Abstract Nerve sheath tumors are the most common benign tumors of the spine after meningiomas. They include schwannomas, neurofibroma, and malignant peripheral nerve sheath tumors. These can arise ...sporadically or in association with tumor predisposition syndromes, including Neurofibromatosis type 1, Neurofibromatosis type 2, and Schwannomatosis. Though surgery is the traditional mainstay of treatment for these tumors, the discovery of the genetic and molecular basis of these diseases in recent decades has prompted investigation into targeted therapies. Here, we give a clinical overview of spinal nerve sheath tumors, their imaging features, current management practices, and explore ongoing advances in systemic therapies.
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 < 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 < 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.
The invasive capacity of GBM is one of the key tumoral features associated with treatment resistance, recurrence, and poor overall survival. The molecular machinery underlying GBM invasiveness ...comprises an intricate network of signaling pathways and interactions with the extracellular matrix and host cells. Among them, PI3k/Akt, Wnt, Hedgehog, and NFkB play a crucial role in the cellular processes related to invasion. A better understanding of these pathways could potentially help in developing new therapeutic approaches with better outcomes. Nevertheless, despite significant advances made over the last decade on these molecular and cellular mechanisms, they have not been translated into the clinical practice. Moreover, targeting the infiltrative tumor and its significance regarding outcome is still a major clinical challenge. For instance, the pre- and intraoperative methods used to identify the infiltrative tumor are limited when trying to accurately define the tumor boundaries and the burden of tumor cells in the infiltrated parenchyma. Besides, the impact of treating the infiltrative tumor remains unclear. Here we aim to highlight the molecular and clinical hallmarks of invasion in GBM.
Abstract
BTFC travel award recipient
Vestibular schwannoma (VS) is the most common tumour of the cerebellopontine angle and poses a significant morbidity for patients. While many exhibit benign ...behaviour, others have a more aggressive nature and pattern of growth. Predicting who will fall into which category consistently remains uncertain. There is a need for a better understanding of the molecular landscape, and important subgroups therein, of this disease.
METHODS: We select all vestibular schwannomas from our tumour bank with both methylation and RNA profiling available. Unsupervised clustering methods were used to define two distinct molecular subgroups of VS which were explored using computational techniques including bulk deconvolution analysis, gene pathway enrichment analysis, and drug repurposing analysis. Methylation data from two other cohorts were used to validate our findings, given a paucity of external samples with available multi-omic data. RESULTS: A total of 75 tumours were analyzed. Consensus clustering and similarity network fusion defined two subgroups ("immunogenic" and "proliferative”) with significant differences in immune, stroma, and tumour cell abundance (p<0.05). Gene network analysis and computational drug repurposing found critical differences in targets of immune checkpoint inhibition PD-1 and CTLA-4, the MEK pathway, and the epithelial to mesenchymal transition program, suggesting a need for subgroup-specific targeted treatment/trial design in the future. CONCLUSIONS: We leverage computational tools with multi-omic molecular data to define two robust subgroups of vestibular schwannoma with differences in microenvironment and therapeutic vulnerabilities.
Background
Vestibular schwannoma (VS) is the most common tumour of the cerebellopontine angle and poses a significant morbidity for patients. While many exhibit benign behaviour, others have a more ...aggressive nature and pattern of growth. Predicting who will fall into which category consistently remains uncertain. There is a need for a better understanding of the molecular landscape, and important subgroups therein, of this disease.
Methods
We select all vestibular schwannomas from our tumour bank with both methylation and RNA profiling available. Unsupervised clustering methods were used to define two distinct molecular subgroups of VS which were explored using computational techniques including bulk deconvolution analysis, gene pathway enrichment analysis, and drug repurposing analysis. Methylation data from two other cohorts were used to validate our findings, given a paucity of external samples with available multi-omic data.
Results
A total of 75 tumours were analyzed. Consensus clustering and similarity network fusion defined two subgroups (“immunogenic” and “proliferative”) with significant differences in immune, stroma, and tumour cell abundance (p < 0.05). Gene network analysis and computational drug repurposing found critical differences in targets of immune checkpoint inhibition PD-1 and CTLA-4, the MEK pathway, and the epithelial to mesenchymal transition program, suggesting a need for subgroup-specific targeted treatment/trial design in the future.
Conclusions
We leverage computational tools with multi-omic molecular data to define two robust subgroups of vestibular schwannoma with differences in microenvironment and therapeutic vulnerabilities.
Abstract
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.
There is scarce data on the quality of life of people with neurofibromatosis type 1 (NF1) and type 2 (NF2) in Canada.
A cross-sectional study of adults with NF1 and NF2 attending a tertiary center. ...Patients completed generic measures (SF-36, EQ-5D-5L, and PROMIS pain interference) and disease-specific questionnaires (PedsQL NF1 module and the NFTI-QOL for NF2). We compared generic scores between NF1 and NF2 individuals and used regression models to assess factors associated with quality of life.
Hundred and eighty-four participants were enrolled. Mean age was 33 years in NF1 and 40 years in NF2. NF1 and NF2 individuals had lower employment rates and lower scores in all domains of the SF-36 compared to the general Canadian population (
< .005). Using the EQ-5D-5L, there was a high proportion of pain (64% in NF1 and 74% in NF2) and anxiety/depression (60% in NF1 and 68% in NF2). Pain interference correlated with poor quality of life in NF1 and NF2; perceived physical appearance was the main predictor of mental well-being in NF1.
Individuals with NF1 and NF2 have low quality of life, and this correlates with pain, anxiety, and depression, which are prevalent in NF1 and NF2. Perceived physical appearance predicts quality of life in NF1. A multidisciplinary approach is necessary for patients with NF1 and NF2, including mental health and pain management.
Abstract
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.
Loss of H3K27me3 in meningiomas Nassiri, Farshad; Wang, Justin Z; Singh, Olivia ...
Neuro-oncology,
08/2021, Letnik:
23, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Abstract
Background
There is a critical need for objective and reliable biomarkers of outcome in meningiomas beyond WHO classification. Loss of H3K27me3 has been reported as a prognostically ...unfavorable alteration in meningiomas. We sought to independently evaluate the reproducibility and prognostic value of H3K27me3 loss by immunohistochemistry (IHC) in a multicenter study.
Methods
IHC staining for H3K27me3 and analyses of whole slides from 181 meningiomas across three centers was performed. Staining was analyzed by dichotomization into loss and retained immunoreactivity, and using a 3-tiered scoring system in 151 cases with clear staining. Associations of grouping with outcome were performed using Kaplan-Meier survival estimates.
Results
A total of 21 of 151 tumors (13.9%) demonstrated complete loss of H3K27me3 staining in tumor with retained endothelial staining. Overall, loss of H3K27me3 portended a worse outcome with shorter times to recurrence in our cohort, particularly for WHO grade 2 tumors which were enriched in our study. There were no differences in recurrence-free survival (RFS) for WHO grade 3 patients with retained vs loss of H3K27me3. Scoring by a 3-tiered system did not add further insights into the prognostic value of this H3K27me3 loss. Overall, loss of H3K27me3 was not independently associated with RFS after controlling for WHO grade, extent of resection, sex, age, and recurrence status of tumor on multivariable Cox regression analysis.
Conclusions
Loss of H3K27me3 identifies a subset of WHO grade 2 and possibly WHO grade 1 meningiomas with increased recurrence risk. Pooled analyses of a larger cohort of samples with standardized reporting of clinical definitions and staining patterns are warranted.
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