High grade spinal meningiomas: a rare but formidable challenge.
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ABSTRACT:
SUBMITTER: El-Hajj VG
PROVIDER: S-EPMC10425664 | biostudies-literature | 2023 Jul
REPOSITORIES: biostudies-literature
Publications
High grade spinal meningiomas: a rare but formidable challenge.
El-Hajj Victor Gabriel VG Edström Erik E Elmi-Terander Adrian A
Translational cancer research 20230620 7
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Project description:High-grade meningiomas frequently recur and are associated with high rates of morbidity and mortality. To determine the factors that promote the development and evolution of these tumors, we analyzed the genomes of 134 high-grade meningiomas and compared this information with data from 587 previously published meningiomas. High-grade meningiomas had a higher mutation burden than low-grade meningiomas but did not harbor any statistically significant mutated genes aside from NF2. High-grade meningiomas also possessed significantly elevated rates of chromosomal gains and losses, especially among tumors with monosomy 22. Meningiomas previously treated with adjuvant radiation had significantly more copy number alterations than radiation-induced or radiation-naïve meningiomas. Across serial recurrences, genomic disruption preceded the emergence of nearly all mutations, remained largely uniform across time, and when present in low-grade meningiomas, correlated with subsequent progression to a higher grade. In contrast to the largely stable copy number alterations, mutations were strikingly heterogeneous across tumor recurrences, likely due to extensive geographic heterogeneity in the primary tumor. While high-grade meningiomas harbored significantly fewer overtly targetable alterations than low-grade meningiomas, they contained numerous mutations that are predicted to be neoantigens, suggesting that immunologic targeting may be of therapeutic value.
| S-EPMC5506858 | biostudies-literature
Project description:BackgroundAlthough typically benign, 5% of spinal meningiomas (SMs) present with higher-grade features (World Health Organization grades 2 and 3). High-grade SMs are poorly studied and the role of adjuvant radiotherapy in their management remains controversial. We hence aimed to study the demographic characteristics of this rare tumor and investigate the outcomes associated with the use of surgery with adjuvant therapy in contrast to surgery alone.MethodsThe National Cancer Database was queried for patients with SMs from 2004 to 2017. Basic statistics were used to identify differences between low- and high-grade tumors in terms of baseline characteristics. Surgery with and without adjuvant radiotherapy were compared after (1:1) propensity-score matching. Kaplan-Meier survival analysis was conducted to study overall survival. All analyses were performed on R.ResultsA total of 13 184 patients diagnosed with SMs were included, of whom only 5% (n = 669) had high-grade SMs. Patients with high-grade SMs presented at a younger median age (57 years [IQR: 44-68] versus 65 years [54-75]; P < .001) and were more commonly males (33% vs 20%; P < .001). After propensity-score matching, survival analysis revealed similar overall survival outcomes in patients with high-grade SM undergoing both surgery and radiotherapy as compared to those only receiving surgery (P = .19).ConclusionsThis study reveals major demographic differences between high- and low-grade SMs. There were no benefits associated with the use of adjuvant radiotherapy. However, due to confounding, overall survival outcomes between patients receiving surgery alone and those receiving surgery with adjuvant radiotherapy are not causally interpretable.
| S-EPMC10896623 | biostudies-literature
Project description:BackgroundPatients with meningiomas have widely divergent clinical courses. Some entirely recover following surgery alone, while others have relentless tumor recurrences. This clinical conundrum is exemplified by rhabdoid meningiomas, which are designated in the World Health Organization Classification of Tumours as high grade, despite only a subset following an aggressive clinical course. Patient management decisions are further exacerbated by high rates of interobserver variability, biased against missing possibly aggressive tumors. Objective molecular determinants are needed to guide classification and clinical decision making.MethodsTo define genomic aberrations of rhabdoid meningiomas, we performed sequencing of cancer-related genes in 27 meningiomas from 18 patients with rhabdoid features and evaluated breast cancer [BRCA]1-associated protein 1 (BAP1) expression by immunohistochemistry in 336 meningiomas. We assessed outcomes, germline status, and family history in patients with BAP1-negative rhabdoid meningiomas.ResultsThe tumor suppressor gene BAP1, a ubiquitin carboxy-terminal hydrolase, is inactivated in a subset of high-grade rhabdoid meningiomas. Patients with BAP1-negative rhabdoid meningiomas had reduced time to recurrence compared with patients with BAP1-retained rhabdoid meningiomas (Kaplan-Meier analysis, 26 mo vs 116 mo, P < .001; hazard ratio 12.89). A subset of patients with BAP1-deficient rhabdoid meningiomas harbored germline BAP1 mutations, indicating that rhabdoid meningiomas can be a harbinger of the BAP1 cancer predisposition syndrome.ConclusionWe define a subset of aggressive rhabdoid meningiomas that can be recognized using routine laboratory tests. We implicate ubiquitin deregulation in the pathogenesis of these high-grade malignancies. In addition, we show that familial and sporadic BAP1-mutated rhabdoid meningiomas are clinically aggressive, requiring intensive clinical management.
| S-EPMC5464371 | biostudies-literature
Project description:AimDespite current treatments, high-grade meningiomas continue to have a poor prognosis. Immunotherapy targeting immune checkpoints, such as PD-L1, has demonstrated significant success in controlling numerous malignancies. In this study, we investigate the extent of systemic and local immunosuppression in meningiomas to assess the potential benefit of immune checkpoint inhibitors for the treatment of high-grade meningiomas.MethodsPeripheral blood was collected from patients undergoing resection of meningiomas (WHO grade I, n = 18; grade II, n = 25; grade III, n = 10). Immunosuppressive myeloid cells (CD45+CD11b+PD-L1+), myeloid-derived suppressor cells (MDSCs) (CD11b+CD33+HLA-DRlow), and regulatory T cells (Tregs) (CD3+CD4+CD25+FoxP3+) were quantified through flow cytometry. Tissue sections from the same patients were assessed for PD-L1 expression and T cell infiltration via immunohistochemistry.ResultsPatients with grade III meningiomas demonstrated increased peripheral monocyte PD-L1 compared to patients with grade I/II meningiomas and healthy controls. Peripheral MDSC abundance was increased in grades II and III meningioma patients. PD-L1 staining of meningioma tissue demonstrated increased positivity in grade III meningiomas. Intratumoral PD-L1 was not associated with progression-free survival. High-grade meningiomas had increased T-cell infiltration. However, a significant proportion of these T cells were exhausted PD1+ T cells and immunosuppressive Tregs.ConclusionsPatients with meningiomas exhibit signs of peripheral immunosuppression, including increased PD-L1 on myeloid cells and elevated MDSC abundance proportional to tumor grade. Additionally, the tumors express substantial PD-L1 proportional to tumor grade. These results suggest a role for immune checkpoint inhibitors targeting the PD-L1/PD-1 pathway in combination with standard therapies for the treatment of high-grade meningiomas.
| S-EPMC6531348 | biostudies-literature
Project description:BackgroundAlthough spinal meningiomas respond favorably to surgical excision, their surgical management is impacted by several factors. This study utilized a surgery-based grading system to discuss the optimal surgical strategy.MethodsTwenty-three consecutive patients who underwent surgery for spinal meningiomas were included in this retrospective study. The patients' neurological condition was assessed using the modified McCormick functional schema (mMFS) and sensory pain scale (SPS), and tumor removal was assessed using Simpson grade. Major factors contributing to surgical difficulty included; tumor size, extent/severity of cord compression, location of tumor attachment, spinal level, and anatomical relationships plus tumor extending in a dumbbell shape and local postoperative recurrence.ResultsFifteen cases were classified as ventral attachment (65.2%). There were two dumbbell-shaped tumors and three local recurrences at the primary site. Simpson grade 1 or 2 resections were performed in 18 of 20 cases (90%) with preoperative surgical grades 0 to 3. Simpson grade 4 resections were achieved in all three cases with preoperative surgical grades 4 to 5. Overall neurological assessment after surgery revealed the satisfactory or acceptable recovery on mMFS and SPS analysis.ConclusionsLower preoperative grade yielded better results, while the higher the preoperative grade, the more likely tumor was insufficiently removed. A preoperative surgical grading system appeared to be helpful when considering the surgical strategy. Ventral meningiomas could be safely resected via the posterolateral or lateral approach using technical modifications. Recurrent tumors, especially with ventral attachment, were hard to resolve, and primary surgery appears to be important.
| S-EPMC4173305 | biostudies-literature
Project description:Meningiomas are the most common primary brain tumors in adults. Although generally benign, a subset is of higher grade, recurs even after multiple surgeries, and frequently fatal. Around half of meningiomas harbor inactivating mutations in NF2. While low-grade NF2 mutant meningiomas harbor few additional mutations in addition to NF2 inactivation, high-grade NF2 mutant tumors frequently harbor a highly aberrant genome. We and others have previously shown that NF2 inactivation leads to YAP1 activation and that YAP1 acts as an oncogene in NF2 mutant meningiomas. Here, we show that high-grade NF2 mutant meningiomas downregulate YAP1 signaling, in part through upregulating the expression of the YAP1 competitor VGLL4 and the YAP1 upstream regulators FAT3/4. Overexpression of VGLL4 resulted in the downregulation of YAP activity and the growth inhibition of low-grade NF2 mutant meningioma cells. Our results have important implications for the efficacy of therapies targeting oncogenic YAP1 in high-grade NF2 mutant meningiomas.
2024-08-26 | GSE263122 | GEO
Project description:PurposeIn meningiomas, TERT promotor mutations are rare but qualify the diagnosis of anaplasia, directly impacting adjuvant therapy. Effective screening for patients at risk for promotor mutations could enable more targeted molecular analyses and improve diagnosis and treatment.MethodsSemiautomatic segmentation of intracranial grade 2/3 meningiomas was performed on preoperative magnetic resonance imaging. Discriminatory power to predict TERT promoter mutations was analyzed using a random forest algorithm with an increasing number of radiomic features. Two final models with five and eight features with both fixed and differing radiomics features were developed and adjusted to eliminate random effects and to avoid overfitting.ResultsA total of 117 image sets including training (N = 94) and test data (N = 23) were analyzed. To eliminate random effects and demonstrate the robustness of our approach, data partitioning and subsequent model development and testing were repeated a total of 100 times (each time with repartitioned training and independent test data). The established five- and eight-feature models with both fixed and different radiomics features enabled the prediction of TERT with similar but excellent performance. The five-feature (different/fixed) model predicted TERT promotor mutation status with a mean AUC of 91.8%/94.3%, mean accuracy of 85.5%/88.9%, mean sensitivity of 88.6%/91.4%, mean specificity of 83.2%/87.0%, and a mean Cohen's Kappa of 71.0%/77.7%. The eight-feature (different/fixed) model predicted TERT promotor mutation status with a mean AUC of 92.7%/94.6%, mean accuracy of 87.3%/88.9%, mean sensitivity of 89.6%/90.6%, mean specificity of 85.5%/87.5%, and a mean Cohen's Kappa of 74.4%/77.6%. Of note, the addition of further features of up to N = 8 only slightly increased the performance.ConclusionsRadiomics-based machine learning enables prediction of TERT promotor mutation status in meningiomas with excellent discriminatory performance. Future analyses in larger cohorts should include grade 1 lesions as well as additional molecular alterations.
| S-EPMC10486806 | biostudies-literature
Project description:ObjectiveTo determine whether angiomatous and microcystic meningiomas which mimic high grade meningiomas based on extent of peritumoral edema can be reliably differentiated as low grade tumors using normalized apparent diffusion coefficient (ADC) values.MethodsPreoperative magnetic resonance imaging (MRI) of seventy patients with meningiomas was reviewed. Morphologically, the tumors were divided into 3 groups. Group 1 contained 12 pure microcystic, 3 pure angiomatoid and 7 mixed angiomatoid and microcystic tumors. Group 2 included World Health Organization (WHO) grade II and WHO grade III tumors, of which 28 were atypical and 9 were anaplastic meningiomas. Group 3 included WHO grade I tumors of morphology different than angiomatoid and microcystic. Peritumoral edema, normalized ADC, and cerebral blood volume (CBV) were obtained for all meningiomas.ResultsEdema index of tumors in group 1 and group 2 was significantly higher than in group 3. Normalized ADC value in group 1 was higher than in group 2, but not statistically significant between groups 1 and 3. CBV values showed no significant group differences.ConclusionA combination of peritumoral edema index and normalized ADC value is a novel approach to preoperative differentiation between true aggressive meningiomas and mimickers such as angiomatous and microcystic meningiomas.
| S-EPMC4248374 | biostudies-literature
Project description:PurposePatients suffering from recurrent and residual grade 2 (WHO) meningiomas after subtotal excision should be considered as high-risk groups with an uncertain prognosis. Adjuvant radiotherapy seems to be the best approach to reduce disease progression. The primary aim of this phase II explorative, monocentric, single arm study was to evaluate the safety of adjuvant multisession radiosurgery (mRS) in this group of patients; the efficacy in terms of tumour local control was the secondary endpoint.MethodsPatients recruited from April 2017 to May 2019 were over 18 years old, had a histologically-documented intracranial recurrent or residual Grade 2 meningioma (WHO 2016) and a KPS > 70. Patients with NF2, concomitant neoplasm or pregnancy were excluded. Descriptive statistics were provided for categorical variables. Progression free survival (PFS) was modelled using the Kaplan-Meier method.ResultsTwenty-four patients were enrolled. All 24 patients underwent mRS: twenty-two patients received 28 Gy in 4 fractions, 2 patients received 24 Gy in 4 Treatment related adverse events (CTCAE 4.3) were limited to grade 2 in 1 patient (4.1%). At a median follow-up of 28 months, 8 patients (33.3%) had disease progression, either out-of-field or infield, compared with the planning target volume. Considering both infield and out-of-field progressions, 3-year PFS was 47% (95% confidence interval, CI, 22-69%); considering only the infield ones, 3-year PFS was 86% (95% CI 55-96%), and local control at last follow-up was 92%.ConclusionmRS provides good local control of the tumour volume (TV) and is associated with a low rate of toxicity. These results call for further investigation to confirm favourable outcomes in patients with high-risk meningioma.Trial informationNCT05081908, October 18, 2021, retrospectively registered.
| S-EPMC8979484 | biostudies-literature
Project description:High-grade meningiomas are associated with neuro-cognitive morbidity and have limited treatments. High-grade meningiomas harbor an immunosuppressive tumor microenvironment (TME) and programmed death-ligand 1 (PD-L1) expression may contribute to their aggressive phenotype. Here, we present the results of a single-arm, open-label phase 2 trial (NCT03279692) evaluating the efficacy of pembrolizumab, a PD-1 inhibitor, in a cohort of 25 evaluable patients with recurrent and progressive grade 2 and 3 meningiomas. The primary endpoint is the proportion of patients alive and progression-free at 6 months (PFS-6). Secondary endpoints include progression-free and overall survival, best intracranial response, and toxicity. Our study has met its primary endpoint and achieved a PFS-6 rate of 0.48 (90% exact CI: 0.31-0.66) and a median PFS of 7.6 months (90% CI: 3.4-12.9 months). Twenty percent of patients have experienced one (or more) grade-3 or higher treatment-related adverse events. These results suggest that pembrolizumab exerts promising efficacy on a subset of these tumors. Further studies are needed to identify the biological facets within the meningioma TME that may drive response to immune-based therapies.
| S-EPMC8921328 | biostudies-literature