Molecular and translational advances in meningiomas.

Meningiomas are the most common primary intracranial neoplasm. The current World Health Organization (WHO) classification categorizes meningiomas based on histopathological features, but emerging molecular data demonstrate the importance of genomic and epigenomic factors in the clinical behavior of these tumors. Treatment options for symptomatic meningiomas are limited to surgical resection where possible and adjuvant radiation therapy for tumors with concerning histopathological features or recurrent disease. At present, alternative adjuvant treatment options are not available in part due to limited historical biological analysis and clinical trial investigation on meningiomas. With advances in molecular and genomic techniques in the last decade, we have witnessed a surge of interest in understanding the genomic and epigenomic landscape of meningiomas. The field is now at the stage to adopt this molecular knowledge to refine meningioma classification and introduce molecular algorithms that can guide prediction and therapeutics for this tumor type. Animal models that recapitulate meningiomas faithfully are in critical need to test new therapeutics to facilitate rapid-cycle translation to clinical trials. Here we review the most up-to-date knowledge of molecular alterations that provide insight into meningioma behavior and are ready for application to clinical trial investigation, and highlight the landscape of available preclinical models in meningiomas

Imaging and diagnostic advances for intracranial meningiomas

The archetypal imaging characteristics of meningiomas are among the most stereotypic of all central nervous system (CNS) tumors. In the era of plain film and ventriculography, imaging was only performed if a mass was suspected, and their results were more suggestive than definitive. Following more than a century of technological development, we can now rely on imaging to non-Invasively diagnose meningioma with great confidence and precisely delineate the locations of these tumors relative to their surrounding structures to inform treatment planning. Asymptomatic meningiomas may be identified and their growth monitored over time; moreover, imaging routinely serves as an essential tool to survey tumor burden at various stages during the course of treatment, thereby providing guidance on their effectiveness or the need for further intervention. Modern radiological techniques are expanding the power of imaging from tumor detection and monitoring to include extraction of biologic information from advanced analysis of radiological parameters. These contemporary approaches have led to promising attempts to predict tumor grade and, in turn, contribute prognostic data. In this supplement article, we review important current and future aspects of imaging in the diagnosis and management of meningioma, including conventional and advanced imaging techniques using CT, MRI, and nuclear medicine

Advances in multidisciplinary therapy for meningiomas

Surgery has long been established as the first-line treatment for the majority of symptomatic and enlarging meningiomas, and evidence for its success is derived from retrospective case series. Despite surgical resection, a subset of meningiomas display aggressive behavior with early recurrences that are difficult to treat. The decision to radically resect meningiomas and involved structures is balanced against the risk for neurological injury in patients. Radiation therapy has largely been used as a complementary and safe therapeutic strategy in meningiomas with evidence primarily stemming from retrospective, single-Institution reports. Two of the first cooperative group studies (RTOG 0539 and EORTC 22042) evaluating the outcomes of adjuvant radiation therapy in higher-risk meningiomas have shown promising preliminary results. Historically, systemic therapy has resulted in disappointing results in meningiomas. However, several clinical trials are under way evaluating the efficacy of chemotherapies, such as trabectedin, and novel molecular agents targeting Smoothened, AKT1, and focal adhesion kinase in patients with recurrent meningiomas

DNA methylation profiling to predict recurrence risk in meningioma: development and validation of a nomogram to optimize clinical management

Abstract Background Variability in standard-of-care classifications precludes accurate predictions of early tumor recurrence for individual patients with meningioma, limiting the appropriate selection of patients who would benefit from adjuvant radiotherapy to delay recurrence. We aimed to develop an individualized prediction model of early recurrence risk combining clinical and molecular factors in meningioma. Methods DNA methylation profiles of clinically annotated tumor samples across multiple institutions were used to develop a methylome model of 5-year recurrence-free survival (RFS). Subsequently, a 5-year meningioma recurrence score was generated using a nomogram that integrated the methylome model with established prognostic clinical factors. Performance of both models was evaluated and compared with standard-of-care models using multiple independent cohorts. Results The methylome-based predictor of 5-year RFS performed favorably compared with a grade-based predictor when tested using the 3 validation cohorts (ΔAUC = 0.10, 95% CI: 0.03–0.018) and was independently associated with RFS after adjusting for histopathologic grade, extent of resection, and burden of copy number alterations (hazard ratio 3.6, 95% CI: 1.8–7.2, P &lt; 0.001). A nomogram combining the methylome predictor with clinical factors demonstrated greater discrimination than a nomogram using clinical factors alone in 2 independent validation cohorts (ΔAUC = 0.25, 95% CI: 0.22–0.27) and resulted in 2 groups with distinct recurrence patterns (hazard ratio 7.7, 95% CI: 5.3–11.1, P &lt; 0.001) with clinical implications. Conclusions The models developed and validated in this study provide important prognostic information not captured by previously established clinical and molecular factors which could be used to individualize decisions regarding postoperative therapeutic interventions, in particular whether to treat patients with adjuvant radiotherapy versus observation alone. </jats:sec

Life after surgical resection of a meningioma: A prospective cross-sectional study evaluating health-related quality of life

Background Few studies have evaluated the health-related quality of life (HRQoL) of patients with meningiomas. Here, we report the largest prospective, longitudinal cross-sectional cohort study of HRQoL in meningiomas to date, in order to identify possible actionable determinants of global HRQoL. Methods Adults who had undergone resection of a grade I intracranial meningioma and were in routine follow-up at a single large tertiary center underwent HRQoL assessment using the QLQ-C30 questionnaire administered opportunistically at follow-up visits. Averaged transformed QLQ-C30 scores at 12-month intervals were compared with scores from a normative reference population, with reference to known minimal clinically meaningful difference (CMD) in scores. To evaluate for possible determinants of changes in global HRQoL, global HRQoL scores were correlated (Spearman's Rho) with subdomain and symptom scores and with interval time from surgical resection. Results A total of 291 postoperative patients with histologically confirmed and surgically treated grade I meningiomas consented to participation and a total of 455 questionnaires were included for analysis. Patients with meningiomas reported reduced global HRQoL at nearly every 12-month interval with clinically and statistically significant impairments at 12, 48, 108, and 120 months postoperative compared with the normative population (P &lt; 0.05). Meningioma patients at the 12-month interval also reported a reduction of each subdomain of HRQoL assessment (P &lt; 0.05); however, a CMD was only seen in cognitive functioning. Physical, emotional, cognitive, and social subdomains, as well as fatigue and sleep/insomnia, were significantly associated with global HRQoL at the first 12-month interval. Overall, there was no significant correlation between time from surgery and global HRQoL or the subdomain functional or symptom sections of the QLQ-C30. Conclusions Meningioma patients report considerable limitations in HRQoL for more than 120 months after surgery, particularly in cognitive, emotional, and social function, as well as suffering significant fatigue and sleep impairment compared with a normative reference population. The majority of these reported functional impairments and symptoms are strongly associated with global HRQoL and thus can be considered determinants of global HRQoL that if treated, have the potential to improve HRQoL for our meningioma patients. This hypothesis requires future study of targeted interventions to determine their efficacy

Imaging and diagnostic advances for intracranial meningiomas

The archetypal imaging characteristics of meningiomas are among the most stereotypic of all central nervous system (CNS) tumors. In the era of plain film and ventriculography, imaging was only performed if a mass was suspected, and their results were more suggestive than definitive. Following more than a century of technological development, we can now rely on imaging to non-Invasively diagnose meningioma with great confidence and precisely delineate the locations of these tumors relative to their surrounding structures to inform treatment planning. Asymptomatic meningiomas may be identified and their growth monitored over time; moreover, imaging routinely serves as an essential tool to survey tumor burden at various stages during the course of treatment, thereby providing guidance on their effectiveness or the need for further intervention. Modern radiological techniques are expanding the power of imaging from tumor detection and monitoring to include extraction of biologic information from advanced analysis of radiological parameters. These contemporary approaches have led to promising attempts to predict tumor grade and, in turn, contribute prognostic data. In this supplement article, we review important current and future aspects of imaging in the diagnosis and management of meningioma, including conventional and advanced imaging techniques using CT, MRI, and nuclear medicine

Life after surgical resection of a meningioma: A prospective cross-sectional study evaluating health-related quality of life

Background Few studies have evaluated the health-related quality of life (HRQoL) of patients with meningiomas. Here, we report the largest prospective, longitudinal cross-sectional cohort study of HRQoL in meningiomas to date, in order to identify possible actionable determinants of global HRQoL. Methods Adults who had undergone resection of a grade I intracranial meningioma and were in routine follow-up at a single large tertiary center underwent HRQoL assessment using the QLQ-C30 questionnaire administered opportunistically at follow-up visits. Averaged transformed QLQ-C30 scores at 12-month intervals were compared with scores from a normative reference population, with reference to known minimal clinically meaningful difference (CMD) in scores. To evaluate for possible determinants of changes in global HRQoL, global HRQoL scores were correlated (Spearman's Rho) with subdomain and symptom scores and with interval time from surgical resection. Results A total of 291 postoperative patients with histologically confirmed and surgically treated grade I meningiomas consented to participation and a total of 455 questionnaires were included for analysis. Patients with meningiomas reported reduced global HRQoL at nearly every 12-month interval with clinically and statistically significant impairments at 12, 48, 108, and 120 months postoperative compared with the normative population (P &lt; 0.05). Meningioma patients at the 12-month interval also reported a reduction of each subdomain of HRQoL assessment (P &lt; 0.05); however, a CMD was only seen in cognitive functioning. Physical, emotional, cognitive, and social subdomains, as well as fatigue and sleep/insomnia, were significantly associated with global HRQoL at the first 12-month interval. Overall, there was no significant correlation between time from surgery and global HRQoL or the subdomain functional or symptom sections of the QLQ-C30. Conclusions Meningioma patients report considerable limitations in HRQoL for more than 120 months after surgery, particularly in cognitive, emotional, and social function, as well as suffering significant fatigue and sleep impairment compared with a normative reference population. The majority of these reported functional impairments and symptoms are strongly associated with global HRQoL and thus can be considered determinants of global HRQoL that if treated, have the potential to improve HRQoL for our meningioma patients. This hypothesis requires future study of targeted interventions to determine their efficacy

DNA methylation profiling to predict recurrence risk in meningioma: Development and validation of a nomogram to optimize clinical management

Background: Variability in standard-of-care classifications precludes accurate predictions of early tumor recurrence for individual patients with meningioma, limiting the appropriate selection of patients who would benefit from adjuvant radiotherapy to delay recurrence. We aimed to develop an individualized prediction model of early recurrence risk combining clinical and molecular factors in meningioma. Methods: DNA methylation profiles of clinically annotated tumor samples across multiple institutions were used to develop a methylome model of 5-year recurrence-free survival (RFS). Subsequently, a 5-year meningioma recurrence score was generated using a nomogram that integrated the methylome model with established prognostic clinical factors. Performance of both models was evaluated and compared with standard-of-care models using multiple independent cohorts. Results: The methylome-based predictor of 5-year RFS performed favorably compared with a grade-based predictor when tested using the 3 validation cohorts (ΔAUC = 0.10, 95% CI: 0.03-0.018) and was independently associated with RFS after adjusting for histopathologic grade, extent of resection, and burden of copy number alterations (hazard ratio 3.6, 95% CI: 1.8-7.2, P &lt; 0.001). A nomogram combining the methylome predictor with clinical factors demonstrated greater discrimination than a nomogram using clinical factors alone in 2 independent validation cohorts (ΔAUC = 0.25, 95% CI: 0.22-0.27) and resulted in 2 groups with distinct recurrence patterns (hazard ratio 7.7, 95% CI: 5.3-11.1, P &lt; 0.001) with clinical implications. Conclusions: The models developed and validated in this study provide important prognostic information not captured by previously established clinical and molecular factors which could be used to individualize decisions regarding postoperative therapeutic interventions, in particular whether to treat patients with adjuvant radiotherapy versus observation alone

Molecular and translational advances in meningiomas

Meningiomas are the most common primary intracranial neoplasm. The current World Health Organization (WHO) classification categorizes meningiomas based on histopathological features, but emerging molecular data demonstrate the importance of genomic and epigenomic factors in the clinical behavior of these tumors. Treatment options for symptomatic meningiomas are limited to surgical resection where possible and adjuvant radiation therapy for tumors with concerning histopathological features or recurrent disease. At present, alternative adjuvant treatment options are not available in part due to limited historical biological analysis and clinical trial investigation on meningiomas. With advances in molecular and genomic techniques in the last decade, we have witnessed a surge of interest in understanding the genomic and epigenomic landscape of meningiomas. The field is now at the stage to adopt this molecular knowledge to refine meningioma classification and introduce molecular algorithms that can guide prediction and therapeutics for this tumor type. Animal models that recapitulate meningiomas faithfully are in critical need to test new therapeutics to facilitate rapid-cycle translation to clinical trials. Here we review the most up-to-date knowledge of molecular alterations that provide insight into meningioma behavior and are ready for application to clinical trial investigation, and highlight the landscape of available preclinical models in meningiomas