NEW POTENTIAL TREATMENT FOR BRAIN GLIOMA

According to the latest statistics, brain gliomas are the most common cause of death from CNS tumors. Brain gliomas are also ranked as the second (after stroke) cause of brain surgery The mortality rate from gliomas is high and sometimes reaches 80 %. It is because the tumor grows from undifferentiated cells, which causes its peracute development and malignant transformation. Symptoms of glioma occur at stages 3 and 4, when all treatment is symptomatic, and operations are palliative. In this regard, it is necessary to develop and introduce methods for non-surgical glioma treatment. These methods include the use of antisense oligonucleotides, optogenetics, and oncolytic viruses. The aim of antisense oligonucleotides is to replace a section in a glioma cell genome with a foreign one, which disrupts cell division and leads to apoptosis and necrosis of the entire tumor. Optogenetics excludes the introduction of substances into the body. It provides a certain light signal to glioma cells, which also suppresses the growth of an undifferentiated tumor. Oncolytic viruses are genetically modified viruses that identify tumor cells, penetrate into them and start a cascade of apoptotic reactions Despite all success, such methods are still studied at the laboratory level, their implementation in practical medicine is slow and cautious. However, insufficient knowledge retards the widespread use of potentially promising and effective drugs. Scientists around the world are developing methods to treat brain gliomas at different stages of their development. This article reflects modern achievements of scientists and neurosurgeons, describing new methods for brain glioma treatment. Key words: brain glioma, optogenetics, antisense oligonucleotides, oncolytic viruses, p53 gene. Согласно последним данным статистики, глиомы мозга являются наиболее частой причиной смертей от онкологии центральной нервной системы, а также занимают второе место по частоте как причина хирургических вмешательств на головной мозг, уступая инсультам. Смертность от глиом высока и порой достигает 80 %. Причина этого заключается в том, что опухоль растет из недифференцированных клеток, что обусловливает её молниеносный рост и быстрое озлокачествление. Симптомы глиомы возникают на 3–4 стадии развития, когда все лечение направлено на ликвидацию симптомов, а операции носят паллиативный характер. В связи с этим необходима разработка и внедрение методов по нехирургическому лечению глиом. Такими методами являются использование антисмысловых олигонуклеотидов, оптогенетика, применение онколитических вирусов. Суть использования антисмысловых олигонуклеотидов заключается в замене участка генома клетки глиомы на инородный, попавший извне, что нарушает деление клеток и приводит к апоптозу и некрозу всей опухоли. Оптогенетика исключает введение веществ в организм и заключается в подаче определенного светового сигнала на глиозные клетки, что также тормозит рост недифференцированной опухоли. Онколитические вирусы – это генномодифицированные вирусы, которые определяют опухолевые клетки, проникают в них и запускают каскад апоптотических реакций. Несмотря на все успехи, данные методы продолжают изучаться на уровне лабораторий, их внедрение в практическую медицину происходит медленно и со страхом. Однако недостаточная изученность тормозит широкое применение потенциально перспективных и эффективных лекарств. Учеными мира разрабатываются методы, позволяющие лечить глиомы мозга на разных стадиях их развития. Данная статья отображает современные достижения ученых и нейрохирургов в поисках возможности применения такого рода методов. Ключевые слова: глиома мозга, оптогенетика, антисмысловые олигонуклеотиды, онколитические вирусы, ген р53.

Unusual Case of Head Injury Presented with Brain Gliomas

Seven years female child came with parents who gave us history that 1month back, child during playing had fall on face and lost consciousness which remained for 30 min followed by convulsion. On examination patient was conscious, responds to command, vitals were stable, aphasia was present, pupils were equal and reactive to light bilaterally and horizontal gaze was restricted. There was no facial weakness, Tone increase more in left upper and lower limb .Deep tendon reflexes (DTR) increase in left side. Plantar reflex were extensors. MRI was done which shows intra axial space occupying lesion in brainstem with expansion of brainstem with hydrocephalus. Pt was inoperable and ventriculoperitoneal shunt was done for hydrocephalus. Post operatively patient was kept on assisted ventilation. Conclusion: Unusual presentation of brainstem gliomas as head injury.

Assessment of Structural Disconnections In Gliomas: Comparison of Indirect And Direct Approaches

Gliomas are amongst the most common primary brain tumours in adults and are often associated with poor prognosis. Understanding the extent of white matter (WM) which is affected outside the tumoral lesion may be of paramount importance to explain cognitive deficits and the clinical progression of the disease. To this end, we explored both direct (i.e., tractography based) and indirect (i.e., atlas based) approaches to quantifying WM structural disconnections in a cohort of 50 high- and low-grade glioma patients. While these methodologies have recently gained popularity in the context of stroke, to our knowledge this is the first time they are applied in patients with brain tumours. More specifically, in this work we present a quantitative comparison of the disconnection maps provided by the two methodologies by applying well known metrics of spatial similarity, extension and correlation. Given the important role the oedematous tissue plays in the physiopathology of tumours, we performed these analyses both by including and excluding it in the definition of the tumoral lesion. This was done to investigate possible differences determined by this choice.We found that direct and indirect approaches offer two distinct pictures of structural disconnections in patients affected by brain gliomas, presenting key differences in several regions of the brain. Following the outcomes of our analysis, we eventually discuss the strengths and pitfalls of these two approaches when applied in this critical field.

Combined Application of Sodium Fluorescein and Neuronavigation Techniques in the Resection of Brain Gliomas

Objectives: To explore the effectiveness and safety of the combined application of sodium fluorescein and neuronavigation techniques in the resection of brain gliomas in different locations and patients of different ages.Methods: Fifty clinical cases of brain gliomas treated at the Department of Neurosurgery of Beijing Tiantan Hospital were collected from March 2014 to March 2019. These cases were divided into a supratentorial group (24 cases) and a brainstem group (26 cases) based on location and an adult group (28 cases) and a pediatric group (22 cases) based on age. Fluorescein-guided surgery was performed: the adult group received 5 mg/kg sodium fluorescein before opening the dura, while the pediatric group received 2.5 mg/kg during resection. Tumor visualization was evaluated by the enhancement of yellow fluorescein and considered “satisfactory” if the illumination demarcated the tumor boundary. Additionally, the consistency between fluorescein and neuronavigation was analyzed. The Karnofsky performance score (KPS) of all patients was recorded and assessed at admission, discharge, and the 6-month follow-up.Results: In the 28 adult cases, 4 were unsatisfactory, while in the 22 pediatric cases, 2 were unsatisfactory; in 7 cases, there was an inconsistency between yellow fluorescein enhancement and neuronavigation, 6 were in the supratentorial group, and 1 was in the brainstem group. Statistical analysis showed no significant differences in the satisfactory rate between the adult and pediatric groups (P = 0.575), whereas there were significant differences inconsistency between the supratentorial group and brainstem group (P = 0.031). The mean KPS at admission was between 70 and 100, which was not significantly different from that at discharge (P = 0.839), but the KPS at the 6-month follow-up was significantly higher than that at admission (P = 0.041).Conclusions: The consistency between sodium fluorescein and the neuronavigation system was higher in the brainstem group than in the supratentorial group; a half dose of sodium fluorescein (2.5 mg/kg) was sufficient for pediatric patients. The combined utilization of sodium fluorescein and neuronavigation techniques may confer glioma patients the opportunity to obtain better clinical outcomes after surgery.

Symptomatic Epileptic Seizures in Patients with Brain Gliomas

Introduction. Epileptic seizures are an important problem that significantly worsens the quality of patients’ life with both newly diagnosed and recurrent brain gliomas.Review. The analysis of domestic and foreign literature showed that low-grade gliomas, this symptom occurs on average in 76%, with high-grade gliomas – in 21% of patients. Despite the maximum allowable tumor resection, it is likely that epileptic seizures persist in 18-64% of patients, and in 5% of patients they first appear in the postoperative period. From 15 to 50% of epileptic seizures in cerebral gliomas are drug-resistant. In patients undergoing chemotherapy, it is better to use new antiepileptic drugs because their cross-effects are minimal.Conclusion. There is no generally accepted algorithm for prescribing and discontinuing antiepileptic drugs in patients with symptomatic epileptic seizures with cerebral gliomas. Further research is needed to determine the optimal combination and dosage regimen of antiepileptic drugs, especially during chemotherapy.

Clinicopathological Significance of Nestin Expression as a Diagnostic and Prognostic Marker in Brain Gliomas, Independent of IDH Mutation

Background: Nestin, a type VI intermediate filament, is expressed in neuroepithelial cells during embryogenesis and has been expressed in various human tumors. Recent studies have reported that expression is associated with poor prognosis in brain tumors, but the results are inconclusive. In this study, we evaluated usefulness of Nestin expression using immunohistochemistry as a diagnostic and prognostic biomarker for IDH mutation and the new World Health Organization (WHO) classification.Methods: To investigate Nestin expression, immunohistochemistry was performed on 92 adult brain gliomas using tissue microarrays. We further analyzed the clinical characteristics and survival outcomes according to Nestin expression and examined its correlation with another glioma biomarker, IDH mutation.Results: Sixty patients (65.2%) were Nestin-positive (weak and strong). Nestin expression and intensity were significantly correlated with age, location, diagnosis, and IDH mutations. Old age and high-grade gliomas showed a higher frequency and stronger intensity of Nestin expression than those of young age and with low-grade gliomas (p<0.001). Gliomas with IDH mutations that are located in the frontal lobe showed no expression or had weak positivity. Multivariate analysis demonstrated that Nestin expression (weak, hazard ratio [HR] 5.39, p=0.036; strong, HR 8.43, p=0.007) and IDH wildtype (HR 7.63; p=.001) were significant independent prognostic factors. Moreover, patients with tumors expressing Nestin showed shorter survival (p<0.001).Conclusions: Nestin expression exhibits high intensity in high-grade gliomas and is a useful diagnostic marker. High expression and level of Nestin were significantly correlated with worse survival and was considered a significant marker of poor prognosis in new WHO classification, independent of IDH mutation.

Influence of 11C-MET PET acquisition time for differential diagnosis of human brain gliomas

The aim of this work was to study the effect of the reduced acquisition time of PET 11C-MET examination on the quality of primary brain tumors differential diagnosis. 57 patients with histologically verified diagnoses were recruited (glioblastoma n=20, anaplastic astrocytoma n=11, diffuse astrocytoma n=11, oligodendroglioma n=9 and anaplastic oligodendroglioma n=6). The scan time was varied in the range of 2-20 min. Our study demonstrated that in the case of intravenous administration of 11C-MET simultaneously with the start of scanning, the quality of primary gliomas differential diagnosis does not depend on the scan time. Therefor it becomes possible increasing the number of patients and reducing the acquisition time. The T/N60 ratio (T/N ratio measured in the first 60 seconds after 11C-MET intravenous injection) is equally successful parameter for glioma differential diagnosis as the traditional T/N ratio.

Validation and Selection of New Reference Genes for RT-qPCR Analysis in Pediatric Glioma of Different Grades

Gliomas are heterogeneous, solid, and intracranial tumors that originate from glial cells. Malignant cells from the tumor undergo metabolic alterations to obtain the energy required for proliferation and the invasion of the cerebral parenchyma. The alterations in the expression of the genes related to the metabolic pathways can be detected in biopsies of gliomas of different CNS WHO grades. In this study, we evaluated the expression of 16 candidate reference genes in the HMC3 microglia cell line. Then, statistical algorithms such as BestKeeper, the comparative ΔCT method, geNorm, NormFinder, and RefFinder were applied to obtain the genes most suitable to be considered as references for measuring the levels of expression in glioma samples. The results show that PKM and TPI1 are two novel genes suitable for genic expression studies on gliomas. Finally, we analyzed the expression of genes involved in metabolic pathways in clinical samples of brain gliomas of different CNS WHO grades. RT-qPCR analysis showed that in CNS WHO grade 3 and 4 gliomas, the expression levels of HK1, PFKM, GAPDH, G6PD, PGD1, IDH1, FASN, ACACA, and ELOVL2 were higher than those of CNS WHO grade 1 and 2 glioma biopsies. Hence, our results suggest that reference genes from metabolic pathways have different expression profiles depending on the stratification of gliomas and constitute a potential model for studying the development of this type of tumor and the search for molecular targets to treat gliomas.

Decreased Expression of PACSIN1 in Brain Glioma Samples Predicts Poor Prognosis

Gliomas are the most severe brain tumours with a poor prognosis. Although surgery, postoperative radiotherapy and chemotherapy can improve the survival rate of glioma patients, the prognosis of most glioma patients is still poor. In recent years, the influence of gene-targeted therapy on gliomas has been gradually discovered, and intervening the occurrence and development of brain gliomas from the perspective of the gene will significantly improve treatment prognosis. Protein Kinase C and Casein Kinase Substrate in Neurons 1 (PACSIN1) is a member of the conserved peripheral membrane protein family in eukaryotes. Improper expression of PACSIN1 can lead to neurological diseases such as Huntington’s disease and schizophrenia. However, its relationship with tumours or even gliomas has not been explored. The study aims to explore PACSIN1 as a prognostic factor that can predict overall survival (OS) for gliomas. We collected the data from CGGA, TCGA, GEO databases and the pathological glioma tissue specimens from 15 clinical glioma patients surgically resected. The differential expression of PACSIN1 in various clinical indicators, the genes related to PACSIN1 expression, the prognostic value of PACSIN1 and the functional annotations and pathway analysis of differently expressed genes (DEGs) were analysed. The results revealed that PACSIN1 had low expression levels in grade IV, IDH1 wild-type and 1p/19q non-codel group gliomas, and PACSIN1 was considered a mesenchymal molecular subtype marker. PACSIN1 expression is positively correlated with OS in all gliomas and it was found that PACSIN1 influenced the occurrence and development of gliomas through synaptic transmission. The PACSIN1 expression is negatively correlated with the malignant degree of gliomas and positively associated with the OS, indicating that PACSIN1 would play an essential role in the occurrence and development of gliomas and might be a potential new biomarker and targeted therapy site for gliomas.

Bioactive Compounds with Antiglioma Activity from Marine Species

The search for new chemical compounds with antitumor pharmacological activity is a necessary process for creating more effective drugs for each specific malignancy type. This review presents the outcomes of screening studies of natural compounds with high anti-glioma activity. Despite significant advances in cancer therapy, there are still some tumors currently considered completely incurable including brain gliomas. This review covers the main problems of the glioma chemotherapy including drug resistance, side effects of common anti-glioma drugs, and genetic diversity of brain tumors. The main emphasis is made on the characterization of natural compounds isolated from marine organisms because taxonomic diversity of organisms in seawaters significantly exceeds that of terrestrial species. Thus, we should expect greater chemical diversity of marine compounds and greater likelihood of finding effective molecules with antiglioma activity. The review covers at least 15 classes of organic compounds with their chemical formulas provided as well as semi-inhibitory concentrations, mechanisms of action, and pharmacokinetic profiles. In conclusion, the analysis of the taxonomic diversity of marine species containing bioactives with antiglioma activity is performed noting cytotoxicity indicators and to the tumor cells in comparison with similar indicators of antitumor agents approved for clinical use as antiglioblastoma chemotherapeutics.