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Biomaterials Science Feb 2023Glioblastoma (GBM) is an aggressive malignant cancer associated with bleak prognosis and high mortality. The current standard of care for GBM is maximum surgical... (Meta-Analysis)
Meta-Analysis Review
Glioblastoma (GBM) is an aggressive malignant cancer associated with bleak prognosis and high mortality. The current standard of care for GBM is maximum surgical resection plus radiotherapy and temozolomide (TMZ) chemotherapy. The blood brain barrier (BBB) remains the main obstacle for chemotherapy and severely limits the choice of therapeutic agents. Local treatment allows drugs to circumvent the BBB and reduces systemic side effects. Despite much research effort, to date, no drug delivery system (DDS) designed to be directly injected into brain tumors has been clinically approved, and a systematic overview of the progress in this field, or lack thereof, is missing. In this review, a systematic search of pre-clinical literature was conducted which resulted in 36 original articles on injectable DDS for local treatment of GBM which met the inclusion criteria. A wide range of injectable DDS have been developed and tested pre-clinically which include nanoparticles, liposomes, microspheres, hydrogels and others. -Analyses of the included studies showed that, overall, local administration of injectable DDS was beneficial to increase the animal's survival time. Finally, this review summarized the therapeutic effect after local treatment and discussed the shortcomings of the experimental setting in studies.
Topics: Animals; Glioblastoma; Temozolomide; Drug Delivery Systems; Brain Neoplasms; Liposomes
PubMed: 36655634
DOI: 10.1039/d2bm01534j -
Current Issues in Molecular Biology Oct 2022Both (isocitrate dehydrogenase 1) and (isocitrate dehydrogenase 2) mutations play a vital role in the development of gliomas through disruption of normal cellular...
Both (isocitrate dehydrogenase 1) and (isocitrate dehydrogenase 2) mutations play a vital role in the development of gliomas through disruption of normal cellular metabolic processes. Here we describe a case of a patient with an IDH-mutant astrocytoma, in which both and mutations were detected within the same tumour. The patient remains disease-free, nine and a half years after her initial diagnosis. Interrogation of cancer genomic databases and a systematic review was undertaken, demonstrating the rarity of the co-occurrence of and mutations in a variety of cancer types, and in glioma specifically. Due to the favourable outcome observed in this patient, the potential effect of concurrent and mutations on survival was also investigated.
PubMed: 36286062
DOI: 10.3390/cimb44100348 -
European Journal of Cancer (Oxford,... Nov 2022Grading and classification of IDH-mutant astrocytomas has shifted from solely histology towards histology combined with molecular diagnostics. In this systematic review,... (Review)
Review
BACKGROUND
Grading and classification of IDH-mutant astrocytomas has shifted from solely histology towards histology combined with molecular diagnostics. In this systematic review, we give an overview of all currently known clinically relevant molecular markers within IDH-mutant astrocytomas grade 2 to 4.
METHODS
A literature search was performed in five electronic databases for English original papers on patient outcome with respect to a molecular marker as determined by DNA/RNA sequencing, micro-arrays, or DNA methylation profiling in IDH-mutant astrocytomas grade 2 to 4. Papers were included if molecular diagnostics were performed on tumour tissue of at least 15 IDH-mutant astrocytoma patients, and if the investigated molecular markers were not limited to the diagnostic markers MGMT, ATRX, TERT, and/or TP53.
RESULTS
The literature search identified 4508 unique articles, published between August 2012 and December 2021, of which ultimately 44 articles were included. Numerous molecular markers from these papers were significantly correlated to patient outcome. The associations between patient outcome and non-canonical IDH mutations, PI3K mutations, high expression of MSH2, high expression of RAD18, homozygous deletion of CDKN2A/B, amplification of PDGFRA, copy number neutral loss of chromosomal arm 17p, loss of chromosomal arm 19q, the G-CIMP-low DNA methylation cluster, high total CNV, and high tumour mutation burden were confirmed in multiple studies.
CONCLUSIONS
Multiple genetic and epigenetic markers are associated with survival in IDH-mutant astrocytoma patients. Commonly affected are the RB signalling pathway, the RTK-PI3K-mTOR signalling pathway, genomic stability markers, and (epigenetic) gene regulation.
Topics: Astrocytoma; Biomarkers, Tumor; Brain Neoplasms; DNA; DNA-Binding Proteins; Homozygote; Humans; Isocitrate Dehydrogenase; Lymphoma, Follicular; MutS Homolog 2 Protein; Mutation; Phosphatidylinositol 3-Kinases; Sequence Deletion; TOR Serine-Threonine Kinases; Ubiquitin-Protein Ligases
PubMed: 36152406
DOI: 10.1016/j.ejca.2022.08.016 -
Medicine Jun 2021Glioblastoma multiforme (GBM) owes an ominous prognosis: its mean overall survival is 14 months. The extent of surgical resection (ESR) highlights among factors in which... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Glioblastoma multiforme (GBM) owes an ominous prognosis: its mean overall survival is 14 months. The extent of surgical resection (ESR) highlights among factors in which an association has been found to a somewhat better prognosis. However, the association between greater ESR and prolonged overall (OS) survival is not a constant finding nor a proven cause-and-effect phenomenon. To our objective is to establish the strength of association between ESR and OS in patients with GBM through a systematic review and meta-analysis.
METHODS
In accordance with PRISMA-P recommendations, we conducted a systematic literature search; we included studies with adult patients who had undergone craniotomy for GBM. Our primary outcome is overall postoperative survival at 12 and 24 months. We reviewed 180 studies, excluded 158, and eliminated 8; 14 studies that suited our requirements were analyzed.
RESULTS
The initial level of evidence of all studies is low, and it may be degraded to very low according to GRADE criteria because of design issues. The definition of different levels of the extent of resection is heterogeneous and poorly defined. We found a great amount of variation in the methodology of the operation and the adjuvant treatment protocol. The combined result for relative risk (RR) for OS for 12 months analysis is 1.25 [95% confidence interval (95% CI) 1.14-1.36, P < .01], absolute risk reduction (ARR) of 15.7% (95% CI 11.9-19.4), relative risk reduction (RRR) of 0.24 (95% CI 0.18-0.31), number needed to treat (NNT) 6; for 24-month analysis RR is 1.59 (95% CI 1.11-2.26, P < .01) ARR of 11.5% (95% CI 7.7-15.1), relative risk reduction (RRR) of 0.53 (95% CI 0.33-0.76), (NNT) 9. In each term analysis, the proportion of alive patients who underwent more extensive resection is significantly higher than those who underwent subtotal resection.
CONCLUSION
Our results sustain a weak but statistically significant association between the ESR and OS in patients with GBM obtained from observational studies with a very low level of evidence according to GRADE criteria. As a consequence, any estimate of effect is very uncertain. Current information cannot sustain a cause-and-effect relationship between these variables.
Topics: Brain Neoplasms; Glioblastoma; Humans; Neurosurgical Procedures; Observational Studies as Topic; Prognosis; Progression-Free Survival; Risk Assessment
PubMed: 34160432
DOI: 10.1097/MD.0000000000026432 -
Glia Aug 2019Gliomas are a heterogenous group of malignant primary brain tumors that arise from glia cells or their progenitors and rely on accurate diagnosis for prognosis and...
Gliomas are a heterogenous group of malignant primary brain tumors that arise from glia cells or their progenitors and rely on accurate diagnosis for prognosis and treatment strategies. Although recent developments in the molecular biology of glioma have improved diagnosis, classical histological methods and biomarkers are still being used. The glial fibrillary acidic protein (GFAP) is a classical marker of astrocytoma, both in clinical and experimental settings. GFAP is used to determine glial differentiation, which is associated with a less malignant tumor. However, since GFAP is not only expressed by mature astrocytes but also by radial glia during development and neural stem cells in the adult brain, we hypothesized that GFAP expression in astrocytoma might not be a direct indication of glial differentiation and a less malignant phenotype. Therefore, we here review all existing literature from 1972 up to 2018 on GFAP expression in astrocytoma patient material to revisit GFAP as a marker of lower grade, more differentiated astrocytoma. We conclude that GFAP is heterogeneously expressed in astrocytoma, which most likely masks a consistent correlation of GFAP expression to astrocytoma malignancy grade. The GFAP positive cell population contains cells with differences in morphology, function, and differentiation state showing that GFAP is not merely a marker of less malignant and more differentiated astrocytoma. We suggest that discriminating between the GFAP isoforms GFAPδ and GFAPα will improve the accuracy of assessing the differentiation state of astrocytoma in clinical and experimental settings and will benefit glioma classification.
Topics: Animals; Astrocytoma; Biomarkers, Tumor; Central Nervous System Neoplasms; Glial Fibrillary Acidic Protein; Humans; Protein Isoforms
PubMed: 30667110
DOI: 10.1002/glia.23594 -
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 -
Spine Oct 2009Clinically based systematic review. (Review)
Review
STUDY DESIGN
Clinically based systematic review.
OBJECTIVE
To define optimal clinical care for primary intramedullary spinal cord tumors using a systematic review with expert opinion.
METHODS
Focused questions on the treatment of primary intramedullary spinal cord tumors were refined by a panel of spine oncology surgeons, medical and radiation oncologist. Keyword were searched through Medline database and pertinent abstracts and manuscripts obtained. The quality of literature was rated as high, moderate, low, or very low. Using the GRADE evidence based review system the proposed questions were answered using the literature review and expert opinion. These treatment recommendations were then rated as either strong or weak based on the quality of evidence and clinical expertise.
RESULTS
The literature searches revealed low and very low quality evidence with no prospective or randomized studies. The MEDLINE search engine returned 9000 articles which was restricted to articles about human subjects and written in the English language. The subsequent search resulted in a return of: "spinal cord tumor" (5053), "ependymoma" (580), "astrocytoma" (420), and "glioma" (235) articles. Seventeen articles referenced timing of surgical intervention and symptomatology for intramedullary spinal cord tumors. One hundred fifty-eight chemotherapy and 183 radiation therapy articles for intramedullary spinal cord tumors were reviewed.
CONCLUSION
The most important factor in determining the IMSCT patient's long-term neurologic and functional outcome after surgery is the patient's preoperative neurologic status. However, this must be taken in the context of the underlying tumor histology. Therefore, resection is reserved for progressive neurologic decline and serial monitoring for asymptomatic individuals. Adjuvant therapy is an option for high grade astrocytomas (WHO grades 3-4).
Topics: Glioma; Humans; Radiotherapy, Adjuvant; Severity of Illness Index; Spinal Cord Neoplasms; Treatment Outcome
PubMed: 19829279
DOI: 10.1097/BRS.0b013e3181b95c6f -
Glioblastoma research 2006-2010: pattern of citation and systematic review of highly cited articles.Clinical Neurology and Neurosurgery Nov 2012High and continuously increasing research activity related to different aspects of pathogenesis, epidemiology, diagnosis and treatment of glioblastoma has been performed... (Meta-Analysis)
Meta-Analysis Review
High and continuously increasing research activity related to different aspects of pathogenesis, epidemiology, diagnosis and treatment of glioblastoma has been performed between 2006 and 2010. Different measures of impact, visibility and quality of published research are available, each with its own pros and cons. For this review, article citation rate was chosen. Articles were identified through systematic search of the abstract database PubMed followed by analyses of total number of citations and proportion of highly cited articles, arbitrarily defined as those with ≥100, 50-99, and 25-49 citations, respectively (citation database Scopus). Overall 5831 scientific articles on the subject were published during this time period. 1.5% of all articles accumulated at least 100 citations, 3.2% were cited between 50 and 99 times, and 7.5% were cited between 25 and 49 times. Among the 10 most cited articles, 7 reported on genomic analyses, molecular subclasses of glioblastoma and/or stem cells. Overall, 18 randomized clinical trials were published between 2006 and 2010, including those with phase II design. Thirty-nine percent of them accumulated at least 50 citations and 72% were cited at least 25 times. In general, annual citation rate appeared to gradually increase during the first 2-3 years after publication before reaching high levels. A large variety of preclinical and clinical topics achieved at least 25 citations. However, areas such as quality of life, side effects, and end-of-life care were underrepresented. Efforts to increase their visibility might be warranted.
Topics: Animals; Bibliometrics; Brain Neoplasms; Clinical Trials, Phase II as Topic; Genomics; Glioblastoma; Humans; Journal Impact Factor; Meta-Analysis as Topic; Neoplastic Stem Cells; Publishing; Randomized Controlled Trials as Topic
PubMed: 22516416
DOI: 10.1016/j.clineuro.2012.03.049 -
Neurosurgical Review Oct 2022Little is known about the survivorship of glioblastoma (GBM) patients in low- and middle-income countries (LMICs). We hypothesize that this would be lower than published... (Meta-Analysis)
Meta-Analysis
Little is known about the survivorship of glioblastoma (GBM) patients in low- and middle-income countries (LMICs). We hypothesize that this would be lower than published figures for high-income countries due to cancer health disparities. We performed a systematic review and meta-analysis to estimate the median overall survival (OS) of GBM in LMICs and determine factors affecting OS. A systematic review of 12 electronic databases was conducted according to PRISMA guidelines to identify studies of newly diagnosed adult GBM patients done in countries classified as LMIC by the World Bank (WB) from inception to December 2020. Random effects meta-analysis of collected median overall survival data was done. Subgroup analysis and meta-regression were done to determine if WB income classification (WBIC), start year of recruitment (pre- or post-popularization of the standard Stupp protocol), and treatment modality affected OS. The 24 articles (n = 2,552) that met the inclusion criteria were from 8 low-middle income and upper-middle income countries, with 0 articles from low-income countries. Random effects analysis of 24 studies showed a pooled median OS of 14.17 months (95% CI 12.90-15.43, I = 79). Subgroup analysis showed a significant difference (p < 0.05) in the pooled median OS of studies predating Stupp protocol (12.54 mo, 95% CI 11.13-13.96, I = 80%; n = 1027) and studies postdating Stupp protocol (15.64 mo, 95% CI 13.58-17.69, I = 77; n = 1412). Subgroup analysis of WBIC and treatment modalities did not show significant differences. Published data on the survivorship of GBM patients in LMICs is sparse, highlighting the need for good quality pragmatic studies from LMICs. The limited evidence suggests improving survivorship after introduction of the Stupp protocol.
Topics: Adult; Developing Countries; Glioblastoma; Humans; Income
PubMed: 36044130
DOI: 10.1007/s10143-022-01844-x -
Chinese Clinical Oncology Aug 2022Glioma is the most common intracranial primary malignant tumor, and half of it is glioblastoma. Despite receiving the standard treatment, the prognosis of glioblastoma...
BACKGROUND AND OBJECTIVE
Glioma is the most common intracranial primary malignant tumor, and half of it is glioblastoma. Despite receiving the standard treatment, the prognosis of glioblastoma is still poor and its 5-year survival rate in China is only 9%. In addition, new targeted and immunotherapy therapy and tumor treating fields also have certain curative effects on glioblastoma. To help clinicians and patients make appropriate treatment based on current evidences, we summarize the Chinese guidelines on the management of glioma and review the recent management of glioblastoma.
METHODS
We systematically searched PubMed, China National Knowledge Infrastructure (CNKI) and Wanfang databases to retrieve guidelines on glioma in China published from the establishment of the database to 24 January 2022. We performed a narrative review of current clinical study related to the management of glioblastoma, especially in the surgical, targeted and immunotherapy therapy and tumor treating fields.
KEY CONTENT AND FINDINGS
In this review, 19 guidelines were included, including 8 subclassified as the guideline, 8 subclassified as the consensus and 3 subclassified as the standard. Two guidelines reported the contents of the system search, 4 guidelines are updated, and 9 guidelines reported the source of funding. At present, most clinical trials on the immune and targeted therapy of glioblastoma are ongoing in China.
CONCLUSIONS
China's guidelines still need to be improved in terms of preciseness, applicability and editorial independence. In addition, the cooperation in clinical research of glioblastoma in multiple centers needs to be strengthened in China.
Topics: Brain Neoplasms; China; Databases, Factual; Glioblastoma; Glioma; Humans
PubMed: 36098100
DOI: 10.21037/cco-22-18