Adult Malignant Gliomas Research Articles

EXTH-22. TARGETING MITOCHONDRIAL PROTEASE IN DIFFUSE GLIOMAS

Abstract BACKGROUND Targeting mitochondrial function has emerged as a promising therapeutic strategy in cancer treatment. TR107 is characterized as a specific activator of caseinolytic protease proteolytic subunit (ClpP) in the mitochondria, potentially affecting oncogenic pathways. Here, we investigated the effects of TR107 on adult malignant gliomas, IDH-wildtype and IDH-mutant METHODS We utilized patient-derived glioma cells to determine the efficacy of TR107 with cell viability, proliferation, cell cycle, and apoptosis assays. Immunofluorescent staining and electron microscopy (EM) were employed to uncover organelle morphological changes upon treatment. Mitochondrial function and ATP production were assessed in live cells utilizing Seahorse analysis. Global proteomics and RNA sequencing were performed to identify treatment-induced dysregulated pathways in glioma cells RESULTS Both IDH-wildtype and IDH-mutant glioma cell lines were highly sensitive to TR107, showing at least 100 times lower IC50 compared to the related compound ONC201. Genetic knock out of ClpP revealed that the growth inhibitory effects of TR107 are ClpP-dependent. Interestingly, IDH-mutant cell lines showed a more profound disintegration of mitochondrial morphology and dysregulation of mitochondrial function evidenced by an enhanced suppression of oxidative phosphorylation, mitochondrial complexes expression, mtDNA copy number, complex I activity, and ATP production, compared to IDH-wildtype cells. Six days of treatment with TR107 led to a complete inhibition of cell growth and up to 97% of cell death in IDH-mutant cells, while 50% of IDH-wildtype cells remained viable. Western blot, EM, and RNAsequencing analyses uncovered autophagy as a potential pro-survival mechanism in IDH-wildtype cells. Importantly, multiple metabolic and DNA repair-related pathways were affected by the treatment, suggested by global proteomics and RNA sequencing. Finally, TR107 was not affected by ABC transporters, supporting its potential use in brain tumor patients CONCLUSION TR107 demonstrated potent cytotoxic effects in patient-derived glioma cells by disrupting mitochondrial structural and functional integrity. TR107 efficacy in vivo is under investigation.

Circulating tumor RNA and exosomes as disease prognosis and therapy effectivity novel markers in case of malignant gliomas in adults

Malignant gliomas of CNS are the most wide-spread variant of primary brain tumors characteristic of invasive growth, fast evolution, high resistance to therapy and consequently quick recurrence that causes death of the patients. Taking into consideration peculiar features of these neoplasms an acute need has sprung in neurooncologic community for a search of novel low-invasive methods for the assessment of treatment effectivity and determining the progression rate of the disease. During the last decade a great number of studies exploring various circulating tumor ribonucleic acids in case of astrocytoma have been accomplished. The tumor nucleic acids as well as vesicles expressed by glioma may be discovered in blood and spine fluid. Thus these biomarkers are the most perspective targets for realizing these goals. The review presents tumor ribonucleic acids and exosomes, regulatory signaling pathways within tumor glioma cell causing resistance towards alkalizing chemical preparations and directly participating in recurrence. The most prospective nucleic acids as prognosis biomarkers and response to specific antitumor therapy predictors were determined and the most informative methods of their assessment have been depicted. Possibilities of alkalizing agents effectivity rise by means of nucleic acids expression correction have been discussed.

DDDR-10. SIRTUIN 2 INHIBITION SELECTIVELY INDUCES SENESCENCE IN ATRX-DEFICIENT MALIGNANT GLIOMAS BY MODULATING CHROMATIN LANDSCAPES GENOME-WIDE

Abstract Inactivating mutations in ATRX characterize large subgroups of malignant gliomas in adults and children. ATRX deficiency in glioma induces widespread chromatin remodeling, driving transcriptional shifts and oncogenic phenotypes. Effective strategies to therapeutically target these broad epigenomic sequelae remain undeveloped. We utilized integrated mulit-omics and the Broad Institute Connectivity Map (CMAP) to identify drug candidates that could potentially revert ATRX-deficient transcriptional changes. We then employed disease-relevant experimental models to evaluate functional phenotypes, coupling these studies with epigenomic profiling to elucidate molecular mechanim(s). CMAP analysis and transcriptional/epigenomic profiling implicated the Class III HDAC Sirtuin2 (Sirt2) as a central mediator of ATRX-deficient cellular phenotypes and a driver of unfavorable prognosis in ATRX-deficient glioma. Sirt2 inhibitors reverted Atrx-deficient transcriptional signatures in murine neuroprogenitor cells (mNPCs) and impaired cell migration in Atrx/ATRX-deficient mNPCs and human glioma stem cells (GSCs). While effects on cellular proliferation in these contexts were more modest, markers of senescence significantly increased, suggesting that Sirt2 inhibition promotes terminal differentiation in ATRX-deficient glioma. These phenotypic effects were accompanied by genome-wide shifts in enhancer-associated H3K27ac and H4K16ac marks, with the latter in particular demonstrating compelling transcriptional links to Sirt2-dependent phenotypic reversals. Motif analysis of these data identified the transcription factor KLF16 as a mediator of phenotype reversal in Atrx-deficient cells upon Sirt2 inhibition. Finally, Sirt2 inhibition impaired growth and increased senescence in ATRX-deficient GSCs in vivo. Our findings indicate that Sirt2 inhibition selectively targets ATRX-deficient gliomas through global chromatin remodeling, while demonstrating more broadly a viable approach to combat complex epigenetic rewiring in cancer.

PLASMA PROTEOMICS AND MACHINE LEARNING FOR NOVEL BIOMARKER DISCOVERY IN ADULT MALIGNANT GLIOMA

Abstract AIMS Plasma is a valuable source for identifying non-invasive biomarkers, and when combined with an examination of the highly dynamic proteome, it has the potential to lead to the identification of novel biomarkers in glioma. The aim of this study was to uncover plasma-based protein biomarkers for adult malignant glioma. METHOD Mass spectrometry-based proteomics with tandem mass tag (TMT) labelling of plasma from healthy individuals and adult malignant gliomas was performed. A differential abundance analysis was carried out to identify proteins that were deregulated in primary gliomas compared to healthy individuals. Machine learning was employed to identify a diagnostic biomarker panel. RESULTS When comparing plasma from healthy individuals to that of primary gliomas, several high and low abundant proteins were found to be deregulated. To improve the accuracy and ability of biomarkers to detect malignant gliomas, machine learning was employed and led to a development of a classifier, which performed with high accuracy, specificity, and sensitivity. CONCLUSIONS The discovery of a plasma-based protein classifier, once validated, may facilitate an earlier diagnosis of glioma patients, and thereby reduce time-to-treatment.

Sirtuin 2 inhibition modulates chromatin landscapes genome-wide to induce senescence in ATRX-deficient malignant glioma.

Functional inactivation of ATRX characterizes large subgroups of malignant gliomas in adults and children. ATRX deficiency in glioma induces widespread chromatin remodeling, driving transcriptional shifts and oncogenic phenotypes. Effective strategies to therapeutically target these broad epigenomic sequelae remain undeveloped. We utilized integrated multiomics and the Broad Institute Connectivity Map (CMAP) to identify drug candidates that could potentially revert ATRX-deficient transcriptional changes. We then employed disease-relevant experimental models to evaluate functional phenotypes, coupling these studies with epigenomic profiling to elucidate molecular mechanism(s). CMAP analysis and transcriptional/epigenomic profiling implicated the Class III HDAC Sirtuin2 (SIRT2) as a central mediator of ATRX-deficient cellular phenotypes and a driver of unfavorable prognosis in ATRX-deficient glioma. SIRT2 inhibitors reverted Atrx-deficient transcriptional signatures in murine neuroepithelial progenitor cells (mNPCs), impaired cell migration in Atrx/ATRX-deficient mNPCs and human glioma stem cells (GSCs), and increased expression of senescence markers in glioma models. Moreover, SIRT2 inhibition impaired growth and increased senescence in ATRX-deficient GSCs in vivo. These effects were accompanied by genome-wide shifts in enhancer-associated H3K27ac and H4K16ac marks, with the latter in particular demonstrating compelling transcriptional links to SIRT2-dependent phenotypic reversals. Motif analysis of these data identified the transcription factor KLF16 as a mediator of phenotype reversal in Atrx-deficient cells upon SIRT2 inhibition. Our findings indicate that SIRT2 inhibition selectively targets ATRX-deficient gliomas for senescence through global chromatin remodeling, while demonstrating more broadly a viable approach to combat complex epigenetic rewiring in cancer.

Clinical Effects of Immuno-Oncology Therapy on Glioblastoma Patients: A Systematic Review

The most prevalent and deadly primary malignant glioma in adults is glioblastoma (GBM), which has a median survival time of about 15 months. Despite the standard of care for glioblastoma, which includes gross total resection, high-dose radiation, and temozolomide chemotherapy, this tumor is still one of the most aggressive and difficult to treat. So, it is critical to find more potent therapies that can help glioblastoma patients have better clinical outcomes. Additionally, the prognosis for recurring malignant gliomas is poor, necessitating the need for innovative therapeutics. Immunotherapy is a rather new treatment for glioblastoma and its effects are not well studied when it is combined with standard chemoradiation therapy. We conducted this study to evaluate different glioblastoma immunotherapy approaches in terms of feasibility, efficacy, and safety. We conducted a computer-assisted literature search of electronic databases for essays that are unique, involve either prospective or retrospective research, and are entirely written and published in English. We examined both observational data and randomized clinical trials. Eighteen studies met the criteria for inclusion. In conclusion, combining immunotherapy with radiochemotherapy and tumor removal is generally possible and safe, and rather effective in the prolongation of survival measures.

Astrocytoma, Diagnosis and Treatment. Literature Review

Most primary CNS tumors are astrocytic tumors. Glial tumors are classified according to histological criteria. The WHO classification for primary malignant gliomas in adults includes grades II through IV. Terms for tumors that classify in grade II are astrocytomas (A), oligodendrogliomas (ODG), or mixed gliomas (GM). Grade III tumors are named similarly, and preceded by the word anaplastic, for example, anaplastic astrocytoma (AA), anaplastic oligodendroglioma (ODGA), or mixed anaplastic glioma (GAM). The most malignant form, the grade IV tumor, is designated glioblastoma or GBM. GBMs are diagnosed more frequently than lower grade astrocytomas. The recent GBM classifications reflect the genetic aspects involved in the tumor and have prognostic value. The most important prognostic factor in malignant gliomas is the histopathological diagnosis of the tumor. The survival of patients with AA is much higher than that of patients with glioblastoma. Other important factors that are associated with the survival of patients with malignant gliomas are the age of the patients, Karnofsky scale, surgery, radiotherapy, and chemotherapy. There is evidence suggesting an association between younger patients and longer survival in adults with supratentorial AA and glioblastoma

Biomarkers Regulated by Lipid-Soluble Vitamins in Glioblastoma

Glioblastoma (GBM), a highly lethal form of adult malignant gliomas with little clinical advancement, raises the need for alternative therapeutic approaches. Lipid-soluble vitamins have gained attention in malignant brain tumors owing to their pleiotropic properties and their anti-cancer potential have been reported in a number of human GBM cell lines. The aim of this paper is to systematically review and describe the roles of various biomarkers regulated by lipid-soluble vitamins, such as vitamins A, D, E, and K, in the pathophysiology of GBM. Briefly, research articles published between 2005 and 2021 were systematically searched and selected from five databases (Scopus, PubMed, Ovid MEDLINE, EMBASE via Ovid, and Web of Science) based on the study’s inclusion and exclusion criteria. In addition, a number of hand-searched research articles identified from Google Scholar were also included for the analysis. A total of 40 differentially expressed biomarkers were identified from the 19 eligible studies. The results from the analysis suggest that retinoids activate cell differentiation and suppress the biomarkers responsible for stemness in human GBM cells. Vitamin D appears to preferentially modulate several cell cycle biomarkers, while vitamin E derivatives seem to predominantly modulate biomarkers related to apoptosis. However, vitamin K1 did not appear to induce any significant changes to the Raf/MEK/ERK signaling or apoptotic pathways in human GBM cell lines. From the systematic analysis, 12 biomarkers were identified that may be of interest for further studies, as these were modulated by one or two of these lipid-soluble vitamins.

PTBP1 is a Novel Poor Prognostic Factor for Glioma.

Objective Polypyrimidine tract-binding protein 1 (PTBP1) is an RNA-binding protein, which plays a role in pre-mRNA splicing and in the regulation of alternative splicing events. However, little was known about the correlation between PTBP1 and glioma and its prognostic significance in glioma patients. Our aim was to investigate the expression, functional role, and prognostic value of PTBP1 in glioma. Methods We explored the expression of PTBP1 protein using immunohistochemistry in 150 adult malignant glioma tissues and 20 normal brain tissues and evaluated its association with clinicopathological parameters by chi-square test. Kaplan-Meier method was used to evaluate the prognostic effect of PTBP1 in glioma. Univariate/multivariate Cox analyses were used to identify independent prognostic factors. Transcriptional regulation network was constructed based on differentially expressed genes (DEGs) of PTBP1 from TCGA/CGGA database. GO and KEGG enrichment analyses were used to explore the function and pathways of DEGs. Results Out of the 150 malignant glioma tissues (60 LGG and 90 GBMs) and 20 normal brain tissues in our cohort, PTBP1 protein was high expressed in glioma tissues (79/150, 52.7%), but no expression was detected in normal brain tissues (0/20, 0%). The expression of PTBP1 was significantly higher in GBMs (P < 0.001). More than half of GBMs (62/90, 68.9%) were PTBP1 high expression. Chi-square test showed that the expression of PTBP1 was correlated with patient age, WHO grade, Ki-67 index, and IDH status. High expression of PTBP1 was significantly associated with poor prognosis in glioma, and it was an independent risk factor in glioma patients. Furthermore, we shed light on the underlying mechanism of PTBP1 by constructing a miR-218-TCF3-PTBP1 transcriptional network in glioma. Conclusion PTBP1 was high expressed in glioma, and it significantly correlated with poor prognosis, suggesting a potential therapeutic target for glioma, particularly for GBM.

H3.3-K27M drives neural stem cell-specific gliomagenesis in a human iPSC-derived model.

Diffuse intrinsic pontine glioma (DIPG) is an aggressive childhood tumor of the brainstem with currently no curative treatment available. The vast majority of DIPGs carry a histone H3 mutation leading to a lysine 27-to-methionine exchange (H3K27M). We engineered human induced pluripotent stem cells (iPSCs) to carry an inducible H3.3-K27M allele in the endogenous locus and studied the effects of the mutation in different disease-relevant neural cell types. H3.3-K27M upregulated bivalent promoter-associated developmental genes, producing diverse outcomes in different cell types. While being fatal for iPSCs, H3.3-K27M increased proliferation in neural stem cells (NSCs) and to a lesser extent in oligodendrocyte progenitor cells (OPCs). Only NSCs gave rise to tumors upon induction of H3.3-K27M and TP53 inactivation in an orthotopic xenograft model recapitulating human DIPGs. In NSCs, H3.3-K27M leads to maintained expression of stemness and proliferative genes and a premature activation of OPC programs that together may cause tumor initiation.

STMO-01 Cerebral edema and perioperative epilepsy due to placement of BCNU wafer for malignant glioma

Introduction: Cerebral edema is the most frequent adverse event of BCNU wafer, which is used as local chemotherapy of malignant glioma. However, predictive factor of this event is unknown. Moreover, there is no consensus about cerebral edema and perioperative seizure, which is often observed in glioma. Here, we report risk factor of cerebral edema with BCNU placement and relationship with perioperative seizure in malignant glioma cases.Material and Method: Thirty-one case of adult malignant glioma who underwent BCNU placement in our institute between March 2013 to March 2019 were investigated. The patients were dichotomized to two groups; patient with postoperative transient cerebral edema (CE+ group) and patient without postoperative transient cerebral edema (CE- group).Result: Postoperative cerebral edema associated with placement of BCNU was observed in 9 out of 31 patients (29%). Tumor malignancy was significant parameter for postoperative cerebral edema (p=0.003). Other factors such as, age, gender, laterality, tumor location, primary or recurrent, number of BCNU wafers, duration of recurrence were not significant for postoperative cerebral edema. Seizure was seen in 14 patients (45%), and cerebral edema was not significant parameter for seizure. Tumor malignancy was significant parameters for postoperative cerebral edema. Tumor malignancy was significant parameters for seizure (p=0.0004). Although postoperative seizure was observed in 4 patients (44%) with CE+ group, neither maximum volume (mean 61.1 ml) nor change ratio (mean 354%) of FLAIR-high-intensity region were not related with postoperative seizure.Conclusions: Tumor malignancy was important factor for patients who underwent placement of BCNU wafer with postoperative cerebral edema and seizure. On the other hand, there were no relationship between postoperative cerebral edema and perioperative seizure in patients treated with BCNU wafer.

EXTH-62. PRECLINICAL EFFICACY OF THE IMIPRIDONE ONC-206 AGAINST MEDULLOBLASTOMA

Abstract Treatment for medulloblastoma (MB) is typically ineffective for MYC amplified or metastatic SHH, Group 3 and 4 subgroups. Promising preclinical and clinical results have been obtained for adult and pediatric malignant glioma treated with ONC-201, a selective antagonist of DRD2, a G-protein coupled receptor that regulates prosurvival pathways. Herein, we report the activity of ONC-201 and ONC-206, which has increased non-competitive antagonism of DRD2, against MB. We treated three different MB cell types representative of SHH- and Group 3-like cells, with varied levels of DRD2 expression, and consistently observed increased cell death in a dose-dependent manner at lower doses of ONC-206 compared to ONC-201. We also evaluated ClpP as an additional drug target in MB. ClpP is a mitochondrial protease that has been shown to directly bind and be activated by ONC 201, and is highly expressed at the protein level across pediatric MB, malignant glioma and ATRT, but not normal brain. We observed that similar to ONC-201, ONC-206 treatment of MB cells induces the restoration of mitochondrial membrane potential to the non-proliferative state, degradation of the mitochondrial substrate SDHB, reduction in survivin and elevation in ATF4 (integrated stress response). Importantly, ONC-206 treatment induced significant cell death of patient-derived SHH, WNT, and Group 3 tumors ex vivo and Group 4 cells in vitro, while having no observable toxicity in normal brain. ONC-206 treatment of a transgenic mouse model of Shh MB in vivo significantly reduces tumor growth and doubles survival time in a dose-dependent manner following 2 weeks of therapy. Additional in vivo data will be reported in preparation for a planned Phase I study of ONC-206 in children with malignant brain tumors.

Bone Morphogenetic Protein 4 Targeting Glioma Stem-Like Cells for Malignant Glioma Treatment: Latest Advances and Implications for Clinical Application.

Malignant gliomas are heterogeneous neoplasms. Glioma stem-like cells (GSCs) are undifferentiated and self-renewing cells that develop and maintain these tumors. These cells are the main population that resist current therapies. Genomic and epigenomic analyses has identified various molecular subtypes. Bone morphogenetic protein 4 (BMP4) reduces the number of GSCs through differentiation and induction of apoptosis, thus increasing therapeutic sensitivity. However, the short half-life of BMP4 impedes its clinical application. We previously reviewed BMP4 signaling in central nervous system development and glioma tumorigenesis and its potential as a treatment target in human gliomas. Recent advances in understanding both adult and pediatric malignant gliomas highlight critical roles of BMP4 signaling pathways in the regulation of tumor biology, and indicates its potential as a therapeutic molecule. Furthermore, significant progress has been made on synthesizing BMP4 biocompatible delivery materials, which can bind to and markedly extend BMP4 half-life. Here, we review current research associated with BMP4 in brain tumors, with an emphasis on pediatric malignant gliomas. We also summarize BMP4 delivery strategies, highlighting biocompatible BMP4 binding peptide amphiphile nanostructures as promising novel delivery platforms for treatment of these devastating tumors.

Particle radiation therapy in the management of adult high-grade glioma: A narrative review

This narrative review summarizes the current status of the use of particle radiation therapy on the treatment of adult malignant gliomas. Due to the unique physical property, particle (e.g., proton or carbon-ion) beam radiation therapy can improve radiation dose distribution, thereby therapeutic radio for patients with brain malignancy. Therefore, particle beam radiation therapy is associated with low adverse events which have implications for improving quality of life for long-term survivors. In addition, there is a potential for safe dose escalation in selected patients. Malignant glioma is considered radioresistant; thus, particle beams of higher relative biological effectiveness, carbon-ion beam, for example, may further improve disease control in theory. Data on carbon-ion beam RT alone for the management of brain tumor are scarce. Most literature described proton beam alone or the use of combined proton/photon and carbon-ion beam boost for the treatment of glioma. Existing clinical evidence describes virtually no acute high-grade toxicities and limited late effects. Prospective clinical trials are needed to confirm the improved efficacy and favorable toxicity profile of particle beam radiation therapy on adult malignant glioma described in retrospective studies. Currently, multiple prospective trials are ongoing to answer such questions.

A retrospective survival analysis of Glioblastoma patients treated with selective serotonin reuptake inhibitors

Glioblastoma (GBM) is the most common and aggressive form of malignant glioma in adults with a median overall survival (OS) time of 16–18 months and a median age of diagnosis at 64 years old. Recent work has suggested that depression and psychosocial distress are associated with worse outcomes in patients with GBM. We therefore hypothesized that the targeted neutralization of psychosocial distress with selective serotonin reuptake inhibitor (SSRI) antidepressant treatment would be associated with a longer OS among patients with GBM. To address this hypothesis, we retrospectively studied the association between adjuvant SSRI usage and OS in GBM patients treated by Northwestern Medicine-affiliated providers. The medical records of 497 GBM patients were analyzed after extraction from the Northwestern Medicine Enterprise Data Warehouse. Data were retrospectively studied using a multivariable Cox model with SSRI use defined as a time-dependent variable for estimating the association with OS. Of the 497 patients, 315 individuals died, while 182 were censored due to the loss of follow-up or were alive at the end of our study. Of the 497 patients, 151 had a recorded use of SSRI treatment during the disease course. Unexpectedly, SSRI usage was not associated with an OS effect in both naïve (HR ​= ​0.81, 95% CI ​= ​0.64–1.03) and adjusted time-dependent (HR ​= ​1.26, 95% CI ​= ​0.97–1.63) Cox models. Ultimately, we failed to find an association between SSRI treatment and an improved OS of patients with GBM. Additional work is necessary for understanding the potential therapeutic effects of SSRIs when combined with other treatment approaches, and immunotherapies in particular, for subjects with GBM.

EPID-23. PURSUIT OF AN INTERNATIONAL LANGUAGE OF GLIOMA RESEARCH: COMMON DATA ELEMENTS FOR THE LONGITUDINAL STUDY OF ADULT MALIGNANT GLIOMA

Abstract As an uncommon cancer, clinical and translational studies of glioma rely on multi-center collaborations, confirmatory studies, and meta-analyses. Unfortunately, interpretation of results across studies is hampered by the absence of uniformly coded clinical data. Common Data Elements (CDE) represent a set of clinical features for which the language has been standardized for consistent data capture across studies, institutions and registries. We constructed CDE for the longitudinal study of adult malignant glioma. To identify the minimum set of CDE needed to describe the clinical course of glioma, we surveyed clinical standards, ongoing trials, published studies, and data repositories for frequently used data elements. We harmonized the identified clinical variables, filled in gaps, and structured them in a modular schema, defining CDE for patient demographics, medical history, diagnosis, surgery, chemotherapy, radiotherapy, other treatments, and outcomes. Multidisciplinary experts from the Glioma Longitudinal AnalySiS (GLASS) consortium, representing clinical, molecular, and data research perspectives, were consulted regarding CDE. The validity and capture feasibility of the CDE were assessed through harmonization across published studies, then validated with single institution retrospective chart abstraction. The refined CDE library is implemented in the Research Electronic Data Capture (REDCap) System, a secure web application for building and managing online surveys and databases. The work was motivated by the GLASS consortium, which supports the aggregation and analysis of complex genetic datasets used to define molecular trajectories for glioma. The goal is that modular REDCap implementation of CDE allows broad adoption in glioma research. To accommodate novel aspects, the CDE sets can be expanded through additional modules. In contrast, for efficient initiation of focused studies, subsets of CDE can be selected. Broad adoption of CDE will improve the ability to compare results and share data between studies, thereby maximizing the value of existing data sources and small patient populations.

Proton Therapy and Src Family Kinase Inhibitor Combined Treatments on U87 Human Glioblastoma Multiforme Cell Line.

Glioblastoma Multiforme (GBM) is the most common of malignant gliomas in adults with an exiguous life expectancy. Standard treatments are not curative and the resistance to both chemotherapy and conventional radiotherapy (RT) plans is the main cause of GBM care failures. Proton therapy (PT) shows a ballistic precision and a higher dose conformity than conventional RT. In this study we investigated the radiosensitive effects of a new targeted compound, SRC inhibitor, named Si306, in combination with PT on the U87 glioblastoma cell line. Clonogenic survival assay, dose modifying factor calculation and linear-quadratic model were performed to evaluate radiosensitizing effects mediated by combination of the Si306 with PT. Gene expression profiling by microarray was also conducted after PT treatments alone or combined, to identify gene signatures as biomarkers of response to treatments. Our results indicate that the Si306 compound exhibits a radiosensitizing action on the U87 cells causing a synergic cytotoxic effect with PT. In addition, microarray data confirm the SRC role as the main Si306 target and highlights new genes modulated by the combined action of Si306 and PT. We suggest, the Si306 as a new candidate to treat GBM in combination with PT, overcoming resistance to conventional treatments.

Correction to: Phase II study of weekly carboplatin in pretreated adult malignant gliomas

In the original article, the names of authors Mariantonia Carosi and Tatiana Koudriavtseva were incorrectly captured, and author Francesco Cognetti's affiliation was incorrect. The information is correctly shown here.

P14.120 Phase II study of weekly carboplatin in pretreated adult malignant gliomas

Abstract BACKGROUND Patients with relapse of recurrent glioma have a poor outcome and limited treatment options. The aim of this study is to investigate the clinical benefit and tolerability of weekly intravenous administration of carboplatin-based monotherapy in adult glioma patients who had progressed from previous chemotherapy lines based on temozolomide and nitrosoureas MATERIAL AND METHODS This was a single arm, Phase II study. Eligibility criteria included progressive or recurrent malignant glioma after radiotherapy and chemotherapy-based treatments and Karnofsky Performance Status (KPS) &gt; 60. RESULTS Thirty-two patients (median age: 43.5 y) were enrolled to receive weekly carboplatin monotherapy in intravenous mode of administration. The median duration of response was 7.3 months with an overall disease control rate of 31.3%. Median progression-free survival (PFS) was 2.3 months while overall survival (OS) was 5.5 months. Patients achieving clinical benefit exhibited a longer PFS (4.6 vs 1.5 months; p&gt;0.001) and OS (7.9 vs 3.2 months; p=0.041) compared to those not achieving clinical benefit. CONCLUSION Our findings show that single agent, weekly, intravenous carboplatin may have a role in the treatment patients with recurrent malignant glioma

Performance of 18F-FDG, 11C-Methionine, and 18F-FET PET for Glioma Grading: A Meta-analysis.

Gliomas constitute the most frequent primary brain tumors. Glioblastoma, the most common and malignant glioma in adults, has dismal prognosis with any current therapy. On the other hand, low-grade gliomas, the second most common type of gliomas, are potentially curative with appropriate treatment. We conducted a meta-analysis to assess the performance of PET tracers with the best available evidence, namely, fluorodeoxyglucose (FDG), C-methionine (MET), and F-fluoroethyltyrosine (FET), in differentiating low- from high-grade gliomas. Twenty-three studies with a total of 994 participants were included in this meta-analysis. The pooled sensitivities of both MET PET and FET PET were found to be significantly higher than of FDG PET (94%, 88%, and 63% respectively, P < 0.001). The pooled specificity of FDG PET was found to be significantly greater compared with both MET PET and FET PET (89%, 55%, and 57%, respectively; P = 0.002). Fluorodeoxyglucose PET was superior in terms of higher positive likelihood ratio values compared with both FET PET and MET PET. This meta-analysis indicated that both MET and FET were superior to FDG in terms of sensitivity for identifying glioma grade.