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BioMedicine 2023Glioblastoma multiforme, commonly known as GBM or glioblastoma is a grade IV astrocytoma. Brain tumors are difficult to treat and lead to poor prognosis and survival in... (Review)
Review
BACKGROUND
Glioblastoma multiforme, commonly known as GBM or glioblastoma is a grade IV astrocytoma. Brain tumors are difficult to treat and lead to poor prognosis and survival in patients. Gliomas are categorized into four different grades among which GBM is the worst grade primary brain tumor with a survival of less than a year. The genomic heterogeneity of the brain tumor results in different profiles for patients diagnosed with glioblastoma. Precision medicine focuses on this specific tumor type and suggests specialized treatment for better prognosis and overall survival (OS).
PURPOSE
With the recent advancements in Genome-Wide Studies (GWS) and various characterizations of brain tumors based on genetic, transcriptomic, proteomic, epigenetic, and metabolomics, this review discusses the advancements and opportunities of precision medicine therapeutics, drugs, and diagnosis methods based on the different profiles of glioblastoma.
METHODS
This review has exhaustively surveyed several pieces of works from various literature databases.
CONCLUSION
It is evident that most primary brain tumors including glioblastoma require specific and precision therapeutics for better prognosis and OS. In present and future, molecular understanding and discovering specific therapies are essential for treatment in the field of neurooncology.
PubMed: 37937301
DOI: 10.37796/2211-8039.1403 -
International Journal of Molecular... Oct 2023Glioblastoma (GBM) is characterized by aggressive growth and high rates of recurrence. Despite the advancements in conventional therapies, the prognosis for GBM patients... (Review)
Review
Glioblastoma (GBM) is characterized by aggressive growth and high rates of recurrence. Despite the advancements in conventional therapies, the prognosis for GBM patients remains poor. Immunotherapy has recently emerged as a potential treatment option. The aim of this systematic review is to assess the current strategies and future perspectives of the GBM immunotherapy strategies. A systematic search was conducted across major medical databases (PubMed, Embase, and Cochrane Library) up to 3 September 2023. The search strategy utilized relevant Medical Subject Heading (MeSH) terms and keywords related to "glioblastomas," "immunotherapies," and "treatment." The studies included in this review consist of randomized controlled trials, non-randomized controlled trials, and cohort studies reporting on the use of immunotherapies for the treatment of gliomas in human subjects. A total of 1588 papers are initially identified. Eligibility is confirmed for 752 articles, while 655 are excluded for various reasons, including irrelevance to the research topic (627), insufficient method and results details (12), and being case-series or cohort studies (22), systematic literature reviews, or meta-analyses (3). All the studies within the systematic review were clinical trials spanning from 1995 to 2023, involving 6383 patients. Neuro-oncology published the most glioma immunotherapy-related clinical trials (15/97, 16%). Most studies were released between 2018 and 2022, averaging nine publications annually during this period. Adoptive cellular transfer chimeric antigen receptor (CAR) T cells were the primary focus in 11% of the studies, with immune checkpoint inhibitors (ICIs), oncolytic viruses (OVs), and cancer vaccines (CVs) comprising 26%, 12%, and 51%, respectively. Phase-I trials constituted the majority at 51%, while phase-III trials were only 7% of the total. Among these trials, 60% were single arm, 39% double arm, and one multi-arm. Immunotherapies were predominantly employed for recurrent GBM (55%). The review also revealed ongoing clinical trials, including 9 on ICIs, 7 on CVs, 10 on OVs, and 8 on CAR T cells, totaling 34 trials, with phase-I trials representing the majority at 53%, and only one in phase III. Overcoming immunotolerance, stimulating robust tumor antigen responses, and countering immunosuppressive microenvironment mechanisms are critical for curative GBM immunotherapy. Immune checkpoint inhibitors, such as PD-1 and CTLA-4 inhibitors, show promise, with the ongoing research aiming to enhance their effectiveness. Personalized cancer vaccines, especially targeting neoantigens, offer substantial potential. Oncolytic viruses exhibited dual mechanisms and a breakthrough status in the clinical trials. CAR T-cell therapy, engineered for specific antigen targeting, yields encouraging results, particularly against IL13 Rα2 and EGFRvIII. The development of second-generation CAR T cells with improved specificity exemplifies their adaptability.
Topics: Humans; Glioblastoma; Immune Checkpoint Inhibitors; Cancer Vaccines; Neoplasm Recurrence, Local; Glioma; Immunotherapy; Immunotherapy, Adoptive; Brain Neoplasms; Tumor Microenvironment
PubMed: 37894718
DOI: 10.3390/ijms242015037 -
Journal of Neurological Surgery Reports Oct 2023Despite advances in multimodal oncologic therapies and molecular genetics, overall survival (OS) in patients with high-grade astrocytomas remains poor. We present an...
Despite advances in multimodal oncologic therapies and molecular genetics, overall survival (OS) in patients with high-grade astrocytomas remains poor. We present an illustrative case and systematic review of rare, predominantly extra-axial World Health Organization (WHO) grade 4 astrocytomas located within the cerebellopontine angle (CPA) and explore the impact of anatomic location on diagnosis, management, and outcomes. A systematic review of adult patients with predominantly extra-axial WHO grade 4 CPA astrocytomas was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines through December 2022. Eighteen articles were included comprising 21 astrocytomas: 13 exophytic tumors arising from the cerebellopontine parenchyma and 8 tumors originating from a cranial nerve root entry zone. The median OS was 15 months with one-third of cases demonstrating delayed diagnosis. Gross total resection, molecular genetic profiling, and use of ancillary treatment were low. We report the only patient with an integrated isocitrate dehydrogenase 1 (IDH-1) mutant diagnosis, who, after subtotal resection and chemoradiation, remains alive at 40 months without progression. The deep conical-shaped corridor and abundance of eloquent tissue of the CPA significantly limits both surgical resection and utility of device-based therapies in this region. Prompt diagnosis, molecular characterization, and systemic therapeutic advances serve as the predominant means to optimize survival for patients with rare skull base astrocytomas.
PubMed: 37854309
DOI: 10.1055/a-2172-7770 -
BMC Cancer Oct 2023Extracellular vesicles (EVs) hold promise for improving our understanding of radiotherapy response in glioblastoma due to their role in intercellular communication...
Shooting the messenger: a systematic review investigating extracellular vesicle isolation and characterisation methods and their influence on understanding extracellular vesicles-radiotherapy interactions in glioblastoma.
BACKGROUND
Extracellular vesicles (EVs) hold promise for improving our understanding of radiotherapy response in glioblastoma due to their role in intercellular communication within the tumour microenvironment (TME). However, methodologies to study EVs are evolving with significant variation within the EV research community.
METHODS
We conducted a systematic review to critically appraise EV isolation and characterisation methodologies and how this influences our understanding of the findings from studies investigating radiotherapy and EV interactions in glioblastoma. 246 articles published up to 24/07/2023 from PubMed and Web of Science were identified using search parameters related to radiotherapy, EVs, and glioblastoma. Two reviewers evaluated study eligibility and abstracted data.
RESULTS
In 26 articles eligible for inclusion (16 investigating the effects of radiotherapy on EVs, five investigating the effect of EVs on radiation response, and five clinical studies), significant heterogeneity and frequent omission of key characterisation steps was identified, reducing confidence that the results are related to EVs and their cargo as opposed to co-isolated bioactive molecules. However, the results are able to clearly identify interactions between EVs and radiotherapy bi-directionally within different cell types within the glioblastoma TME. These interactions facilitate transferable radioresistance and oncogenic signalling, highlighting that EVs are an important component in the variability of glioblastoma radiotherapy response.
CONCLUSIONS
Future multi-directional investigations interrogating the whole TME are required to improve subsequent clinical translation, and all studies should incorporate up to date controls and reporting requirements to increase the validity of their findings. This would be facilitated by increased collaboration between less experienced and more experienced EV research groups.
Topics: Humans; Glioblastoma; Signal Transduction; Cell Communication; Extracellular Vesicles; Tumor Microenvironment
PubMed: 37798728
DOI: 10.1186/s12885-023-11437-6 -
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 -
Journal of Translational Medicine Aug 2023Accurately predicting the outcome of isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) remains hitherto challenging. This study aims to Construct and Validate...
BACKGROUND
Accurately predicting the outcome of isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) remains hitherto challenging. This study aims to Construct and Validate a Robust Prognostic Model for IDH wild-type GBM (COVPRIG) for the prediction of overall survival using a novel metric, gene-gene (G × G) interaction, and explore molecular and cellular underpinnings.
METHODS
Univariate and multivariate Cox regression of four independent trans-ethnic cohorts containing a total of 800 samples. Prediction efficacy was comprehensively evaluated and compared with previous models by a systematic literature review. The molecular underpinnings of COVPRIG were elucidated by integrated analysis of bulk-tumor and single-cell based datasets.
RESULTS
Using a Cox-ph model-based method, six of the 93,961 G × G interactions were screened to form an optimal combination which, together with age, comprised the COVPRIG model. COVPRIG was designed for RNA-seq and microarray, respectively, and effectively identified patients at high risk of mortality. The predictive performance of COVPRIG was satisfactory, with area under the curve (AUC) ranging from 0.56 (CGGA693, RNA-seq, 6-month survival) to 0.79 (TCGA RNAseq, 18-month survival), which can be further validated by decision curves. Nomograms were constructed for individual risk prediction for RNA-seq and microarray-based cohorts, respectively. Besides, the prognostic significance of COVPRIG was also validated in GBM including the IDH mutant samples. Notably, COVPRIG was comprehensively evaluated and externally validated, and a systemic review disclosed that COVPRIG outperformed current validated models with an integrated discrimination improvement (IDI) of 6-16%. Moreover, integrative bioinformatics analysis predicted an essential role of METTL1 neural-progenitor-like (NPC-like) malignant cell in driving unfavorable outcome.
CONCLUSION
This study provided a powerful tool for the outcome prediction for IDH wild-type GBM, and preliminary molecular underpinnings for future research.
Topics: Humans; Glioblastoma; Isocitrate Dehydrogenase; Brain Neoplasms; Prognosis; Nomograms; Methyltransferases
PubMed: 37553713
DOI: 10.1186/s12967-023-04382-2 -
Journal of Nanobiotechnology Aug 2023Lymph nodes targeted drug delivery is an attractive approach to improve cancer immunotherapy outcomes. Currently, the depth of understanding of afferent and efferent... (Review)
Review
Lymph nodes targeted drug delivery is an attractive approach to improve cancer immunotherapy outcomes. Currently, the depth of understanding of afferent and efferent arms in brain immunity reveals the potential clinical applications of lymph node targeted drug delivery in brain tumors, e.g., glioblastoma. In this work, we systematically reviewed the microenvironment of glioblastoma and its structure as a basis for potential immunotherapy, including the glial-lymphatic pathway for substance exchange, the lymphatic drainage pathway from meningeal lymphatic vessels to deep cervical lymph nodes that communicate intra- and extracranial immunity, and the interaction between the blood-brain barrier and effector T cells. Furthermore, the carriers designed for lymph nodes targeted drug delivery were comprehensively summarized. The challenges and opportunities in developing a lymph nodes targeted delivery strategy for glioblastoma using nanotechnology are included at the end.
Topics: Humans; Glioblastoma; Lymph Nodes; Brain Neoplasms; Brain; Drug Delivery Systems; Tumor Microenvironment
PubMed: 37542241
DOI: 10.1186/s12951-023-02011-0 -
Journal of Neuro-oncology Aug 2023Tumor Treating Fields (TTFields) therapy, an electric field-based cancer treatment, became FDA-approved for patients with newly diagnosed glioblastoma (GBM) in 2015... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
Tumor Treating Fields (TTFields) therapy, an electric field-based cancer treatment, became FDA-approved for patients with newly diagnosed glioblastoma (GBM) in 2015 based on the randomized controlled EF-14 study. Subsequent approvals worldwide and increased adoption over time have raised the question of whether a consistent survival benefit has been observed in the real-world setting, and whether device usage has played a role.
METHODS
We conducted a literature search to identify clinical studies evaluating overall survival (OS) in TTFields-treated patients. Comparative and single-cohort studies were analyzed. Survival curves were pooled using a distribution-free random-effects method.
RESULTS
Among nine studies, seven (N = 1430 patients) compared the addition of TTFields therapy to standard of care (SOC) chemoradiotherapy versus SOC alone and were included in a pooled analysis for OS. Meta-analysis of comparative studies indicated a significant improvement in OS for patients receiving TTFields and SOC versus SOC alone (HR: 0.63; 95% CI 0.53-0.75; p < 0.001). Among real-world post-approval studies, the pooled median OS was 22.6 months (95% CI 17.6-41.2) for TTFields-treated patients, and 17.4 months (95% CI 14.4-21.6) for those not receiving TTFields. Rates of gross total resection were generally higher in the real-world setting, irrespective of TTFields use. Furthermore, for patients included in studies reporting data on device usage (N = 1015), an average usage rate of ≥ 75% was consistently associated with prolonged survival (p < 0.001).
CONCLUSIONS
Meta-analysis of comparative TTFields studies suggests survival may be improved with the addition of TTFields to SOC for patients with newly diagnosed GBM.
Topics: Humans; Glioblastoma; Temozolomide; Electric Stimulation Therapy; Brain Neoplasms; Combined Modality Therapy
PubMed: 37493865
DOI: 10.1007/s11060-023-04348-w -
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 -
Brain and Behavior Aug 2023Secondary tumoral parkinsonism is a rare phenomenon that develops as a direct or indirect result of brain neoplasms or related conditions. (Review)
Review
Tumoral parkinsonism-Parkinsonism secondary to brain tumors, paraneoplastic syndromes, intracranial malformations, or oncological intervention, and the effect of dopaminergic treatment.
INTRODUCTION
Secondary tumoral parkinsonism is a rare phenomenon that develops as a direct or indirect result of brain neoplasms or related conditions.
OBJECTIVES
The first objective was to explore to what extent brain neoplasms, cavernomas, cysts, paraneoplastic syndromes (PNSs), and oncological treatment methods cause parkinsonism. The second objective was to investigate the effect of dopaminergic therapy on the symptomatology in patients with tumoral parkinsonism.
METHODS
A systematic literature review was conducted in the databases PubMed and Embase. Search terms like "secondary parkinsonism," "astrocytoma," and "cranial irradiation" were used. Articles fulfilling inclusion criteria were included in the review.
RESULTS
Out of 316 identified articles from the defined database search strategies, 56 were included in the detailed review. The studies, which were mostly case reports, provided research concerning tumoral parkinsonism and related conditions. It was found that various types of primary brain tumors, such as astrocytoma and meningioma, and more seldom brain metastases, can cause tumoral parkinsonism. Parkinsonism secondary to PNSs, cavernomas, cysts, as well as oncological treatments was reported. Twenty-five of the 56 included studies had tried initiating dopaminergic therapy, and of these 44% reported no, 48% low to moderate, and 8% excellent effect on motor symptomatology.
CONCLUSION
Brain neoplasms, PNSs, certain intracranial malformations, and oncological treatments can cause parkinsonism. Dopaminergic therapy has relatively benign side effects and may relieve motor and nonmotor symptomatology in patients with tumoral parkinsonism. Dopaminergic therapy, particularly levodopa, should therefore be considered in patients with tumoral parkinsonism.
Topics: Humans; Parkinsonian Disorders; Brain Neoplasms; Dopamine; Astrocytoma; Paraneoplastic Syndromes; Meningeal Neoplasms; Cysts
PubMed: 37433071
DOI: 10.1002/brb3.3151