Malignant Glial Tumors Research Articles

Perifocal Edema in Gliomas. Pathogenesis, Clinical Picture, Treatment

Surgical treatment of malignant glial tumor is a complex task due to the lack of clear boundaries and contours, its high invasiveness in healthy brain tissues and the formation of intense edema, due to low differentiation in color and consistency between tumor and brain tissue. The main symptomatology of glial tumors is due to peritumoral edema, which can lead to severe symptoms, including neurological dysfunction, dislocation of structures and brain hernia. The main task of neurologists, neurosurgeons and resuscitators in the pre- and postoperative periods is to reduce the aggressive mass effect of the perifocal edema zone in gliomas. In recent years, steroid therapy has been the standard treatment for perifocal edema in space-occupying lesions of the brain. In recent years, the study of the role of cerebral lymphatic vessels involved in the regulation of cerebrospinal fluid and the formation of cerebral edema has changed views on the treatment of perifocal edema in gliomas. The aim of this study was to study the pathogenesis, clinical features and treatment of peritumoral edema in gliomas. The known mechanisms causing peritumoral edema in glial tumors of the brain have been studied and summarized. A comparative analysis and discussion of the results of modern methods for treating perifocal cerebral edema in glial tumors have been carried out and prospects for future methods for treating cerebral edema are presented. Further studies of perifocal edema around a glial tumor of the brain are needed to improve the prognosis of the pre- and postoperative periods and increase the effectiveness of edema treatment.

Immunotherapy with autologous dendritic cells in the complex treatment of malignant gliomas - results.

Malignant gliomas are the most common primary brain tumor. Despite the variety of modern treatments, it is still a fatal disease with an extremely poor prognosis. The use of immunotherapy as a technique for the treatment of malignant tumors has great promise, retraining and exploiting the patient's immune response against tumors. Evaluation of the effectiveness of dendritic cell vaccine in patients with malignant brain gliomas in the structure of complex treatment in comparison with the control group of patients without immunotherapy in the structure of treatment. In a single-center, prospective, cohort study, taking place on the basis of the RNSI named after prof. A.L. Polenov, 91 patients with morphologically established malignant glial tumor (glioblastoma) took part. The main group of 41 patients who, in addition to standard treatment (surgical, radiation and chemotherapy), underwent specific antitumor immunotherapy. 50 patients received only standard treatment, without immunotherapy. Median survival was 21.7 months in the immunotherapy group (95% CI 4-37 months) and 15.8 months (95% CI 3-22 months) in the non-immunotherapy group (p = 0.002). The median relapse-free period in the group with immunotherapy was 13.8 months (95% CI 1-20 months), and in the group without immunotherapy 7.9 months (95% CI 1-12 months) (p = 0.003). In general, the use of immunotherapy in the structure of complex treatment of patients with malignant gliomas demonstrates a clear positive trend in terms of overall survival and median relapse-free period. But nevertheless, immunotherapy requires further development as a therapeutic tool, study and improvement, which will take into account immunosuppression in malignant gliomas and means of overcoming it, optimization in terms of target antigen selection, cell preparation and integration of dendritic vaccines into other treatment regimens.

Achievements and prospects in dendritic cell vaccine therapy in patients with malignant glial tumors

Vaccine therapy as a method of immunotherapy is a promising direction in neurooncology, the ultimate goal of which is to increase the effectiveness of the treatment of patients with malignant glial tumors of the brain. In this article, based on the analysis of domestic and foreign literature sources devoted to the creation and application of vaccine therapy in neurooncology, the main principles of vaccine therapy used in the treatment of glioblastomas are considered, and the results of the most significant clinical studies in this area are presented. The article discusses the prospects for the use of vaccine therapy as an additional treatment for glioblastoma and possible obstacles to its widespread use.

The role of complete exomic sequencing in the administration of targeted drugs in patients with multiform glioblastoma

Introduction. Glioblastoma is the most common primary malignant glial tumor of the brain in adult patients. Median overall survival for this pathology varies between 3 and 12 months, and only 5 % of patients live for more than 5 years. Current treatment methods allow to slightly increase lifespan of the patients with glioblastoma but not in all cases.Aim – to determine the utility of full exome sequencing of biopsy materials of patients with glioblastoma using expanded gene panel for prescription of new targeted therapy.Materials and methods. The study included 28 patients with glioblastoma multiforme. Foundation One CDx assay was performed using DNA extraction from a paraffin block and next-generation sequencing. In total, 4 classes of genomic changes in 324 genes, introns of 34 genes taking part in rearrangements, as well as microsatellite instability and tumor mutation load were evaluated. For every tumor profile, individual therapy options were identified in accordance with the current knowledge, references for the relevant scientific studies were included. From some patients, feedback was received allowing to evaluate the dynamics of their condition and changes in therapy after the performed study.Results. Genes in which mutations are the most common were identified: EGFR – in 11 patients, CDKN2A – in 13, TP53 – in 9, TERT (frequent mutations in TERT gene promoters с.-124C>T and c.-146C>T) – in 15, MTAP – in 10. Mean mutation level was 4.5 mutations/ MB and tumors did not have microsatellite instability. For 6 patients, appropriate targeted therapy was identified.Conclusion. Sequencing using an extended gene panel is justified and recommended for patients with glioblastoma multiforme for selection of new targeted therapy.

Peculiarities of the Application of Diffusion-Curtosis MRI in the Differential Diagnosis of Glial Brain Tumors and Solitary Metastasis

Purpose: To improve the differential diagnosis of high-grade gliomas and solitary metastases by introducing the diffusion-kurtosis magnetic resonance imaging technique into the MRI scan protocol.Material and methods: The study included 43 patients who underwent examination and treatment at the N.N. Blokhin National Research Medical Center of Oncology from October 2019 to March 2022, in which, according to magnetic resonance imaging, solitary formations in the brain substance were detected. A total of 43 neoplasms were found in the substance of the brain, of which: 17 glioblastomas in 17 patients (40 %), 25 solitary metastatic tumors of lung, breast, melanoma and kidney cancer (60 %). We evaluated the tumor size, diffusion and kurtosis parameters, such as mean kurtosis (MK), axial kurtosis (AK), radial kurtosis (RK), kurtosis anisotropy (KA), radial diffusion (RD), fractional anisotropy (FA), relative anisotropy (RA), tortuosity of the trajectory (TTD).Results: Statistically significant differences (р < 0.05) in such parameters of diffusion and kurtosis in the tumor as kurtosis anisotropy (KA), fractional anisotropy (FA) and tortuosity of the trajectory (TT) were revealed. Significant differences between solitary metastases and malignant glial tumors based on diffusion and kurtosis values such as mean kurtosis (MK), axial kurtosis (AK), radial kurtosis (RK), radial diffusion (RD), and relative anisotropy (RA) (criteria where р > 0.05) was not detected.

The development of a rapid patient-derived xenograft model to predict chemotherapeutic drug sensitivity/resistance in malignant glial tumors.

High-grade gliomas (HGG) are aggressive brain tumors associated with short median patient survival and limited response to therapies, driving the need to develop tools to improve patient outcomes. Patient-derived xenograft (PDX) models, such as mouse PDX, have emerged as potential Avatar platforms for personalized oncology approaches, but the difficulty for some human grafts to grow successfully and the long time required for mice to develop tumors preclude their use for HGG. We used a rapid and efficient ex-ovo chicken embryo chorioallantoic membrane (CAM) culture system to evaluate the efficacy of oncologic drug options for HGG patients. Implantation of fresh glioma tissue fragments from 59 of 60 patients, that include difficult-to-grow IDH-mutated samples, successfully established CAM tumor xenografts within 7 days, with a tumor take rate of 98.3%. These xenografts faithfully recapitulate the histological and molecular characteristics of the primary tumor, and the ability of individual fragments to form tumors was predictive of poor patient prognosis. Treatment of drug-sensitive or drug-resistant xenografts indicates that the CAM-glioma assay enables testing tumor sensitivity to temozolomide and carboplatin at doses consistent with those administered to patients. In a proof-of-concept study involving 14 HGG patients, we observed a correlation of 100% between the CAM xenograft response to temozolomide or carboplatin and the clinical response of patients. The CAM-glioma model is a fast and reliable assay that has the potential to serve as a complementary model to drug discovery and a real-time Avatar platform to predict the best treatment for HGG patients.

Feasibility Study on the nIORT® Adjuvant Treatment of Glioblastoma Multiforme through the Irradiation Field of Fast Neutrons Produced by a Compact Generator

The glioblastoma multiforme (GBM) is the most malignant glial brain tumour with average survival time of 6÷18 months. Emerging evidence suggests that GBM cells appears to reprogram their tumour microenvironment, which is a highly heterogeneous and complex system, so that an efficient GBM radiotherapy (RT) should cover both the cells of the GBM and those of its microenvironment. Relying on a 5-year collaborative research study on the intra-operative radiotherapy (IORT) with fast neutrons - the so-called neutron-IORT (nIORT®) technique - the authors think that this objective could be achieved by using an ionizing radiation field of fast neutrons that behave in the biological tissues as a “foam field” hitting both the GBM cancer cells and the neighbouring microenvironment. The nIORT® research activities - conducted by TheranostiCentre Srl, Berkion Technology LLC and ENEA - led to the fabrication of the first prototype of a compact neutron generator (CNG) that, through the deuterium-deuterium fusion reaction, produces neutrons of 2.45 MeV energy having: i) high linear energy transfer; ii) very high relative biological effectiveness (RBE), about 16 times higher than X-rays (and electrons) used in standard RT and IORT treatments; iii) reduced oxygen enhancement ratio, and hence resulting be very effective in cancer cells necrosis and apoptosis. The CNG is self-shielded, limited in size and weight (~120 kg) and manageable remotely by a robotic arm. A new prototype equipped by a cylindrical applicator to be inserted in the surgical cavities is currently under construction, with some technical advancements making possible its installation in an operating room dedicated to nIORT® treatments without posing any safety and environmental concern. In this article the nIORT® potentiality was investigated in the view of the GBM treatment, but the study is however generalisable for the neutron irradiation of other brain cancer pathologies. Accurate Monte Carlo simulations, modelling the CNG equipped with a couple of cylindrical applicators of 4 and 6 cm in diameter inserted in the brain surgical cavity after craniotomy, demonstrated that the nIORT® device operated at 100 kV-10 mA DC supplies a neutron flux ~108 cm-2 s-1 and can deliver equivalent dose rates ~5 Gy (RBE)/min in the centre of the tumour bed. Thus, it could administer the clinical endpoints foreseen by the standard IORT protocols (~10-20 Gy (RBE)) in treatment times of few minutes, by providing a sort of “switching on and off neutron brachytherapy tool” without using needles of radioisotopes (e.g., 252Cf). The near isotropic neutron emission allows to irradiate the tumour bed margins, normally filled by potential quiescent cancer cells, with lower (but still significant) dose levels. This should improve the local control of the tumour through the reduction of local recurrences and metastasis in the tumour microenvironment, and at the same time to avoid adverse effects of the administered neutron radiation field on the surrounding brain central nervous system. Also, the rapid decrease in tissue depth of the dose gradient (within few centimetres) should avoid any adverse effect on normal brain tissues and the neighbouring organs.

Intraoperative photodynamic therapy in complex treatment of malignant gliomas

To demonstrate the possibilities of chlorin e6-mediated photodynamic therapy for malignant glial tumors. There were 161 patients with malignant supratentorial glial tumors who were treated at the Polenov Russian Neurosurgery Institute between 2009 and 2016. Eighty patients comprised the main group (photodynamic therapy), 81 ones - control group (without photodynamic therapy). Photodynamic therapy in complex treatment of malignant brain gliomas significantly increases overall survival in patients with Grade III gliomas up to 39.1±5.5 months (control group - 22.8±3.3 months) and Grade IV gliomas up to 20.7±4.7 months (control group - 13.5±2.3 months) (p=0.0002). This method also increases relapse-free period in patients with Grade III gliomas up to 21.7±3.4 months (control group - 15.8±3.1 months) (p=0.0002) and Grade IV gliomas up to 11.1±2.1 months (control group - 8.0±2.3 months) (p=0.0001).

Single-Cell RNA Sequencing Unravels Upregulation of Immune Cell Crosstalk in Relapsed Pediatric Ependymoma.

Ependymoma (EPN) is a malignant glial tumor occurring throughout central nervous system, which commonly presents in children. Although recent studies have characterized EPN samples at both the bulk and single-cell level, intratumoral heterogeneity across subclones remains a confounding factor that impedes understanding of EPN biology. In this study, we generated a high-resolution single-cell dataset of pediatric ependymoma with a particular focus on the comparison of subclone differences within tumors and showed upregulation of cilium-associated genes in more highly differentiated subclone populations. As a proxy to traditional pseudotime analysis, we applied a novel trajectory scoring method to reveal cellular compositions associated with poor survival outcomes across primary and relapsed patients. Furthermore, we identified putative cell–cell communication features between relapsed and primary samples and showed upregulation of pathways associated with immune cell crosstalk. Our results revealed both inter- and intratumoral heterogeneity in EPN and provided a framework for studying transcriptomic signatures of individual subclones at single-cell resolution.

Development of adaptive stereotactic radiotherapy method in treatment of primary malignant glial tumors in the brain

At present, there are some scattered evidence data pertaining to the use of an adaptive technique of radiotherapy in treatment of malignant glial tumors of the brain. Our evidence data obtained in MRI in the course of treatment show that the initial treatment plan may become irrelevant due to some changes observed in the tumor configuration. In its turn, it bears witness to the topicality of developing and introducing adaptive methods and techniques in the brain tumor treatment, which are capable to increase efficacy and tolerability in patients with primary malignant tumors of the brain. Aim. Our aim has been to develop an adaptive stereotactic method of radiotherapy in treatment of primary malignant brain tumors, which shall be capable to increase efficacy and tolerability of radiation therapy as well as reduce radiation dose to normal structures in the brain. Materials and methods. Our method has been elaborated with recruiting a group of 10 patients diagnosed with primary glioblastoma G IV, which have received specialized treatment at the National Medical Research Centre for Oncology at the Ministry of Health, the Russian Federation, in the period 2021-2022. The average age of the above patients is 43,4 years. All patients have undergone microsurgery covering the total resection of the tumor (3 patients) and subtotal removal of the malignant tumor (7 patients). The average time interval between the surgery and radiotherapy is 32,5 days. Before treatment, an intravenous contrast enhancement MRI of the brain with an axial pitch of 1 mm has been conducted employing the contrast T1, contrast-free T1 and T2 FLAIR modes. Planning of radiotherapy for this sort of patients has been carried out employing BrainLab Elements и Varian Medical Systems Eclipse. The CTV was defined as a 2,0 cm margin around GTV with an anatomical correction. The CTV-to-PTV margin was 0,1 cm. Doses have been administered as follows: a single dose of 2 Gy up to a total dose of 60 Gy in 30 fractions. The brain has been MRI-scanned in all patients with the use of intravenously introduced contrast agents with an axial pitch of 1 mm employing enhanced contrast/contrast-free T1 sequences and T2 FLAIR to redefine the radiotherapy targets (GTV, CTV, PTV). At fraction 30 we have completed MRI in order to estimate the treatment outcome. In the average, the radiotherapy course has taken 42-45 days, holidays included. For the purpose of the radiation therapy, used have been the Novalis Tx Varian Tx linear accelerator of kinetic energy of the beam of 6 MeV. Results We have developed our own adaptive stereotactic method of radiotherapy to treat the primary malignant glial tumors in the brain, which is capable of tracing the configuration of the post-surgery cavity, the residual tumor and the brain structures in the course of radiotherapy and adapting the therapy plan thereto that makes possible to reduce tissue volumes exposed to radiation due to a decrease in the tumoral and peritumoral volumes of the tumor and post-operative cavity. Conclusion. Our analysis has shown that in the course of radiotherapy some anatomical changes in the tumor configuration are found. An adaptive approach applied to radiation therapy allows monitoring the above changing volumes and correcting the treatment plan.

Proline Metabolism in Malignant Gliomas: A Systematic Literature Review.

Simple SummaryStudies of various types of cancers have found proline metabolism to be a key player in tumor development, involved in basic metabolic pathways, regulating cell proliferation, survival, and signaling. Here, we systematically searched the literature to find data on proline metabolism in malignant glial tumors. Despite limited availability, existing studies have found several ways in which proline metabolism may affect the development of gliomas, involving the maintenance of redox balance, providing essential glutamate, and affecting major signaling pathways. Metabolomic profiling has revealed the importance of proline as a link to basic cell metabolic cycles and shown it to be correlated with overall survival. Emerging knowledge on the role of proline in general oncology encourages further studies on malignant gliomas.Background: Proline has attracted growing interest because of its diverse influence on tumor metabolism and the discovery of the regulatory mechanisms that appear to be involved. In contrast to general oncology, data on proline metabolism in central nervous system malignancies are limited. Materials and Methods: We performed a systematic literature review of the MEDLINE and EMBASE databases according to PRISMA guidelines, searching for articles concerning proline metabolism in malignant glial tumors. From 815 search results, we identified 14 studies pertaining to this topic. Results: The role of the proline cycle in maintaining redox balance in IDH-mutated gliomas has been convincingly demonstrated. Proline is involved in restoring levels of glutamate, the main glial excitatory neurotransmitter. Proline oxidase influences two major signaling pathways: p53 and NF- κB. In metabolomics studies, the metabolism of proline and its link to the urea cycle was found to be a prognostic factor for survival and a marker of malignancy. Data on the prolidase concentration in the serum of glioblastoma patients are contradictory. Conclusions: Despite a paucity of studies in the literature, the available data are interesting enough to encourage further research, especially in terms of extrapolating what we have learned of proline functions from other neoplasms to malignant gliomas.

Differentiation between High Grade Glioma and Solitary Brain Metastasis Using Combined Diffusion-Weighted Imaging and Diffusion Tensor Imaging

Background: High-grade gliomas (HGGs) and brain metastases (BMs) can display similar imaging characteristics on conventional MRI. In HGGs, the peritumoral edema is infiltrated by the malignant cells, which was not observed in BMs. Our study aims to determine whether the fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values could differentiate HGGs from BMs. Results: Twenty patients with provisional MRI diagnosis of high grade gliomas WHO grade III & IV versus metastatic brain tumors, examination was done on 1.5 tesla scanner, patients were divided into two groups based on pathology results, the fraction anisotropy (FA) was measured in the enhancing tumor parts and immediate peri-tumoral edema. The minimum and mean ADC in the enhancing tumor (ADCmin, ADCmean) and the minimum ADC in the peritumoral region (ADCedema) were measured from ADC maps. Values of FA and ADC measured in the peri-tumoral edema were significantly high in the metastatic than primary high malignant glial tumors, yet no significant differences in the values of FA and ADC measured in the enhancing tumor parts of the two groups. According to ROC curve analysis, a cutoff value of 0.119 for the FA measured in the peri-tumoral edema with sensitivity (100%) and specificity (75%) and a cutoff value of 1.7 x 10-3 for the ADCedema with sensitivity (87.5%) and specificity (75%) generated the best combination of for distinguishing between HGGs and BMs. Conclusion: FA and ADC values were found to distinguish between HGGs and solitary BMs. The peritumoral FA and ADC values are better than the intratumoral FA and ADC values in predicting the tumor type.

The Inhibitory Effects of Terminalia catappa L. Extract on the Migration and Invasion of Human Glioblastoma Multiforme Cells.

Glioblastoma multiforme (GBM) is one of the most aggressive and common types of brain tumor. Due to its high proliferation ability, a high lethality rate has been observed with this malignant glial tumor. Terminalia catappa L. (T. catappa) is currently known to have anti-inflammatory and anti-carcinogenesis effects. However, few studies have examined the mechanisms of the leaf extracts of T. catappa (TCE) on GBM cells. In the current study, we demonstrated that TCE can significantly inhibit the migration and invasion capabilities of GBM cell lines without showing biotoxic effects. Matrix metalloproteinases-2 (MMP-2) activity and protein expression were attenuated by reducing the p38 phosphorylation involved in the mitogen-activated protein kinase (MAPK) pathway. By treating with TCE and/or p38 inhibitor (SB203580), we confirmed that p38 MAPK is involved in the inhibition of cell migration. In conclusion, our results demonstrated that TCE inhibits human GBM cell migration and MMP-2 expression by regulating the p38 pathway. These results reveal that TCE contains potent therapeutic compounds which could be applied for treating GBM brain tumors.

Investigation of the anti-tumor effects of bevacizumab on glioblastoma cells

Aim: Glioblastoma multiforme (GBM) is the most malignant glial tumor. Angiogenesis which provides nutrient and oxygen support to proliferating cells plays an essential role in GBM development, proliferation, and metastasis. The development of antiangiogenetic agents is a promising treatment approach as blood vessels are essential for the vitality of tumor cells. For this purpose, in this study, the effects of bevacizumab on cell viability and apoptosis were analyzed using glioblastoma cells.
 Material and method: U-87 MG and T98G cells were treated with various concentrations of bevacizumab for 24 hours, 48 hours, and 72 hours. Cell viability was analyzed after administration of bevacizumab. Cytotoxicity was determined using MTT. Apoptosis rate was determined with cell death detection kit.
 Results: Cell viability analysis showed that when 8 mg / ml bevacizumab was administered to glioblastoma cells for 48 hours and 72 hours, cell proliferation was only 50% compared to proliferation of cells without bevacizumab. Additionally, apoptosis rates for U-87 MG and T98G cell lines treated with various concentrations of bevacizumab for 48 hours and 72 hours showed results similar to those of cell viability. 
 Conclusions: This study showed that while high concentration treatment of U-87 MG cells caused an increase in cell viability in a time-dependent manner, high dose treatment of T98G cells resulted in a decrease in cell viability in a time-dependent manner. This means that some glioblastoma cells can still survive under high doses of bevacizumab. This, in turn, demonstrated that glioblastoma cells developed resistance against bevacizumab.

ETMM-08 METABOLIC REGULATION OF THE EPIGENOME DRIVES LETHAL INFANTILE EPENDYMOMA

Ependymomas are malignant glial tumours that occur throughout the central nervous system. Of the nine distinct molecular subgroups of ependymoma, Posterior Fossa A (PFA), is the most prevalent, occurring in the hindbrain of infants and young children. Lacking highly recurrent somatic mutations, PFAs are thought to be a largely epigenetically driven entity, defined by hypomethylation at the histone 3 lysine 27 residue. Previous transcriptional analysis of PFAs revealed an enrichment of hypoxia signaling genes. Thus, we hypothesized that hypoxic signaling, in combination with a unique metabolic milieu, drive PFA oncogenesis through epigenetic regulation. In this study, we identified that PFA cells control the availability of specific metabolites under hypoxic conditions, resulting in diminished H3K27 trimethylation and increased H3K27 acetylation in vitro and in vivo. Unique to PFA cells, transient exposure to ambient oxygen results in irreversible cellular toxicity. Furthermore, perturbation of key metabolic pathways is sufficient to inhibit growth of PFA primary cultures in vitro. PFA cells sequester s-adenosylmethionine while upregulating EZHIP, a polycomb repressive complex 2 (PRC2) inhibitor, resulting in decreased H3K27 trimethylation. Furthermore, hypoxia fine-tunes the abundance of alpha-ketoglutarate and acetyl-CoA to fuel demethylase and acetyltransferase activity. Paradoxically, a genome-wide CRISPR knockout screen identified the core components of PRC2 as uniquely essential in PFAs. Our findings suggest that PFAs thrive in a narrow “Goldilocks” zone, whereby they must maintain a unique epigenome and deviation to increased or decreased H3K27 trimethylation results in diminished cellular fitness. Previously, we showed that PFAs have a putative cell of origin arising in the first trimester of development. Using single-cell RNAseq and metabolomics, we demonstrate that PFAs resemble the natural metabolic-hypoxic milieu of normal development. Therefore, targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma.

Giant Cell Variant of Glioblastoma Multiforme: Report of a Rare Variant in a Child

Malignant glial tumors are rare in children. Giant cell variant is a rare subtype of glioblastoma, accounting for about 0.8% of brain tumors and 5% of glioblastoma tumors. Giant cell glioblastoma is a male predominant tumor in children and adults. Due to the low prevalence of this variant, available information is limited. An 11-year-old female child was referred with a chief complaint of a progressive persistent headache. MRI showed a well-defined cystic lesion with a solid mural component in the right parietal lobe with a compression effect on the ipsilateral ventricular system. Surgery was done. After the pathologist reported glioblastoma multiforme, a giant cell variant, the patient received 30 sessions of radiation therapy. The patient was readmitted 18 months later with a headache, and the pathologist confirmed the recurrence of the tumor. Based on radiology, the giant cell glioblastoma cannot be distinguished from the common subtype glioblastoma. The pathologists must be aware of this entity, and histologic differential diagnoses are warranted for diagnostic, prognostic, and therapeutic purposes.

Management of Malignants Gliomas: About 20 Cases Treated in the Medical Oncology Department of Fattouma Bourguiba University Hospital-Monastir

Introduction: Malignant gliomas refer to grade III or IV brain tumors defined according to the World Health Organization (WHO) classification. They are a heterogeneous group of pathologies and represent a serious health problem by their frequency, severity and treatment difficulties. The prognosis of malignant gliomas remains poor despite all the medical advances. Materials and Methods: It is a retrospective study included 20 cases of malignant glial tumors treated at the medical oncology department, Fattouma Bourguiba hospital in Monastir between 2012 and 2016, according to the STUPP protocol. Results: These were 12 men and 8 women with a median age of 43. Clinical signs were not very specific, dominated by intracranial hypertension and deficit signs. Imagery referred to the diagnosis of malignant gliomas in 1st intention. Surgery consisted of a macroscopically complete exeresis in (15%) cases, a partial exeresis in (50%), the rest of the patients had a stereotactic biopsy. Histology found GBM in 16 patients (80%), 2 cases of Grade III anaplastic astrocytoma (10%), 1 case of anaplastic oligodendroglioma (5%), and 1 case of Grade III anaplastic eppendymoma (5%). Most of our patients received concurrent radio-chemotherapy and adjuvant TMZ chemotherapy was administered in 15 patients, 7 of whom received the full 6 scheduled cures. A relapse treatment was decided in only one of the 12 patients who relapsed. 6 patients are still alive. The median survival is 11.27 months. In our series, overall survival was related to histological type (p = 0.006) and neurological status assessed at the end of RT-CT (p = 0.001). While age, general condition score, type of surgery, and post-therapeutic development did not show a statistically significant relationship, although survival rates were consistent with the criteria assessed. Conclusion: Malignant gliomas are rare tumors, bad prognosis, aggravated in Tunisia by a diagnostic delay. The creation of a multidisciplinary neuro-oncology group can help to improve management.

SURG-10. SPECTROSCOPIC MEASUREMENT OF 5-ALA-INDUCED INTRACELLULAR PROTOPORPHYRIN IX IN PEDIATRIC BRAIN TUMORS

OBJECTIVE5-ALA guided resection of glioma in adults enables better delineation between tumor and normal brain, allowing improved resection and improved patients’ outcome. Recently, several reports were published regarding 5-ALA for resection of pediatric brain tumors. The aim of the study was to determine the intracellular fluorescence of PPIX in pediatric brain tumors by hyperspectral imaging and to compare it with visually observed intraoperative fluorescence.METHODS5-ALA was administered orally four hours prior to surgery. During tumor resection the surgeon assessed the fluorescence signal to be strong, weak or absent. Subsequently, fluorescence intensity of samples was measured via spectroscopy. In addition, clinical data, imaging and laboratory data were analyzed.RESULTSEleven children (1–16 years) were operated. Tumor entities included: three medulloblastomas, two pilocytic astrocytomas (PA), two anaplastic ependymomas and one diffuse astrocytoma, anaplastic astrocytoma, pilomyxoid astrocytoma and anaplastic pleomorphic xanthoastrocytoma. Strong fluorescence was visible in all anaplastic tumors and one PA; one PA demonstrated weak fluorescence. Visible fluorescence was strongly associated with intracellular fluorescence intensity and PPIX concentration (P<0.05). Within all tumors with visible fluorescence the intracellular PPIX concentration was greater than 4 µg/ml. Except for moderate and transient elevation of liver enzymes, no 5-ALA related adverse events were reported.CONCLUSIONWe demonstrate a strong association between intraoperative observations and spectrometric measurements of PPIX fluorescence in tumor tissue. As in former studies, fluorescence signal was more commonly observed in malignant glial tumors. Further prospective controlled trials should be conducted to investigate the feasibility of 5-ALA guided resection of pediatric brain tumors.

TAMI-59. METABOLIC REGULATION OF THE EPIGENOME DRIVES LETHAL INFANTILE EPENDYMOMA

Abstract Ependymomas are malignant glial tumors that occur throughout the central nervous system. Of the nine distinct molecular types of ependymoma, Posterior Fossa A(PFA) ependymomas, found in the hindbrain of infants and young children, are the most prevalent type. They rarely harbor recurrent somatic single nucleotide or copy number aberrations, but rather display epigenetic dysregulations. Transcriptional analyses show that PFAs, but not other molecular ependymoma variants, have elevated hypoxic signaling. We hypothesized that the metabolic environment of the developing human fetal hindbrain contributes to PFA ependymomas through the intermediary metabolic mechanism. Hypoxia microenvironment is essential for PFA survival and upholding their epigenetic dysregulation. Hypoxia blocks methyltransferase activity by upregulating EZHIPs expression and restricting SAM abundance. Fine-tuning the abundance of a-KG and acetyl-CoA, hypoxia fuels demethylase, and acetyltransferase activity which collectively resulting in H3K27 hypomethylation and hyperacetylation. Genome-wide essentially screen further underscore that minimal basal level of H3K27me3 is essential for PFA survival and further attenuation of H3K27me3 decreases the fitness of PFAs. PFA Ependymomas have a unique epigenome, suggesting a model in which they thrive in a narrow Goldilocks zone, with deviation to either increased or decreased H3K27me3 levels leading to diminished cellular fitness. PFAs are maintained under hypoxia, associated with restricted availability of specific metabolites to diminish histone methylation and increase histone demethylation and acetylation at H3K27. PFAs initiate from a cell lineage in the first trimester of human development that resides in restricted oxygen. Unlike other ependymomas, transient exposure of PFA cells to ambient oxygen induces irreversible cellular toxicity. PFA tumors exhibit a low basal level of H3K27me3 and, paradoxically, inhibition of H3K27 methylation specifically disrupts PFA growth. Microenvironmental regulation of PFA ependymoma epigenome appears to play a major role in tumorigenesis. Targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma.

NCOG-43. NEUROCOGNITIVE IMPAIRMENT AND FRAILTY IN GERIATRIC PATIENTS WITH HIGH GRADE GLIOMA AND THORACIC MALIGNANCY

Abstract BACKGROUND The median age at diagnosis for high grade glioma is 64 years. With peak incidence 75-84, malignant glial tumors are frequently a disease of the elderly. Common assessment measures fail to accurately gauge geriatric cancer patient fitness. Comprehensive Geriatric Assessment (CGA) is recommended in patients older than 65 to gauge risk of toxicity and tolerance of therapeutic intervention. We reviewed data for older patients with high grade glioma (HGG) and thoracic malignancy (TM) who underwent CGA via Senior Oncology Clinic (SOC) at Levine Cancer Institute. METHODS From 2015 to 2019 104 thoracic malignancy patients and 19 high grade glioma patients completed CGA via SOC before treatment or a required change in therapy. Data was incorporated into the LCI Senior Oncology Database by the REDCap secure web application, allowing for both quantitative and qualitative data analysis. RESULTS The median age was 77 in the HGG cohort compared to 80 years with TM. The physician rated Karnofsky Performance Status (KPS) for HGG and TM were similar (76% v 79%) as were the percentages of patients that were frail or prefrail (90% v 87%). Montreal Cognitive Assessment scores were lower in HGG (20 v 23). Considerably more HGG had falls in the 6 months before their assessment (58% v 30%) and gait speed was slower (0.76 m/s v 0.85 m/s). CONCLUSIONS Older patients with high grade gliomas compared to similar thoracic malignancies had more neurocognitive impairment, falls in the preceding 6 months, and slower gait speed. Physician rated KPS and frailty were similar in both groups. The results illustrate the limitations of physician-rated performance measures and highlight the importance of CGA in older brain tumor patients.