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Upsala Journal of Medical Sciences 2024Meningiomas, the most common primary brain tumors in adults, are often benign and curable by surgical resection. However, a subset is of higher grade, shows aggressive... (Review)
Review
Meningiomas, the most common primary brain tumors in adults, are often benign and curable by surgical resection. However, a subset is of higher grade, shows aggressive growth behavior as well as brain invasion, and often recurs even after several rounds of surgery. Increasing evidence suggests that tumor classification and grading primarily based on histopathology do not always accurately predict tumor aggressiveness and recurrence behavior. The underlying biology of aggressive treatment-resistant meningiomas and the impact of specific genetic aberrations present in these high-grade tumors is still only insufficiently understood. Therefore, an in-depth research into the biology of this tumor type is warranted. More recent studies based on large-scale molecular data such as whole exome/genome sequencing, DNA methylation sequencing, and RNA sequencing have provided new insights into the biology of meningiomas and have revealed new risk factors and prognostic subtypes. The most common genetic aberration in meningiomas is functional loss of NF2 and occurs in both low- and high-grade meningiomas, whereas NF2-wildtype meningiomas are enriched for recurrent mutations in TRAF7, KLF4, AKT1, PI3KCA, and SMO and are more frequently benign. Most meningioma mouse models are based on patient-derived xenografts and only recently have new genetically engineered mouse models of meningioma been developed that will aid in the systematic evaluation of specific mutations found in meningioma and their impact on tumor behavior. In this article, we review recent advances in the understanding of meningioma biology and classification and highlight the most common genetic mutations, as well as discuss new genetically engineered mouse models of meningioma.
Topics: Adult; Humans; Animals; Mice; Meningioma; Meningeal Neoplasms; Kruppel-Like Factor 4; Mutation; Prognosis
PubMed: 38571886
DOI: 10.48101/ujms.v129.10579 -
Acta Neuropathologica Communications Jul 2023Trimethylation of lysine 27 on histone 3 (H3K27me3) loss has been implicated in worse prognoses for patients with meningiomas. However, there have been challenges in... (Meta-Analysis)
Meta-Analysis Review
Trimethylation of lysine 27 on histone 3 (H3K27me3) loss has been implicated in worse prognoses for patients with meningiomas. However, there have been challenges in measuring H3K27me3 loss, quantifying its impact, and interpreting its clinical utility. We conducted a systematic review across Pubmed, Embase, and Web of Science to identify studies examining H3K27me3 loss in meningioma. Clinical, histopathological, and immunohistochemistry (IHC) characteristics were aggregated. A meta-analysis was performed using a random-effects model to assess prevalence of H3K27me3 loss and meningioma recurrence risk. Study bias was characterized using the NIH Quality Assessment Tool and funnel plots. Nine publications met inclusion criteria with a total of 2376 meningioma cases. The prevalence of H3K27me3 loss was 16% (95% CI 0.09-0.27), with higher grade tumors associated with a significantly greater proportion of loss. H3K27me3 loss was more common in patients who were male, had recurrent meningiomas, or required adjuvant radiation therapy. Patients were 1.70 times more likely to have tumor recurrence with H3K27me3 loss (95% CI 1.35-2.15). The prevalence of H3K27me3 loss in WHO grade 2 and 3 meningiomas was found to be significantly greater in tissue samples less than five years old versus tissue of all ages and when a broader definition of IHC staining loss was applied. This analysis demonstrates that H3K27me3 loss significantly associates with more aggressive meningiomas. While differences in IHC and tumor tissue age have led to heterogeneity in studying H3K27me3 loss, a robust prognostic signal is present. Our findings suggest an opportunity to improve study design and standardize tissue processing to optimize clinical viability of this epigenetic marker.
Topics: Child, Preschool; Female; Humans; Male; Biomarkers, Tumor; Histones; Meningeal Neoplasms; Meningioma; Prognosis
PubMed: 37491289
DOI: 10.1186/s40478-023-01615-9 -
Journal of Molecular Cell Biology Apr 2024Meningioma is one of the most common primary neoplasms in the central nervous system, but no specific molecularly targeted therapy has been approved for the clinical...
Meningioma is one of the most common primary neoplasms in the central nervous system, but no specific molecularly targeted therapy has been approved for the clinical treatment of aggressive meningiomas. There is hence an urgent demand to decrypt the biological and molecular landscape of malignant meningioma. Here, through the in-silica prescreening and 10-year follow-up studies of 445 meningioma patients, we uncovered that CBX7 expression progressively decreases with malignancy grade and neoplasia stage in meningioma, and a high CBX7 expression level predicts a favorable prognosis in meningioma patients. CBX7 restoration significantly induces cell cycle arrest and inhibits meningioma cell proliferation. iTRAQ-based proteomics analysis indicated that CBX7 restoration triggers the metabolic shift from glycolysis to oxidative phosphorylation. The mechanistic study demonstrated that CBX7 promotes the proteasome-dependent degradation of c-MYC protein by transcriptionally inhibiting the expression of a c-MYC deubiquitinase, USP44, consequently attenuates c-MYC-mediated transactivation of LDHA transcripts, and further inhibits glycolysis and subsequent cell proliferation. More importantly, the functional role of CBX7 was further confirmed in subcutaneous and orthotopic meningioma xenograft mouse models and meningioma patients. Altogether, our results shed light on the critical role of CBX7 in meningioma malignancy progression and identify the CBX7/USP44/c-MYC/LDHA axis as a promising therapeutic target against meningioma progression.
Topics: Humans; Proto-Oncogene Proteins c-myc; Animals; Cell Proliferation; Polycomb Repressive Complex 1; Mice; Meningioma; Ubiquitin Thiolesterase; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Glycolysis; Disease Progression; Female; Meningeal Neoplasms; Male; Mice, Nude; Middle Aged; L-Lactate Dehydrogenase
PubMed: 37791390
DOI: 10.1093/jmcb/mjad057 -
In Vivo (Athens, Greece) 2023Meningiomas are one of the most common intracranial tumors, accounting for 30% of the tumors of the central nervous system. MicroRNAs (miRNAs) are noncoding RNAs...
BACKGROUND/AIM
Meningiomas are one of the most common intracranial tumors, accounting for 30% of the tumors of the central nervous system. MicroRNAs (miRNAs) are noncoding RNAs containing approximately 18-22 nucleotides that regulate gene expression by interfering with transcription or inhibiting translation. Recent studies have reported that miRNAs could provide information about the molecular pathogenesis of several types of tumors. This study aimed to examine the expression levels of miRNA-885 and -451 and to determine their potential roles as biomarkers in meningioma.
MATERIALS AND METHODS
In total, 29 patients with meningioma (9 males and 20 females) were included in this study. The expression levels of miRNA were determined using real-time polymerase chain reaction. In addition, receiver operating characteristic curve analysis was used to analyze the predictive potential of miRNAs.
RESULTS
Our results indicated a significant increase in miRNA-451 expression levels (p=0.003); however, there was no significant change in miRNA-885 expression levels (p=0.139) in patients with meningioma compared with the control group. Moreover, miRNA-885 and miRNA-451 expression levels did not differ significantly based on the histopathological grade of meningioma.
CONCLUSION
miRNA-451 may be a novel potential marker for the diagnosis and prognosis, and a target for meningioma treatment.
Topics: Male; Female; Humans; MicroRNAs; Meningioma; Prognosis; Biomarkers; Meningeal Neoplasms; Gene Expression Profiling
PubMed: 37905647
DOI: 10.21873/invivo.13354 -
World Neurosurgery: X Jul 2023The coexistence of meningioma and dural arteriovenous fistula (dAVF) is a rare, but highly complex condition. Various pathophysiological mechanisms underlie intracranial... (Review)
Review
BACKGROUND
The coexistence of meningioma and dural arteriovenous fistula (dAVF) is a rare, but highly complex condition. Various pathophysiological mechanisms underlie intracranial meningiomas with continuous or distant dAVFs. We describe a case of coexisting meningioma and dAVF with a systematic review of the literature.
RESULT
Including the present case, there are 21 reported cases of coexisting intracranial dAVF and meningioma. The patients' ages ranged from 23 to 76 years, with a mean age of 61 years. The most common presenting symptom was headache. The dAVFs were commonly located at the transverse-sigmoid sinus (43%) and superior sagittal sinus (24%). The most common meningioma locations were the tentorium and parietal convexity. In 76% of the cases, the meningioma occluded the sinus. The most common dAVF treatment was transcatheter arterial embolization, followed by tumor resection (52%). Among the 20 cases with available outcome data, 90% reported favorable outcomes.
CONCLUSION
This report highlights some of the features of coexisting dAVF and meningioma and presents a systematic review of other reports on this phenomenon. Through an in-depth analysis of the literature, we highlight some of the leading theories regarding the causes of concomitant dAVF and meningiomas. Our report supports one of the leading theories that impaired venous return, whether through the occlusion of sinuses or sinus manipulation during surgery, plays a role in the development of dAVF. Further understanding may help guide future clinical decision-making and surgical planning.
PubMed: 37235061
DOI: 10.1016/j.wnsx.2023.100217 -
European Radiology Apr 2024The purpose of this study was to develop and validate a nomogram combined multiparametric MRI and clinical indicators for identifying the WHO grade of meningioma.
OBJECTIVE
The purpose of this study was to develop and validate a nomogram combined multiparametric MRI and clinical indicators for identifying the WHO grade of meningioma.
MATERIALS AND METHODS
Five hundred and sixty-eight patients were included in this study, who were diagnosed pathologically as having meningiomas. Firstly, radiomics features were extracted from CE-T1, T2, and 1-cm-thick tumor-to-brain interface (BTI) images. Then, difference analysis and the least absolute shrinkage and selection operator were orderly used to select the most representative features. Next, the support vector machine algorithm was conducted to predict the WHO grade of meningioma. Furthermore, a nomogram incorporated radiomics features and valuable clinical indicators was constructed by logistic regression. The performance of the nomogram was assessed by calibration and clinical effectiveness, as well as internal validation.
RESULTS
Peritumoral edema volume and gender are independent risk factors for predicting meningioma grade. The multiparametric MRI features incorporating CE-T1, T2, and BTI features showed the higher performance for prediction of meningioma grade with a pooled AUC = 0.885 (95% CI, 0.821-0.946) and 0.860 (95% CI, 0.788-0.923) in the training and test groups, respectively. Then, a nomogram with a pooled AUC = 0.912 (95% CI, 0.876-0.961), combined radiomics score, peritumoral edema volume, and gender improved diagnostic performance compared to radiomics model or clinical model and showed good calibration as the true results. Moreover, decision curve analysis demonstrated satisfactory clinical effectiveness of the proposed nomogram.
CONCLUSIONS
A novel nomogram is simple yet effective in differentiating WHO grades of meningioma and thus can be used in patients with meningiomas.
CLINICAL RELEVANCE STATEMENT
We proposed a nomogram that included clinical indicators and multi-parameter radiomics features, which can accurately, objectively, and non-invasively differentiate WHO grading of meningioma and thus can be used in clinical work.
KEY POINTS
• The study combined radiomics features and clinical indicators for objectively predicting the meningioma grade. • The model with CE-T1 + T2 + brain-to-tumor interface features demonstrated the best predictive performance by investigating seven different radiomics models. • The nomogram potentially has clinical applications in distinguishing high-grade and low-grade meningiomas.
Topics: Humans; Multiparametric Magnetic Resonance Imaging; Meningioma; Retrospective Studies; Nomograms; Brain Neoplasms; Meningeal Neoplasms; Machine Learning; Edema; World Health Organization
PubMed: 37812296
DOI: 10.1007/s00330-023-10252-8 -
BMJ (Clinical Research Ed.) Mar 2024To assess the risk of intracranial meningioma associated with the use of selected progestogens.
OBJECTIVE
To assess the risk of intracranial meningioma associated with the use of selected progestogens.
DESIGN
National case-control study.
SETTING
French National Health Data System (ie, ).
PARTICIPANTS
Of 108 366 women overall, 18 061 women living in France who had intracranial surgery for meningioma between 1 January 2009 and 31 December 2018 (restricted inclusion periods for intrauterine systems) were deemed to be in the case group. Each case was matched to five controls for year of birth and area of residence (90 305 controls).
MAIN OUTCOME MEASURES
Selected progestogens were used: progesterone, hydroxyprogesterone, dydrogesterone, medrogestone, medroxyprogesterone acetate, promegestone, dienogest, and intrauterine levonorgestrel. For each progestogen, use was defined by at least one dispensation within the year before the index date (within three years for 13.5 mg levonorgestrel intrauterine systems and five years for 52 mg). Conditional logistic regression was used to calculate odds ratio for each progestogen meningioma association.
RESULTS
Mean age was 57.6 years (standard deviation 12.8). Analyses showed excess risk of meningioma with use of medrogestone (42 exposed cases/18 061 cases (0.2%) 79 exposed controls/90 305 controls (0.1%), odds ratio 3.49 (95% confidence interval 2.38 to 5.10)), medroxyprogesterone acetate (injectable, 9/18 061 (0.05%) 11/90 305 (0.01%), 5.55 (2.27 to 13.56)), and promegestone (83/18 061 (0.5%) 225/90 305 (0.2 %), 2.39 (1.85 to 3.09)). This excess risk was driven by prolonged use (≥one year). Results showed no excess risk of intracranial meningioma for progesterone, dydrogesterone, or levonorgestrel intrauterine systems. No conclusions could be drawn concerning dienogest or hydroxyprogesterone because of the small number of individuals who received these drugs. A highly increased risk of meningioma was observed for cyproterone acetate (891/18 061 (4.9%) 256/90 305 (0.3%), odds ratio 19.21 (95% confidence interval 16.61 to 22.22)), nomegestrol acetate (925/18 061 (5.1%) 1121/90 305 (1.2%), 4.93 (4.50 to 5.41)), and chlormadinone acetate (628/18 061 (3.5%) 946/90 305 (1.0%), 3.87 (3.48 to 4.30)), which were used as positive controls for use.
CONCLUSIONS
Prolonged use of medrogestone, medroxyprogesterone acetate, and promegestone was found to increase the risk of intracranial meningioma. The increased risk associated with the use of injectable medroxyprogesterone acetate, a widely used contraceptive, and the safety of levonorgestrel intrauterine systems are important new findings.
Topics: Female; Humans; Middle Aged; Progestins; Progesterone; Levonorgestrel; Meningioma; Medroxyprogesterone Acetate; Dydrogesterone; Medrogestone; Promegestone; Case-Control Studies; Meningeal Neoplasms
PubMed: 38537944
DOI: 10.1136/bmj-2023-078078 -
Neuro-oncology Advances 2024Knowledge about meningioma growth characteristics is needed for developing biologically rational follow-up routines. In this study of untreated meningiomas followed with...
BACKGROUND
Knowledge about meningioma growth characteristics is needed for developing biologically rational follow-up routines. In this study of untreated meningiomas followed with repeated magnetic resonance imaging (MRI) scans, we studied growth dynamics and explored potential factors associated with tumor growth.
METHODS
In a single-center cohort study, we included 235 adult patients with radiologically suspected intracranial meningioma and at least 3 MRI scans during follow-up. Tumors were segmented using an automatic algorithm from contrast-enhanced T1 series, and, if needed, manually corrected. Potential meningioma growth curves were statistically compared: linear, exponential, linear radial, or Gompertzian. Factors associated with growth were explored.
RESULTS
In 235 patients, 1394 MRI scans were carried out in the median 5-year observational period. Of the models tested, a Gompertzian growth curve best described growth dynamics of meningiomas on group level. 59% of the tumors grew, 27% remained stable, and 14% shrunk. Only 13 patients (5%) underwent surgery during the observational period and were excluded after surgery. Tumor size at the time of diagnosis, multifocality, and length of follow-up were associated with tumor growth, whereas age, sex, presence of peritumoral edema, and hyperintense T2-signal were not significant factors.
CONCLUSIONS
Untreated meningiomas follow a Gompertzian growth curve, indicating that increasing and potentially doubling subsequent follow-up intervals between MRIs seems biologically reasonable, instead of fixed time intervals. Tumor size at diagnosis is the strongest predictor of future growth, indicating a potential for longer follow-up intervals for smaller tumors. Although most untreated meningiomas grow, few require surgery.
PubMed: 38187869
DOI: 10.1093/noajnl/vdad157 -
Neuro-oncology Sep 2023Neurofibromatosis 2 (NF2) is an inherited disorder caused by bi-allelic inactivation of the NF2 tumor suppressor gene. NF2-associated tumors, including schwannoma and...
BACKGROUND
Neurofibromatosis 2 (NF2) is an inherited disorder caused by bi-allelic inactivation of the NF2 tumor suppressor gene. NF2-associated tumors, including schwannoma and meningioma, are resistant to chemotherapy, often recurring despite surgery and/or radiation, and have generally shown cytostatic response to signal transduction pathway inhibitors, highlighting the need for improved cytotoxic therapies.
METHODS
Leveraging data from our previous high-throughput drug screening in NF2 preclinical models, we identified a class of compounds targeting the ubiquitin-proteasome pathway (UPP), and undertook studies using candidate UPP inhibitors, ixazomib/MLN9708, pevonedistat/MLN4924, and TAK-243/MLN7243. Employing human primary and immortalized meningioma (MN) cell lines, CRISPR-modified Schwann cells (SCs), and mouse Nf2-/- SCs, we performed dose response testing, flow cytometry-based Annexin V and cell cycle analyses, and RNA-sequencing to identify potential underlying mechanisms of apoptosis. In vivo efficacy was also assessed in orthotopic NF2-deficient meningioma and schwannoma tumor models.
RESULTS
Testing of three UPP inhibitors demonstrated potent reduction in cell viability and induction of apoptosis for ixazomib or TAK-243, but not pevonedistat. In vitro analyses revealed that ixazomib or TAK-243 downregulates expression of c-KIT and PDGFRα, as well as the E3 ubiquitin ligase SKP2 while upregulating genes associated with endoplasmic reticulum stress-mediated activation of the unfolded protein response (UPR). In vivo treatment of mouse models revealed delayed tumor growth, suggesting a therapeutic potential.
CONCLUSIONS
This study demonstrates the efficacy of proteasomal pathway inhibitors in meningioma and schwannoma preclinical models and lays the groundwork for use of these drugs as a promising novel treatment strategy for NF2 patients.
Topics: Animals; Humans; Mice; Meningeal Neoplasms; Meningioma; Neurilemmoma; Neurofibromatosis 2; Neurofibromin 2
PubMed: 36806881
DOI: 10.1093/neuonc/noad037