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International Journal of Molecular... Jun 2023Gliomas are the most common brain tumor in adults, and molecularly targeted therapies to treat gliomas are becoming a frequent topic of investigation. The current state... (Review)
Review
Gliomas are the most common brain tumor in adults, and molecularly targeted therapies to treat gliomas are becoming a frequent topic of investigation. The current state of molecular targeted therapy research for adult-type diffuse gliomas has yet to be characterized, particularly following the 2021 WHO guideline changes for classifying gliomas using molecular subtypes. This systematic review sought to characterize the current state of molecular target therapy research for adult-type diffuse glioma to better inform scientific progress and guide next steps in this field of study. A systematic review was conducted in accordance with PRISMA guidelines. Studies meeting inclusion criteria were queried for study design, subject (patients, human cell lines, mice, etc.), type of tumor studied, molecular target, respective molecular pathway, and details pertaining to the molecular targeted therapy-namely the modality, dose, and duration of treatment. A total of 350 studies met the inclusion criteria. A total of 52 of these were clinical studies, 190 were laboratory studies investigating existing molecular therapies, and 108 were laboratory studies investigating new molecular targets. Further, a total of 119 ongoing clinical trials are also underway, per a detailed query on clinicaltrials.gov. GBM was the predominant tumor studied in both ongoing and published clinical studies as well as in laboratory analyses. A few studies mentioned IDH-mutant astrocytomas or oligodendrogliomas. The most common molecular targets in published clinical studies and clinical trials were protein kinase pathways, followed by microenvironmental targets, immunotherapy, and cell cycle/apoptosis pathways. The most common molecular targets in laboratory studies were also protein kinase pathways; however, cell cycle/apoptosis pathways were the next most frequent target, followed by microenvironmental targets, then immunotherapy pathways, with the wnt/β-catenin pathway arising in the cohort of novel targets. In this systematic review, we examined the current evidence on molecular targeted therapy for adult-type diffuse glioma and discussed its implications for clinical practice and future research. Ultimately, published research falls broadly into three categories-clinical studies, laboratory testing of existing therapies, and laboratory identification of novel targets-and heavily centers on GBM rather than IDH-mutant astrocytoma or oligodendroglioma. Ongoing clinical trials are numerous in this area of research as well and follow a similar pattern in tumor type and targeted pathways as published clinical studies. The most common molecular targets in all study types were protein kinase pathways. Microenvironmental targets were more numerous in clinical studies, whereas cell cycle/apoptosis were more numerous in laboratory studies. Immunotherapy pathways are on the rise in all study types, and the wnt/β-catenin pathway is increasingly identified as a novel target.
Topics: Adult; Humans; Animals; Mice; Molecular Targeted Therapy; beta Catenin; Mutation; Glioma; Brain Neoplasms; Oligodendroglioma; Isocitrate Dehydrogenase
PubMed: 37445633
DOI: 10.3390/ijms241310456 -
Clinical Neurology and Neurosurgery Aug 2022High-grade gliomas cause cognitive impairment in those who suffer from them. However, there is a lack of precise data describing the cognitive deficit that occurs in... (Review)
Review
INTRODUCTION
High-grade gliomas cause cognitive impairment in those who suffer from them. However, there is a lack of precise data describing the cognitive deficit that occurs in this population, which would allow to better focus neuropsychological evaluations and make better clinical decisions in favor of the patient's recovery and quality of life. For this purpose, a systematic review of the literature was carried out to search for studies on neurocognitive alterations in patients with malignant brain tumors.
MATERIALS AND METHODS
The systematic review was conducted under the criteria of the PRISMA guideline for reporting systematic review and meta-analysis reports, with a search of the PubMed database (MEDLINE). Descriptive and analytical observational studies between 2015 and 2020 were considered.
RESULTS
506 articles were identified, of which 16 met the inclusion criteria and were selected in the qualitative synthesis and described in the manuscript.
CONCLUSIONS
High-grade gliomas cause significant alterations in cognitive domains such as language, attention, memory, empathy and executive functions. However, more studies focused on describing the neuropsychological alterations in this population are needed in order to make better clinical treatment and rehabilitation decisions.
Topics: Adult; Brain Neoplasms; Cognition; Cognitive Dysfunction; Glioma; Humans; Observational Studies as Topic; Quality of Life
PubMed: 35662053
DOI: 10.1016/j.clineuro.2022.107296 -
Journal of Controlled Release :... Sep 2022Gliomas are the deadliest of all primary brain tumors, and they constitute a serious global health problem. MicroRNAs (miRNAs) are gene expression regulators associated... (Review)
Review
Gliomas are the deadliest of all primary brain tumors, and they constitute a serious global health problem. MicroRNAs (miRNAs) are gene expression regulators associated with glioma pathogenesis. Thus, miRNAs represent potential therapeutic agents for treating gliomas. However, miRNAs have not been established as part of the regular clinical armamentarium. This systemic review evaluates current molecular and pre-clinical studies with the aim of defining the most appealing supramolecular platform for administering therapeutic miRNA to patients with gliomas. An integrated analysis suggested that cationic lipid nanoparticles, functionalized with octa-arginine peptides, represent a potentially specific, practical, non-invasive intervention for treating gliomas. This supramolecular platform allows loading both hydrophilic (miRNA) and hydrophobic (anti-tumor drugs, like temozolomide) molecules. This systemic review is the first to describe miRNA delivery systems targeted to gliomas that integrate several types of molecules as active ingredients. Further experimental validation is warranted to confirm the practical value of miRNA delivery systems.
Topics: Arginine; Brain Neoplasms; Glioma; Humans; Liposomes; MicroRNAs; Nanoparticles; Peptides; Temozolomide
PubMed: 35905783
DOI: 10.1016/j.jconrel.2022.07.027 -
BMC Cancer Jun 2020Whilst epidemiological studies have provided evidence of associations between certain risk factors and glioma onset, inferring causality has proven challenging. Using... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Whilst epidemiological studies have provided evidence of associations between certain risk factors and glioma onset, inferring causality has proven challenging. Using Mendelian randomization (MR), we assessed whether associations of 36 reported glioma risk factors showed evidence of a causal relationship.
METHODS
We performed a systematic search of MEDLINE from inception to October 2018 to identify candidate risk factors and conducted a meta-analysis of two glioma genome-wide association studies (5739 cases and 5501 controls) to form our exposure and outcome datasets. MR analyses were performed using genetic variants to proxy for candidate risk factors. We investigated whether risk factors differed by subtype diagnosis (either glioblastoma (n = 3112) or non-glioblastoma (n = 2411)). MR estimates for each risk factor were determined using multiplicative random effects inverse-variance weighting (IVW). Sensitivity analyses investigated potential pleiotropy using MR-Egger regression, the weighted median estimator, and the mode-based estimator. To increase power, trait-specific polygenic risk scores were used to test the association of a genetically predicated increase in each risk factor with glioma onset.
RESULTS
Our systematic search identified 36 risk factors that could be proxied using genetic variants. Using MR, we found evidence that four genetically predicted traits increased risk of glioma, glioblastoma or non-glioblastoma: longer leukocyte telomere length, liability to allergic disease, increased alcohol consumption and liability to childhood extreme obesity (> 3 standard deviations from the mean). Two traits decreased risk of non-glioblastoma cancers: increased low-density lipoprotein cholesterol (LDLc) and triglyceride levels. Our findings were similar across sensitivity analyses that made allowance for pleiotropy (genetic confounding).
CONCLUSIONS
Our comprehensive investigation provides evidence of a causal link between both genetically predicted leukocyte telomere length, allergic disease, alcohol consumption, childhood extreme obesity, and LDLc and triglyceride levels, and glioma. The findings from our study warrant further research to uncover mechanisms that implicate these traits in glioma onset.
Topics: Cholesterol, LDL; Genetic Predisposition to Disease; Genome-Wide Association Study; Glioma; Humans; Hypersensitivity; Mendelian Randomization Analysis; Obesity; Polymorphism, Single Nucleotide; Risk Factors; Telomere Homeostasis; Triglycerides
PubMed: 32493226
DOI: 10.1186/s12885-020-06967-2 -
Acta Neurochirurgica Jan 2017Fluorescence-guided surgery (FGS) is a technique used to enhance visualization of tumor margins in order to increase the extent of tumor resection in glioma surgery. In... (Review)
Review
BACKGROUND
Fluorescence-guided surgery (FGS) is a technique used to enhance visualization of tumor margins in order to increase the extent of tumor resection in glioma surgery. In this paper, we systematically review all clinically tested fluorescent agents for application in FGS for glioma and all preclinically tested agents with the potential for FGS for glioma.
METHODS
We searched the PubMed and Embase databases for all potentially relevant studies through March 2016. We assessed fluorescent agents by the following outcomes: rate of gross total resection (GTR), overall and progression-free survival, sensitivity and specificity in discriminating tumor and healthy brain tissue, tumor-to-normal ratio of fluorescent signal, and incidence of adverse events.
RESULTS
The search strategy resulted in 2155 articles that were screened by titles and abstracts. After full-text screening, 105 articles fulfilled the inclusion criteria evaluating the following fluorescent agents: 5-aminolevulinic acid (5-ALA) (44 studies, including three randomized control trials), fluorescein (11), indocyanine green (five), hypericin (two), 5-aminofluorescein-human serum albumin (one), endogenous fluorophores (nine) and fluorescent agents in a pre-clinical testing phase (30). Three meta-analyses were also identified.
CONCLUSIONS
5-ALA is the only fluorescent agent that has been tested in a randomized controlled trial and results in an improvement of GTR and progression-free survival in high-grade gliomas. Observational cohort studies and case series suggest similar outcomes for FGS using fluorescein. Molecular targeting agents (e.g., fluorophore/nanoparticle labeled with anti-EGFR antibodies) are still in the pre-clinical phase, but offer promising results and may be valuable future alternatives.
Topics: Aminolevulinic Acid; Animals; Brain Neoplasms; Fluorescent Dyes; Glioma; Humans; Neurosurgical Procedures; Photosensitizing Agents
PubMed: 27878374
DOI: 10.1007/s00701-016-3028-5 -
JAMA Neurology Oct 2014Over the past 4 years, our understanding of gliomagenesis and the practice of neuro-oncology have been radically changed by the discovery of mutations involving the... (Review)
Review
IMPORTANCE
Over the past 4 years, our understanding of gliomagenesis and the practice of neuro-oncology have been radically changed by the discovery of mutations involving the isocitrate dehydrogenase (IDH) enzymes. IDH mutation has been found to be an inciting event in gliomagenesis and to have a profound effect on the molecular and genetic route of oncogenic progression and on clinical outcome.
OBJECTIVES
To review the role of IDH enzymes in normal physiology and describe aberrations in the IDH pathway that are associated with gliomagenesis, to review recent work examining the effect of IDH-targeted therapy in cancers harboring IDH mutation, and to determine how this work has expanded our understanding of the role of IDH in the development and progression of glioma.
EVIDENCE REVIEW
A systematic review of the literature dating from 2008, when IDH mutation was discovered to be clinically significant in glioma, to 2013 was performed using the PubMed database. The following search terms were used: IDH, IDH1, IDH2, and isocitrate dehydrogenase, in conjunction with glioma or leukemia. The search was limited to articles published in English. Further hand searching was performed using a review of the pertinent references from the identified publications. All identified original articles were investigated for content and critiqued by Z.T. and S.D.
FINDINGS
IDH mutation is an early event in gliomagenesis and has significant implications for glioma progression and tumor behavior. Early evidence suggests that IDH may be a therapeutic target in IDH-mutant gliomas.
CONCLUSIONS AND RELEVANCE
IDH mutation is a central and defining event in the development and progression of glioma and may be a key target for future therapies for these types of neoplasms.
Topics: Brain Neoplasms; Disease Progression; Glioma; Humans; Isocitrate Dehydrogenase; Mutation
PubMed: 25155243
DOI: 10.1001/jamaneurol.2014.1205 -
Cellular and Molecular Neurobiology Nov 2023Liquid biopsy research on Low-Grade gliomas (LGG) has remained less conspicuous than that on other malignant brain tumors. Reliable serum markers would be precious for... (Review)
Review
Liquid biopsy research on Low-Grade gliomas (LGG) has remained less conspicuous than that on other malignant brain tumors. Reliable serum markers would be precious for diagnosis, follow- up and treatment. We propose a clinical utility score (CUS) for biomarkers in LGG that mirrors their clinical usefulness. We conducted a PRISMA review. We examined each biomarker classifying them by CUS and Level of Evidence (LOE). We identified four classes of biomarkers: (1). Circulating protein-(a) vitronectin discriminates LGG from HGG (Sn:98%, Sp:91%, CUS: 3, LOE: III), (b) CTLA-4 discriminates LGG from HGG, (cutoff: 220.43 pg/ml, Sn: 82%, Sp: 78%, CUS:3, LOE:III), (c) pre-operative TGF b1 predict astrocytoma (cutoff: 2.52 ng/ml, Sn: 94.9%, Sp: 100%, CUS:3, LOE:VI). (2). micro-RNA (miR)-(a) miR-16 discriminates between WHO IV and WHO II and III groups (AUC = 0.98, CUS:3, LOE: III), (b) miR-454-3p is higher in HGG than in LGG (p = 0.013, CUS:3, LOE: III), (c) miR-210 expression is related to WHO grades (Sn 83.2%, Sp 94.3%, CUS: 3, LOE: III). (3). Circulating DNA-(a) IDH1R132H mutation detected in plasma by combined COLD and digital PCR (Sn: 60%, Sp: 100%, CUS: 3, LOE: III). 4. Exosomes-(a) SDC1 serum levels could discriminate GBM from LGG (Sn: 71%, Sp: 91%, CUS: 2C, LOE: VI). Our investigation showed that miRs appear to have the highest clinical utility. The LOE of the studies assessed is generally low. A combined approach between different biomarkers and traditional diagnostics may be considered. We identified four main classes of biomarkers produced by LGG. We examined each biomarker, classifying them by clinical utility score (CUS) and level of evidence (LOE). Micro-RNA (miRs) appears to have the highest CUS and LOE.
Topics: Humans; Glioma; Brain Neoplasms; Biomarkers, Tumor; Liquid Biopsy; MicroRNAs; Neoplasm Grading
PubMed: 37704931
DOI: 10.1007/s10571-023-01406-9 -
International Journal of Molecular... Feb 2022Glioblastoma (GBM) is the most common and malignant tumour of the central nervous system. Recent appreciation of the heterogeneity amongst these tumours not only changed... (Review)
Review
Glioblastoma (GBM) is the most common and malignant tumour of the central nervous system. Recent appreciation of the heterogeneity amongst these tumours not only changed the WHO classification approach, but also created the need for developing novel and personalised therapies. This systematic review aims to highlight recent advancements in understanding the molecular pathogenesis of the GBM and discuss related novel treatment targets. A systematic search of the literature in the PubMed library was performed following the PRISMA guidelines for molecular pathogenesis and therapeutic advances. Original and meta-analyses studies from the last ten years were reviewed using pre-determined search terms. The results included articles relevant to GBM development focusing on the aberrancy in cell signaling pathways and intracellular events. Theragnostic targets and vaccination to treat GBM were also explored. The molecular pathophysiology of GBM is complex. Our systematic review suggests targeting therapy at the stemness, p53 mediated pathways and immune modulation. Exciting novel immune therapy involving dendritic cell vaccines, B-cell vaccines and viral vectors may be the future of treating GBM.
Topics: Adult; Brain Neoplasms; Glioblastoma; Humans; Signal Transduction
PubMed: 35269752
DOI: 10.3390/ijms23052607 -
Journal of Neuro-oncology Aug 2022Gliosarcomas are extremely rare malignant brain tumors, which can be classified as primary gliosarcoma (PGS) if the tumors arise de novo or secondary gliosarcoma (SGS)... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Gliosarcomas are extremely rare malignant brain tumors, which can be classified as primary gliosarcoma (PGS) if the tumors arise de novo or secondary gliosarcoma (SGS) in patients who had previously been treated for glioblastoma. Given their rarity, it is unclear if PGS is clinically and genetically different from SGS. This meta-analysis aimed to investigate the clinicopathological features, prognostic survivals, and molecular profiles of these rare tumors.
METHODS
We searched PubMed and Web of Science for relevant studies. Odds ratio (OR), hazard ratio (HR), and their 95% confidence intervals (CI) were pooled using the random-effect model.
RESULTS
We included eight studies with 239 PGS and 79 SGS for meta-analyses. Compared to PGS, SGS occurred at a younger age and had lower rates of gross total resection and radiation therapy. Bevacizumab was more commonly administered in SGS. SGS patients had a significantly worse PFS (HR 0.60; 95% CI 0.40-0.89) and OS (HR 0.46; 95% CI 0.31-0.68) in comparison to PGS. The incidences of EGFR mutation, IDH mutation, and MGMT methylation were not statistically different between PGS and SGS.
CONCLUSION
Our results demonstrated that PGS and SGS had distinct clinicopathological profiles and prognoses but shared similar genetic profiles. This study facilitates our understanding of how these two malignant brain tumors behave clinically, but future studies will be required to elucidate the genetic pathways of PGS and SGS.
Topics: Brain Neoplasms; Glioblastoma; Gliosarcoma; Humans; Mutation; Prognosis
PubMed: 35768633
DOI: 10.1007/s11060-022-04057-w -
Cancer Control : Journal of the Moffitt... 2022Pediatric gliomas represent the most common brain tumor in children and its higher grades are associated with higher recurrence and low survival rate. All therapeutic...
INTRODUCTION
Pediatric gliomas represent the most common brain tumor in children and its higher grades are associated with higher recurrence and low survival rate. All therapeutic modalities are reported to be insufficient to achieve satisfactory result, with follow-up treatment such as adjuvant radiotherapy and chemotherapy recommended to increase survival and hinder tumor progression. Nimotuzumab is a monoclonal antibody that acts as an inhibitor of epidermal growth factor receptor found on the surface of glioma cells and had been studied for its usage in pediatric gliomas in recent years.
METHODS
A systematic review is performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. A through literature search was conducted on PubMed, Scopus, Cochrane, and clinicaltrials.gov database. Articles were selected systematically based on the PRISMA protocol and reviewed completely. The relevant data were summarized and discussed. We measured overall survival, progression-free survival, and adverse Events (AE) for nimotuzumab usage as an adjunct therapy in pediatric glioma population.
RESULT
From 5 studies included for qualitative analysis, 151 patients are included with overall survival (OS) that vary from 3.2-22.8 mo, progression-free survival (PFS) from 1.7-21.6 mo, and relatively low serious adverse events (0-21) are recorded. Follow-up ranged from 2.4-66 mo with four studies reporting diffuse intrinsic pontine glioma (DIPG) patients and only one study reporting nimotuzumab usage in pediatric high-grade glioma (HGG) patients with better outcome in HGG patients than DIPG.
CONCLUSION
There are no significant differences in the PFS and OS of nimotuzumab as adjunct therapy for pediatric compared to result of standard therapy in majority of previous studies. There were also no differences in the AE of nimotuzumab for pediatric glioma between studies, and low event of serious adverse events indicating its safety. But still there is an evidence of possible benefit of nimotuzumab as adjuvant therapy in pediatric glioma. We recommend further studies with larger number of patients that may lead to possibly different results. There should also be more studies with better level of evidence to further validate the effect of nimozutumab on pediatric glioma.
Topics: Adolescent; Antibodies, Monoclonal, Humanized; Brain Neoplasms; Brain Stem Neoplasms; Child; Combined Modality Therapy; Glioma; Humans
PubMed: 35191733
DOI: 10.1177/10732748211053927