Aggressive Meningiomas Research Articles

Genetic analysis of a malignant meningioma and associated metastases.

To identify genes altered in a highly aggressive metastatic meningioma primary as well as its metastases. Exome sequencing of a primary anaplastic meningioma and metastatic lesions in which DNA could be extracted and compared to germline DNA. Genetic analysis of the metastatic sites found 31 common mutations among the primary tumor and two metastatic sites. Additionally, genetic mutations were identified which were either infrequently (MUC3A, ALDH1A3, HOXA1) or not at all previously described in meningiomas (CASS4, CMKLR1). Exome sequencing of a metastatic meningioma and its distant metastases outside the CNS identified mutations that were not previously well described.

AKT1E17K‐mutated meningioma cell lines respond to treatment with the AKT inhibitor AZD5363

AbstractAimsMeningiomas are the most frequent primary brain tumours. Recently, knowledge about the molecular drivers underlying aggressive meningiomas has been expanded. A hotspot mutation in the AKT1 gene (AKT1E17K), which is found in meningiomas at the convexity and especially at the skull base, has been associated with earlier tumour recurrence.MethodsHere, we analysed the effects of the AKT1E17K mutation and treatment response to the Akt inhibitor AZD5363 in transgenic meningioma cell clones and mouse xenografts modelling convexity or skull base meningiomas.ResultsWe show that the AKTE17K mutation significantly enhances meningioma cell proliferation and colony size in vitro, resulting in significantly shortened survival times of mice carrying convexity or skull base AKT1E17K xenografts. Treatment of mutant cells or xenografts (150 mg/kg/d) with AZD5363 revealed a significant decrease in cell proliferation and colony size and a prolongation of mouse survival. Western blots revealed activation of AKT1 kinase (phosphorylation at Ser273 and Thr308) by the E17K mutation in human meningioma samples and in our in vitro and in vivo models.ConclusionsOur data suggest that AKT1E17K mutated meningiomas are a promising selective target for AZD5363.

Clinicopathological features, imaging characteristics and surgical management in a novel tumour entity - aggressive meningiomas

Meningiomas are common neoplasms of the central nervous system, comprising between 24 and 30% of primary intracranial tumours, most commonly affecting females in their middle age or later adult life [1] [2].
 Meningiomas are classified as benign, atypical or anaplastic meningiomas depending mostly on histopathological criteria known to be associated with worse prognosis in terms of tumour progression, recurrence risk after surgery and overall survival. The 2016 edition of the World Health Organization (WHO) classification of Central Nervous System (CNS) tumours recognizes brain invasion as an independent criterion for diagnosing an atypical grade II meningioma [3]. Meningioma grading based on the WHO classification of CNS tumours thoroughly impacts therapeutic management and tumour prognosis.
 Aggressive meningiomas, a different phenotype of tumours, characterized by rapid growth and involvement of adjacent brain tissue, blood vessels and bone, was not previously listed as an independent entity in the WHO classification of meningothelial-cell tumours. 
 Regarding the increasing importance of tumour grading in meningioma treatment strategies, the authors here provide an overview of clinicopathological and radiographic features, surgical management and long-term prognosis of this novel meningothelial tumour entity, the aggressive meningioma. In particular, we aimed to describe pre-, intra- and postoperative methods for recognizing aggressive meningiomas and explore the implications of this diagnosis on both surgical strategies and adjuvant therapy.

Imaging characteristics, histopathological features and surgical considerations regarding aggressive meningiomas

Meningiomas are tumours of the meninges that arise primarily from arachnoidal cap cells, but they can also occur rarely as primary tumours in other localizations, such as within the ventricles. They stand for 24-30% of primary intracranial tumours and affect mostly women in their middle age or later adult life [1, 2]. Meningiomas can be classified, according to the World Health Organization (WHO) classification of Central Nervous System (CNS) tumours, as benign (grade I, most frequently encountered type), atypical (grade II) or anaplastic (grade III), based mostly on histopathological criteria known to be associated with tumour progression, recurrence risk and survival. Since meningioma grading based on the WHO classification is the most important factor determining therapeutic management and tumour prognosis, there has been an increasing interest in adding new criteria for better characterization of these tumours. Thus, the 2016 edition of the WHO classification recognized brain invasion as an independent criterion for atypical (grade II) meningioma diagnosis [3]. However, meningiomas that display aggressive features such as rapid growth and higher recurrence rate, can also involve blood vessels and bone. Hence, the authors aim to describe a different entity, aggressive meningiomas, not previously listed as a tumour phenotype in the WHO classification of meningothelial-cell tumours, with regard to pre-, intra- and postoperative methods for diagnosis and explore the implications on surgical strategies and adjuvant therapy.

Receptor-Tyrosine Kinase Inhibitor Ponatinib Inhibits Meningioma Growth In Vitro and In Vivo.

Simple SummaryThe clinical management for aggressive meningiomas remains challenging due to the lack of systemic treatment options. Receptor tyrosine kinases (RTKs) are frequently overexpressed in meningiomas and are associated with poor patient survival. In this study, we evaluated the clinically approved pan-RTK inhibitor ponatinib as a novel candidate for the treatment of aggressive meningiomas. Ponatinib decreased cell viability and proliferation of meningioma cells and subsequently induced programmed cell death. Furthermore, the drug demonstrated a considerable tumor growth inhibition without causing any adverse effects in mice. Mechanistically, this was presumably caused by blocking the PDGFR signaling pathway accompanied by induction of mitochondrial dysfunction. Altogether, the multi-RTKi ponatinib may serve as a promising candidate for targeted therapy for aggressive meningiomas.To date, there is no standard-of-care systemic therapy for the treatment of aggressive meningiomas. Receptor tyrosine kinases (RTK) are frequently expressed in aggressive meningiomas and are associated with poor survival. Ponatinib is a FDA- and EMA-approved RTK inhibitor and its efficacy in meningioma has not been studied so far. Therefore, we investigated ponatinib as a potential drug candidate against meningioma. Cell viability and cell proliferation of ponatinib-treated meningioma cells were assessed using crystal violet assay, manual counting and BrdU assay. Treated meningioma cell lines were subjected to flow cytometry to evaluate the effects on cell cycle and apoptosis. Meningioma-bearing mice were treated with ponatinib to examine antitumor effects in vivo. qPCR was performed to assess the mRNA levels of tyrosine kinase receptors after ponatinib treatment. Full-length cDNA sequencing was carried out to assess differential gene expression. IC50 values of ponatinib were between 171.2 and 341.9 nM in three meningioma cell lines. Ponatinib induced G0/G1 cell cycle arrest and subsequently led to an accumulation of cells in the subG1-phase. A significant induction of apoptosis was observed in vitro. In vivo, ponatinib inhibited meningioma growth by 72.6%. Mechanistically, this was associated with downregulation of PDGFRA/B and FLT3 mRNA levels, and mitochondrial dysfunction. Taken together, ponatinib is a promising candidate for targeted therapy in the treatment of aggressive meningioma.

QOLP-22. THE PSYCHO-ONCOLOGICAL BURDEN OF PATIENTS WITH AGGRESSIVE MENINGIOMA – RESULTS FROM A RETROSPECTIVE CROSS-SECTIONAL STUDY

Abstract Despite the perception of meningioma as a benign disease, up to 35% of patients experience a clinically aggressive course with debilitating treatment and poor outcome. In contrast to the growing interest in novel therapies, the impact on health-related quality of life (HRQoL) is still understudied. Here, we analysed the psycho-oncological burden of patients with aggressive meningioma. Our institutional cohort was searched for meningioma patients with surgery as first intervention and HRQoL was assessed retrospectively at one time point with standardized self-assessment questionnaires (HADS-D, EORTC-QLQ-C30). Aggressive meningioma was defined as WHO grade 2 or 3 or recurrence of a WHO grade 1 meningioma within 5 years after index surgery. Results were correlated with demographic, tumor- and treatment-related factors by multivariate linear regression and compared to internal control patients (WHO grade 1 meningioma, no recurrence within the first 5 years). 400 out of 653 patients returned the questionnaires (62%). Of those, 95 patients (24%) were classified as aggressive meningioma while 305 patients served as internal control. Patients with and without aggressive meningioma differed with regard to sex (p=0.019), age (p=0.015), extent of resection (p< 0.0001) and adjuvant radiotherapy (p< 0.0001) at index surgery and KPS at 1st follow-up (p=0.037). 34% and 24% of aggressive meningioma patients were screened positive on the anxiety and depression subscales of HADS-D as opposed to 33% and 23% of internal controls (not significant). Aggressive meningioma patients fared significantly worse on most of the function scales of QLQ-C30 (QL: p=0.004; PF: p=0.049; RF: p=0.003; CF: p=0.01; SF: p=0.018) and reported more financial difficulties (FI: p=0.015). In multivariate regression analysis, female sex, KPS at 1st follow-up < 70 and aggressive meningioma were independent factors of impaired HRQoL. This cross-sectional analysis demonstrates that HRQoL is impaired in aggressive meningioma patients who should be screened and treated for their psycho-oncological needs.

Chemotherapy and targeted therapies for meningiomas: what is the evidence?

Although most meningiomas are slow growing tumors mainly controlled by surgery with or without radiotherapy, aggressive meningiomas that fail these conventional treatments constitute a rare situation, a therapeutic challenge and an unmet need in neuro-oncology. Mutational landscape in recurrent high-grade meningiomas includes mainly NF2 mutation or 22q chromosomal deletion, whereas telomerase reverse transcriptase promoter, BAP-1 and CDK2NA mutations were also found in aggressive meningiomas. Pi3K-Akt-mTOR pathway is currently the most relevant intracellular signaling pathway target in meningiomas with preliminary clinical activity observed. Assessment of drug activity with progression free survival rate at 6 months is challenging in regard to meningioma growth rate heterogeneity, so that 3-dimensional growth rate before and during treatment could be considered in the future to selected new active drugs. Despite a low evidence level, some systemic therapies may be considered for patients with recurrent meningioma not amenable to further surgery or radiotherapy. In recurrent high-grade meningioma, everolimus-octreotide combination, bevacizumab, sunitinib and peptide receptor radionuclide therapy exhibit a signal of activity that may justify their clinical use. Despite a lack of clear signal of activity to date, immunotherapy may offer new perspectives in the treatment of these refractory tumors.

P14.57 WHO grade II and III meningioma: a large mono-institutional retrospective series

Abstract BACKGROUND Meningiomas are usually considered benign lesions, however a part of them can show very aggressive behavior with tendency to metastasize. This subgroup is known as high-grade meningiomas (HGM). Due to the rarity of the disease, effective medical treatments are lacking, especially at the time of recurrence. We aim to describe the clinical, radiological and molecular features of a large population of HGM diagnosed between 2010 and 2018. The secondary aim was to evaluate survival (PFS) and overall survival (OS). MATERIAL AND METHODS We collected clinical and survival data from primitive WHO grade II and III meningioma patients treated at Fondazione IRCCS Istituto Neurologico Carlo Besta from January 2010 to December 2018. Records were collected on a web-based platform (Microsoft Excel) that was customized for this study. The database, contained epidemiological, diagnostic (radiological and histological/molecular), surgical, therapeutic and recurrence information, as well as survival data. RESULTS 183 patients (105 females and 78 males), with median age of 58 years (25–88), were included; 168 were atypical, 12 anaplastic, 3 rhabdoid. Overall, m-PFS was 4.2 years, and m-OS was 10.3 years. Gross-total resection had a 5-year survival rate of 95% compared with subtotal/partial resection (86% and 67%) (p=0.002). Higher expression of Ki-67/MIB-1 seems associated with higher risk of death (HR:1.06 with 95% CI, 1.00–1.12, p=0.03). No statistically significant differences were seen in survival between the group managed with a wait-and-see strategy vs the group treated with RT/SRS while a difference on PFS was seen (4.1 years vs 5.2 years p=0.03). After second recurrence, the most employed treatments were systemic therapies with a very limited effect on disease control. CONCLUSION Data confirmed the aggressive behavior of HGM. The extent of resection seems to correlate with a favorable outcome regardless histological subtypes. The role of RT/SRS remains controversial, with no statistically significant impact on OS but a possible role on PFS. At relapse, no chemotherapies are able to achieve disease control and recurrent HGM remains the real challenge for future research, focusing on biological/molecular predictors in order to achieve a patient-tailored treatment.This retrospective study allowed to analyzed the largest national recent series of aggressive meningiomas with the purpose of identify relevant outcome measures for future prospective studies. Our findings could be important to give a snapshot of the current attitude to treat aggressive meningiomas but also to inspire national and international collaboration in order to provide evidence-based management strategies trying to obtain a standard of care.

Aggressive Radiation-Induced Cavernous Sinus Meningioma: 2-Dimensional Operative Video.

Radiation-induced meningiomas are the most common radiation-induced neoplasms. They exhibit a distinct aggressive clinical behavior as rapid growth, recurrences, multiplicity, and malignant progression are common features.1-4 Atypical histological findings and aberrant cytogenetics are increasingly identified.5-7 Radical resection of aggressive radiation-induced meningiomas is the best treatment option and would offer the best chance for control of the disease. Wide bone and dural margins should be pursued in the resection. Parasellar extension creates significant surgical challenges. Cavernous sinus exploration through the multidirectional axis provided by the cranioorbital zygomatic approach allows radical resection of the tumor, cranial nerve decompression, and carotid artery preservation and control.8-11 This article describes a cavernous sinus radiation-induced meningioma after radiation for Cushing disease. It demonstrates the details of the extra- and intradural exploration and dissection of the neurovascular structures in the cavernous sinus, with proximal and distal control of the carotid artery. However, even after radical resection, recurrence is a common finding in this malignant behavioral radiation-induced tumor. Patient consented for surgery. Image at 9:41 comes from the Science Museum Group, United Kingdom. Refer to the Wellcome blog post (archive). This image is licensed under the CC-BY 4.0 International license.

FOXM1 and β-catenin in meningiomas

Objectives Forkhead box protein M1 (FOXM1) is a recently recognized biologic marker of increased cell proliferation and poor clinical outcomes in meningiomas. Alterations of Wnt signaling pathway, involving β-catenin, is one of FOXM1 key mechanisms and plays a pivotal role in meningioma progression. In this study, we aimed to analyze the expression of FOXM1, β-catenin, and Ki-67 in meningiomas of different WHO grades and correlated such expression with proliferation indices and tumor recurrence. This would delineate any potential predictive/prognostic value of these markers and investigate their eligibility as targets in meningioma therapy. Materials and methods We studied the immunohistochemical expression of FOXM1, β-catenin, and Ki-67 in 91 meningiomas: 43 WHO grade I, 34 WHO grade II, and 14 WHO grade III meningiomas. Results A statistically significant higher FOXM1 expression was reported with increasing WHO meningioma grade. β-catenin expression was lower in meningiomas WHO grade II/III than WHO grade I, and a significant association between lower β-catenin expression and tumor recurrence was detected. Increased FOXM1 expression correlated with tumor recurrence probability, increased proliferation indices, and lower β-catenin expression. Conclusion The study highlighted the patterns of FOXM1 and β-catenin in meningiomas. There was a trend for FOXM1 upregulation in high-grade and aggressive meningiomas, suggesting its consideration as a therapeutic target in cases with poor response to current management options. We also emphasize the potential roles of β-catenin in meningioma progression and recurrence.

Influence of Human Telomerase Reverse Transcriptase Mutation on the Aggressiveness and Recurrence in Meningiomas.

Background: Over 200 human telomerase reverse transcriptase (hTERT) polymorphism combinations have been implicated in the development of cancer. This study aimed to evaluate hTERT mutations in meningioma tissue and its association with meningioma.Material and Methods: A total of 90 patients who underwent surgery between 2006 and 2015 and were histopathologically diagnosed with meningioma (WHO 2016) were included.Results: Among the 90 participants included herein, 50 (55.5%) and 40 (44.5%) were female and male, respectively, with an average age of 56.2 ± 14 years. Mean Ki-67 values were 10.56% (SD 12.41, range 0-60), while the mean follow-up duration was 39.1 months (SD 26.3). Low- and high-grade patients had a mean Ki-67 score of 4.31% (SD 3.58, range 0-16) and 19.92% (SD 14.91, range 2-60) (p = 0.0001). Our results showed a moderate positive correlation between Ki-67 score and the presence of hTERT mutation (Pearson correlation test, r = 0.5161; p = 0.0001). Patients with an hTERT mutation > 30% had significantly higher risk for reoperation than those with lower levels of mutation (p = 0.016, chi square test). None of the patients requiring reoperation had an hTERT mutation < 10%. Moreover, high-grade patients had a 7.2 times higher risk of reoperation than those with an hTERT mutation > 30%.Conclusion: The presence of hTERT mutation, in addition to high Ki-67, indicated a more aggressive meningioma disease course and potentially increased risk of recurrence.

Proton therapy: A therapeutic opportunity for aggressive pediatric meningioma

Meningiomas are an extremely rare histology among pediatric brain tumors, and there is a shortage of literature on their management. Proton therapy is currently used safely and effectively for many types of both pediatric and adult cancer, and its main advantage is the sparing of healthy tissues from radiation, which could translate in the reduction of late side effects. We review the literature on radiotherapy and proton therapy for pediatric meningiomas and report clinical outcomes for two aggressive pediatric meningiomas we treated with protons. Proton therapy might be a safe and effective therapeutic option for this rare subgroup of tumors.

KIF11 inhibitors filanesib and ispinesib inhibit meningioma growth in vitro and in vivo.

Treatment of aggressive meningiomas remains challenging due to a high rate of recurrence in higher-grade meningiomas, frequent subtotal resections, and the lack of effective systemic treatments. Substantial overexpression associated with a poor prognosis has been demonstrated for kinesin family member 11 (KIF11) in high-grade meningiomas. Due to anti-tumor activity for KIF11 inhibitors (KIF11i) filanesib and ispinesib in other cancer types, we sought to investigate their mode of action and efficacy for the treatment of aggressive meningiomas. Dose curve analysis of both KIF11i revealed IC50 values of less than 1nM in anaplastic and benign meningioma cell lines. Both compounds induced G2/M arrest and subsequent subG1 increase in all cell lines. Profound induction of apoptosis was detected in the anaplastic cell lines determined by annexin V staining. KIF11i significantly inhibited meningioma growth in xenotransplanted mice by up to 83%. Furthermore, both drugs induced minor hematological side effects, which were less pronounced for filanesib. We identified substantial in vitro and in vivo anti-tumor effects of the KIF11 inhibitors filanesib and ispinesib, with filanesib demonstrating better tolerability, suggesting future use of filanesib for the treatment of aggressive meningioma.

Advanced MRI shape analysis as a predictor of histologically aggressive supratentorial meningioma

Background and purposeA subset of aggressive meningioma is associated with higher morbidity and requires a different therapeutic management. This subset consists of World Health Organization (WHO) grade II and III meningioma, characterized particularly with microscopic brain invasion. Numerous studies tried to screen aggressive meningioma on pre-operative MRI. The objective of the study was to determine if an advanced shape analysis of supratentorial meningioma outlines could reliably predict WHO II–III grade and histological brain invasion. Materials and methodsWe performed a retrospective analysis for all consecutive patients who underwent surgery for supratentorial histologically-proven meningioma from 2010 to 2018. Pre-operative MRI T1WI contrast enhanced axial, coronal and sagittal slices were collected from 101 patients. Advanced shape analysis including fractal analysis and topological skeleton analysis was performed. Shape analysis parameters were correlated with histopathological WHO grading and brain invasion on surgical pieces. ResultsShape analysis features such as a low circularity, a low solidity, a high fractal dimension and a high number of skeleton’s branches were significantly correlated with both WHO II–III meningioma and histological brain invasion. Cross-validated regression models including these features were predictive of WHO II–III meningioma and brain invasion with respective AUC of 0.71 and 0.72. ConclusionsMRI shape analysis provides informative imaging biomarkers to predict high WHO grade and histological brain invasion of supratentorial meningioma. Further prospective studies including the evaluation of a fully-automatized and totally reproducible process are required to confirm the results.

Outcome After Protontherapy for Progression or Recurrence of Surgically Treated Meningioma.

BackgroundTo assess the outcome after meningioma surgery and protontherapy (PT).MethodsWe processed the French Système National des Données de Santé database to retrieve appropriate cases of meningiomas operated and irradiated between 2008 and 2017. Survival methods were implemented.ResultsOne hundred ninety-three patients who received PT after meningioma surgery over a 10-year period were identified. Of the 193 patients, 75.6% were female. Median age at surgery was 50 years (interquartile range [IQR] 41–62). The median number of PT fractions was 31 (IQR 30–39) given over a median duration of 52 days (IQR 44–69). Fourteen patients (7.3%) also received photon radiotherapy and six patients (3.1%) stereotactic radiosurgery. Median follow-up was 4.4 years (IQR 3.86–4.71). Five-year progression-free survival (PFS) rate was 69% (95% confidence interval [CI] 62.1–76.6). For benign, atypical, and malignant meningioma, 5-year PFS rates were 71.5% (95% CI 64.4–79.4), 55.6% (95% CI 32.5–95), and 35.6% (95% CI 12.8–98.9), respectively (p<0.01). In the adjusted regression, tumour location (hazard ratio [HR]=0.1, 95% CI 0.05–0.22, p<0.001), aggressive meningioma (HR=2.26, 95% CI 1.1–4.66, p=0.027), and the need of cerebrospinal fluid (CSF) insertion for hydrocephalus (HR=3.51, 95% CI 1.32–9.31, p=0.012) remained significantly associated to the PFS. All grades considered, 5-year overall survival (OS) rates was 89.7% (95% CI 84.6–95.1). For benign, atypical, and malignant meningioma, 5-year OS rates were 93% (95% CI 88.7–97.4), 76.4% (95% CI 51.4–100), and 44.4% (95% CI 16.7–100), respectively (p<0.01). In the multivariable regression, an older age above 70 years (HR=5.95, 95% CI 2.09–16.89, p<0.001) associated to a high level of comorbidities (HR=5.31, 95% CI 1.43–19.78, p=0.013) and a malignant meningioma (HR=5.68, 95% CI 1.54–20.94, p=0.009) remained significantly associated to a reduced OS.ConclusionFive-year PFS and OS after meningioma surgery and PT is favourable but impaired for older patients with high level of morbidities, tumour of the convexity, malignant histopathology and for those requiring CSF shunting. Further inclusion and prolonged follow-up is required to assess other predictors such as sex, tumour volume, or given dose.

The effects of palbociclib in combination with radiation in preclinical models of aggressive meningioma.

BackgroundMeningiomas are the most common tumor arising within the cranium of adults. Despite surgical resection and radiotherapy, many meningiomas invade the brain, and many recur, often repeatedly. To date, no chemotherapy has proven effective against such tumors. Thus, there is an urgent need for chemotherapeutic options for treating meningiomas, especially those that enhance radiotherapy. Palbociclib is an inhibitor of cyclin-dependent kinases 4 and 6 that has been shown to enhance radiotherapy in preclinical models of other cancers, is well-tolerated in patients, and is used to treat malignancies elsewhere in the body. We, therefore, sought to determine its therapeutic potential in preclinical models of meningioma.MethodsPatient-derived meningioma cells were tested in vitro and in vivo with combinations of palbociclib and radiation. Outputs included cell viability, apoptosis, clonogenicity, engrafted mouse survival, and analysis of engrafted tumor tissues after therapy.ResultsWe found that palbociclib was highly potent against p16-deficient, Rb-intact CH157 and IOMM-Lee meningioma cells in vitro, but was ineffective against p16-intact, Rb-deficient SF8295 meningioma cells. Palbociclib also enhanced the in vitro efficacy of radiotherapy when used against p16-deficient meningioma, as indicated by cell viability and clonogenic assays. In vivo, the combination of palbociclib and radiation extended the survival of mice bearing orthotopic p16 deficient meningioma xenografts, relative to each as a monotherapy.ConclusionsThese data suggest that palbociclib could be repurposed to treat patients with p16-deficient, Rb-intact meningiomas, and that a clinical trial in combination with radiation therapy merits consideration.

Advances in meningioma genomics, proteomics, and epigenetics: insights into biomarker identification and targeted therapies.

Meningiomas are a heterogeneous group of tumors, defined histo-pathologically by World Health Organization (WHO) grading. The WHO grade of meningiomas does not always correlate with clinical aggressiveness. Despite maximal surgical resection and adjuvant radiation, a subset of tumors are clinically aggressive; displaying early recurrence and invasion. Current methods for identifying aggressive meningiomas solely focus on genomics, proteomics, or epigenetics and not a combination of all for developing a real-time clinical biomarker. Improved methods for the identification of these outlying tumors can facilitate better classification and potentially adjuvant treatment planning. Understanding the pathways of oncogenesis using multiple markers driving aggressive meningiomas can provide a foundation for targeted therapies, which currently do not exist.

Resection and Surgically Targeted Radiation Therapy for Initial or Salvage Treatment of Aggressive Meningioma

Resection and Surgically Targeted Radiation Therapy for Initial or Salvage Treatment of Aggressive Meningioma

CTNI-58. A PROSPECTIVE TRIAL OF RESECTION AND SURGICALLY TARGETED RADIATION THERAPY FOR INITIAL OR SALVAGE TREATMENT OF AGGRESSIVE MENINGIOMA

Abstract INTRODUCTION Achieving durable local control (LC) for aggressive or recurrent meningiomas remains problematic. Resection (R) alone is insufficient and even with the addition of radiation therapy (RT), outcomes are suboptimal in many series. OBJECTIVE Hypothesizing R plus Surgically Targeted Radiation Therapy (STaRT) may improve LC, we evaluated a permanently implanted brachytherapy device consisting of Cs-131 seeds positioned within modular resorbable collagen carrier/spacer tiles (GammaTile, GT Medical Technologies, Tempe AZ). METHODS From 2/2013-2/2018 recurrent and newly diagnosed aggressive meningiomas were treated on a prospective single-arm study (NCT#03088579). At completion of maximum safe resection the tumor bed was lined with collagen tiles imbedded with Cs-131, delivering 60–80 Gy at 5 mm depth. No additional local therapy was given absent progression. RESULTS 35 meningiomas in 28 patients were treated; 29 recurrent (22 prior R+RT, 6 R only, and 1 RT only) and 6 without prior therapy. WHO grade was I in 2 patients, II in 28, and III in 5. Median age was 66 years (range 37–82), KPS 80 (70–100), female: male ratio 15:13. Mean time for implantation was 5 minutes. At a median radiographic follow-up of 25.5 months (range 0.1–71) LC was 80% (28/35) and median time to progression had not been reached (95% CI &amp;gt; 35.6 months). LC at 12/24/36/48 months was 100/89/72/72% for all tumors, 100/93/79/79% for Grade II, and 100/50/0/0% for Grade III, respectively. No patient receiving STaRT as their initial RT failed. Median overall survival was 50 months. Four symptomatic adverse events occurred, 2 wound breakdowns requiring surgery and 2 radiation-related brain changes, medically treated. CONCLUSION R+STaRT demonstrates favorable safety and LC outcomes in this single-arm prospective trial that includes heavily pre-treated patients. A commercial version of the device recently received FDA clearance for use in newly diagnosed malignant or recurrent intracranial neoplasms including meningiomas.

PATH-34. GENETIC PROFILING OF AGGRESSIVE MENINGIOMAS REVEAL DIVERSE SPECTRUM OF ACCOMPANYING ALTERATIONS BEYOND NF2 INACTIVATION

Abstract BACKGROUND Meningiomas are the most common primary central nervous system tumor in adults. The majority are clinically indolent and WHO grade I. However, 20-30% are WHO grade II and 1-3% are WHO grade III, which have shorter progression-free (PFS) and overall survival. A subset of grade I meningiomas also follow an aggressive course, requiring serial resection and/or radiotherapy, similar to high-grade meningiomas. The objective of this study was to characterize the genetic alterations in meningiomas with an aggressive clinical course. METHODS Targeted next-generation sequencing (NGS) of 40 aggressive meningiomas was performed using the UCSF500 cancer panel, which assesses ~500 cancer-related genes. Information on patient demographics, tumor histopathology, and treatment history was also collected. RESULTS Meningiomas analyzed included 15 (38%) WHO grade I, 11 (28%) WHO grade II, and 13 (33%) WHO grade III. At the time of genetic profiling, 71% of patients had received prior treatment (68% surgery, 48% fractionated radiotherapy, 23% radiosurgery). The most commonly altered gene was NF2, with 71% of tumors demonstrating biallelic inactivation. Other common alterations included biallelic CDKN2A/B deletion (15%) and TERT amplification or promoter mutation (13%). Other recurrent alterations involved SUFU (8%), and ARID1A, ATM, BAP1, DMD, KDM6A, and PTEN (each 5%). Genes which are commonly altered in indolent WHO grade I meningiomas, such as AKT1, KLF4, PIK3CA, SMO, and TRAF7, were intact in this cohort. CONCLUSIONS The additional genetic alterations beyond NF2 inactivation that drive aggressive meningiomas are diverse and include homozygous deletion of CDKN2A (negative regulator of cyclin-dependent kinases 4/6), inactivating mutations in SUFU (a negative regulator of Hedgehog signaling), homozygous deletion of PTEN (a negative regulator of mTOR signaling), and mutations/deletions in epigenetic regulatory factors (e.g. ARID1A, KDM6A). Clinical trials are needed to assess the efficacy of therapeutics targeting these specific pathways in patients with meningiomas refractory to conventional treatments.