoma multiforme.

The Karnofsky Performance Scale (KPS) score is a widespread metric to stratify patient prognosis and determine appropriate management in glioblastoma multiforme(GBM). Low preoperative KPS values have been associated with shorter overall survival (OS). However, surgical resection can have a dramatic effect on a patient's functional status which subsequently alters their KPS score. To determine the predictive value of preoperative verses postoperative KPS scores in terms of OS in patients with GBM. We conducted a retrospective review of 163 patients who underwent initial surgical intervention for pathologically proven GBM at our institution between 2003 and 2013. Pre and postoperative performance status, demographic, operative, and treatment variables were recorded for each patient. Multivariate regression analysis identified predictors of prolonged OS. The adequacy index was calculated to compare the predictive value of preoperative and postoperative KPS score. Median preoperative and postoperative KPS scores were 70 and 80, respectively. Overall, 92 (57 %) patients experienced an improvement in their KPS score, 40 (25 %) remained stable, and 29 (18 %) declined. Higher postoperative KPS (P = 0.0001), radiation therapy (P < 0.0001), younger age (P = 0.0443) and the absence of diabetes (P = 0.0006) were each independently associated with increased OS in a multivariate regression model. Postoperative KPS score has superior predictive value compared to pre-operative KPS score (A = 0.758 vs. 1.002). Postoperative KPS scores have superior predictive capabilities in terms of OS in GBM and should replace preoperative KPS scores when estimating prognosis in this population.

Abstract 297: Protein markers predict overall survival in glioblastoma multiforme

Abstract Unrealized needs in the care of patients diagnosed with primary glioblastoma multiforme (GBM) are accurate and clinically relevant predictors of patient prognosis. Patients receiving standard therapy (surgery plus concurrent radiation and temozolomide) have variable clinical outcomes. Available prognostic indicators such as MGMT DNA methylation, IDH1 mutation, and the G-CIMP phenotype are only relevant for a small proportion of those diagnosed with primary GBM. Protein markers of GBM prognosis would not only provide a potential route for classifying and stratifying patients into treatment groups they could also provide an opportunity to identify potential novel drug targets. In this study, using reverse-phase protein array data from Cancer Genome Atlas (TCGA) GBMs, we have constructed and validated a PROTein signature predictive of GLIOblastoma survival (PROTGLIO). Using L1 penalized cox regression, we have identified six protein markers most associated with overall survival in a training set of 107 TCGA GBMs. Three proteins (annexin, cox-2, and FOX03) were associated with shorter overall survival, and three proteins (phosphorylated RPS6KA1, phosphorylated RB1, and TGM2) were associated with longer overall survival. PROTGLIO scores were defined as a linear combination of protein expression levels of the six proteins and the associated Cox regression coefficients, where a higher score indicates a worse prognosis. Based on PROTGLIO scores cases were classified into high and low risk groups. Kaplan-Meier survival analysis showed a significant difference (p = 0.01) in overall survival between the high and low risk groups in our training set. The performance of the PROTGLIO score was validated in a testing set, which consisted of 107 TCGA cases not included in the training set. In the validation set there was a significant difference in overall survival between the high and low risk groups (p = 0.02). We have verified that our signature is independent of known prognostic variables such as age, treatment pattern, and molecular subtype by applying multivariate analysis using a Cox proportional hazard model. The annexin family of proteins has been previously associated with glioma migration and growth and the cox-2 protein has been reported as a marker of poor prognosis among diffuse glioma patients. Our work points to these proteins, along with FOX03, as being negative prognosticators for GBMs and potential avenues for therapeutic intervention. Additionally, we report on the protective effects of phosphorylated RB1 expression, which is supported by previous studies recommending clinical stratification of patients based on RB1 alterations. Further work is needed to elucidate the protective mechanisms of RPS6KA1 and TGM2. Note: This abstract was not presented at the meeting. Citation Format: Lindsay C. Stetson, Jill S. Barnholtz-Sloan. Protein markers predict overall survival in glioblastoma multiforme. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 297. doi:10.1158/1538-7445.AM2014-297

Erratum to: Overexpression and constitutive nuclear localization of cohesin protease Separase protein correlates with high incidence of relapse and reduced overall survival in glioblastoma multiforme

Erratum to: Overexpression and constitutive nuclear localization of cohesin protease Separase protein correlates with high incidence of relapse and reduced overall survival in glioblastoma multiforme

Overexpression and constitutive nuclear localization of cohesin protease Separase protein correlates with high incidence of relapse and reduced overall survival in glioblastoma multiforme.

Separase, an enzyme that cleaves the chromosomal cohesin during mitosis, is overexpressed in a wide range of human epithelial cancers of breast, bone and prostate (Meyer et al., Clin Cancer Res 15(8):2703-2710, 2009). Overexpression of Separase in animal models results in aneuploidy and tumorigenesis. We have examined the expression and localization of Separase protein in adult and pediatric glioblastoma and normal brain specimens. Immunofluorescence microscopy and Western blot analysis showed significant overexpression of Separase in all adult and a subset of pediatric glioblastoma cells. Tumor status and patient survival strongly correlate with the mislocalization of Separase into the nucleus throughout all stages of the cell cycle. Unlike exclusively nuclear localization in mitotic control cells, glioblastoma samples have a significantly higher number of resting (interphase) cells with strong nuclear Separase staining. Additionally, patient survival analysis demonstrated a strong correlation between overexpression of Separase protein in adult glioblastoma and a high incidence of relapse and reduced overall survival. These results further strengthen our hypothesis that Separase is an oncogene whose overexpression induces tumorigenesis, and indicate that Separase overexpression and aberrant nuclear localization are common in many tumor types and may predict outcome in some human malignancies.

Glutamine synthetase expression as a valuable marker of epilepsy and longer survival in newly diagnosed glioblastoma multiforme

Glutamine synthetase (GS) is an astrocytic enzyme catalyzing the conversion of glutamate and ammonia to glutamine. Its up-regulation has been related to higher tumor proliferation and poor prognosis in extra-cerebral tumors. We have previously reported a GS deficiency in patients with glioblastoma multiforme (GBM) who also developed epilepsy, which is a favorable prognostic factor in glioma. Here, we investigated the prognostic value of GS expression in patients with GBM with or without epilepsy and its correlation with survival. We conducted a clinical and histopathological study on 83 (52 males) consecutive patients with newly diagnosed GBM. Immunohistochemical expression of GS was scored semi-quantitatively on the basis of cell number, staining intensity, and distribution of immunoreactive cells. Several clinical and neuropathological variables were analyzed in relation to survival and GS expression. Median age at diagnosis was 62 years. At the last evaluation, with a median follow-up of 11.5 months (range, 1.5-58 months), 5 patients (6%) were still alive and 78 (94%) were dead. GS expression patterns in neoplastic cells were inversely correlated to the presence of epilepsy (P < .0001 for intensity and P < .009 for homogeneity of GS distribution, respectively). Univariate analysis showed that RPA score, epilepsy, O6-methylguanine-DNA methyltransferase (MGM)T status, application of Stupp protocol, and GS intensity pattern had a significant impact on survival. Absent/low intensity of GS expression was significantly associated with a longer survival in both uni- (19 vs 8 months; P < .0005) and multivariate (P = .003) analyses. Absent/low-intensity GS expression pattern represents a valuable biomarker of both epilepsy and overall survival in GBM.

Effect of pretreatment clinical factors on overall survival in glioblastoma multiforme: a Surveillance Epidemiology and End Results (SEER) population analysis

BackgroundGlioblastoma Multiforme (GBM) is one of the most aggressive primary brain tumors and is associated with a dismal prognosis. The median survival after the primary diagnosis remains poor, even after multimodal treatment approaches. However, a few patients have been reported to have long term survival greater than three years. A number of studies have attempted to define factors capable of predicting long term outcomes in specific patient groups. This article reports the outcomes of a very large group of patients diagnosed with GBM, and analyzes specific prognostic factors known to influence survival in these patients.MethodsWe used the Surveillance, Epidemiology, and End Results (SEER) database of the US National Cancer Institute (NCI) to investigate various patient-related and treatment- related factors that could influence the long term survival in patients diagnosed with glioblastoma. A total of 34,664 patients aged 20 years or older with a diagnosis of GBM during the years 1973 to 2008 were studied. Overall survival outcomes were examined with Kaplan-Meier survival analysis and Cox hazard models.ResultsAsian/Pacific Islanders had a better survival compared to the white population (P = <0.001). Patients diagnosed with GBM during the years 2000 to 2008 had a superior survival rate when compared with earlier decades (P = <0 .001). Statistically significant improvements in overall survival were also found for patients who received surgical resections, and adjuvant radiation treatment versus no radiation (P-values <0.001). Young age was also found to be highly predictive of improved overall survival rates when separated into age groups as well as when studied as a continuous variable.ConclusionsClinical pretreatment and treatment factors, including young age at diagnosis, Asian/Pacific Islander ethnicity, recent year of diagnosis, surgical resection and the use of adjuvant radiation therapy favorably influence survival in patients diagnosed with glioblastoma.Trial RegistrationAll data were obtained from the United States Surveillance Epidemiology and End Results (SEER) database.

VEGFR2 Expression and TGF-β Signaling in Initial and Recurrent High-Grade Human Glioma

Objective: Bevacizumab has promising activity against glioma, although reasons for poor efficacy and variable response rates in certain patients are unclear. Vascular endothelial growth factor receptor 2 (VEGFR2) is heterogeneously expressed within the microvasculature of various malignancies. Moreover, transforming growth factor β (TGF-β), a negative prognostic factor for glioma, is intimately involved in angiogenesis including VEGFR2 regulation. Our objective was to associate expression of VEGFR2 and TGF-β activity with clinicopathological features of human glioma. Methods: Expression patterns determined by immunohistochemistry for VEGFR2 and phosphorylated Smad2 in human gliomas were compared to overall survival, progression-free survival (PFS), initial versus recurrent tumors and tumor grade. Results: Endothelial VEGFR2 expression was low or undetectable in normal tissue but the proportion of VEGFR2-positive vessels increased with tumor grade. Decreased PFS was associated with tumors whose vessels had increased proportions of VEGFR2 at recurrence. Neither parenchymal nor endothelial cell p-Smad2 was associated with tumor grade; however, the former was negatively correlated with overall survival in glioblastoma multiforme. Conclusions: The molecular phenotype of the vasculature based on the status of VEGFR2 but not p-Smad2 is related to aspects of glioma progression and patient response. Changes in VEGFR2-positive vessels may account for variable therapeutic efficacy of anti-angiogenic agents.