Updates on management of gliomas in the molecular age

Gliomas are primary brain tumors derived from glial cells of the central nervous system,afflicting both adults and children with distinct characteristics and therapeutic challenges.Recent developments have ushered in novel clinical and molecular prognostic factors,reshaping treatment paradigms based on classi-fication and grading,determined by histological attributes and cellular lineage.This review article delves into the diverse treatment modalities tailored to the specific grades and molecular classifications of gliomas that are currently being discussed and used clinically in the year 2023.For adults,the therapeutic triad typically consists of surgical resection,chemotherapy,and radiotherapy.In contrast,pediatric gliomas,due to their diversity,require a more tailored approach.Although complete tumor excision can be curative based on the location and grade of the glioma,certain non-resectable cases demand a chemotherapy approach usually involving,vincristine and carboplatin.Addi-tionally,if surgery or chemotherapy strategies are unsuccessful,Vinblastine can be used.Despite recent advancements in treatment methodologies,there remains a need of exploration in the literature,particularly concerning the efficacy of treatment regimens for isocitrate dehydrogenase type mutant astrocytomas and fine-tuned therapeutic approaches tailored for pediatric cohorts.This review article explores into the therapeutic modalities employed for both adult and pediatric gliomas in the context of their molecular classification.

Construction and Verification of an RNA-Binding Protein-Associated Prognostic Model for Gliomas

Objective To construct and verificate an RNA-binding protein(RBP)-associated prognostic model for gliomas using integrated bioinformatics analysis.Methods RNA-sequencing and clinic pathological data of glioma patients from The Cancer Genome Atlas(TCGA)database and the Chinese Glioma Genome Atlas database(CGGA)were downloaded.The aberrantly expressed RBPs were investigated between gliomas and normal samples in TCGA database.We then identified prognosis related hub genes and constructed a prognostic model.This model was further validated in the CGGA-693 and CGGA-325 cohorts.Results Totally 174 differently expressed genes-encoded RBPs were identified,containing 85 down-regulated and 89 up-regulated genes.We identified five genes-encoded RBPs(ERI1,RPS2,BRCA1,NXT1,and TRIM21)as prognosis related key genes and constructed a prognostic model.Overall survival(OS)analysis revealed that the patients in the high-risk subgroup based on the model were worse than those in the low-risk subgroup.The area under the receiver operator characteristic curve(AUC)of the prognostic model was 0.836 in the TCGA dataset and 0.708 in the CGGA-693 dataset,demonstrating a favorable prognostic model.Survival analyses of the five RBPs in the CGGA-325 cohort validated the findings.A nomogram was constructed based on the five genes and validated in the TCGA cohort,confirming a promising discriminating ability for gliomas.Conclusion The prognostic model of the five RBPs might serve as an independent prognostic algorithm for gliomas.

Drug clinical trials on high-grade gliomas: challenges and hopes

Gliomas are the most common group of malignant central nervous system tumors across all ages and have high heterogeneity.According to histopathologic criteria and molecular pathology,gliomas are classified as grades 1–4.High-grade gliomas(HGG),including the most aggressive subtype,glioblastoma(GBM),belong to grade 3 or 4.Although a standard therapy comprising surgical resection,chemotherapy,and radiation is available,almost all patients with HGG experience recurrence within several months and a dismal prognosis1.

Exploratory therapy for brainstem gliomas

Brainstem gliomas comprise both slow-growing and highly aggressive tumors,the latter carrying a dismal prognosis of approximately 10 months in children.Given their common locations along the brainstem,they are often not amenable to surgical resection.There are currently a host of exploratory therapies under investigation ranging from immunotherapy,small molecular inhibitors,epigenetic-modifying agents,and radiation protocols to combat these difficult-to-treat tumors.Recent discoveries highlighting the role of H3 histone mutations in diffuse midline glioma oncogenesis have yielded a variety of new targetable antigens and aberrant signaling pathways.Although many of these studies have shown promise in terms of inhibiting tumor growth and disease progression,results to date have been modest in their ability to translate into meaningful clinical benefit.This review will serve as an updated report on the current state of literature concerning pre-clinical and clinical therapies being investigated for brainstem glioma.In addition,this review will serve as a guide for clinicians as we review the evolving nomenclature of brainstem gliomas,commonly presenting symptoms,diagnostic tools,and standard therapies.

Microvesicles in Gliomas and Medulloblastomas: An Overview

Microvesicles (MVs) or shedding membrane vesicles have recently been described as a novel model of intercellular communication. Previously, MVs were considered as unnecessary or secreted cellular debris, but MVs have lately been described as having roles in a variety of biological functions, such as cell homeostasis and the cellular processes involved in the oncogenesis of many types of tumors. Carrying several key molecules that contribute to tumor development and progression, similar to mRNAs, microRNAs and other non-coding RNAs, DNA and even small proteins, MVs can be considered as a ubiquitous form of novel cell communication that is present in most somatic cells. Although tumor-derived MVs have been demonstrated in different types of cancers, the literature data on MVs in primary central nervous system (CNS) tumors are relatively scarce. In this review, we address the involvement of MVs in diffuse astrocytomas, particularly glioblastomas, as well as oligodendrogliomas and medulloblastomas. We placed particular focus on the cellular crosstalk between tumor and “normal” cells, the putative mechanisms how the tumor microenvironment is modulated and the spread of aggressive phenotypes. Additionally, a better understanding of the participation of tumor-derived MVs in the regulation of key cancer pathways will offer new insights into tumor pathogenesis and the mechanisms of multidrug resistance, and may help to develop new strategies for novel therapies against these infiltrative CNS tumors.

Re-irradiation for high-grade gliomas:Has anything changed?

Optimal management after recurrence or progression of high-grade gliomas is still undefined and remains a challenge for neuro-oncology multidisciplinary teams.Improved radiation therapy techniques,new imaging methods,published experience,and a better radiobiological knowledge of brain tissue have positioned re-irradiation(re-RT)as an option for many of these patients.Decisions must be individualized,taking into account the pattern of relapse,previous treatment,and functional status,as well as the patient’s preferences and expected quality of life.Many questions remain unanswered with respect to re-RT:Who is the most appropriate candidate,which dose and fractionation are most effective,how to define the target volume,which imaging technique is best for planning,and what is the optimal timing?This review will focus on describing the most relevant studies that include re-RT as salvage therapy,with the aim of simplifying decision-making and designing the best available therapeutic strategy.

Repeated operations for infiltrative low - grade gliomas without intervening therapy.

OBJECT:Progression of infiltrative low-grade gliomas(LGGs)has been reported previously.The limitations ofsuch studies include diverse histological grading systems,intervening therapy,and the lack of histological confir-mation of malignant tumor progression.The aim of this study was to determine tumor progression in adult patientswith an initial diagnosis of infiltrative LGG who subsequently underwent a repeated operation,but no other inter-vening therapy.The authors examined factors that may be associated with tumor progression.

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.

Risk factors of extraneural spreading in astrocytomas and oligodendrogliomas in donors with gliomas: A systematic review

BACKGROUND Patients with a history of primary brain tumors can be eligible for organ donation under extended criteria.The risk assessment of tumor transmission via organ transplant in primary brain tumors is primarily based on the assessment of tumor histotype and grade.Previous surgeries,chemo-/radiotherapy,and ventriculoperitoneal shunt placement can lead to a disruption of the blood-brain barrier,concurring to an increase in the transmission risk.AIM To investigate the role of tumor transmission risk factors in donors with oligodendrogliomas and astrocytomas.METHODS We searched PubMed and EMBASE databases for studies reporting extraneural spreading of oligoden-drogliomas and astrocytomas and extracted clinical-pathological data on the primary tumor histotype and grade,the elapsed time from the diagnosis to the onset of metastases,sites and number of metastases,prior surgeries,prior radiotherapy and/or chemotherapy,ventriculoatrial or ventriculo-peritoneal shunt placement,and the presence of isocitrate dehydrogenase 1/2 mutation and 1p/19q codeletion.Statistical analysis was performed using R software.Statistical correlation between chemotherapy or radiotherapy and the presence of multiple extra-central nervous system metastases was analyzed usingχ2 and Fischer exact test.The Kaplan-Meier method was used to evaluate the presence of a correlation between the metastasis-free time and:(1)Localization of metastases;(2)The occurrence of intracranial recurrences;and(3)The occurrence of multiple metastases.RESULTS Data on a total of 157 patients were retrieved.The time from the initial diagnosis to metastatic spread ranged from 0 to 325 mo in patients with oligodendrogliomas and 0 to 267 mo in those with astrocytomas.Respectively,19%and 39%of patients with oligodendroglioma and astrocytoma did not receive any adjuvant therapy.The most frequent metastatic sites were bone,bone marrow,and lymph nodes.The lungs and the liver were the most commonly involved visceral sites.There was no significant correlation between the occurrence of multiple metastases and the administration of adjuvant chemo-/radiotherapy.Patients who developed intracranial recurrences/metastases had a significantly longer extraneural metastasis-free time compared to those who developed extraneural metastases in the absence of any intra-central nervous system spread.CONCLUSION A long follow-up time does not exclude the presence of extraneural metastases.Therefore,targeted imaging of bones and cervical lymph nodes may improve safety in the management of these donors.

Brain gliomas Biological characteristics and correlation with the status of adjacent corticospinal tracts

Malignant behaviors of brain gliomas include proliferation and infiltration.It remains unclear which behavior influences the status of adjacent corticospinal tracts.Diffusion tensor imaging can show the status of brain white matter fiber tracts.Ki-67 and CD44/matrix metalloproteinase 9 are sensitive markers for reflecting the proliferation and infiltration of tumor cells.The present study analyzed pre-operative diffusion tensor images of 24 patients with pathologically confirmed World Health Organization glioma（Ⅰ-Ⅳ）.We observed lapse,infiltration and destruction of the peri-tumor corticospinal tract following reconstruction,and simultaneously detected the expression of Ki-67,CD44/matrix metalloproteinase 9 in samples.Expression of CD44 and matrix metalloproteinase 9was not significantly correlated to the status of the peri-tumor corticospinal tract（r = 1.597,4.859;P = 0.450,0.088）,while Ki-67 expression significantly correlated to its status（r= 6.590,P = 0.037）.These findings demonstrate that highly proliferative gliomas result in damage to the peripheral corticospinal tract.

Radiotherapy delays malignant transformation and prolongs survival in patients with IDH-mutant gliomas

Objective:IDH-mutant lower-grade gliomas(LGGs,grade 2 or 3)eventually transform into secondary grade 4 astrocytomas(sAIDHmut/G4).Here,we sought to describe the transformation time,risk factors,and outcomes in malignant transformation of IDHmutant LGGs.Methods:We screened data for 108 patients with sAIDHmut/G4 in the Chinese Glioma Genome Atlas who had initial IDH-mutant LGGs and underwent reoperation during 2005–2021.We evaluated the transformation time from IDH-mutant LGGs to sAIDHmut/G4,and associated risk factors and outcomes.Malignant transformation was defined as pathological confirmation of grade 4 astrocytoma.Results:The median age of the 108 patients with IDH-mutant LGGs was 35 years(range,19–54);the median age at transformation was 40 years(range,25–62);and the median follow-up time for all patients was 146 months(range,121–171).The average transformation time was 58.8 months for all patients with LGGs(range,5.9–208.1);63.5 and 51.9 months for grade 2 and 3 gliomas,respectively;and 58.4 and 78.1 months for IDH-mutant/1p/19q-non-codeleted astrocytomas and IDH-mutant/1p/19q-codeleted oligodendrogliomas,respectively.Univariate and multivariate analysis indicated that radiotherapy[hazard ratio(HR),0.29;95%confidence interval(CI),0.137–0.595;P=0.001]and non-A blood type(HR,0.37;95%CI,0.203–0.680;P=0.001)were protective factors against delayed malignant transformation.Radiotherapy was associated with improved survival after transformation(HR,0.44;95%CI,0.241–0.803;P=0.008),overall survival(HR,0.50;95%CI,0.265–0.972;P=0.041),and progression-free survival(HR,0.25;95%CI,0.133–0.479;P<0.0001)in patients with IDH-mutant gliomas.Conclusions:Radiotherapy is associated with delayed malignant transformation and improved survival in patients with IDHmutant gliomas.

THE USE OF ANTIHUMAN GLIOMA MONOCLONAL ANTIBODIES FOR TARGETING CHEMOTHERAPY OF BRAIN GLIOMAS(POTENT SUPPRESSION OF MALIGNANT GLIOMA GROWTH WITH IMMUNOCONJUGATES IN VIVO)

Athymic nude mice bearing subcutaneous and intracerebral human glioma xenografts were used to assess the therapeutic efficacy of monoclonal anti-body-adriamycin immunoconjugates against malignant gliomas in vivo. Immunoconjugates showed a significantly stronger antitumor effect with a T/C (treated/ control tumor volume) of 30% as compared with free drug (T/C of 84%). The targeting treatment with immunoconjugates significantly prolonged 54% of median survival time of nude mice. Side effects of immunoconjugates on the normal bone marrow and small intestines were much slighter than those of the free drug. The results of this study indicate that the use of monoclonal antibodies as carriers of anti-tumor agents may have many therapeutic advantages and potential for the treatment of brain gliomas.

THE USE OF ANTI-HUMAN GLIOMA MONOCLONAL ANTIBODIES FOR TARGETING CHEMOTHERAPY OF BRAIN GLIOMAS(PREPARATION AND CYTOTOXIC PROPERTIES OF ANTIBODY-ADRIAMYCIN IMMUNOCONJUGATES)

Immunoconjugates are antibody-drug hybrid molecules which combine the exquisite selectivity or monoclonal antibodies with the potent toxicity of anticancer agents. A monoclonal antibody SZ39 against human brain gliomas was used as a drug carrier. Adriamycin (ADR) was bound covalently to SZ39 to form a SZ39-ADR conjugate. The cytotoxic activity of the SZ39-ADR conjugate was tested in vitro and demonstrated potent and specific killing of cells derived from a human malignant glioma. 50% inhibitory concentration (IC50) for SZ39-ADR to 'target' cells was 8.14×10-9 M. An index of specificity between 'target' and 'non-target' cells was calculated to be 88-fold. These data suggest that the SZ39-ADR may use as a potent and cell type-specific agent and is a likely candidate for the targeting chemotherapy of malignant gliotnas.

Follistatin, a Novel Biomarker for Malignant Gliomas

Molecular biomarkers are commonly used for the management of several types of malignant tumours in routine clinical practice. However, this is not the case for malignant gliomas. Cytokines and Angiogenesis factors are potential candidates due to their intrinsic role in tumourigenesis. Pre- and post-operative serum from 36 malignant glioma patients and 36 controls was analysed using the Bio-Plex Pro Angiogenesis and Cytokines Assay (Bio-Rad, USA). Amongst the molecules tested, the serum concentration of follistatin was significantly higher in patients than in controls. Moreover, the serum concentration of follistatin of the patients postoperatively was significantly reduced compared to that preoperatively. Factors such as age and gender did not affect the concentrations of follistatin measured in the serum of patients pre- and post-operatively as well as healthy controls. This is the first report of follistatin as potential biomarker for the detection of malignant gliomas.

Cerebral Gliomas Patterns at the General Hospital of Douala, Cameroon

The diagnosis and management of cerebral gliomas are challenging. The goal of this study was to evaluate the pattern of cerebral gliomas at the General Hospital Douala, Cameroon. A retrospective study was carried out over a period of 10 years. Non-glial lesions were not included. Data were analyzed with Epi info version 7.2.2.6 (Microsoft, Seattle, USA). 220 cases of brain tumors, comprising 56 gliomas (25.46% of all brain tumors) were managed during the study period. The mean age of the patients was 42.93 ± 16.90 years. 35 cases (62.5%) were males. Patients over 15 years of age represented 91.07% (n = 51) of the cases. The most frequent presenting complaints were headache and vomiting with 52 cases (92.86%) and 47 cases (83.93%) respectively. Brain computed tomography was done for all patients. The most frequent histological type was astrocytoma with 22 cases (39.29%) followed by glioblastoma with 20 cases (35.71%). The most performed surgical technique was partial removal with 33 cases (58.93%), followed by open biopsy with 14 cases (25.00%). Radiotherapy was administered to 54 patients (96.43%). The outcome ranged from full recovery in 8 cases (14.29%), recovery with persisting symptoms, in 15 cases (26.79%) and death in 26 cases (46.43%). Seven patients (12.50%) were lost to view. In this series, cerebral gliomas affected most often adult males. Most of them presented with signs of raised intracranial pressure. The outcome was poor with 46.43% of patients dying before 2 years after diagnosis.

Role of the circulatory interleukin-6 in the pathogenesis of gliomas:A systematic review

BACKGROUND Glioma is the most common primary tumor in the brain originating from glial cells.In spite of extensive research,the overall survival rate is not enhanced.A number of published articles observed differentially circulating levels of cytokines in glioma.Interleukin-6(IL-6)protein coded by IL-6 gene is regulated by the immune system and it has been found to have a significant role in progression and apoptosis resistance of glioma.AIM To review the role of circulatory IL-6 in the development and progression of glioma and its utility as a biomarker.METHODS Preferred Reporting Items for Systematic Reviews and Meta-analysis(PRISMA)guidelines were applied to filter the relevant studies based on inclusion and exclusion criteria.We used a combination of keywords and the Reference Citation Analysis(RCA)tool to search the potential studies and performed data extraction from selected studies.RESULTS The published results were inconsistent;however,most studies showed a significantly higher IL-6 level in glioma cases as compared to controls.Comparative IL-6 level among the different grades of glioma showed a higher level with low-grade gliomas and lower level with high-grade gliomas.CONCLUSION IL-6 level significantly differed between cases and controls,and among different cancer stages,which shows its potential as a diagnostic and prognostic marker.

Temozolomide chemotherapy based on MGMT protein expression for patients with malignant gliomas:a report of 40 cases

Objective This study is to evaluate the efficacy and toxicity of temozolomide (TMZ) chemotherapy based on O 6 -methylguanine-DNA methyltransferase (MGMT) protein expression in patients with malignant gliomas. Methods A total of 40 patients with pathologically confirmed malignant gliomas were enrolled. All patients had pretreated with radiotherapy and had assessable lesions.

Resection of thalamic gliomas via transcortico-ventriculo-choroidal approach

Objective To evaluate the effect of surgical treatment of thalamic gliomas via transcortico-ventriculo-choroidal approach. Methods 20 cases of thalamic gliomas were included in this group. The part of middle frontal gyrus was removed to get to the lateral ventricule and from there,according to the direction of the

Clinicopathological aspects correlated with 1p/19q co-deletion in gliomas

Objective This study aims to select clinical and pathological aspects correlated with 1p /19q co-deletion in gliomas. Methods Samples of 56 glioma patients were collected. The status of chromosome 1p and 19q was detected by Fluorescence in Situ Hybridization (FISH) and the expression levels of nine

The expression of MMPs and TIMPs in gliomas of the limbic system

To investigate the function of matrix metalloproteinase-2(MMP-2),matrix metalloproteinase-9(MMP-9) and tissue inhibitors of metalloproteinase-2(TIMP-2) in the invasion of gliomas of the limbic system.Methods The expression of MMP-2,MMP-9 and TIMP-2 in low and high-grade gliomas and meningiomas was detected by using immunohistochemical technique.Results (1) The expression levels of MMP-2 and MMP-9 were significantly higher in high grade gliomas than those in low grade gliomas (P<0.05 and P<0.01 respectively).They were also significantly higher in low grade gliomas than those in meninginomas (P<0.05 and P<0.01 respectively).(2) The TIMP-2 expression level was obviously lower in gliomas of grade Ⅲ and grade Ⅳthan that in gliomas of grade Ⅰ and grade Ⅱ.Also,the expression of TIMP-2 in gliomas of grade Ⅰ and grade Ⅱ was significantly lower than that in meningiomas. Conclusion (1) The expression of MMP-2 and MMP-9 in human brain gliomas is related to malignant progression of gliomas.They might be used as the indicators to evaluate the malignancy and prognosis of gliomas.(2) Imbalance between MMP-s and TIMP-s may be one of the improtant factors promoting glioma invasion.5 refs,3 figs.