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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 -
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 -
The Cochrane Database of Systematic... Jul 2023Potential benefits of rapamycin or rapalogs for treating people with tuberous sclerosis complex (TSC) have been shown. Currently everolimus (a rapalog) is only approved... (Review)
Review
BACKGROUND
Potential benefits of rapamycin or rapalogs for treating people with tuberous sclerosis complex (TSC) have been shown. Currently everolimus (a rapalog) is only approved for TSC-associated renal angiomyolipoma and subependymal giant cell astrocytoma (SEGA), but not other manifestations of TSC. A systematic review needs to establish evidence for rapamycin or rapalogs for various manifestations in TSC. This is an updated review.
OBJECTIVES
To determine the effectiveness of rapamycin or rapalogs in people with TSC for decreasing tumour size and other manifestations and to assess the safety of rapamycin or rapalogs in relation to their adverse effects.
SEARCH METHODS
We identified relevant studies from the Cochrane-Central-Register-of-Controlled-Trials (CENTRAL), Ovid MEDLINE and ongoing trials registries with no language restrictions. We searched conference proceedings and abstract books of conferences. Date of the last searches: 15 July 2022.
SELECTION CRITERIA
Randomised controlled trials (RCTs) or quasi-RCTs of rapamycin or rapalogs in people with TSC.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data and assessed the risk of bias of each study; a third review author verified the extracted data and risk of bias decisions. We assessed the certainty of the evidence using GRADE.
MAIN RESULTS
The current update added seven RCTs, bringing the total number to 10 RCTs (with 1008 participants aged 3 months to 65 years; 484 males). All TSC diagnoses were by consensus criteria as a minimum. In parallel studies, 645 participants received active interventions and 340 placebo. Evidence is low-to-high certainty and study quality is mixed; mostly a low risk of bias across domains, but one study had a high risk of performance bias (lack of blinding) and three studies had a high risk of attrition bias. Manufacturers of the investigational products supported eight studies. Systemic administration Six studies (703 participants) administered everolimus (rapalog) orally. More participants in the intervention arm reduced renal angiomyolipoma size by 50% (risk ratio (RR) 24.69, 95% confidence interval (CI) 3.51 to 173.41; P = 0.001; 2 studies, 162 participants, high-certainty evidence). In the intervention arm, more participants in the intervention arm reduced SEGA tumour size by 50% (RR 27.85, 95% CI 1.74 to 444.82; P = 0.02; 1 study; 117 participants; moderate-certainty evidence) ,and reported more skin responses (RR 5.78, 95% CI 2.30 to 14.52; P = 0.0002; 2 studies; 224 participants; high-certainty evidence). In one 18-week study (366 participants), the intervention led to 25% fewer seizures (RR 1.63, 95% CI 1.27 to 2.09; P = 0.0001) or 50% fewer seizures (RR 2.28, 95% CI 1.44 to 3.60; P = 0.0004); but there was no difference in numbers being seizure-free (RR 5.30, 95% CI 0.69 to 40.57; P = 0.11) (moderate-certainty evidence). One study (42 participants) showed no difference in neurocognitive, neuropsychiatry, behavioural, sensory and motor development (low-certainty evidence). Total adverse events (AEs) did not differ between groups (RR 1.09, 95% CI 0.97 to 1.22; P = 0.16; 5 studies; 680 participants; high-certainty evidence). However, the intervention group experienced more AEs resulting in withdrawal, interruption of treatment, or reduced dose (RR 2.61, 95% CI 1.58 to 4.33; P = 0.0002; 4 studies; 633 participants; high-certainty evidence and also reported more severe AEs (RR 2.35, 95% CI 0.99 to 5.58; P = 0.05; 2 studies; 413 participants; high-certainty evidence). Topical (skin) administration Four studies (305 participants) administered rapamycin topically. More participants in the intervention arm showed a response to skin lesions (RR 2.72, 95% CI 1.76 to 4.18; P < 0.00001; 2 studies; 187 participants; high-certainty evidence) and more participants in the placebo arm reported a deterioration of skin lesions (RR 0.27, 95% CI 0.15 to 0.49; 1 study; 164 participants; high-certainty evidence). More participants in the intervention arm responded to facial angiofibroma at one to three months (RR 28.74, 95% CI 1.78 to 463.19; P = 0.02) and three to six months (RR 39.39, 95% CI 2.48 to 626.00; P = 0.009; low-certainty evidence). Similar results were noted for cephalic plaques at one to three months (RR 10.93, 95% CI 0.64 to 186.08; P = 0.10) and three to six months (RR 7.38, 95% CI 1.01 to 53.83; P = 0.05; low-certainty evidence). More participants on placebo showed a deterioration of skin lesions (RR 0.27, 95% CI 0.15 to 0.49; P < 0.0001; 1 study; 164 participants; moderate-certainty evidence). The intervention arm reported a higher general improvement score (MD -1.01, 95% CI -1.68 to -0.34; P < 0.0001), but no difference specifically in the adult subgroup (MD -0.75, 95% CI -1.58 to 0.08; P = 0.08; 1 study; 36 participants; moderate-certainty evidence). Participants in the intervention arm reported higher satisfaction than with placebo (MD -0.92, 95% CI -1.79 to -0.05; P = 0.04; 1 study; 36 participants; low-certainty evidence), although again with no difference among adults (MD -0.25, 95% CI -1.52 to 1.02; P = 0.70; 1 study; 18 participants; low-certainty evidence). Groups did not differ in change in quality of life at six months (MD 0.30, 95% CI -1.01 to 1.61; P = 0.65; 1 study; 62 participants; low-certainty evidence). Treatment led to a higher risk of any AE compared to placebo (RR 1.72, 95% CI 1.10, 2.67; P = 0.02; 3 studies; 277 participants; moderate-certainty evidence); but no difference between groups in severe AEs (RR 0.78, 95% CI 0.19 to 3.15; P = 0.73; 1 study; 179 participants; moderate-certainty evidence).
AUTHORS' CONCLUSIONS
Oral everolimus reduces the size of SEGA and renal angiomyolipoma by 50%, reduces seizure frequency by 25% and 50% and implements beneficial effects on skin lesions with no difference in the total number of AEs compared to placebo; however, more participants in the treatment group required a dose reduction, interruption or withdrawal and marginally more experienced serious AEs compared to placebo. Topical rapamycin increases the response to skin lesions and facial angiofibroma, an improvement score, satisfaction and the risk of any AE, but not severe adverse events. With caution regarding the risk of severe AEs, this review supports oral everolimus for renal angiomyolipoma, SEGA, seizure, and skin lesions, and topical rapamycin for facial angiofibroma.
Topics: Adult; Male; Humans; MTOR Inhibitors; Sirolimus; Everolimus; Angiofibroma; Angiomyolipoma; Tuberous Sclerosis; Astrocytoma; Kidney Neoplasms
PubMed: 37432030
DOI: 10.1002/14651858.CD011272.pub3 -
Clinical & Translational Oncology :... Feb 2024Glioblastoma (GBM) constitutes the most common primary brain tumor in adults. The challenges in GBM therapeutics have shed light on zebrafish used as a promising animal... (Review)
Review
Glioblastoma (GBM) constitutes the most common primary brain tumor in adults. The challenges in GBM therapeutics have shed light on zebrafish used as a promising animal model for preclinical GBM xenograft studies without a standardized methodology. This systematic review aims to summarize the advances in zebrafish GBM xenografting, compare research protocols to pinpoint advantages and underlying limitations, and designate the predominant xenografting parameters. Based on the PRISMA checklist, we systematically searched PubMed, Scopus, and ZFIN using the keywords "glioblastoma," "xenotransplantation," and "zebrafish" for papers published from 2005 to 2022, available in English. 46 articles meeting the review criteria were examined for the zebrafish strain, cancer cell line, cell labeling technique, injected cell number, time and site of injection, and maintenance temperature. Our review designated that AB wild-type zebrafish, Casper transparent mutants, transgenic Tg(fli1:EGFP), or crossbreeding of these predominate among the zebrafish strains. Orthotopic transplantation is more commonly employed. A number of 50-100 cells injected at 48 h post-fertilization in high density and low infusion volume is considered as an effective xenografting approach. U87 cells are used for GBM angiogenesis studies, U251 for GBM proliferation studies, and patient-derived xenograft (PDX) to achieve clinical relevance. Gradual acclimatization to 32-33 °C can partly address the temperature differential between the zebrafish and the GBM cells. Zebrafish xenograft models constitute valuable tools for preclinical studies with clinical relevance regarding PDX. The GBM xenografting research requires modification based on the objective of each research team. Automation and further optimization of the protocol parameters could scale up the anticancer drug trials.
Topics: Animals; Humans; Glioblastoma; Transplantation, Heterologous; Zebrafish; Heterografts; Brain Neoplasms; Cell Line, Tumor; Xenograft Model Antitumor Assays; Disease Models, Animal
PubMed: 37400666
DOI: 10.1007/s12094-023-03258-7 -
Neurosurgical Review Jun 2023Glioblastoma (GBM) is the most common and aggressive glioma histological subtype, associated with high disability and poor survival. The etiology of this condition is... (Meta-Analysis)
Meta-Analysis Review
Glioblastoma (GBM) is the most common and aggressive glioma histological subtype, associated with high disability and poor survival. The etiology of this condition is still mostly unknown, and evidence about risk factors is elusive. The aim of this study is to identify modifiable risk factors for GBM. Electronic search was performed by two reviewers independently using the keywords and MeSH terms 'glioblastoma' OR 'glioma' OR 'brain tumor' AND 'risk factor'. The inclusion criteria were (1) observational studies or experimental studies on humans, (2) studies assessing the association between glioblastoma and exposure to modifiable conditions, and (3) studies published in English or Portuguese. Studies on the pediatric population or about exposure to ionizing radiation were excluded. A total of 12 studies were included. Seven were case-control studies, and five were cohort studies. The risk factors assessed included body mass index, alcohol consumption, exposure to magnetic fields, diabetes mellitus type 2 (DM2), and use of non-steroidal anti-inflammatory drugs (NSAID). No significant link was found between GBM incidence and DM2 or magnetic field exposure. On the other hand, higher BMI, alcohol consumption, and NSAID use demonstrated a protective effect on GMB risk. However, given the limited number of studies, it is not possible to obtain a behavioral recommendation; instead, these findings are relevant to guide future basic scientific studies on GBM oncogenesis.
Topics: Humans; Child; Glioblastoma; Risk Factors; Glioma; Brain Neoplasms; Diabetes Mellitus, Type 2; Anti-Inflammatory Agents, Non-Steroidal
PubMed: 37340151
DOI: 10.1007/s10143-023-02051-y -
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 -
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 -
Biochimica Et Biophysica Acta. Reviews... Jul 2023Glioblastoma multiforme (GBM) is an aggressive brain cancer showing poor prognosis. Currently, treatment methods of GBM are limited with adverse outcomes and low... (Review)
Review
Glioblastoma multiforme (GBM) is an aggressive brain cancer showing poor prognosis. Currently, treatment methods of GBM are limited with adverse outcomes and low survival rate. Thus, advancements in the treatment of GBM are of utmost importance, which can be achieved in recent decades. However, despite aggressive initial treatment, most patients develop recurrent diseases, and the overall survival rate of patients is impossible to achieve. Currently, researchers across the globe target signaling events along with tumor microenvironment (TME) through different drug molecules to inhibit the progression of GBM, but clinically they failed to demonstrate much success. Herein, we discuss the therapeutic targets and signaling cascades along with the role of the organoids model in GBM research. Moreover, we systematically review the traditional and emerging therapeutic strategies in GBM. In addition, we discuss the implications of nanotechnologies, AI, and combinatorial approach to enhance GBM therapeutics.
Topics: Humans; Glioblastoma; Signal Transduction; Tumor Microenvironment
PubMed: 37182666
DOI: 10.1016/j.bbcan.2023.188913 -
Annales D'endocrinologie Aug 2023
Topics: Humans; Astrocytoma; Brain Neoplasms; Magnetic Resonance Imaging; Pituitary Gland; Multiple Endocrine Neoplasia Type 1; Male; Adolescent
PubMed: 37169283
DOI: 10.1016/j.ando.2023.04.004 -
World Neurosurgery Jul 2023Glioblastoma is the most common type of malignant glioma and is 1 of the most frequent primary tumors during adult life. The platelet-lymphocyte ratio (PLR) has been... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Glioblastoma is the most common type of malignant glioma and is 1 of the most frequent primary tumors during adult life. The platelet-lymphocyte ratio (PLR) has been studied as an inflammatory marker associated with the prognosis of glioblastoma in previous studies. Considering the morbidity associated with this condition, it is important that there are other ways of assessing the prognosis that do not require invasive methods. Therefore, we performed this systematic review in order to determine the prognostic value of the PLR.
METHODS
We conducted an English language, literature-based search for papers published from 2012 to 2022, using the PubMed, Cochrane, Biblioteca Virtual em Saúde and Biomed Central Journal. We use the Preferred Reporting Items for Systematic Reviews and Meta-analyses recommendations. Titles and abstracts were evaluated independently by 2 authors, after which articles were selected for final analysis based on application of inclusion criteria (patients diagnosed with glioblastoma; address the use of PLR as a prognostic factor; hazard ratio; adults; clinical trials and observational studies) and exclusion criteria (inclusion of pediatric or animals, case reports, letters, conference abstracts, meta-analysis, and nonclinical studies or did not include hazard ratio) during full text screen. Each included article was then assessed for quality using Newcastle-Ottawa scale and relevant variables were extracted for synthesis.
RESULTS
Of 127 results, 11 articles were included for final analysis. There were 7 studies from China, 1 from Italy, 1 from Portugal, 1 from Turkey, and 1 from India. The years of publications were between 2015 and 2022. All the studies used PLR from the preoperative blood sample. Among the studies that analyzed the relationship between PLR and overall survival, 7 found a predictive relationship, 3 found no association, and 1 found an association between PLR and progression free survival in patients with glioblastoma.
CONCLUSIONS
Studies have shown that PLR can be a useful marker to aid in the prognosis of glioblastoma. Due to the ease of obtaining, rapid analysis and low cost, the PLR can be particularly beneficial in health centers with limited financial resources.
Topics: Humans; Blood Platelets; Glioblastoma; Glioma; Lymphocytes; Prognosis
PubMed: 37105273
DOI: 10.1016/j.wneu.2023.04.086