Proposal for a new risk stratification classification for meningioma based on patient age, WHO tumor grade, size, localization, and karyotype

Domingues, Patrícia H.; Sousa, Pablo; Otero, Álvaro; Gonçalves, Jesús María; Ruíz, Laura; Oliveira, Catarina R.; Lopes, María Celeste; Órfão, Alberto; Tabernero, María Dolores

doi:10.1093/neuonc/not325

Cited by 109 publications

(109 citation statements)

References 34 publications

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“…Large series have independently confirmed tight association between WHO 2000/2007 histopathologic grade and patient outcomes. 8,9,17,31,39 A secondary analysis from NRG Oncology RTOG 0539, a comparison of histopathologic concordance between the enrolling institution and central review, was recently published. 42 We found a concordance rate of 87.8% for WHO grade II, statistically inferior to WHO grades I and III, for which the rates were, respectively 93.0% and 93.6% (p < .0001).…”

Section: Discussionmentioning

confidence: 99%

Intermediate-risk meningioma: initial outcomes from NRG Oncology RTOG 0539

Rogers

Zhang

Vogelbaum

et al. 2018

Journal of Neurosurgery

189

102

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Objective(s) This is the first clinical outcomes report of NRG Oncology RTOG 0539, detailing the primary endpoint, 3-year progression-free survival (3yPFS), compared to a predefined historical control for intermediate-risk meningioma, and secondarily evaluating overall survival (OS), local failure, and prospectively scored adverse events (AEs). Methods NRG Oncology RTOG 0539 was a phase II clinical trial allocating meningioma patients to 1 of 3 prognostic groups and management strategies according to WHO grade, recurrence status, and resection extent. For the intermediate-risk group (Group 2), eligible patients had either newly diagnosed WHO grade II meningioma with gross total resection (GTR, Simpson I-III) or recurrent WHO grade I of any resection extent. Pathology and imaging were centrally reviewed. Patients were treated with radiation therapy (RT), either intensity modulated (IMRT) or 3D conformal (3DCRT), 54 Gy in 30 fractions. The RT target volume was defined as the tumor bed and any nodular enhancement (e.g. recurrent WHO grade I patients) with a minimum 8 mm and maximum 15 mm margin, depending upon tumor locale and set-up reproducibility of RT method. The primary endpoint was 3yPFS. Results were compared to historical controls (3yPFS 70% following GTR alone and 90% with GTR + RT). AEs were scored using NCI Common Toxicity Criteria. Results Fifty-six patients enrolled in the intermediate-risk group; 3 were ineligible. Additionally, 1 did not receive RT, and 4 withdrew without recurrence before 3 years. Thus 52 patients received protocol therapy, and 48 were evaluable for the primary endpoint, 3y PFS which was 93.8% (p=.0003). Within 3 years there were 3 PFS events: 1 WHO grade II patient died of disease, 1 WHO grade II patient progressed and remained alive, and 1 recurrent WHO grade I patient died from undetermined cause without progression. Three-year local failure was 4.1%, and 3-year OS 96%. After 3 years 2 additional patients progressed: 1 recurrent WHO grade I, and the other WHO grade II; both remain alive. Among 52 evaluable patients who received protocol treatment, 36 (69.2%) were WHO II with GTR, and 16 (30.8%) recurrent WHO I. There was no significant difference in PFS between these subgroups (p=.52, HR 0.56, 95% CI 0.09 to 3.35), validating their consolidation. Of the 52 evaluable patients, 44 (84.6%) received IMRT, and 50 (96.2%) were treated per protocol or with acceptable variation. AEs (definitely, probably or possibly related to protocol treatment) were limited to grade 1 or 2, with no reported grade 3 events. Conclusion This is the first clinical outcomes report from NRG Oncology RTOG 0539. Patients with intermediate-risk meningioma treated with RT experienced excellent 3yPFS with a low rate of local failure, and a low risk of adverse events. These results support the use of post-operative RT for newly diagnosed gross totally resected WHO grade II, or recurrent WHO grade I meningioma irrespective of resection extent. They also document minimal toxicity and high rates of tumor contr...

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Section: Discussionmentioning

confidence: 99%

Intermediate-risk meningioma: initial outcomes from NRG Oncology RTOG 0539

Rogers

Zhang

Vogelbaum

et al. 2018

Journal of Neurosurgery

189

102

View full text Add to dashboard Cite

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“…However the most challenging group of patients from a clinical management perspective are those with WHO grade II tumors where recurrence is expected in approximately 40% of cases. It is hard to accurately predict tumor recurrence for individual patients with atypical meningioma and therefore is difficult to decide which patients should receive adjuvant radiation therapy versus close monitoring by imaging [72,17,2,43,41,54]. …”

Section: Introductionmentioning

confidence: 99%

“…Although numerous molecular alterations have been described in meningioma [62,10,13,65,1,16,9] few of which were linked to prognosis, like 1p36 loss [39,45], 9p21 loss [61], complex karyotypes [17,45], and recently TERT promoter mutations [65], these alterations are not yet integrated with the morphological diagnosis in the most recent, revised WHO classification [41] and molecular testing is not routinely performed in the clinic for patients with meningioma. Meningioma recurrence may warrant adjuvant radiation therapy or increased monitoring [54] but these patients are not accurately identified by the current meningioma classification system.…”

Section: Introductionmentioning

confidence: 99%

Global epigenetic profiling identifies methylation subgroups associated with recurrence-free survival in meningioma

Olar

Wani

Wilson³

et al. 2017

Acta Neuropathol

154

118

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Meningioma is the most common primary brain tumor and carries a substantial risk of local recurrence. Methylation profiles of meningioma and their clinical implications are not well understood. We hypothesized that aggressive meningiomas have unique DNA methylation patterns that could be used to better stratify patient management. Samples (n=140) were profiled using the Illumina HumanMethylation450 BeadChip. Unsupervised modeling on a training set (n=89) identified 2 molecular methylation subgroups of meningioma (MM) with significantly different recurrence free survival (RFS) times between the groups: a prognostically unfavorable subgroup (MM-UNFAV) and a prognostically favorable subgroup (MM-FAV). This finding was validated in the remaining 51 samples and led to a baseline meningioma methylation classifier (bMMC) defined by 283 CpG loci (283-bMMC). To further optimize a recurrence predictor, probes subsumed within the baseline classifier were subject to additional modeling using a similar training/validation approach, leading to a 64-CpG loci meningioma methylation predictor (64-MMP). After adjustment for relevant clinical variables [WHO grade, mitotic index, Simpson grade, sex, location, and copy number aberrations (CNA)] multivariable analyses for RFS showed that the baseline methylation classifier was not significant (p=0.0793). The methylation predictor however was significantly associated with tumor recurrence (p<0.0001). CNA were extracted from the 450k intensity profiles. Tumor samples in the MM-UNFAV subgroup showed an overall higher proportion of CNAs compared to the MM-FAV subgroup tumors and the CNAs were complex in nature. CNAs in the MM-UNFAV subgroup included recurrent losses of 1p, 6q, 14q and 18q, and gain of 1q, all of which were previously identified as indicators of poor outcome. In conclusion, our analyses demonstrate robust DNA methylation signatures in meningioma that correlate with CNAs and stratify patients by recurrence risk.

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“…A subset of meningioma (the angiomatous subtype) harbor chromosomal polysomies [18] and the clear cell subtype can have mutations in SMARCE1 [19]. High-grade meningioma characteristically bear recurrent whole arm chromosomal losses [20-24] and TERT promoter mutations associated with histological progression [25]. Because none of these additional genetic aberrations can currently be targeted with selective therapeutics, strategies using broadly active agents may be needed for effective disease-management in most patients with high-grade meningioma.…”

Section: Introductionmentioning

confidence: 99%

Increased expression of the immune modulatory molecule PD-L1 (CD274) in anaplastic meningioma

et al. 2014

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There are no effective medical treatments for WHO grade III (anaplastic) meningioma. Patients with this high-grade malignancy have a median survival of less than two years. Therapeutics that modulate the mechanisms that inhibit local immune responses in the tumor microenvironment are showing significant and durable clinical responses in patients with treatment refractory high-grade tumors. We examined the immune infiltrate of 291 meningiomas including WHO grade I-III meningiomas using immunohistochemistry and we examined the expression of PD-L1 mRNA by RNAscope in situ hybridization and PD-L1 protein by immunohistochemistry. In meningioma, the tumor infiltrating lymphocytes are predominantly T cells. In anaplastic meningioma, there is a sharp decrease in the number of T cells, including the numbers of CD4+ and CD8+ T cells and cells expressing PD-1 and there is also an increase in the number of FOXP3 expressing immunoregulatory (Treg) cells. PD-L1 expression is increased in anaplastic meningioma – both mRNA and protein. Using patient derived meningioma cell, we confirm that PD-L1 is expressed in meningioma cells themselves, and not solely in infiltrating immune cells. This work indicates that high-grade meningioma harbor an immunosuppressive tumor microenviroment and that increased Treg cells and elevated PD-L1 may contribute to the aggressive phenotype of these tumors.

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Proposal for a new risk stratification classification for meningioma based on patient age, WHO tumor grade, size, localization, and karyotype

Abstract: Based on this risk-stratification classification, different strategies may be adopted for follow-up, and eventually also for treatment, of meningioma patients at different risks for relapse.

Cited by 109 publications

References 34 publications

Intermediate-risk meningioma: initial outcomes from NRG Oncology RTOG 0539

Intermediate-risk meningioma: initial outcomes from NRG Oncology RTOG 0539

Global epigenetic profiling identifies methylation subgroups associated with recurrence-free survival in meningioma

Increased expression of the immune modulatory molecule PD-L1 (CD274) in anaplastic meningioma

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