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Simple Summary: Laser interstitial thermal therapy (LITT) is a minimally invasive, MRI-guided procedure that causes localized tissue hyperthermia. This results in the ablation of targeted cells and disruption of the blood–brain barrier. LITT offers an alternative treatment option to standard-of-care resection for glioma in addition to potentially enhancing drug delivery of adjuvant therapy. Here, we present the first meta-analysis since the fifth edition of the WHO Classification of Tumors of the Central Nervous System (WHO CNS5) to assess the current literature on the safety and efficacy of LITT in the upfront treatment of primary brain tumors. This study summarizes the current relevant literature on LITT and supports its viability as a treatment option for glioblastoma and IDH-mutant astrocytoma. Although primary studies have reported the safety and efficacy of LITT as a primary treatment in glioma, they are limited by sample sizes and institutional variation in stereotactic parameters such as temperature and laser power. The current literature has yet to provide pooled statistics on outcomes solely for primary brain tumors according to the 2021 WHO Classification of Tumors of the Central Nervous System (WHO CNS5). In the present study, we identify recent articles on primary CNS neoplasms treated with LITT without prior intervention, focusing on relationships with molecular profile, PFS, and OS. This meta-analysis includes the extraction of data from primary sources across four databases using the Covidence systematic review manager. The pooled data suggest LITT may be a safe primary management option with tumor ablation rates of 94.8% and 84.6% in IDH-wildtype glioblastoma multiforme (GBM) and IDH-mutant astrocytoma, respectively. For IDH-wildtype GBM, the pooled PFS and OS were 5.0 and 9.0 months, respectively. Similar to rates reported in the prior literature, the neurologic and non-neurologic complication rates for IDH-wildtype GBM were 10.3% and 4.8%, respectively. The neurologic and non-neurologic complication rates were somewhat higher in the IDH-mutant astrocytoma cohort at 33% and 8.3%, likely due to a smaller cohort size. [ABSTRACT FROM AUTHOR]

Objectives: Angiogenesis is one of the main characteristic features of malignant gliomas. Phosphorylated signal transducer and activator of transcription factor 3 (pSTAT3) is not only involved in glioma cell proliferation, anti-apoptosis, and immunosuppression but also plays a key role in cell migration and invasion. Constitutively, activated pSTAT3 induces expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR, leading to endothelial cell proliferation and abnormal microvascular formation causing peritumoral edema (PTE). PTE is one of the significant contributors to mortality in malignant gliomas. Therefore, understanding the molecular mechanism involved in the evolution of gliomas is necessary. This study was to assess the level of expression of pSTAT3, VEGF, and VEGFR in malignant gliomas and analyze the extent of PTE and the extent of expression of one or more of these markers. Materials and Methods: This study included 84 patients categorized as per the World Health Organization classification of central nervous system tumors into grade IV, III, and II gliomas to investigate the expression of pSTAT3, VEGF, and VEGFR by immunohistochemistry. Furthermore, the presence or absence of PTE was determined using magnetic resonance imaging/computed tomography scans in these patients. Results: The association between the markers (pSTAT3, VEGFR, and VEGF) and the extent of PTE in these patients was statistically significant (P < 0.05). Conclusion: The pSTAT3, VEGF-R, and VEGF signaling pathways could contribute to peritumoral edema and might be a regulatory mechanism during PTE formation during tumorigenesis and progression. [ABSTRACT FROM AUTHOR]

Background: World Health Organization (WHO) grade IV glioma remains one of the most lethal tumors with a dismal prognosis and inevitable recurrence. We evaluated the safety and efficacy of immunotherapy with radiotherapy in this population of patients. Methods: This study was a single-arm, open-label, phase I trial based on patients with recurrent WHO grade IV glioma. Patients were treated with intracranial and systemic immunoadjuvants in combination with low-dose reirradiation. The primary endpoint of the present trial was safety. Secondary endpoints were overall survival (OS) and progression-free survival (PFS). This trial is registered at ClinicalTrials.gov, NCT03392545. Results: Thirty patients were enrolled. The most common adverse events (AEs) were fever (66.7%), vomiting (33.3%), headache (30.0%), and fatigue (23.3%). Only a single patient experienced grade 3 fever, and no grade 4 AEs or deaths related to treatment were observed. Of the 30 patients, 1 (3.3%) had a complete response, 5 (16.7%) had a partial response, 9 (30.0%) had stable disease, and 15 (50.0%) had progressive disease, resulting in an objective response rate of 20.0%. The median PFS of the entire cohort was 88.0 (61.0-254.0) days, and the median OS was 362.0 (197.0-601.0) days. Patients could be divided into responders and non-responders, and these groups exhibited a significant difference in terms of survival time, T lymphocyte subsets, frequency of cell division cycle 27 (CDC27) mutation status, and CD15 and CD68 expression (P <0.05). Conclusion: The combination of immunotherapy and radiotherapy is well tolerated and may provide clinical benefit for patients with recurrent WHO grade IV glioma. A prospective phase II study is needed to further validate the efficacy of our therapeutic regimen. [ABSTRACT FROM AUTHOR]

Background and Objective: Possible treatment strategies for recurrent malignant gliomas include surgery, chemotherapy, radiotherapy, and combined treatments. Among different reirradiation modalities, the CyberKnife System has shown promising results. We conducted a systematic review of the literature and a meta-analysis to establish the efficacy and safety of CyberKnife treatment for recurrent malignant gliomas. Methods: We searched PubMed, MEDLINE, and EMBASE from 2000 to 2021 for studies evaluating the safety and efficacy of CyberKnife treatment for recurrent WHO grade III and grade IV gliomas of the brain. Two independent reviewers selected studies and abstracted data. Missing information was requested from the authors via email correspondence. The primary outcomes were median Overall Survival, median Time To Progression, and median Progression-Free Survival. We performed subgroup analyses regarding WHO grade and chemotherapy. Besides, we analyzed the relationship between median Time To Recurrence and median Overall Survival from CyberKnife treatment. The secondary outcomes were complications, local response, and recurrence. Data were analyzed using random-effects meta-analysis. Results: Thirteen studies reporting on 398 patients were included. Median Overall Survival from initial diagnosis and CyberKnife treatment was 22.6 months and 8.6 months. Median Time To Progression and median Progression-Free Survival from CyberKnife treatment were 6.7 months and 7.1 months. Median Overall Survival from CyberKnife treatment was 8.4 months for WHO grade IV gliomas, compared to 11 months for WHO grade III gliomas. Median Overall Survival from CyberKnife treatment was 4.4 months for patients who underwent CyberKnife treatment alone, compared to 9.5 months for patients who underwent CyberKnife treatment plus chemotherapy. We did not observe a correlation between median Time To Recurrence and median Overall Survival from CyberKnife. Rates of acute neurological and acute non-neurological side effects were 3.6% and 13%. Rates of corticosteroid dependency and radiation necrosis were 18.8% and 4.3%. Conclusions: Reirradiation of recurrent malignant gliomas with the CyberKnife System provides encouraging survival rates. There is a better survival trend for WHO grade III gliomas and for patients who undergo combined treatment with CyberKnife plus chemotherapy. Rates of complications are low. Larger prospective studies are warranted to provide more accurate results. [ABSTRACT FROM AUTHOR]

Context: The most common type of brain tumors are gliomas, among which glioblastoma multiforme is the most life-threatening. In spite of the existing treatments, malignant gliomas often do not respond to treatment. Objectives: The aim of this study was to investigate the antitumor activity of vitamin D3 in malignant gliomas through the study of in vitro and in vivo articles. Data Sources: The electronic databases, including PubMed, ScienceDirect, Webof Science, Google Scholar, and the Cochrane Central Register of Clinical Trials (last updated April 12th, 2019) were searched, using medical subject headings (MeSH) keywords "vitamin D AND brain malignancy". Data Extraction: There was no limitation on the date and language of the articles. A review of all the found articles at the level of titles and abstracts was made to find eligible articles. Our work is in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. The quality of the articles was judged in accordance with the GRADE tool for in vitro studies and CIRCLEs RoB tool for in vivo studies. Results: Totally, 88 articles were identified and after careful examination, 16 eligible articles meeting the inclusion criteria were selected. These studies showed that vitamin D3 and its analogs suppress self-renewal ability, cell viability and/or cell growth, migration rate, and invasive capacity; in addition, they induce autophagy and cell death. They also reduce tumor size in animal models. Evidence was mainly of moderate to high quality. Conclusions: Based on the in vitro and in vivo evidence of this systematic review, vitamin D3, compared to the control group, induced cell death and reduced cell growth, invasion, and migratory capacity in gliomas cell culture. As well as, vitamin D analogs were able to show the same effects without the hypercalcemic effect in vivo. We suggest performing future high-quality studies with the aim of shedding light on the relevant mechanisms and the effects of vitamin D3 derivatives and its analogs on health status and clinical outcomes in patients with malignant gliomas. [ABSTRACT FROM AUTHOR]

Background: D2C7-IT is a novel immunotoxin (IT) targeting wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFR variant III (EGFRvIII) proteins in glioblastoma. In addition to inherent tumoricidal activity, immunotoxins induce secondary immune responses through the activation of T cells. However, glioblastoma-induced immune suppression is a major obstacle to an effective and durable immunotoxin-mediated antitumor response. We hypothesized that D2C7-IT-induced immune response could be effectively augmented in combination with αCTLA-4/αPD-1/αPD-L1 therapies in murine models of glioma. Methods: To study this, we overexpressed the D2C7-IT antigen, murine EGFRvIII (dmEGFRvIII), in established glioma lines, CT-2A and SMA560. The reactivity and therapeutic efficacy of D2C7-IT against CT-2A-dmEGFRvIII and SMA560- dmEGFRvIII cells was determined by flow cytometry and in vitro cytotoxicity assays, respectively. Antitumor efficacy of D2C7-IT was examined in immunocompetent, intracranial murine glioma models and the role of T cells was assessed by CD4+ and CD8+ T cell depletion. In vivo efficacy of D2C7-IT/αCTLA-4/αPD-1 monotherapy or D2C7-IT+αCTLA-4/ αPD-1 combination therapy was evaluated in subcutaneous unilateral and bilateral CT-2A-dmEGFRvIII glioma-bearing immunocompetent mice. Further, antitumor efficacy of D2C7-IT+αCTLA-4/αPD-1/αPD-L1/αTim-3/αLag-3/αCD73 combination therapy was evaluated in intracranial CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII glioma-bearing mice. Pairwise differences in survival curves were assessed using the generalized Wilcoxon test. Results: D2C7-IT effectively killed CT-2A-dmEGFRvIII (IC50 = 0.47 ng/mL) and SMA560-dmEGFRvIII (IC50 = 1.05 ng/mL) cells in vitro. Treatment of intracranial CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII tumors with D2C7-IT prolonged survival (P = 0.0188 and P = 0.0057, respectively), which was significantly reduced by the depletion of CD4+ and CD8+ T cells. To augment antitumor immune responses, we combined D2C7-IT with αCTLA-4/αPD-1 in an in vivo subcutaneous CT-2A-dmEGFRvIII model. Tumor-bearing mice exhibited complete tumor regressions (4/10 in D2C7-IT+αCTLA-4 and 5/10 in D2C7-IT+αPD-1 treatment groups), and combination therapy-induced systemic antitumor response was effective against both dmEGFRvIII-positive and dmEGFRvIII-negative CT-2A tumors. In a subcutaneous bilateral CT-2A-dmEGFRvIII model, D2C7-IT+αCTLA-4/αPD-1 combination therapies showed dramatic regression of the treated tumors and measurable regression of untreated tumors. Notably, in CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII intracranial glioma models, D2C7-IT+αPD-1/αPD-L1 combinations improved survival, and in selected cases generated cures and protection against tumor re-challenge. Conclusions: These data support the development of D2C7-IT and immune checkpoint blockade combinations for patients with malignant glioma. [ABSTRACT FROM AUTHOR]

Management of malignant gliomas is challenging and has evolved significantly. In the last decade, a solid body of evidence integrated molecular markers to the histological findings, severely changing the landscape of high-grade gliomas classification, helping carve more detailed subgroups with different prognosis and potential responsiveness to therapy. Moreover, technical development of surgery and radiotherapy and emergency of new systemic approaches have modified clinical practice both in the initial and recurrent setting. All these aspects are integrated and revised in this updating article. [ABSTRACT FROM AUTHOR]

The lack of effective glioma therapeutics mandates the development of novel treatment strategies. Hepatoma-derived growth factor (HDGF) has been considered as a potential glioma therapeutic target, and its expression level in gliomas is positively related to the malignant grade. Although there are no effective and specific inhibitors against this target, small interfering RNA targeting HDGF (siHDGF)-mediated RNA interference (RNAi) can inhibit the target protein function by knockdown of HDGF expression. However, the application of siHDGF in glioma research and therapy is hampered by the challenge to safe and effective in vivo systemic delivery of siHDGF to gliomas. To address this question, we develop the peptide H 7 K(R 2) 2 -modified pH-sensitive self-assembled hybrid nanoparticles encapsulating siHDGF (H 7 K(R 2) 2 -PSNPs (siHDGF)). The acidic glioma microenvironment is beneficial to the membrane penetration of H 7 K(R 2) 2 -PSNPs and the encapsulated siHDGF. Following systemic administration, H 7 K(R 2) 2 -PSNPs (siHDGF) can effectively deliver siHDGF into the brain and malignant glioma cells, and therefore can significantly downregulate HDGF expression, inhibit malignant phenotypes of glioma cells, result in reduced tumor volumes and prolonged survival times in nude mice bearing U251 human glioblastoma. Thus, systemic administration of H 7 K(R 2) 2 -PSNPs (siHDGF) offers an effective way for the targeted delivery of siHDGF and may serve as a practical malignant glioma therapy. Unlabelled Image • H 7 K(R 2) 2 -PSNPs were developed to deliver siHDGF for malignant glioma treatment. • Acidic microenvironment attenuates the interaction of PLGA core and polyhistidine. • The pH responsiveness confers the tumor targeting to H 7 K(R 2) 2 -PSNPs. • Intravenously administrated H 7 K(R 2) 2 -PSNPs deliver siHDGF into malignant gliomas. • H 7 K(R 2) 2 -PSNPs (siHDGF) have potent anti-glioma effects in vitro and vivo. [ABSTRACT FROM AUTHOR]

• Malignant glioma cells highly expressed layilin, compared to astrocytes. • Layilin was mainly localized in the cytoplasm of A172 and T98G cells. • Layilin up-regulated SNAI1 to increase expression of MMP2, MMP9 and COL1A1. • Transcription of SNAI1 was up-regulated via down-regulation of MTA3 by layilin. • Layilin enhanced the invasive ability of malignant glioma cells. Malignant gliomas are characterized by high invasive ability. In this study, we investigated roles of layilin, a C-type lectin-homologous protein, in the invasive ability of malignant glioma cells. Expression of layilin was investigated by western blotting in the malignant glioma cell lines of U251-MG, A172, and T98G and in astrocytes. The effects of layilin-knockdown on the expression and protein levels of snail family transcriptional repressor 1 (SNAI1), a transcriptional factor involved in the acquisition and enhancement of invasive ability in malignant gliomas, and on the expression of its target genes, matrix metalloproteinase 2 (MMP2), MMP9 , and collagen type I alpha 1 chain (COL1A1), were investigated by qPCR and/or western blotting. Furthermore, the effects of layilin-knockdown on the expression and protein levels of metastasis associated 1 family member 3 (MTA3), a transcriptional repressor of SNAI1 , were also investigated by qPCR and western blotting. Finally, the effects of layilin-knockdown on the invasive ability of the cells were investigated by a wound healing assay. All the tested malignant glioma cells highly expressed layilin, compared to astrocytes, one of representative glial cell types. Layilin-knockdown reduced SNAI1 both at the mRNA and protein levels in A172 cells, and consequently mRNA levels of MMP2, MMP9, and COL1A1 were also reduced. Furthermore, layilin-knockdown increased nuclear protein levels of MTA3 in A172 cells. Notably, layilin-knockdown suppressed the invasive ability of the cells. Layilin up-regulates the expression of SNAI1 via down-regulation of MTA3. This process enhances the invasive ability of malignant glioma cells. [ABSTRACT FROM AUTHOR]

Gene therapy of malignant gliomas has shown a lack of clinical success to date due in part to inability of conventional gene vectors to achieve widespread gene transfer throughout highly disseminated tumor areas within the brain. Here, we demonstrate that newly engineered polymer-based DNA-loaded nanoparticles (DNA-NP) possessing small particle diameters (~50 nm) and non-adhesive surface polyethylene glycol (PEG) coatings efficiently penetrate brain tumor tissue as well as healthy brain parenchyma. Specifically, this brain-penetrating nanoparticle (BPN), following intracranial administration via convection enhanced delivery (CED), provides widespread transgene expression in heathy rodent striatum and an aggressive brain tumor tissue established orthotopically in rats. The ability of BPN to efficiently traverse both tissues is of great importance as the highly invasive glioma cells infiltrated into normal brain tissue are responsible for tumor recurrence. Of note, the transgene expression within the orthotopic tumor tissue occurred preferentially in glioma cells over microglial cells. We also show that three-dimensional (3D) multicellular spheroids established with malignant glioma cells, unlike conventional two-dimensional (2D) cell cultures, serve as an excellent in vitro model reliably predicting gene vector behaviors in vivo. Briefly, DNA-NP possessing greater surface PEG coverage exhibited more uniform and higher-level transgene expression both in the 3D model and in vivo , whereas the trend was opposite in 2D culture. The finding here alerts that gene transfer studies based primarily on 2D cultures should be interpreted with caution and underscores the relevance of 3D models for screening newly engineered gene vectors prior to their in vivo evaluation. Unlabelled Image [ABSTRACT FROM AUTHOR]

There is a distinct need for new and second-line therapies to delay or prevent local tumor regrowth after current standard of care therapy. Intracavitary radioimmunotherapy, in combination with radiotherapy, is discussed in the present review as a therapeutic strategy of high potential. We performed a systematic literature search following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). The available body of literature on intracavitary radioimmunotherapy (iRIT) in glioblastoma and anaplastic astrocytomas is presented. Several past and current phase I and II clinical trials, using mostly an anti-tenascin monoclonal antibody labeled with I-131, have shown median overall survival of 19–25 months in glioblastoma, while adverse events remain low. Tenascin, followed by EGFR and variants, or smaller peptides have been used as targets, and most clinical studies were performed with I-131 or Y-90 as radionuclides while only recently Re-188, I-125, and Bi-213 were applied. The pharmacokinetics of iRIT, as well as the challenges encountered with this therapy, is comprehensively discussed. This promising approach deserves further exploration in future studies by incorporating several innovative modifications. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was assess acute and early delayed radiation-induced changes in normal-appearing brain tissue perfusion as measured with perfusion magnetic resonance imaging (MRI) and the dependence of these changes on the fractionated radiotherapy (FRT) dose level. Patients and methods: Seventeen patients with glioma WHO grade III-IV treated with FRT were included in this prospective study, seven were excluded because of inconsistent FRT protocol or missing examinations. Dynamic susceptibility contrast MRI and contrast-enhanced 3D-T1-weighted (3D-T1w) images were acquired prior to and in average (standard deviation): 3.1 (3.3), 34.4 (9.5) and 103.3 (12.9) days after FRT. Pre-FRT 3D-T1w images were segmented into white- and grey matter. Cerebral blood volume (CBV) and cerebral blood flow (CBF) maps were calculated and co-registered patient-wise to pre-FRT 3D-T1w images. Seven radiation dose regions were created for each tissue type: 0–5 Gy, 5–10 Gy, 10–20 Gy, 20–30 Gy, 30–40 Gy, 40–50 Gy and 50–60 Gy. Mean CBV and CBF were calculated in each dose region and normalised (nCBV and nCBF) to the mean CBV and CBF in 0-5 Gy white- and grey matter reference regions, respectively. Results: Regional and global nCBV and nCBF in white- and grey matter decreased after FRT, followed by a tendency to recover. The response of nCBV and nCBF was dose-dependent in white matter but not in grey matter. Conclusions: Our data suggest that radiation-induced perfusion changes occur in normal-appearing brain tissue after FRT. This can cause an overestimation of relative tumour perfusion using dynamic susceptibility contrast MRI, and can thus confound tumour treatment evaluation. [ABSTRACT FROM AUTHOR]

Primary malignant glioma cell lines are being used for initial screening of anticancer agents. We utilized a simple mechanical disaggregation method for deriving cell lines from tumor tissues; and a Coverslip Culture-Acridine Orange Staining method to study cellular damage. Cell lines could be grown for up to three passages within three weeks after surgery. Cell proliferation, total cellular damage, and MTT assay were studied as parameters of cytotoxic response. Frequencies of damaged cells varied in different cell lines; and increased after cytotoxic treatments under clinically relevant conditions. These methods could contribute to preclinical evaluation of treatment response before commencement of radio-chemotherapy. [ABSTRACT FROM AUTHOR]

Malignant gliomas are a group of aggressive neoplasms among human cancers. The curative effects of current treatments are finite for improving the prognosis of patients. Hyperthermia (HT) is an effective treatment for cancers; however, the effects of HT with different temperatures in treatment of MG and relevant mechanisms remain unclear. MTT assay and Annexin V-fluorescein isothiocyanate/propidium iodide staining were used for investigating the proliferation and apoptosis of C6 cells, respectively. Western blotting was applied to detect the expression of proteins. Ultrasonography was employed to evaluate the tumor formation rate, growth rate, angiogenesis rate and degree of hardness of tumors in vivo. The authors certified that HT with 42-46°C x 1 h, 1 t could inhibit proliferation, promote apoptosis, reduce tumor formation rate, growth rate, angiogenesis rate, degree of hardness of tumors, ischemic tolerance and anoxic tolerance, and have synergy with temozolomide in C6 cells. Long-term HT (43°C x 1 h, 1 t/5 d, 90 d) did not cut down the sensitivity of C6 cells to HT, and sustainably inhibited the proliferation of C6 cells. Furthermore, the authors proved HT produced these effects primarily through inhibition of the EGFR/STAT3/HIF-1A/VEGF-A pathway. [ABSTRACT FROM AUTHOR]

Malignant gliomas are high‑grade gliomas, which are derived from glial cells in the spine or brain. To examine the mechanisms underlying malignant gliomas in the present study, the expression profile of GSE54004, which included 12 grade II astrocytomas, 33 grade III astrocytomas and 98 grade IV astrocytomas, was downloaded from the Gene Expression Omnibus. Using the Limma package in R, the differentially expressed genes (DEGs) in grade III, vs. grade II astrocytoma, grade IV, vs. grade II astrocytoma, and grade IV, vs. grade III astrocytoma were analyzed. Venn diagram analysis and enrichment analyses were performed separately for the DEGs using VennPlex software and the Database for Annotation, Visualization and Integrated Discovery. Protein‑protein interaction (PPI) networks were visualized using Cytoscape software, and subsequent module analysis of the PPI networks was performed using the ClusterONE tool. Finally, glioma‑associated genes and glioma marker genes among the DEGs were identified using the CTD database. A total of 27, 1,446 and 776 DEGs were screened for the grade III, vs. grade II, grade IV, vs. grade II, and grade IV, vs. grade III astrocytoma comparison groups, respectively. Functional enrichment analyses showed that matrix metalloproteinase 9 (MMP9) and chitinase 3‑like 1 (CHI3L1) were enriched in the extracellular matrix and extracellular matrix structural constituent, respectively. In the PPI networks, annexin A1 (ANXA1) had a higher degree and MMP9 had interactions with vascular endothelial growth factor A (VEGFA). There were 10 common glioma marker genes between the grade IV, vs. grade II and the grade IV, vs. grade III comparison groups, including MMP9, CHI3L1, VEGFA and S100 calcium binding protein A4 (S100A4). This suggested that MMP9, CHI3L1, VEGFA, S100A4 and ANXA1 may be involved in the progression of malignant gliomas. [ABSTRACT FROM AUTHOR]

The purpose of this study was to further evaluate the role of myxoma virus (MYXV) as an oncolytic agent against experimental human gliomas in vitro, and analyze the effect of MYXV on malignant glioma cells at different incubation periods and infected at different multiplicities of infection. Neuroglioma cell lines U251 and A172 were cultured with various infective doses of myxoma virus at different time points (0-3 days) and cellular survival rates were evaluated using an MTT assay. Cell viability and cell death rates were assessed using Annexin V/propidium iodide and applying flow cytometry. Furthermore, the expression levels of phosphorylated AKT (p-AKT) in malignant gliomas were detected by western blot analysis to investigate the possible cell signaling targets in the pathway. MYXV exhibited a dose and time-dependent cytotoxic effect on neuroglioma cells, and there was increased expression of p-AKT in malignant gliomas. The present study confirms that MYXV induces oncolysis of malignant gliomas through regulating the activation of AKT. As such, MYXV is a potential therapeutic agent against human malignant gliomas. [ABSTRACT FROM AUTHOR]

Convection-enhanced delivery (CED) is a promising technique that generates a pressure gradient at the tip of an infusion catheter to deliver therapeutics directly through the interstitial spaces of the central nervous system. It addresses and offers solutions to many limitations of conventional techniques, allowing for delivery past the blood-brain barrier in a targeted and safe manner that can achieve therapeutic drug concentrations. CED is a broadly applicable technique that can be used to deliver a variety of therapeutic compounds for a diversity of diseases, including malignant gliomas, Parkinson's disease, and Alzheimer's disease. While a number of technological advances have been made since its development in the early 1990s, clinical trials with CED have been largely unsuccessful, and have illuminated a number of parameters that still need to be addressed for successful clinical application. This review addresses the physical principles behind CED, limitations in the technique, as well as means to overcome these limitations, clinical trials that have been performed, and future developments. [ABSTRACT FROM AUTHOR]

Background Recently, it has been reported that hypoxia highly enhances expression of peptidylarginine deiminase (PAD) 4 and production of citrullinated proteins in some tumor cells. However, little is known about malignant gliomas on this issue. Therefore, we here investigated whether expression of PADs was induced by hypoxia and whether PADs citrullinated intracellular proteins if induced using U-251 MG cells of a human malignant glioma cell line. Methods Expression of PADs in U-251 MG cells, cultured under hypoxia or normoxia for 24 h, was investigated by quantitative polymerase chain reaction (qPCR). Citrullination of proteins in the cells and the cell lysates incubated for 48 h with or without Ca 2+ was detected by western blotting. Citrullinated proteins were identified by mass spectrometry. Results The mRNA levels of PAD1, 2, 3, and 4 were up-regulated by hypoxia in a hypoxia-inducible factor-1-dependent manner in U-251 MG cells. In spite of the increased expression, intracellular proteins were not citrullinated. However, the induced PADs citrullinated U-251 MG cell-derived proteins when the cells were lysed. Multiple proteins citrullinated by hypoxia-induced PADs were identified. In addition, the extracellular domain of vascular endothelial growth factor receptor 2 was citrullinated by human PAD2 in vitro . Conclusion Our data may contribute to understanding of pathophysiology of malignant gliomas from the aspects of protein citrullination. [ABSTRACT FROM AUTHOR]

Brain tumors display the highest mortality rates of all childhood cancers, and over the last decade its prevalence has steadily increased in elderly. To date, effective treatments for brain tumors and particularly for malignant gliomas remain a challenge mainly due to the low permeability and high selectivity of the blood-brain barrier (BBB) to conventional anticancer drugs. In recent years, the elucidation of the cellular mechanisms involved in the transport of substances into the brain has boosted the development of therapeutic-targeted nanoparticles (NPs) with the ability to cross the BBB. Here, we present a comprehensive overview of the available therapeutic strategies developed against malignant gliomas based on 'actively targeted' NPs, the challenges of crossing the BBB and blood-brain tumor barrier as well as its mechanisms and a critical assessment of clinical studies that have used targeted NPs for the treatment of malignant gliomas. Finally, we discuss the potential of actively targeted NP-based strategies in clinical settings, its possible side effects and future directions for therapeutic applications. First draft submitted: 4 October 2016; Accepted for publication: 14 October 2016; Published online: 23 November 2016 [ABSTRACT FROM AUTHOR]

A humanized line of rat C6 glioma cells expressing human poliovirus receptor was obtained and tested for the sensitivity to oncolytic effects of vaccine strains of type 1, 2, and 3 polioviruses. Presentation of the poliovirus receptor on the surface of C6 glioma cells was shown to be a necessary condition for the interaction of cells with polioviruses, but insufficient for complete poliovirus oncolysis. [ABSTRACT FROM AUTHOR]

It has been reported previously that the expression of glucose transporter member 3 (GLUT3) is increased in malignant glioma cells compared with normal glial cells. However, the regulating mechanism that causes this phenomenon remains unknown. The present study investigated the regulating role of transcription factor specific protein 1 (Sp1) in GLUT3 expression in a human glioma cell line. In the present study, Sp1 was identified to directly bind to the GLUT3 5'-untranslated region in human glioma U251 cells. Small interfering RNA- and the Sp1-inhibitor mithramycin A-mediated Sp1 knockdown experiments revealed that Sp1 depletion decreased glucose uptake and inhibited cell growth and invasion of U251 cells by downregulating GLUT3 expression. Therefore Sp1 is an important positive regulator for the expression of GLUT3 in human glioma cells, and may explain the overexpression of GLUT3 in U251 cells. These results suggest that Sp1 may have a role in glioma treatment. [ABSTRACT FROM AUTHOR]

Background: We have reported that handheld confocal laser endomicroscopy (CLE) can be used with various nonspecific fluorescent dyes to improve the microscopic identification of brain tumor and its boundaries. Here, we show that CLE can be used experimentally with tumorspecific fluorescent labeling to define glioma margins in vivo. Methods: Thirteen rats underwent craniectomy and in vivo imaging 21 days after implantation with green fluorescent protein (GFP)labeled U251 (n = 7) cells or epidermal growth factor receptor (EGFR) overexpressing F98 cells (n = 6). Fluorescein isothiocyanate (FITC) conjugated EGFR fluorescent antibody (FITCEGFR) was applied for contrast in F98 tumors. Confocal images of normal brain, obvious tumor, and peritumoral zones were collected using the CLE system. Benchtop confocal microscopy and hematoxylin and eosinstained sections were correlated with CLE images. Results: GFP and FITCEGFR fluorescence of glioma cells were detected by in vivo visiblewavelength fluorescence CLE. CLE of GFPlabeled tumors revealed bright individual satellite tumor cells within peritumoral tissue, a definitive tumor border, and subcellular structures. Imaging with FITCEGFR labeling provided weaker contrast in F98EGFR tumors but was able to delineate tumor cells. Imaging with both methods in various tumor regions correlated with standard confocal imaging and clinical histology. Conclusions: These data suggest that in vivo CLE of selectively tagged neoplasms could allow specific interactive identification of tumoral areas. Imaging of GFP and FITCEGFR provides realtime histologic information precisely related to the site of microscopic imaging of tumor. [ABSTRACT FROM AUTHOR]

Objective : Malignant gliomas with neuronal marker expression (MGwNM) are rare and poorly characterized. Increasingly diverse types of MGwNM have been described and these reported cases underscore the dilemmas in the classification and diagnosis of those tumors. The aim of this study is to provide additional insights into MGwNM and present the clinicopathological features of 18 patients. Methods : We reviewed the medical records of 18 patients diagnosed as MGwNM at our institute between January 2006 and December 2012. Macroscopic total resection was performed in 11 patients (61%). We evaluated the methylation status of O6-methylguanine-DNA methyltransferase (MGMT) and expression of isocitrate dehydrogenase 1 (IDH-1) in all cases, and deletions of 1p and 19q in available cases. Results : The estimated median overall survival was 21.2 months. The median progression-free survival was 6.3 months. Six patients (33%) had MGMT methylation but IDH1 mutation was found in only one patient (6%). Gene analysis for 1p19q performed in nine patients revealed no deletion in six, 19q deletion only in two, and 1p deletion only in one. The extent of resection was significantly correlated with progression free survival on both univariate analysis and multivariate analysis (p=0.002 and p=0.013, respectively). Conclusion : In this study, the overall survival of MGwNM was not superior to glioblastoma. The extent of resection has a significant prognostic impact on progression-free survival. Further studies of the prognostic factors related to chemo-radio therapy, similar to studies with glioblastoma, are mandatory to improve survival. [ABSTRACT FROM AUTHOR]

Background and objective: Possible treatment strategies for recurrent malignant gliomas include surgery, chemotherapy, radiotherapy, and combined treatments. Among different reirradiation modalities, the CyberKnife System has shown promising results. We conducted a systematic review of the literature and a meta-analysis to establish the efficacy and safety of CyberKnife treatment for recurrent malignant gliomas. Methods: We searched PubMed, MEDLINE, and EMBASE from 2000 to 2021 for studies evaluating the safety and efficacy of CyberKnife treatment for recurrent WHO grade III and grade IV gliomas of the brain. Two independent reviewers selected studies and abstracted data. Missing information was requested from the authors via email correspondence. The primary outcomes were median Overall Survival, median Time To Progression, and median Progression-Free Survival. We performed subgroup analyses regarding WHO grade and chemotherapy. Besides, we analyzed the relationship between median Time To Recurrence and median Overall Survival from CyberKnife treatment. The secondary outcomes were complications, local response, and recurrence. Data were analyzed using random-effects meta-analysis. Results: Thirteen studies reporting on 398 patients were included. Median Overall Survival from initial diagnosis and CyberKnife treatment was 22.6 months and 8.6 months. Median Time To Progression and median Progression-Free Survival from CyberKnife treatment were 6.7 months and 7.1 months. Median Overall Survival from CyberKnife treatment was 8.4 months for WHO grade IV gliomas, compared to 11 months for WHO grade III gliomas. Median Overall Survival from CyberKnife treatment was 4.4 months for patients who underwent CyberKnife treatment alone, compared to 9.5 months for patients who underwent CyberKnife treatment plus chemotherapy. We did not observe a correlation between median Time To Recurrence and median Overall Survival from CyberKnife. Rates of acute neurological and acute non-neurological side effects were 3.6% and 13%. Rates of corticosteroid dependency and radiation necrosis were 18.8% and 4.3%. Conclusions: Reirradiation of recurrent malignant gliomas with the CyberKnife System provides encouraging survival rates. There is a better survival trend for WHO grade III gliomas and for patients who undergo combined treatment with CyberKnife plus chemotherapy. Rates of complications are low. Larger prospective studies are warranted to provide more accurate results. [ABSTRACT FROM AUTHOR]

Objective Radiation-induced malignant gliomas (RIMGs) are known uncommon risks of brain irradiation. We describe 4 cases of RIMG that occurred at our institution and conduct the largest comprehensive review of the literature to characterize RIMGs better. Methods Patients were identified through the PubMed database. Pearson R linear correlation test was used to evaluate the correlation between radiotherapy (RT) dose and age and latency period. Student t test was used to evaluate differences between latency periods for original tumor lesions. A normalized biologic equivalent dose analysis was performed to indicate the minimum and maximum radiation threshold for neoplasia. A Kaplan-Meier analysis was used to illustrate the overall survival curves. Results The analysis included 172 cases from the PubMed database and 4 cases occurring at our institution. The median RT dose administered was 35.6 Gy, with the most common dosage ranges being 21–30 Gy (31%) and 41–50 Gy (21.5%). Median latency period was 9 years until diagnosis of RIMG, and RIMG occurred within 15 years in 82% of the patients. There was no correlation between the age of the patient at the time RT was administered ( R 2 = 0.00081) or amount of RT ( R 2 = 0.00005) and latency period for RIMG. The mean biologic equivalent dose for neoplasia of a RIMG was 63.3 Gy. The median survival of patients with RIMG improved over time ( P = 0.004), with median survival of 9 months before 2007 and 11.5 months after 2007. Conclusions The risk of RIMG appears to be the same for all age groups, histologies, and RT dosages. Although the risk is low, patients should be aware of RIMG as a possible complication of brain irradiation. [ABSTRACT FROM AUTHOR]

Introduction Conventional imaging (intraoperative ultrasound and intraoperative magnetic resonance imaging) as well as enhanced visualization (aminolevulinic acid [ALA]-based fluorescence-guided resection) have both been used to improve the resection of malignant gliomas. Each modality has its pros and cons and may not be suitable for all cases. We describe our experience with these two complementary techniques. Methods Eight patients underwent resection for malignant gliomas using combined navigable three-dimensional ultrasound (3D-US) and ALA-induced fluorescence. These were analyzed formagnetic resonance imaging characteristics, resectability, and extent of resection. The utility of navigable 3D-US and the fluorescence were assessed for each case to stratify cases that may benefit from either or both of these techniques. Results Four subjects had predominant contrast-enhancing potentially resectable gliomas. Intraoperative strong fluorescence was seen, which was the primary guide for resection control. Navigable 3D-US was additionally useful for planning the craniotomy and localizing the subcortical lesions. All four tumors were gross-totally excised. Four other tumors were minimally enhancing and diffuse. Fluorescence was patchy and not used for resection control; instead, navigable 3D-US was the primary guide for resection. However, the fluorescence helped locating the focally higher grade parts within the tumors. Gross-total resection could be achieved in one patient. Conclusions Navigable 3D-US and ALA-induced fluorescence provide information regarding different aspects of tumor extent and combined together enhance the extent of resection. Fluorescence-guided resection may be sufficient for enhancing tumors, but nonenhancing tumors are better resected with navigable 3D-US. [ABSTRACT FROM AUTHOR]

Malignant gliomas are the most common primary brain tumor found in adults. Unfortunately, the prognosis for these type of tumors remains dismal despite aggressive treatment with surgical resection, radiation and chemotherapy. Therefore, therapeutics aimed at disrupting the angiogenesis of these tumors is being utilized in to improve survival outcomes and quality of life. This paper reviews the history of antiangiogenic agents in malignant gliomas, discusses the FDA approval of bevacizumab as monotherapy in recurrent glioblastoma and the subsequent controversy, and analyzes the most recent newly diagnosed trials of RTOG 0825 and AVAglio. Additionally, the results of the latest trials with antiangiogenic agents and possible biomarkers are reviewed. Multiple questions remain regarding the potential benefit of antiangiogenic treatments in patients with glioblastoma. Future clinical trials should be designed to learn more about these drugs, to optimize their future use. [ABSTRACT FROM AUTHOR]

The survival outcome of patients with malignant gliomas is still poor, despite advances in surgical techniques, radiation therapy and the development of novel chemotherapeutic agents. The heterogeneity of molecular alterations in signaling pathways involved in the pathogenesis of these tumors contributes significantly to their resistance to treatment. Several molecular targets for therapy have been discovered over the last several years. Therapeutic agents targeting these signaling pathways may provide more effective treatments and may improve survival. This review summarizes the important molecular therapeutic targets and the outcome of published clinical trials involving targeted therapeutic agents in glioma patients. [ABSTRACT FROM AUTHOR]

Malignant gliomas consist of glioblastomas, anaplastic astrocytomas, anaplastic oligodendrogliomas and anaplastic oligoastrocytomas, and some less common tumors such as anaplastic ependymomas and anaplastic gangliogliomas. Malignant gliomas have high morbidity and mortality. Even with optimal treatment, median survival is only 12-15 months for glioblastomas and 2-5 years for anaplastic gliomas. However, recent advances in imaging and quantitative analysis of image data have led to earlier diagnosis of tumors and tumor response to therapy, providing oncologists with a greater time window for therapy management. In addition, improved understanding of tumor biology, genetics, and resistance mechanisms has enhanced surgical techniques, chemotherapy methods, and radiotherapy administration. After proper diagnosis and institution of appropriate therapy, there is now a vital need for quantitative methods that can sensitively detect malignant glioma response to therapy at early follow-up times, when changes in management of nonresponders can have its greatest effect. Currently, response is largely evaluated by measuring magnetic resonance contrast and size change, but this approach does not take into account the key biologic steps that precede tumor size reduction. Molecular imaging is ideally suited to measuring early response by quantifying cellular metabolism, proliferation, and apoptosis, activities altered early in treatment. We expect that successful integration of quantitative imaging biomarker assessment into the early phase of clinical trials could provide a novel approach for testing new therapies, and importantly, for facilitating patient management, sparing patients from weeks or months of toxicity and ineffective treatment. This review will present an overview of epidemiology, molecular pathogenesis and current advances in diagnoses, and management of malignant gliomas. [ABSTRACT FROM AUTHOR]

Malignant gliomas account for approximately 60% of all primary brain tumors in adults. The prognosis for patients with malignant glioma has not changed significantly in recent years. Despite debulking surgery, radiotherapy and cytotoxic chemotherapy, the median survival time is nine to 12 months, and very few, if any, patients are cured from this illness. Fotemustine is an alkylating agent characterized by the grafting of a phosphonoalanine group onto the nitrosourea radical with consequent high lipophilicity and improved diffusion through the cell membrane and the blood-brain barrier. Fotemustine has been registered for use in two indications: disseminated malignant melanoma, including cerebral metastases, and primary brain tumors. Fotemustine is currently used in Europe, particularly in France and Italy, as a salvage therapy for recurrent malignant gliomas. Myelosuppression, leucopenia and thrombocytopenia are the most frequent side effects of treatment with fotemustine. The objective response to this treatment is between 26% and 70%, and the reported median survival time is 10 months. New drug combinations containing fotemustine and angiogenesis inhibitors, such as bevacizumab, are currently under development. In this review, we describe all the combinations of fotemustine currently used in clinical practice for recurrent malignant gliomas. [ABSTRACT FROM AUTHOR]

Abstract: Previous clinical trials of dendritic cell (DC)-based immunotherapy in patients with glioblastoma multiforme (GBM) have reported induction of systemic immune responses and prolonged survival. From 2003 to 2005, we performed a clinical trial in which patients with malignant glioma underwent surgery for maximal cytoreduction followed by a 6-month 10-injection course of autologous DC-tumor vaccine therapy, each injection containing 1–6×107 DC. Of the 17 treated patients (16 with World Health Organization grade IV and one with grade III glioma), eight (47.1%) had an initial transient elevation in aspartate aminotransferase (AST)/alanine aminotransferase (ALT). Vaccination caused some tumor shrinkage and increased concentration of tumor-infiltrating CD8(+) lymphocytes. Median survival and 5-year survival were 525days and 18.8%, respectively, for 16 patients with grade IV glioma (381days and 12.5% for eight newly diagnosed; 966days and 25% for eight relapsed patients) compared to 380days and 0% for 63 historical control patients. We concluded that autologous DC-tumor immunotherapy benefits patients with malignant glioma but may cause transient but reversible elevation of serum AST/ALT levels. [Copyright &y& Elsevier]

Abstract: Background and purpose: Malignant gliomas represent a major therapeutic challenge because no efficient treatment is currently available. p-[131I]iodo-l-phenylalanine ([131I]IPA) is a glioma avid radiopharmaceutical that demonstrated antiproliferative and tumoricidal effects in gliomas. The present study validated the therapeutic efficiency of [131I]IPA combined with external beam radiotherapy in experimental gliomas. Materials and methods: Glioma cells derived from the primary human A1207, T5135, Tx3868 and M059K glioblastoma cell lines or rat F98 glioma cell line were treated with various doses of [131I]IPA, external photon irradiation (RT) or combined [131I]IPA/RT treatment. Responsiveness of glioma cells to the different therapy modalities was investigated at 24, 48 and 72 h after treatments by trypan blue, WST-1 assay, propidium iodide and bisbenzimide staining as well as by clonogenic assay. In addition, the therapy-induced DNA damage and repair were evaluated using phosphorylated histone H2AX (γ-H2AX). In vivo, the effectiveness of the combination treatment was validated in human Tx3868 and A1207 glioblastoma xenografts in CD1 nu/nu mice and RNU rats. Results: In vitro, the combination treatment resulted in a greater than additive increase in cytotoxic effect in glioma cell lines. Cell survival rate following a treatment with 1.0 μCi (37 kBq) of [131I]IPA amounted to 70%±15% and 60%±10% after 48 and 72 h, respectively, and decreased under 20% after additional RT with 5 Gy. At higher RT doses, cell survival rate decreased below 5%. As a measure of DNA double-strand break, nuclear γ-H2AX foci were determined as a function of time. Within 24 h, the number of γ-H2AX foci per cell was significantly greater after combined modality compared with the individual treatments. In vivo, when combined with RT, the radionuclide therapy with [131I]IPA resulted in an extended tumor growth delay, a reduction of the initial tumor volume and an enhanced radiosensitivity in Tx3868 and A1207 glioblastoma xenografts in CD1 nu/nu mice and RNU rats. On day 90 after monotherapy with [131I]IPA (20 MBq) or RT (20 Gy), 35%–50% of the treated rats were still alive. In comparison, up to 70%–80% survival rates were registered after combined [131I]IPA/RT treatment on day 100 for all animal models. Conclusions: These preclinical data convincingly demonstrated that [131I]IPA plus external beam photon radiotherapy is a safe and highly effective treatment for experimental gliomas, which may merit a clinical trial to ascertain its potential as a therapeutic approach in patients. As only a low [131I]IPA activity and a low RT dose were applied, further optimization strategies should be pursued experimentally, including application of higher radiation doses and conventional fractionated regimens or use of methods aiming to increase target doses and maximize dose effects. [Copyright &y& Elsevier]

Malignant gliomas account for approximately 60% of all primary brain tumors in adults. Prognosis for these patients has not significantly changed in recent years-despite debulking surgery, radiotherapy and cytotoxic chemotherapy-with a median survival of 9-12 months. Virtually no patients are cured of their illness. Malignant gliomas are usually locally invasive tumors, though extra-neural metastases can sometimes occur late in the course of the disease (median of two years). They generally appear after craniotomy although spontaneous metastases have also been reported. The incidence of these metastases from primary intra-cranial malignant gliomas is low; it is estimated at less than 2% of all cases. Extra-neural metastases from gliomas frequently occur late in the course of the disease (median of two years), and generally appear after craniotomy, but spontaneous metastases have also been reported. Malignant glioma metastases usually involve the regional lymph nodes, lungs and pleural cavity, and occasionally the bone and liver. In this review, we present three cases of extra-neural metastasis of malignant gliomas from our department, summarize the main reported cases in literature, and try to understand the mechanisms underlying these systemic metastases. [ABSTRACT FROM AUTHOR]

Significant progress has been made in the molecular diagnostic subtyping of brain tumors, in particular gliomas. In contrast to the classical molecular markers in this field, p53 and epidermal growth factor receptor ( EGFR) status, the clinical significance of which has remained controversial, at least three important molecular markers with clinical implications have now been identified: 1p/19q codeletion, O-methylguanine methyltransferase ( MGMT) promoter methylation and isocitrate dehydrogenase-1 ( IDH1) mutations. All three are favorable prognostic markers. 1p/19q codeletion and IDH1 mutations are also useful to support and extend the histological classification of gliomas since they are strongly linked to oligodendroglial morphology and grade II/III gliomas, as opposed to glioblastoma, respectively. MGMT promoter methylation is the only potentially predictive marker, at least for alkylating agent chemotherapy in glioblastoma. Beyond these classical markers, the increasing repertoire of anti-angiogenic agents that are currently explored within registration trials for gliomas urgently calls for efforts to identify molecular markers that predict the benefit derived from these novel treatments, too. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Podoplanin/aggrus is a mucin-like sialoglycoprotein that is highly expressed in malignant gliomas. Podoplanin has been reported to be a novel marker to enrich tumor-initiating cells, which are thought to resist conventional therapies and to be responsible for cancer relapse. The purpose of this study was to determine whether an anti-podoplanin antibody is suitable to target radionuclides to malignant gliomas. Methods: The binding affinity of an anti-podoplanin antibody, NZ-1 (rat IgG2a), was determined by surface plasmon resonance and Scatchard analysis. NZ-1 was radioiodinated with 125I using Iodogen [125I-NZ-1(Iodogen)] or N-succinimidyl 4-guanidinomethyl 3-[131I]iodobenzoate ([131I]SGMIB-NZ-1), and paired-label internalization assays of NZ-1 were performed. The tissue distribution of 125I-NZ-1(Iodogen) and that of [131I]SGMIB-NZ-1 were then compared in athymic mice bearing glioblastoma xenografts. Results: The dissociation constant (K D) of NZ-1 was determined to be 1.2×10−10 M by surface plasmon resonance and 9.8×10−10 M for D397MG glioblastoma cells by Scatchard analysis. Paired-label internalization assays in LN319 glioblastoma cells indicated that [131I]SGMIB-NZ-1 resulted in higher intracellular retention of radioactivity (26.3±0.8% of initially bound radioactivity at 8 h) compared to that from the 125I-NZ-1(Iodogen) (10.0±0.1% of initially bound radioactivity at 8 h). Likewise, tumor uptake of [131I]SGMIB-NZ-1 (39.9±8.8 %ID/g at 24 h) in athymic mice bearing D2159MG xenografts in vivo was significantly higher than that of 125I-NZ-1(Iodogen) (29.7±6.1 %ID/g at 24 h). Conclusions: The overall results suggest that an anti-podoplanin antibody NZ-1 warrants further evaluation for antibody-based therapy against glioblastoma. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) is the most frequently encountered malignant cerebral tumor. Despite significant improvements in the treatment of GBM, this disease remains associated with a high morbidity and mortality, with more than half of all affected patients dying within the first year after diagnosis. Typical symptoms include focal neurological symptoms, seizures, personality changes and neurocognitive symptoms. GBM can be identified by means of cerebral imaging modalities and subsequently confirmed histopathologically through biopsy or resection. At present, surgical resection followed by radiotherapy with concomitant chemotherapy with temozolomide and subsequent adjuvant chemotherapy with temozolomide is considered the standard therapy for patients with GBM. Currently, many interdisciplinary studies with glioblastoma patients are accomplished with the aim to further improve the prognosis of the affected patients. [ABSTRACT FROM AUTHOR]

Oncolytic viruses constitute a promising therapy against malignant gliomas (MGs). However, virus-induced type I IFN greatly limits its clinical application. The kinase mammalian target of rapamycin (mTOR) stimulates type I IFN production via phosphorylation of its effector proteins, 4E-BP5 and S6K5. Here we show that mouse embryonic fibroblasts and mice lacking 56K1 and S6K2 are more susceptible to vesicular stomatitis virus (VSV) infection than their WT counterparts as a result of an impaired type I IFN response. We used this knowledge to employ a pharmacoviral approach to treat MGs. The highly specific inhibitor of mTOR rapamycin, in combination with an IFN-sensitive VSV-mutant strain (VSVΔM51), dramatically increased the survival of immunocompetent rats bearing MG5. More importantly. VSVΔM51 selectively killed tumor, but not normal cells, in MG-bearing rats treated with rapamycin. These results demonstrate that reducing type I IFN5 through inhibition of mTORC1 is an effective strategy to augment the therapeutic activity of VSVΔM51. [ABSTRACT FROM AUTHOR]

Angiogenesis is considered to be a regulating factor of vascular development and growth for malignant gliomas, including glioblastoma multiforme (GBM) and anaplastic astrocytomas. The mechanism of angiogenesis is primarily mediated by hypoxia through chronic activation of the HIF pathway leading to the production of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor. Alternatively, it can be triggered by genetic factors. The VEGF/VEGFR-2 is the predominant angiogenic signalling pathway in malignant gliomas. Currently, anti-angiogenic molecularly targeted therapies, including administration of monoclonal antibodies or tyrosine kinase inhibitors (TKIs), are being increasingly adopted for treating GBMs. This approach is based on the ability of anti-VEGFRs monoclonal antibodies to decrease vascular permeability and perfusion, whereas the use of TKIs is mainly based on their capacity to interfere with cell communication, receptor signaling and growth of tumours. Our aim is to review current knowledge on angiogenesis as a molecular pathogenetic mechanism of malignant gliomas and to critically look at and discuss antiangiogenic molecularly targeted therapies for these brain malignancies. We also highlight areas of future research to pursue. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Malignant gliomas, among others the glioblastoma multiforme, are the most frequent brain tumors. The glioblastoma itself represents the most unfavorable tumor. In Switzerland, about 450 humans contract a glioblastoma each year. The median survival time is under 12 months, thus the prognosis is dismal despite a combination of surgery, radiotherapy and chemotherapy. Surgical resection presents the major constituent in the management of patients with a glioblastoma. Post-operative radio- and chemotherapy have beneficial effects on the survival time and quality of life. Surgical removal of glioblastomas is challenging due to their infiltrative growth pattern. Therefore, the target extent of resection can only be achieved partially. For some time now, a new in Germany developed method is used in the Neurosurgical Clinic of the Cantonal Hospital in St. Gallen: the 5 ALA-guided microsurgical resection method allows a targeted and secure surgical resection at the tumor. A preoperative administered substance colors the tumor and makes it better visible for the neurosurgeon. Consequently, the healthy brain tissue can be better distinguished from the tumor. This permits not only a larger complete surgical resection of the tumor but also minimizes the resection of healthy tissue. [ABSTRACT FROM AUTHOR]

Fotemustine is a nitrosourea compound used for the treatment of malignant gliomas, especially in France. Recently, an EORTC-NCIC study has shown that a concomitant combination of radiotherapy plus temozolomide (an oral cytotoxic drug) improved survival in glioblastoma patients. We set out to test a concurrent combination of radiotherapy and fotemustine for newly malignant gliomas. A prospective single-center phase II study opened for accrual in September 2004. Patients over 18 years of age able to give informed consent and with histologically proven, newly diagnosed supratentorial malignant gliomas were eligible. All patients were treated by a standard cranial irradiation (conformal irradiation, tumor bulk plus a margin of 2.5 cm) and concomitant daily administration of 10 mg/m2 of fotemustine (5 days per week, 6 weeks, 1 h 30 min before radiation therapy). Adjuvant chemotherapy, fotemustine, was administered at tumor progression as standard and classic regimen. Twenty-two patients were enrolled, 16 men and 6 women, median age 56 years (range 32–74), median Karnofsky performance status 70 (range 60–90). Histology included 16 glioblastomas, 3 anaplastic astrocytomas, 2 anaplastic oligodendrogliomas and 1 mixed glioma. Eight patients underwent surgery (three total resections). Fourteen patients had a stereotactic biopsy. The concurrent radiotherapy–fotemustine combination was well tolerated: toxicity was mild and three hematologic toxicities grade 3–4 were observed. Median survival from the initial diagnosis was 9.9 months, two patients are currently alive. Median survival was 11 months for surgery and 9 months for stereotactic biopsy. Concomitant radiotherapy–fotemustine combination is safe and well tolerated. Overall survival of over 10 months for the whole population compares favorably with other reports. [ABSTRACT FROM AUTHOR]

2-deoxy-D-glucose (2-DG), an inhibitor of glucose transport and glycolysis, enhances radiation damage selectively in tumor cells by modulating damage response pathways resulting in cell death in vitro and local tumor control. Phase I and II clinical trials in patients with malignant glioma have shown excellent tolerance to a combined treatment of orally administered 2-DG and hypofractionated radiotherapy without any acute toxicity and late radiation damage. Phase III efficacy trials are currently at an advanced stage. Re-exploratory surgery performed in 13 patients due to persistent symptoms of elevated ICP and mass effect at different follow-up periods revealed extensive tumor necrosis with well-preserved normal brain tissue adjoining the tumor included in the treatment volume as revealed by a histological examination. These observations are perhaps the first clinical evidences for differential effects of 2-DG on tumors and normal tissues in conformity with earlier in vitro and in vivo studies in normal and tumor-bearing mice. [ABSTRACT FROM AUTHOR]

This is a phase-I study of gefitinib in combination with temozolomide in patients with gliomas. The goal of the study was to define the maximum tolerated dose (MTD) and to characterize the pharmacokinetics of gefitinib when combined with temozolomide. Patients were stratified according to co-administration of enzyme-inducing anti-epileptic drugs (EIAEDs). There were 26 evaluable patients enrolled (16 on EIAEDs, 10 not on EIAEDs). All but seven patients had Glioblastoma Multiforme (GBM), and only six cases had a Karnosfsky Performance Status (KPS) of less than 80; median age was 51 years. All had received prior radiotherapy and 14 patients had no prior chemotherapy. The starting dose of temozolomide was 150 mg/m2/day for 5 days every 28 days and could be escalated to a maximum dose of 200 mg/m2/day in subsequent cycles. The starting dose of gefitinib was 500 mg/day given by mouth on a continuous basis. Dose-limiting toxicity was assessed in cycle one only. For patients on EIAEDs, the MTD of gefitinib was 1,000 mg/day in combination with temozolomide. Dose-limiting toxicity (DLT) was due to diarrhea, nausea and vomiting. For patients not on EIAEDs, the MTD was 250 mg/day in combination with temozolomide. The DLT was due to increases in liver transaminases. Rash was not a significant toxicity at these dose levels. The peak concentration and AUC0-24hr at the 500 mg dose level was 1.8 and 2.5-fold lower, respectively, in the EIAED group compared to the non-EIAED group; trough levels of gefitinib increased in both groups consistent with the reported terminal half-life ranging from 27 to 51 h. The recommended phase-2 dose of gefitinib when used in combination with temozolomide is 1,000 and 250 mg/day, respectively, for patients on or not on EIAEDs. [ABSTRACT FROM AUTHOR]

Temozolomide (TMZ) is widely used in Europe and the United States. For the safe use of TMZ in the Japanese, as representative of Asians, the pharmacokinetics of TMZ was investigated in Japanese patients and compared to that in Caucasians. The pharmacokinetics and safety of TMZ following oral administration of 150 and 200 mg/m2 per day for the first 5 days of a 28-day treatment cycle were investigated in six Japanese patients with relapsed gliomas. The time-to-maximum plasma concentration (tmax) of TMZ was about 1 h and the elimination half-life of terminal excretion phase (t1/2λz) was about 2 h. A dose-dependent increase was observed in maximum plasma concentration (Cmax) and AUC, while values for t1/2λz, apparent total body clearance (CL/F), and apparent distribution volume (Vz/F) were independent of dose. After administration for 5 days, changes in pharmacokinetics and accumulation were not observed. The plasma 5-(3-methyl)1-triazen-1-yl-imidazole-4-carboxamide (MTIC) concentration changed in parallel with the TMZ plasma concentration, and the Cmax and AUC of MTIC were about 2% of those of TMZ. The pharmacokinetic parameters of TMZ and MTIC in Japanese patients in this study were comparable to those previously determined in Caucasian subjects. Adverse events occurred in all patients, but toxicities were mostly mild or moderate, and continuation of administration was possible by adjusting the dose and by delaying the start of the next treatment cycle. The pharmacokinetic and safety profile of TMZ in Japanese patients was comparable to that in Caucasians. The treatment regimen used in Europe and the United States will be suitable for Asian patients, including Japanese. [ABSTRACT FROM AUTHOR]

Study objectives. To re-evaluate the cost effectiveness and median overall survival (OS) achieved in patients with recurrent malignant gliomas treated with temozolomide in British Columbia, as compared to previous lomustine use in the same patient population based on updated outcomes data. Results were also compared to temozolomide literature reports. Methods. A retrospective medical record review was performed to identify patients who received single agent temozolomide or lomustine during successive, prespecified time periods. Data were collected on survival, duration of therapy, drug cost, labour and supplies, and successive or prior chemotherapy. Results. Forty-one patients in the temozolomide group and 25 patients in the lomustine group were analysed. The median OS was 33.3 weeks (95% CI 28.4, 42.1 weeks) and 37.7 weeks (95% CI 25.0, 88.4 weeks) respectively (P = 0.783). Temozolomide patients received a mean of 5.1 cycles of drug treatment, with a mean cost per patient of $10746 (CAD). In contrast, lomustine patients received a mean of 3.3 cycles of therapy, with a mean cost per patient of $129 (CAD). The cost-effectiveness analysis showed that temozolomide was generally not a cost-effective strategy and that lomustine was the dominant strategy. In the sensitivity analysis, in scenarios where median OS was prolonged with temozolomide as compared to lomustine, the incremental cost-effectiveness ratio for each life year gained ranged from $32,247 to $162,186. Conclusion. No difference in survival was observed between patients treated with single agent lomustine and temozolomide. Based on the higher cost and lack of additional clinical benefit of temozolomide, lomustine is a more cost-effective treatment strategy. [ABSTRACT FROM AUTHOR]

Purpose: To estimate a plausible set of radiobiologic parameters such as α, α/β values, from clinical outcomes for biologically based radiation treatment planning of brain tumors. Methods and Materials: Linear-quadratic (LQ) formalism and the concept of equivalent uniform dose were used to analyze a series of published clinical data for malignant gliomas involving different forms of radiation therapy. Results: A plausible set of LQ parameters was obtained for gliomas: α = 0.06 ± 0.05 Gy−1, α/β = 10.0 ± 15.1 Gy, the tumor cell doubling time Td = 50 ± 30 days, with the repair half-time of 0.5 h. The present estimated biologic parameters can reasonably predict the effectiveness of most of the recently reported clinical results employing either single or combined radiation therapy modalities. Different LQ parameters between Grade 3 and Grade 4 astrocytomas were found, implying the radiosensitivity for different grade tumors may be different. Smaller α, β from in vivo was observed, indicating lower radiosensitivity occurred in vivo as compared with in vitro. Conclusions: A plausible set of radiobiologic parameters for gliomas was estimated based on clinical data. These parameters can reasonably predict most of the clinical results. They may be used to design new treatment fractionation schemes and to evaluate and optimize treatment plans. [Copyright &y& Elsevier]