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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 -
Child's Nervous System : ChNS :... May 2023Medulloblastoma (MB) is the most common malignant pediatric brain tumor. The mainstay of treatment is maximum surgical resection and craniospinal radiation, which may be... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Medulloblastoma (MB) is the most common malignant pediatric brain tumor. The mainstay of treatment is maximum surgical resection and craniospinal radiation, which may be followed by chemotherapy. The debilitating effect of the tumor and the intensive treatment approaches in MB lead to long-term neuropsychological, physical, and chronic medical problems. We conducted a systematic review to assess the quality of life (QoL) in the long-term survivors of MB and the factors leading to compromised QoL.
METHODS
We utilized the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for our review. A comprehensive literature search was performed using PubMed, Cochrane Library, Digital Commons Network, and Wiley Online Library databases to search for articles having quality of life, medulloblastoma, and pediatric survivors in title or abstract. We removed duplicates and screened through titles, and full texts. Twelve articles were included in our study. Articles using and reporting all domains of PaedsQL were included in the meta-analysis. The PaedsQL scores of survivors and their caregivers were compared. Subgroup analysis was conducted for craniospinal and proton radiotherapy groups.
RESULTS
As compared to other posterior fossa tumors, MB survivors have the lowest QoL scores. There is a difference in the perception of QoL of survivors between caregivers and survivors themselves with survivors rating themselves higher in several domains. The overall PaedsQL scores were significantly different for both groups (p < 0.001). Subgroup analysis showed that the difference between those who were treated with craniospinal or proton radiation was not significant (p = 0.76). For the subscales, physical (p = 0.005), psychosocial (p = 0.0003), and school (p = 0.03) perceptions were significantly different for the survivors and their caregivers; however, psychosocial (p = 0.80) and emotional (p = 0.93) scales were not different for the survivors or caregivers. Patient characteristics related to a worse QoL included disease severity, metastatic disease, lesser family income, smaller current ventricle size, need for permanent hydrocephalus treatment, and lesser age at diagnosis.
CONCLUSION
An analysis of various studies, using different measures of QoL, concludes that QoL is compromised in all pediatric survivors of MB; however, the perception of QoL of the survivors is better than objective or caretaker-rated QoL.
Topics: Child; Humans; Medulloblastoma; Quality of Life; Protons; Brain Neoplasms; Survivors; Cerebellar Neoplasms
PubMed: 36826523
DOI: 10.1007/s00381-023-05886-4 -
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 -
Insights Into Imaging Jun 2022Molecular characterization plays a crucial role in glioma classification which impacts treatment strategy and patient outcome. Dynamic susceptibility contrast (DSC) and... (Review)
Review
BACKGROUND
Molecular characterization plays a crucial role in glioma classification which impacts treatment strategy and patient outcome. Dynamic susceptibility contrast (DSC) and dynamic contrast enhanced (DCE) perfusion imaging have been suggested as methods to help characterize glioma in a non-invasive fashion. This study set out to review and meta-analyze the evidence on the accuracy of DSC and/or DCE perfusion MRI in predicting IDH genotype and 1p/19q integrity status.
METHODS
After systematic literature search on Medline, EMBASE, Web of Science and the Cochrane Library, a qualitative meta-synthesis and quantitative meta-analysis were conducted. Meta-analysis was carried out on aggregated AUC data for different perfusion metrics.
RESULTS
Of 680 papers, twelve were included for the qualitative meta-synthesis, totaling 1384 patients. It was observed that CBV, ktrans, Ve and Vp values were, in general, significantly higher in IDH wildtype compared to IDH mutated glioma. Meta-analysis comprising of five papers (totaling 316 patients) showed that the AUC of CBV, ktrans, Ve and Vp were 0.85 (95%-CI 0.75-0.93), 0.81 (95%-CI 0.74-0.89), 0.84 (95%-CI 0.71-0.97) and 0.76 (95%-CI 0.61-0.90), respectively. No conclusive data on the prediction of 1p/19q integrity was available from these studies.
CONCLUSIONS
Future research should aim to predict 1p/19q integrity based on perfusion MRI data. Additionally, correlations with other clinically relevant outcomes should be further investigated, including patient stratification for treatment and overall survival.
PubMed: 35670981
DOI: 10.1186/s13244-022-01230-7 -
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 -
Frontiers in Nutrition 2022Gliomas are the most common primary intracranial tumors in adults. Inappropriate dietary habits are thought to be a risk factor for most human cancer, and glioma is no...
BACKGROUND
Gliomas are the most common primary intracranial tumors in adults. Inappropriate dietary habits are thought to be a risk factor for most human cancer, and glioma is no exception. However, the effect of dietary factors on glioma is not clear.
OBJECTIVE
This review aims to quantitatively evaluate the association between various dietary intakes and glioma using a meta-analysis.
METHODS
We searched articles on PubMed, the Cochrane Library, the Web of Science, and EMBASE from their inception until October 11, 2021. According to heterogeneity, the fixed-effects or random-effects model was selected to obtain the relative risk (RR) of merger. Based on the methods described by Greenland and Longnecker, we explored the dose-response relationship between dietary intakes and the risk of glioma. Subgroup analysis, sensitivity analysis, and publication bias were also used.
RESULTS
This study reviewed 33 articles, including 3,606,015 controls and 8,831 patients with glioma. This study included 12 food groups. Compared with the lowest intakes, the highest intakes of tea ( = 0.82, 95%CI:0.71-0.93), total vegetables ( = 0.84, 95%CI: 0.70-1.00), green vegetables ( = 0.80, 95%CI: 0.66-0.98), and orange vegetables ( = 0.79, 95%CI: 0.66-0.96) significantly reduced the risk of glioma, while the highest intakes of grains (RR = 1.39, 95%CI: 1.16-1.66), processed meats (RR = 1.19, 95%CI: 1.00-1.42), and processed fish (RR = 1.37, 95%CI: 1.03-1.84) significantly increased the risk of glioma. The results of subgroup and sensitivity analyses remained unchanged. In the dose-response relationship, only tea was statistically significant. Taking an extra cup of tea every day reduced the risk of glioma by 4%.
CONCLUSIONS
Our analysis suggests that the intakes of tea, total vegetables, green vegetables, and orange vegetables may reduce the risk of glioma, while the intakes of grains, processed meats, and processed fish may increase the risk of glioma. Therefore, the effect of dietary factors on glioma should not be ignored. https://www.crd.york.ac.uk/prospero/, CRD42022296658.
PubMed: 35237646
DOI: 10.3389/fnut.2022.834258 -
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 -
Neuro-oncology Practice Feb 2023Histone deacetylase inhibitors (HDACi) including valproic acid (VPA) have the potential to improve radiotherapy (RT) efficacy and reduce treatment adverse events (AE)...
BACKGROUND
Histone deacetylase inhibitors (HDACi) including valproic acid (VPA) have the potential to improve radiotherapy (RT) efficacy and reduce treatment adverse events (AE) via epigenetic modification and radio-sensitization of neoplastic cells. This systematic review and meta-analysis aimed to assess the efficacy and AE associated with HDACi used as radio-sensitizers in adult solid organ malignancy patients.
METHODS
A systematic review utilized electronic searches of MEDLINE(Ovid), Embase(Ovid), The Cochrane Library, and the International Clinical Trials Registry Platform to identify studies examining the efficacy and AEs associated with HDACi treatment in solid organ malignancy patients undergoing RT. Meta-analysis was performed with overall survival (OS) reported as hazard ratios (HR) as the primary outcome measure. OS reported as median survival difference, and AEs were secondary outcome measures.
RESULTS
Ten studies reporting on the efficacy and/or AEs of HDACi in RT-treated solid organ malignancy patients met inclusion criteria. All included studies focused on HDACi valproic acid (VPA) in high-grade glioma patients, of which 9 studies ( = 6138) evaluated OS and 5 studies ( = 1055) examined AEs. The addition of VPA to RT treatment protocols resulted in improved OS (HR = 0.80, 95% CI 0.67-0.96). No studies focusing on non-glioma solid organ malignancy patients, or non-VPA HDACi met the inclusion criteria for this review.
CONCLUSIONS
This review suggests that glioma patients undergoing RT may experience prolonged survival due to HDACi VPA administration. Further randomized controlled trials are required to validate these findings. Additionally, more research into the use of HDACi radio-adjuvant treatment in non-glioma solid organ malignancies is warranted.
PubMed: 36659976
DOI: 10.1093/nop/npac078