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Nitric Oxide : Biology and Chemistry Sep 2023Gliomas represent the most prevalent form of brain tumors, among which glioblastomas are the most malignant subtype. Despite advances in comprehending their biology and... (Review)
Review
INTRODUCTION
Gliomas represent the most prevalent form of brain tumors, among which glioblastomas are the most malignant subtype. Despite advances in comprehending their biology and treatment strategies, median survival remains disappointingly low. Inflammatory processes involving nitric oxide (NO), critically contribute to glioma formation. The inducible isoform of NO synthase (iNOS) is highly overexpressed in gliomas and has been linked to resistance against temozolomide (TMZ) treatment, neoplastic transformation, and modulation of immune response. While both in vitro and in vivo studies showed the potential of iNOS inhibitors as effective treatments for gliomas, no clinical trials on gliomas have been published. This review aims to summarize the available evidence regarding iNOS as a target for glioma treatment, focusing on clinically relevant data.
METHODS
Following PRISMA guidelines, we conducted a systematic review by searching PubMed/Medline, and Embase databases in May 2023. We included studies that investigated the impact of NOS inhibitors on glioma cells using L-NMMA, CM544, PBN, 1400W or l-NAME either alone or combined with TMZ. We extracted data on the NOS inhibitor used, subtype, study setting, animal model or cell lines employed, obtained results, and safety profile. Our inclusion criteria encompassed original articles in English or Spanish, studies with an untreated control group, and a primary outcome focused on the biological effects on glioma cells.
RESULTS
Out of 871 articles screened from the aforementioned databases, 37 reports were assessed for eligibility. After excluding studies that did not utilize glioma cells or address the designated outcome, 11 original articles satisfied the inclusion and exclusion criteria. Although no NOS inhibitor has been tested in a published clinical trial, three inhibitors have been evaluated using in vivo models of intracranial gliomas. l-NAME, 1400W, and CM544 were tested in vitro. Co-administration of l-NAME, or CM544 with TMZ showed superior results in vitro compared to individual agent testing.
CONCLUSION
Glioblastomas remain a challenging therapeutic target. iNOS inhibitors exhibit substantial potential as treatment options for oncologic lesions, and they have demonstrated a safe toxicity profile in humans for other pathological conditions. Research endeavors should be focused on investigating their potential effects on brain tumors.
Topics: Animals; Humans; Glioblastoma; NG-Nitroarginine Methyl Ester; Glioma; Temozolomide; Brain Neoplasms; Enzyme Inhibitors; Nitric Oxide Synthase; Nitric Oxide
PubMed: 37279819
DOI: 10.1016/j.niox.2023.06.002 -
Journal of Neuro-oncology Aug 2023To synthesize the evidence on the impact on progression-free survival (PFS) and overall survival (OS) of supramaximal resection (SMR) over gross total resection (GTR) in... (Meta-Analysis)
Meta-Analysis Review
Supramaximal versus gross total resection in Glioblastoma, IDH wild-type and Astrocytoma, IDH-mutant, grade 4, effect on overall and progression free survival: systematic review and meta-analysis.
PURPOSE
To synthesize the evidence on the impact on progression-free survival (PFS) and overall survival (OS) of supramaximal resection (SMR) over gross total resection (GTR) in Glioblastoma, IDH wild-type and Astrocytoma, IDH-mutant, grade 4 (Glioblastoma).
METHODS
The PubMed, Scopus, Web of Science, Ovid and Cochrane databases were systematically searched (up to November 30, 2022). Studies reporting OS and PFS on adult humans with a suspected Glioblastoma, treated either with a SMR or GTR were included. Hazard ratios were estimated for each study and treatment effects were calculated through DerSimonian and Laird random effects models.
RESULTS
The literature search yielded 14 studies published between 2013 and 2022, enrolling a total of 6779 patients. Analysis of the included studies reveals significantly better clinical outcomes favoring SMR over GTR in terms of PFS (HR 0.67; p = 0.0007), and OS (HR 0.7; p = 0.0001).
CONCLUSION
Glioblastoma, IDH wild-type and Astrocytoma, IDH-mutant, grade 4, are aggressive tumors with a very short long-term OS. SMR is an effective therapeutic approach contributing to increased PFS and OS in patients with this catastrophic disease.
Topics: Adult; Humans; Astrocytoma; Brain Neoplasms; Disease-Free Survival; Glioblastoma; Progression-Free Survival; Retrospective Studies
PubMed: 37561356
DOI: 10.1007/s11060-023-04409-0 -
Journal of Neurosurgery. Pediatrics Dec 2023Diffuse intrinsic pontine gliomas (DIPGs) are aggressive and malignant tumors of the brainstem. Stereotactic biopsy can obtain molecular and genetic information for...
OBJECTIVE
Diffuse intrinsic pontine gliomas (DIPGs) are aggressive and malignant tumors of the brainstem. Stereotactic biopsy can obtain molecular and genetic information for diagnostic and potentially therapeutic purposes. However, there is no consensus on the safety of biopsy or effect on survival. The authors aimed to characterize neurological risk associated with and the effect of stereotactic biopsy on survival among patients with DIPGs.
METHODS
A systematic review was performed in accordance with PRISMA guidelines to identify all studies examining pediatric patients with DIPG who underwent stereotactic biopsy. The search strategy was deployed in PubMed, Embase, and Scopus. The quality of studies was assessed using the Grading of Recommendations, Assessment, Development and Evaluation system, and risk of bias was evaluated with the Cochrane Risk of Bias in Nonrandomized Studies-of Interventions tool. Bibliographic, demographic, clinical, and outcome data were extracted from studies meeting inclusion criteria.
RESULTS
Of 2634 resultant articles, 13 were included, representing 192 patients undergoing biopsy. The weighted mean age at diagnosis was 7.5 years (range 0.5-17 years). There was an overall neurosurgical complication rate of 13.02% (25/192). The most common neurosurgical complication was cranial nerve palsy (4.2%, 8/192), of which cranial nerve VII was the most common (37.5%, 3/8). The second most common complication was perioperative hemorrhage (3.6%, 7/192), followed by hemiparesis (2.1%, 4/192), speech disorders (1.6%, 3/192) such as dysarthria and dysphasia, and movement disorders (1.0%, 2/192). Hydrocephalus was less commonly reported (0.5%, 1/192), and there were no complications relating to wound infection/dehiscence (0%, 0/192) or CSF leak (0%, 0/192). No mortality was specifically attributed to biopsy. Diagnostic yield of biopsy revealed a weighted mean of 97.4% (range 91%-100%). Of the studies reporting survival data, 37.6% (32/85) of patients died within the study follow-up period (range 2 weeks-48 months). The mean overall survival in patients undergoing biopsy was 9.73 months (SD 0.68, median 10 months, range 6-13 months).
CONCLUSIONS
Children with DIPGs undergoing biopsy have mild to moderate rates of neurosurgical complications and no excessive morbidity. With reasonably acceptable surgical risk and high diagnostic yield, stereotactic biopsy of DIPGs can allow for characterization of patient-specific molecular and genetic features that may influence prognosis and the development of future therapeutic strategies.
Topics: Humans; Child; Infant; Child, Preschool; Adolescent; Glioma; Diffuse Intrinsic Pontine Glioma; Brain Stem Neoplasms; Biopsy
PubMed: 37724839
DOI: 10.3171/2023.7.PEDS22462 -
Clinical Neurology and Neurosurgery Aug 2023A variety of dietary adjuncts are known to affect the pathophysiology of glioma, making them a potential therapeutic adjunct to standard of care. We systematically... (Review)
Review
BACKGROUND
A variety of dietary adjuncts are known to affect the pathophysiology of glioma, making them a potential therapeutic adjunct to standard of care. We systematically reviewed clinical outcomes in glioma patients treated with one or more nutritional adjunct and/or an antimetabolite drug.
METHODOLOGY
A systematic review of the literature following PRISMA guidelines was performed using Pubmed from inception till February 2023. In total, 22 manuscripts on nutrition representing 828 patients were included in the review. Statistical analyses were performed to compare the outcomes of various adjuncts.
RESULTS
The median overall survival (OS) increased for newly diagnosed (21 months) and recurrent cases (10 months) when compared to historical data. For newly diagnosed cases, a ketogenic diet had the highest median OS of all the adjuncts (42.6 months) while in recurrent cases, a low copper diet coupled with 1 g penicillamine had the highest median OS (18.5 months). However, no statistically significant difference was observed in OS or progression-free survival (PFS) of newly diagnosed or recurrent gliomas.
CONCLUSION
While nutritional adjuncts may offer a therapeutic benefit in the treatment of glioma, more human subject research is needed to derive meaningful conclusions.
Topics: Humans; Neoplasm Recurrence, Local; Glioma; Progression-Free Survival; Brain Neoplasms
PubMed: 37390567
DOI: 10.1016/j.clineuro.2023.107853 -
Brain Tumor Pathology Jul 2023The WHO 2021 classification defines IDH wild type (IDHw) histologically lower-grade glioma (hLGG) as molecular glioblastoma (mGBM) if TERT promoter mutation (pTERTm),... (Meta-Analysis)
Meta-Analysis Review
The WHO 2021 classification defines IDH wild type (IDHw) histologically lower-grade glioma (hLGG) as molecular glioblastoma (mGBM) if TERT promoter mutation (pTERTm), EGFR amplification or chromosome seven gain and ten loss aberrations are indicated. We systematically reviewed articles of IDHw hLGGs studies (49 studies, N = 3748) and meta-analyzed mGBM prevalence and overall survival (OS) according to the PRISMA statement. mGBM rates in IDHw hLGG were significantly lower in Asian regions (43.7%, 95% confidence interval [CI: 35.8-52.0]) when compared to non-Asian regions (65.0%, [CI: 52.9-75.4]) (P = 0.005) and were significantly lower in fresh-frozen specimen when compared to formalin-fixed paraffin-embedded samples (P = 0.015). IDHw hLGGs without pTERTm rarely expressed other molecular markers in Asian studies when compared to non-Asian studies. Patients with mGBM had significantly longer OS times when compared to histological GBM (hGBM) (pooled hazard ratio (pHR) 0.824, [CI: 0.694-0.98], P = 0.03)). In patients with mGBM, histological grade was a significant prognostic factor (pHR 1.633, [CI: 1.09-2.447], P = 0.018), as was age (P = 0.001) and surgical extent (P = 0.018). Although bias risk across studies was moderate, mGBM with grade II histology showed better OS rates when compared to hGBM.
Topics: Humans; Glioblastoma; Brain Neoplasms; Mutation; Isocitrate Dehydrogenase; Telomerase; Glioma; Prognosis
PubMed: 37212969
DOI: 10.1007/s10014-023-00463-8 -
International Immunopharmacology May 2024Glioma is a primary tumor originating from the central nervous system, and despite ongoing efforts to improve treatment, its overall survival rate remains low. There are... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Glioma is a primary tumor originating from the central nervous system, and despite ongoing efforts to improve treatment, its overall survival rate remains low. There are a limited number of reports regarding the clinical grading, prognostic impact, and utility of chemokines. Therefore, conducting a meta-analysis is necessary to obtain convincing and conclusive results.
METHODS
A comprehensive literature search was conducted using various databases, including PubMed, Web of Science, The Cochrane Library, Embase, Ovid Medline, CNKI, Wanfang Database, VIP, and CBM. The search encompassed articles published from the inception of the databases until March 2024. The estimated odds ratio (ORs), standard mean difference (SMDs), and hazard ratio (HR) with their corresponding 95% confidence intervals (95% CI) were calculated to assess the predictive value of chemokine and receptor levels in glioma risk. Additionally, heterogeneity tests and bias tests were performed to evaluate the reliability of the findings.
RESULTS
This meta-analysis included a total of 36 studies, involving 2,480 patients diagnosed with glioma. The results revealed a significant association between the expression levels of CXCR4 (n = 8; OR = 22.28; 95 % CI = 11.47-43.30; p = 0.000), CXCL12 (n = 4; OR = 10.69; 95 % CI = 7.03-16.24; p = 0.000), CCL2 (n = 6; SMD = -0.83; 95 % CI = -0.98--0.67; p = 0.000), CXCL8 (n = 3; SMD = 0.75; 95 % CI = 0.47-1.04; p = 0.000), CXCR7 (n = 3; OR = 20.66; 95 % CI = 10.20-41.82; p = 0.000), CXCL10 (n = 2; SMD = 3.27; 95 % CI = 2.91-3.62; p = 0.000) and the risk of glioma. Additionally, a significant correlation was observed between CXCR4 (n = 8; OR = 4.39; 95 % CI = 3.04-6.32; p = 0.000), (n = 6; SMD = 1.37; 95 % CI = 1.09-1.65; p = 0.000), CXCL12 (n = 6; OR = 6.30; 95 % CI = 3.87-10.25; p = 0.000), (n = 5; ES = 2.25; 95 % CI = 1.15-3.34; p = 0.041), CCL2 (n = 3; OR = 9.65; 95 % CI = 4.55-20.45; p = 0.000), (n = 4; SMD = -1.47; 95 % CI = -1.68--1.26; p = 0.000), and CCL18 (n = 3; SMD = 1.62; 95 % CI = 1.30-1.93; p = 0.000) expression levels and high-grade glioma (grades 3-4). Furthermore, CXCR4 (HR = 2.38, 95 % CI = 1.66-3.40; p = 0.000) exhibited a strong correlation with poor overall survival (OS) rates in glioma patients.
CONCLUSION
The findings of this study showed a robust association between elevated levels of CXCR4, CXCL12, CCL2, CXCL8, CXCL10 and CXCR7 with a higher risk of glioma. Furthermore, the WHO grading system was validated by the strong correlation shown between higher expression of CXCR4, CXCL12, CCL2, and CCL18 and WHO high-grade gliomas (grades 3-4). Furthermore, the results of the meta-analysis suggested that CXCR4 might be a helpful biomarker for predicting the worse prognosis of glioma patients.
Topics: Humans; Glioma; Prognosis; Brain Neoplasms; Biomarkers, Tumor; Chemokines; Receptors, Chemokine; Receptors, CXCR4
PubMed: 38631221
DOI: 10.1016/j.intimp.2024.112047 -
Journal of Neuro-oncology Sep 2023This review compares reirradiation (reRT), systemic therapy and combination therapy (reRT & systemic therapy) with regards to overall survival (OS), progression-free... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
This review compares reirradiation (reRT), systemic therapy and combination therapy (reRT & systemic therapy) with regards to overall survival (OS), progression-free survival (PFS), adverse effects (AEs) and quality of life (QoL) in patients with recurrent high-grade glioma (rHGG).
METHODS
A search was performed on PubMed, Scopus, Embase and CENTRAL. Studies reporting OS, PFS, AEs and/or QoL and encompassing the following groups were included; reirradiation vs systemic therapy, combination therapy vs systemic therapy, combination therapy vs reRT, and bevacizumab-based combination therapy vs reRT with/without non-bevacizumab-based systemic therapy. Meta-analyses were performed utilising a random effects model. Certainty of evidence was assessed using GRADE.
RESULTS
Thirty-one studies (three randomised, twenty-eight non-randomised) comprising 2084 participants were included. In the combination therapy vs systemic therapy group, combination therapy improved PFS (HR 0.57 (95% CI 0.41-0.79); low certainty) and OS (HR 0.73 (95% CI 0.56-0.95); low certainty) and there was no difference in grade 3 + AEs (RR 1.03 (95% CI 0.57-1.86); very low certainty). In the combination therapy vs reRT group, combination therapy improved PFS (HR 0.52 (95% CI 0.38-0.72); low certainty) and OS (HR 0.69 (95% CI 0.52-0.93); low certainty). In the bevacizumab-based combination therapy vs reRT with/without non-bevacizumab-based systemic therapy group, adding bevacizumab improved PFS (HR 0.46 (95% CI 0.27-0.77); low certainty) and OS (HR 0.42 (95% CI 0.24-0.72; low certainty) and reduced radionecrosis (RR 0.17 (95% CI 0.06-0.48); low certainty).
CONCLUSIONS
Combination therapy may improve OS and PFS with acceptable toxicities in patients with rHGG compared to reRT or systemic therapy alone. Particularly, combining bevacizumab with reRT prophylactically reduces radionecrosis.
REGISTRATION
CRD42022291741.
Topics: Humans; Bevacizumab; Quality of Life; Re-Irradiation; Neoplasm Recurrence, Local; Glioma; Randomized Controlled Trials as Topic
PubMed: 37733174
DOI: 10.1007/s11060-023-04441-0 -
International Journal of Molecular... Mar 2024Glioblastoma multiforme (GBM) is the most common and malignant type of primary brain tumor in adults. Despite important advances in understanding the molecular... (Review)
Review
Glioblastoma multiforme (GBM) is the most common and malignant type of primary brain tumor in adults. Despite important advances in understanding the molecular pathogenesis and biology of this tumor in the past decade, the prognosis for GBM patients remains poor. GBM is characterized by aggressive biological behavior and high degrees of inter-tumor and intra-tumor heterogeneity. Increased understanding of the molecular and cellular heterogeneity of GBM may not only help more accurately define specific subgroups for precise diagnosis but also lay the groundwork for the successful implementation of targeted therapy. Herein, we systematically review the key achievements in the understanding of GBM molecular pathogenesis, mechanisms, and biomarkers in the past decade. We discuss the advances in the molecular pathology of GBM, including genetics, epigenetics, transcriptomics, and signaling pathways. We also review the molecular biomarkers that have potential clinical roles. Finally, new strategies, current challenges, and future directions for discovering new biomarkers and therapeutic targets for GBM will be discussed.
Topics: Humans; Glioblastoma; Pathology, Molecular; Brain Neoplasms; Biomarkers; Gene Expression Profiling; Biomarkers, Tumor
PubMed: 38474286
DOI: 10.3390/ijms25053040 -
Journal of Magnetic Resonance Imaging :... Nov 2023As an important genomic marker for oligodendrogliomas, early determination of 1p/19q co-deletion status is critical for guiding therapy and predicting prognosis in... (Review)
Review
As an important genomic marker for oligodendrogliomas, early determination of 1p/19q co-deletion status is critical for guiding therapy and predicting prognosis in patients with glioma. The purpose of this study is to systematically review the literature concerning the magnetic resonance imaging (MRI) with artificial intelligence (AI) methods for predicting 1p/19q co-deletion status in glioma. PubMed, Scopus, Embase, and IEEE Xplore were searched in accordance with the Preferred Reporting Items for systematic reviews and meta-analyses guidelines. Methodological quality of studies was assessed according to the Quality Assessment of Diagnostic Accuracy Studies-2. Finally, 28 studies were included in the quantitative analysis. Diagnostic test accuracy reached an area under the ROC curve of 0.71-0.98 were reported in 24 studies. The remaining four studies with no available AUC provided an accuracy of 0.75-0. 89. The included studies varied widely in terms of imaging sequences, input features, and modeling methods. The current review highlighted that integrating MRI with AI technology is a potential tool for determination 1p/19q status pre-operatively and noninvasively, which can possibly help clinical decision-making. However, the reliability and feasibility of this approach still need to be further validated and improved in a real clinical setting. EVIDENCE LEVEL: 2. TECHNICAL EFFICACY: 2.
Topics: Humans; Artificial Intelligence; Brain Neoplasms; Reproducibility of Results; Chromosome Deletion; Glioma; Isocitrate Dehydrogenase; Oligodendroglioma; Mutation
PubMed: 37083159
DOI: 10.1002/jmri.28737 -
Frontiers in Surgery 2023Augmented reality (AR) is increasingly being explored in neurosurgical practice. By visualizing patient-specific, three-dimensional (3D) models in real time, surgeons... (Review)
Review
BACKGROUND
Augmented reality (AR) is increasingly being explored in neurosurgical practice. By visualizing patient-specific, three-dimensional (3D) models in real time, surgeons can improve their spatial understanding of complex anatomy and pathology, thereby optimizing intra-operative navigation, localization, and resection. Here, we aimed to capture applications of AR in glioma surgery, their current status and future potential.
METHODS
A systematic review of the literature was conducted. This adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. PubMed, Embase, and Scopus electronic databases were queried from inception to October 10, 2022. Leveraging the Population, Intervention, Comparison, Outcomes, and Study design (PICOS) framework, study eligibility was evaluated in the qualitative synthesis. Data regarding AR workflow, surgical application, and associated outcomes were then extracted. The quality of evidence was additionally examined, using hierarchical classes of evidence in neurosurgery.
RESULTS
The search returned 77 articles. Forty were subject to title and abstract screening, while 25 proceeded to full text screening. Of these, 22 articles met eligibility criteria and were included in the final review. During abstraction, studies were classified as "development" or "intervention" based on primary aims. Overall, AR was qualitatively advantageous, due to enhanced visualization of gliomas and critical structures, frequently aiding in maximal safe resection. Non-rigid applications were also useful in disclosing and compensating for intra-operative brain shift. Irrespective, there was high variance in registration methods and measurements, which considerably impacted projection accuracy. Most studies were of low-level evidence, yielding heterogeneous results.
CONCLUSIONS
AR has increasing potential for glioma surgery, with capacity to positively influence the onco-functional balance. However, technical and design limitations are readily apparent. The field must consider the importance of consistency and replicability, as well as the level of evidence, to effectively converge on standard approaches that maximize patient benefit.
PubMed: 37671031
DOI: 10.3389/fsurg.2023.1245851