Preparación psicológica para radioterapia en paciente con tumor en SNC: presentación de un caso / Psychological preparation for radiotherapy on a patient with a brain tumor: case report

Introducción: los meningiomas forman el 27% de los tumores de encéfalo en población adulta. La radioterapia es uno de los tratamientos para tumores primarios del SNC más efectivos, en el cual se administran altas dosis de radiación que destruye el ADN de las células cancerosas para detener su multiplicación o lentificar su crecimiento. Para este tratamiento es necesaria la inmovilización del paciente, que se asegura por medio de máscaras termoplásticas que fijan al paciente a la camilla del acelerador lineal. Este tipo de inmovilización ha representado una incidencia de ansiedad significativa previa al tratamiento y durante el mismo, puede causar niveles altos de estrés, miedo, malestar físico, dolor e incluso claustrofobia. Tomando en cuenta estos aspectos, como preparación psicológica para el tratamiento se sugiere ofrecer información clara previa y durante la simulación, identificar a los pacientes con niveles altos de ansiedad, y brindar estrategias cognitivas y conductuales para regular la misma. Objetivo: Describir un reporte de caso de preparación para radioterapia en SNC. Método: Se presenta el caso de una mujer de 61 años de edad que fue referida a psico-oncología con el objetivo de la preparación psicológica para radioterapia en SNC. El motivo de la referencia a psico-oncología fue evitar la sedación durante la radioterapia debido a los altos niveles de ansiedad que presentaba la paciente. Se realizaron dos sesiones de preparación psicológica en donde se incluyeron estrategias psicoeducativas, de desensibilización sistemática y respiración diafragmática. Resultados: La paciente disminuyó el reporte subjetivo de ansiedad, logró terminar las 25 sesiones de radioterapia sin necesidad de sedación. Conclusión: La preparación psicológica utilizada en esta paciente fue efectiva para disminuir ansiedad. Es importante realizar estudios aleatorizados y controlados para conocer realmente la efectividad.(AU)

Introduction:Meningiomas represent 27% of brain tumors in adults. Radiotherapy is one of the most frequent treatments for CNS tumors, in which high radiation doses destroy cancer cell’s DNA in order to stop their multiplication or to slow their growth. Patient’s inmovilization is necessary in this treatment, so he has to be attached to treatment bed with a thermogenic mask. This inmovilization has represented significant anxiety prior and during treatment, it can also represent a trigger for stress, fears, physical symptoms, pain and even claustrophobia. Considering this, a psychological preparation is suggested before radiotherapy. It is suggested o include clear information before and during simulation, and to identify patients with high levels of anxiety, and to deliver cognitive and behavioral strategies to regulate it. Aim: to describe a case report of a psychological preparation for CNS radiotherapy. Method: A case of a 61 year old woman who was referred to psycho-oncology service with the aim of psychological preparation for CNS radiation. The reason this patient was referred was to avoid sedation during treatment due to high levels of anxiety. Psychologic preparation consisted in two sessions that included psychoeducational, systematic desensibilization and diaphragmatic breathing strategies. Results: Subjective anxiety report was reduced with psychologic preparation, and the patient finished 25 sessions of radiotherapy without sedation. Conclusion: Psychological preparation in this patient was efective in anxiety reduction. It is important to design randomized controled studies in order to know the effectiveness of these strategies.(AU)

Drug target therapy and emerging clinical relevance of exosomes in meningeal tumors.

Meningioma is the most common central nervous system (CNS) tumor. In recent decades, several efforts have been made to eradicate this disease. Surgery and radiotherapy remain the standard treatment options for these tumors. Drug therapy comes to play its role when both surgery and radiotherapy fail to treat the tumor. This mostly happens when the tumors are close to vital brain structures and are nonbenign. Although a wide variety of chemotherapeutic drugs and molecular targeted drugs such as tyrosine kinase inhibitors, alkylating agents, endocrine drugs, interferon, and targeted molecular pathway inhibitors have been studied, the roles of numerous drugs remain unexplored. Recent interest is growing toward studying and engineering exosomes for the treatment of different types of cancer including meningioma. The latest studies have shown the involvement of exosomes in the theragnostic of various cancers such as the lung and pancreas in the form of biomarkers, drug delivery vehicles, and vaccines. Proper attention to this new emerging technology can be a boon in finding the consistent treatment of meningioma.

The association of thromboembolic complications and the use of tranexamic acid during resection of intracranial meningiomas: systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: Antifibrinolytics, such as tranexamic acid (TXA), have been shown to decrease intraoperative blood loss across multiple surgical disciplines. However, they carry the theoretical risk of thromboembolic events secondary to induced hypercoagulability. Therefore, the aim of this study was to systematically review the available literature and perform a meta-analysis on the use of TXA in meningioma resection to assess thromboembolic risks. METHODS: The PubMed, Web of Science, and Google Scholar databases were reviewed for all randomized controlled trials presenting primary data on TXA use during resection of intracranial meningiomas. Data were gathered on operative duration, venous thromboembolic complications, deep venous thrombosis, use of allogeneic blood transfusion, estimated blood loss (EBL), and postoperative hemoglobin. Patients who received TXA were compared with controls who did not receive TXA intraoperatively using random-effects models. RESULTS: A total of 508 unique articles were identified, of which 493 underwent full-text review. Ultimately, 6 studies with 381 total patients (190 receiving TXA) were included in the final analysis. All 6 trials were randomized, blinded, and placebo controlled with a TXA administration rate of a 20-mg/kg load followed by a 1-mg/kg/hr infusion. All studies were performed in lower-middle-income countries. There were no reported instances of venous thromboembolism (VTE) in the TXA and non-TXA cohorts. Patients receiving TXA exhibited fewer allogeneic transfusions (21.5% vs 41.6% [OR 0.26, 95% CI 0.09-0.77], p = 0.02) and lower EBL (MD -282.48 mL [95% CI -367.77 to -197.20 mL], p < 0.001) compared with patients who did not receive TXA, and they also had lower rates of perioperative complications (10.7% vs 19.9% [OR 0.47, 95% CI 0.2-0.95], p = 0.04). CONCLUSIONS: Current literature suggests that TXA is not associated with increased risk for VTE when administered during resection of intracranial meningioma. TXA appears to decrease intraoperative blood loss and allogeneic transfusion requirements during meningioma resection and thus may improve the safety of surgical management of this pathology.

Evaluation of the SSTR2-targeted Radiopharmaceutical 177Lu-DOTATATE and SSTR2-specific 68Ga-DOTATATE PET as Imaging Biomarker in Patients with Intracranial Meningioma.

PURPOSE: There are no effective medical therapies for patients with meningioma who progress beyond surgical and radiotherapeutic interventions. Somatostatin receptor type 2 (SSTR2) represents a promising treatment target in meningiomas. In this multicenter, single-arm phase II clinical study (NCT03971461), the SSTR2-targeting radiopharmaceutical 177Lu-DOTATATE is evaluated for its feasibility, safety, and therapeutic efficacy in these patients. PATIENTS AND METHODS: Adult patients with progressive intracranial meningiomas received 177Lu-DOTATATE at a dose of 7.4 GBq (200 mCi) every eight weeks for four cycles. 68Ga-DOTATATE PET-MRI was performed before and six months after the start of the treatment. The primary endpoint was progression-free survival (PFS) at 6 months (PFS-6). Secondary endpoints were safety and tolerability, overall survival (OS) at 12 months (OS-12), median PFS, and median OS. RESULTS: Fourteen patients (female = 11, male = 3) with progressive meningiomas (WHO 1 = 3, 2 = 10, 3 = 1) were enrolled. Median age was 63.1 (range 49.7-78) years. All patients previously underwent tumor resection and at least one course of radiation. Treatment with 177Lu-DOTATATE was well tolerated. Seven patients (50%) achieved PFS-6. Best radiographic response by modified Macdonald criteria was stable disease (SD) in all seven patients. A >25% reduction in 68Ga-DOTATATE uptake (PET) was observed in five meningiomas and two patients. In one lesion, this corresponded to >50% reduction in bidirectional tumor measurements (MRI). CONCLUSIONS: Treatment with 177Lu-DOTATATE was well tolerated. The predefined PFS-6 threshold was met in this interim analysis, thereby allowing this multicenter clinical trial to continue enrollment. 68Ga-DOTATATE PET may be a useful imaging biomarker to assess therapeutic outcome in patients with meningioma.

Advances in the systemic therapy for recurrent meningiomas and the challenges ahead.

INTRODUCTION: Meningiomas represent the most common primary neoplasms of the central nervous system (CNS). 20% present with atypical (WHO grade II) or malignant (grade III) meningiomas, which show aggressive biologic behavior and high recurrence. Although surgical resection and radiation therapy are the primary treatment options for these tumors, there is a subgroup of patients who do not respond well to or are poor candidates for these approaches, leading to the exploration of systemic therapies as an alternative. AREAS COVERED: The literature on different therapeutic groups of systemic drugs for recurrent meningiomas is reviewed, with a focus on the different molecular targets. Past and current ongoing clinical trials are also discussed. EXPERT OPINION: To date, there is no recognized treatment that has demonstrated a substantial increase in progression-free or overall survival rates. Nonetheless, therapies targeting anti-VEGF have exhibited more encouraging results in general. The examination of genomic and epigenomic traits of meningiomas, along with the integration of molecular markers into the latest WHO tumor grading system, has provided valuable insights. This has opened avenues for exploring numerous intracellular and extracellular pathways, as well as mutations, that have been targeted in ongoing clinical trials.

Drug Repositioning for Refractory Benign Tumors of the Central Nervous System.

Drug repositioning (DR) is the process of identifying novel therapeutic potentials for already-approved drugs and discovering new therapies for untreated diseases. DR can play an important role in optimizing the pre-clinical process of developing novel drugs by saving time and cost compared with the process of de novo drug discovery. Although the number of publications related to DR has rapidly increased, most therapeutic approaches were reported for malignant tumors. Surgical resection represents the definitive treatment for benign tumors of the central nervous system (BTCNS). However, treatment options remain limited for surgery-, chemotherapy- and radiation-refractory BTCNS, as well as malignant tumors. Meningioma, pituitary neuroendocrine tumor (PitNET), and schwannoma are the most common BTCNS. The treatment strategy using DR may be applied for refractory BTCNS, such as Grade 2 meningiomas, neurofibromatosis type 2-related schwannomatosis, and PitNETs with cavernous sinus invasion. In the setting of BTCNS, stable disease can provide significant benefit to the patient. DR may provide a longer duration of survival without disease progression for patients with refractory BTCNS. This article reviews the utility of DR for refractory BTCNS.

Novel Medical Therapies in Meningiomas.

Meningiomas are the most common primary brain tumor in adults and have been historically managed with surgery and radiation therapy. However, in patients with inoperable, recurrent or high-grade tumors, medical therapy is often needed. Traditional chemotherapy and hormone therapy have been largely ineffective. However, with improved understanding of the molecular drivers in meningioma, there has been increasing interest in targeted molecular and immune therapies. In this chapter, we will discuss recent advances in meningioma genetics and biology and review current clinical trials with targeted molecular treatment and other novel therapies.

Molecular predictors for decitabine efficacy in meningiomas - a pilot study.

PURPOSE: Effective chemotherapeutical agents for the treatment of meningiomas are still lacking. Previous in-vitro analyses revealed efficacy of decitabine (DCT), a DNA methyltransferase (DNMT) inhibitor established in the treatment of leukemia, in a yet undefined subgroup of meningiomas. METHODS: Effects of DCT on proliferation and viability was analyzed in primary meningioma cells by immunofluorescence and MTT assays, and cases were classified as drug responders and non-responders. Molecular preconditions for efficacy were analyzed using immunofluorescence for Ki67, DNMT1, and five oncogenes (TRIM58, FAM84B, ELOVL2, MAL2, LMO3) previously found to be differentially methylated after DCT exposition, as well as by genome-wide DNA methylation analyses. RESULTS: Efficacy of DCT (10µM) was found in eight (62%) of 13 meningioma cell lines 48 h after drug exposition (p < .05). DCT significantly reduced DNMT1 expression in all but two cell lines, and median ΔDNMT1 reduction 48 h after drug exposition was lower in DCT-resistant (-11.1%) than in DCT-sensitive (-50.5%, p = .030) cells. Rates of cell lines responsive to DCT exposition distinctly decreased to 25% after 72 h. No significant correlation of the patients´ age, sex, histological subtype, location of the paternal tumor, expression of Ki67, DNMT1 or the analyzed oncogenes with treatment response was found (p > .05, each). DCT efficacy was further independent of the methylation class and global DNA methylation of the paternal tumor. CONCLUSION: Early effects of DCT in meningiomas are strongly related with DNMT1 expression, while clinical, histological, and molecular predictors for efficacy are sparse. Kinetics of drug efficacy might indicate necessity of repeated exposition and encourage further analyses.

Tumor-selective Blockade of CD47 Signaling with CD47 Antibody for Enhanced Anti-tumor Activity in Malignant Meningioma.

BACKGROUND: Patients with WHO grade III meningioma have a poor prognosis with a median survival of less than two years and a high risk of recurrence. However, traditional treatment options have failed to improve prognosis. Therefore, development of novel immunotherapy targets is urgently needed. CD47 acting as a "don't eat me" signal to macrophages can trigger tumor immune escape. However, the role of CD47 in malignant meningioma is not well understood. METHODS: We collected 190 clinical meningioma samples and detected the expression of CD47 and immune infiltration in WHO grade I-III by immunohistochemistry, western blot, qPCR. We also examined the functional effects of anti-CD47 on cell proliferation, migration and invasion, macrophagemediated phagocytosis and tumorigenicity both in vitro and in vivo. RESULTS: We found that the expression of CD47 was increased in malignant meningioma along with a decreased number of T cells and an increase in CD68+ macrophages. Blocking CD47 with anti-CD47 antibody (B6H12) suppressed tumor cell growth, motility and promoted macrophage-mediated phagocytosis in IOMM-Lee cells in vitro. In vivo experiments showed that anti-CD47 antibody (B6H12 or MIAP301) significantly inhibited the tumor growth and this effect was partly blocked by the depletion of macrophages. Finally, p-ERK and EGFR showed higher expression in malignant meningioma with high expression of CD47, which was verified by western blot. CONCLUSION: Our results demonstrated that CD47 maybe involved in the meningioma progression and prognosis and offered a novel therapeutic option by targeting CD47 in malignant meningioma.

Uncovering the molecular landscape of meningiomas and the impact of perioperative steroids on patient survival.

BACKGROUND: The current literature on meningioma reveals a gap in knowledge regarding the impact of genetic factors on patient survival. Furthermore, there is a lack of data on the relationship between the perioperative use of corticosteroids and patient survival in meningioma patients. Our study aims to overcome these gaps by investigating the correlation between genetic factors and overall survival and the effect of postoperative corticosteroids and other clinical characteristics on patient outcomes in meningioma patients. METHODS: A retrospective analysis of the medical records of 85 newly diagnosed meningioma patients treated from 2016 to 2017 with follow-up until December 2022 was performed. RESULTS: NF2 mutations occurred in 60% of tumors, AKT1 mutations in 8.2%, and TRAF7 mutations in 3.6%. Most tumors in the parasagittal region had the NF2 mutation. On the other hand, almost all tumors in the sphenoid ridge area did not have the NF2 mutation. AKT-1-mutated meningiomas had more frequent peritumoral edema. Patients who received steroids perioperatively had worse overall survival (OS) than those without steroids (p = 0.034). Moreover, preoperative peri-meningioma edema also was associated with worse OS (p < 0.003). Contrarily, NF2 mutations did not influence survival. CONCLUSIONS: The combination of clinical, pathomorphological, and genetic data allows us to characterize the tumor better and assess its prognosis. Corticosteroids perioperatively and peri-meningioma edema were associated with shorter OS, according to our study. Glucocorticoids should be used judiciously for the shortest time required to achieve symptomatic relief.

Prognostic factors and Doxorubicin involved in malignant progression of meningioma.

Meningioma was the most primary intracranial tumor, but the molecular characteristics and the treatment of malignant meningioma were still unclear. Nine malignant progression-related genes based prognostic signatures were identified by transcriptome analysis between benign meningioma and malignant meningioma. The external dataset GEO136661 and quantitative Real-time Polymerase Chain Reaction were used to verify the prognostic factors. has-miR-3605-5p, hsa-miR-664b-5p, PNRC2, BTBD8, EXTL2, SLFN13, DGKD, NSD2, and BVES were closed with malignant progression. Moreover, Doxorubicin was identified by Connectivity Map website with the differential malignant progression-related genes. CCK-8 assay, Edu assay, wound healing assay, and trans-well experiment were used to reveal that Doxorubicin could inhibit proliferation, migration and invasion of IOMM-Lee Cells.

A systematic review and meta-analysis of the effects of tranexamic acid in surgical procedure for intracranial meningioma.

PURPOSE: During intracranial meningioma surgery, surgeons experience considerable blood loss. Tranexamic acid (TXA) is used to minimize blood loss in several neurosurgical settings. However, evidence and trials are lacking. Our objective is to establish the most recent evidence on TXA safety and efficacy in intracranial meningioma surgery. METHODOLOGY: Based upon Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), the authors collected fully published English literature on the administration of tranexamic acid for patients undergoing intracranial meningioma surgery using the keywords ["tranexamic acid" and "meningioma"] and its synonyms from Cochrane Central Database, the WHO International Clinical Trials Registry Platform (ICTRP), ClinicalTrials.gov, and PubMed. The primary outcome of the current study was total blood loss. The secondary outcomes include individuals requiring blood transfusion, anesthesia duration, surgical duration, and complication rate. Each included studies' quality was assessed using the JADAD scale. RESULTS: For qualitative and quantitative data synthesis, we included five RCTs (n = 321) with the mean age was 47.5 ± 11.9 years for the intervention group and 47.2 ± 11.9 years for the control group. Our meta-analysis showed that the administration of TXA is associated with decreased total blood loss of standardized mean difference (SMD) of -1.40 (95% CI [-2.49, -0.31]), anesthetic time SMD -0.36 (95% CI [-0.63, -0.09]), and blood transfusion requirements RR 0.58 (95% CI [0.34, 0.99]). CONCLUSIONS: The current study showed that TXA was associated with reduced intraoperative blood loss and intra- and postoperative blood transfusion. However, the studies are small. More RCT studies with a greater sample size are favorable.

Efficacy Endpoints in Phase II Clinical Trials for Meningioma: An Analysis of Recent Clinical Trials.

BACKGROUND: Response Evaluation Criteria in Solid Tumors (RECIST)-based response rates are commonly used as efficacy endpoints in phase II clinical trials for solid tumors. However, no consensus has been reached concerning adequate efficacy endpoints for phase II clinical trials targeting meningioma. Irregularity of lesions after resection, and varying degrees of dysplasia and histologic subtypes make establishing an appropriate efficacy evaluation difficult. METHODS: We analyzed primary efficacy endpoints (PEEs) and background factors from 48 trials retrieved from ClinicalTrials.gov ( https://clinicaltrials.gov/ ) using the search criteria "meningioma," "interventional," "phase II," and "study start 4/1/2001 to 3/31/2021." Primary purpose of the study was efficacy endpoint setting in overall population and three subgroups. RESULTS: Among 45 PEEs set in the 39 trials included; 33 trials with single PEE, and six trials with double PEEs, 17/45 (38%) trials adopted progression-free survival (PFS) rate, 15/45 (33%) trials response rate (seven Macdonald criteria or modified, three RECIST, three volumetric estimation, one RANO criteria, one unknown), 10/45 (22%) PFS, 1/45 (2%) OS, and 2/45 (4%) other endpoints. Although 26 PEEs were time-to-event endpoints, 19 of the 26 PEEs were single-arm studies. CONCLUSIONS: Time-to-event efficacy endpoints were often compared to historical data, and two-dimensional evaluation is more suitable than one-dimensional one. Accumulation of prognostic data is essential to standardize time-to-event efficacy endpoints. Considering the difficulty of setting design for phase II clinical studies targeting meningioma, evaluation might be done with multiple efficacy endpoints.

Hormone therapies in meningioma-where are we?

INTRODUCTION: Meningiomas are associated with several gonadal steroid hormone-related risk factors and demonstrate a predominance in females. These associations led to investigations of the role that hormones may have on meningioma growth and development. While it is now accepted that most meningiomas express progesterone and somatostatin receptors, the conclusion for other receptors has been less definitive. METHODS: We performed a review of what is known regarding the relationship between hormones and meningiomas in the published literature. Furthermore, we reviewed clinical trials related to hormonal agents in meningiomas using MEDLINE PubMed, Scopus, and the NIH clinical trials database. RESULTS: We identify that all steroid-hormone trials lacked receptor identification or positive receptor status in the majority of patients. In contrast, four out of five studies involving somatostatin analogs used positive receptor status as part of the inclusion criteria. CONCLUSIONS: Several clinical trials have recently been completed or are now underway using somatostatin analogs in combination with other therapies that appear promising, but a reevaluation of hormone-based monotherapy is warranted. Synthesizing this evidence, we clarify the remaining questions and present future directions for the study of the biological role and therapeutic potential of hormones in meningioma and discuss how the stratification of patients using features such as grade, receptor status, and somatic mutations, might be used for future trials to select patients most likely to benefit from specific therapies.

Malignant meningioma mTOR mutated and precision medicine.

BACKGROUND: WHO grade II and III meningiomas are more invasive than grade I malignancies and determine patients' shorter overall survival. Their tendency to recur after treatment has represented an important therapeutic challenge because of the limited treatment strategies at recurrence. Angiogenesis and mechanistic target of rapamycin (mTOR) activation are two of the main features of higher grade meningiomas, determining invasiveness and tendency to relapse. While these options prove promising, available clinical data on mTOR inhibitors' efficacy are somewhat limited. CASE STUDY: We report a case of a 25-year-old female patient diagnosed with a right parasagittal occipital anaplastic meningioma (grade III WHO) in 2013. The patient underwent multiple treatments and, in 2019, a further recurrence occurred. The patient reported an mTOR mutation, and it is for this reason that the MTB approved treatment with everolimus and bevacizumab. Therapy was administered in May 2019, and partial response and prolonged disease control was obtained in November 2021, when progression took place. The patient's death occurred in March 2022. CONCLUSIONS: This case report provides evidence on the efficacy of mTOR inhibitors as a treatment option in recurrent meningiomas. Furthermore, it highlights the importance of performing a molecular analysis as a preliminary step towards targeting the mTOR pathway.

Pharmacological Landscape of FDA-Approved Anticancer Drugs Reveals Sensitivities to Ixabepilone, Romidepsin, Omacetaxine, and Carfilzomib in Aggressive Meningiomas.

PURPOSE: To date, there are no systemic treatment options for patients with recurrent or refractory meningioma. EXPERIMENTAL DESIGN: To identify effective drugs, we performed a large-scale drug screening using FDA-approved drugs on several meningioma cell lines. The impact of the top four compounds was assessed on cell viability, proliferation, colony formation, migration, and apoptosis. In addition, the antineoplastic effects of the selected drugs were validated in a heterotopic xenograft mouse model. RESULTS: Analyses of the viability of meningioma cells treated with 119 antineoplastic FDA-approved drugs resulted in categorization into sensitive and resistant drug-response groups based on the mean IC50 values and peak serum concentrations (Cmax) in patients. Eighty drugs, including 15 alkylating agents, 14 antimetabolites, and 13 tyrosine kinase inhibitors, were classified as resistant (IC50 > Cmax). The sensitive drug-response group (n = 29, IC50 < Cmax) included RNA/protein synthesis inhibitors, proteasome inhibitors, topoisomerase, tyrosine-kinase, and partial histone deacetylase and microtubule inhibitors. The IC50 value of the four most effective compounds (carfilzomib, omacetaxine, ixabepilone, and romidepsin) ranged from 0.12 to 9.5 nmol/L. Most of them caused cell-cycle arrest in the G2-M-phase and induced apoptosis. Furthermore, all drugs except romidepsin significantly inhibited tumor growth in vivo. The strongest antineoplastic effect was observed for ixabepilone, which reduced tumor volume by 86%. CONCLUSIONS: In summary, a large-scale drug screening provides a comprehensive insight into the anti-meningioma activities of FDA-approved drugs, and identified carfilzomib, omacetaxine, ixabepilone, and romidepsin as novel potent antineoplastic agents for the treatment of aggressive meningiomas. The most pronounced effects were observed with ixabepilone mandating for further clinical investigation.

Alliance A071401: Phase II Trial of Focal Adhesion Kinase Inhibition in Meningiomas With Somatic NF2 Mutations.

PURPOSE: Patients with progressive or recurrent meningiomas have limited systemic therapy options. Focal adhesion kinase (FAK) inhibition has a synthetic lethal relationship with NF2 loss. Given the predominance of NF2 mutations in meningiomas, we evaluated the efficacy of GSK2256098, a FAK inhibitor, as part of the first genomically driven phase II study in recurrent or progressive grade 1-3 meningiomas. PATIENTS AND METHODS: Eligible patients whose tumors screened positively for NF2 mutations were treated with GSK2256098, 750 mg orally twice daily, until progressive disease. Efficacy was evaluated using two coprimary end points: progression-free survival at 6 months (PFS6) and response rate by Macdonald criteria, where PFS6 was evaluated separately within grade-based subgroups: grade 1 versus 2/3 meningiomas. Per study design, the FAK inhibitor would be considered promising in this patient population if either end point met the corresponding decision criteria for efficacy. RESULTS: Of 322 patients screened for all mutation cohorts of the study, 36 eligible and evaluable patients with NF2 mutations were enrolled and treated: 12 grade 1 and 24 grade 2/3 patients. Across all grades, one patient had a partial response and 24 had stable disease as their best response to treatment. In grade 1 patients, the observed PFS6 rate was 83% (10/12 patients; 95% CI, 52 to 98). In grade 2/3 patients, the observed PFS6 rate was 33% (8/24 patients; 95% CI, 16 to 55). The study met the PFS6 efficacy end point both for the grade 1 and the grade 2/3 cohorts. Treatment was well tolerated; seven patients had a maximum grade 3 adverse event that was at least possibly related to treatment with no grade 4 or 5 events. CONCLUSION: GSK2256098 was well tolerated and resulted in an improved PFS6 rate in patients with recurrent or progressive NF2-mutated meningiomas, compared with historical controls. The criteria for promising activity were met, and FAK inhibition warrants further evaluation for this patient population.

Emerging systemic treatment options in meningioma.

PURPOSE: Meningiomas are the most frequently diagnosed intracranial neoplasms. Usually, they are treated by surgical resection in curative intent. Radiotherapy and stereotactic radiosurgery are commonly applied in the adjuvant setting in newly diagnosed atypical (CNS WHO grade 2), and anaplastic (CNS WHO grade 3) meningioma, especially if gross total resection is not feasible, and in recurrent cases. Conversely, the evidence for pharmacotherapy in meningioma is scarce. METHODS: The available literature of systemic treatment in meningioma was screened using PubMed, and ongoing clinical trials were explored using ClinicalTrials.gov. RESULTS: Classical cytotoxic agents, somatostatin analogs, and antihormone treatments have shown only limited efficacy. In contrast, tyrosine kinase inhibitors and monoclonal antibodies, especially those targeting angiogenic signaling such as sunitinib and bevacizumab, have shown promising antitumoral activity in small phase 2 trials. Moreover, results of recent landmark studies on (epi-)genetic alterations in meningioma revealed potential therapeutic targets which are currently under investigation. These include inhibitors of mammalian target of rapamycin (mTOR), focal adhesion kinase (FAK), cyclin-dependent kinases (CDK), phosphoinositide-3-kinase (PI3K), sonic hedgehog signaling, and histone deacetylases. In addition, clinical trials evaluating immune checkpoint inhibitors such as ipilimumab, nivolumab, pembrolizumab and avelumab are currently being conducted and early results suggest clinically meaningful responses in a subset of patients. CONCLUSIONS: There is a paucity of high-level evidence on systemic treatment options in meningioma. However, interesting novel treatment targets have been identified in the last decade. Positive signals of anti-angiogenic agents, genomically targeted agents and immunotherapy in early phase trials should be confirmed in large prospective controlled trials.

Docetaxel targets aggressive methylation profiles and serves as a radiosensitizer in high-risk meningiomas.

BACKGROUND: Meningioma is the most common primary intracranial tumor in adults. A subset of these tumors recur and invade the brain, even after surgery and radiation, resulting in significant disability. There is currently no standard-of-care chemotherapy for meningiomas. As genomic DNA methylation profiling can prognostically stratify these lesions, we sought to determine whether any existing chemotherapies might be effective against meningiomas with high-risk methylation profiles. METHODS: A previously published dataset of meningioma methylation profiles was used to screen for clinically significant CpG methylation events and associated cellular pathways. Based on these results, patient-derived meningioma cell lines were used to test candidate drugs in vitro and in vivo, including efficacy in conjunction with radiotherapy. RESULTS: We identified 981 genes for which methylation of mapped CpG sites was related to progression-free survival in meningiomas. Associated molecular pathways were cross-referenced with FDA-approved cancer drugs, which nominated Docetaxel as a promising candidate for further preclinical analyses. Docetaxel arrested growth in 17 meningioma cell sources, representing all tumor grades, with a clinically favorable IC50 values ranging from 0.3 nM to 10.7 mM. The inhibitory effects of this medication scaled with tumor doubling time, with maximal benefit in fast-growing lesions. The combination of Docetaxel and radiation therapy increased markers of apoptosis and double-stranded DNA breaks, and extended the survival of mice engrafted with meningioma cells relative to either modality alone. CONCLUSIONS: Global patterns of DNA methylation may be informative for the selection of chemotherapies against meningiomas, and existing drugs may enhance radiation sensitivity in high-risk cases.