Abstract BACKGROUND Surgery is the mainstay of meningioma treatment, but improvements in meningioma risk stratification are needed and indications for postoperative radiotherapy are controversial. DNA methylation profiling, copy number variants (CNVs), exome sequencing, and RNA sequencing have improved understanding of meningioma biology, but have not superseded histologic grading, or revealed biomarkers for radiotherapy responses. To address these unmet needs, we optimized and validated a targeted gene expression biomarker predicting meningioma outcomes and responses to radiotherapy. METHODS Targeted gene expression profiling was performed on a discovery cohort of 173 meningiomas (median follow-up 8.1 years) and a validation cohort of 331 meningiomas (median follow-up 6.1 years) treated with surgery (n=504) and postoperative radiotherapy (n=73) at independent, international institutions (70% WHO grade 1, 24% WHO grade 2, 6% WHO grade 3). Optimized targeted gene expression models predicting clinical outcomes (34 genes) or radiotherapy responses (12 genes) were developed from the discovery cohort, and compared to histologic and molecular classification systems by performing DNA methylation profiling, CNV analysis, exome sequencing, and RNA sequencing on the same meningiomas. RESULTS Targeted gene expression profiling achieved a concordance-index of 0.75 ± 0.03 (SEM) for local freedom from recurrence (LFFR) and 0.72 ± 0.03 for overall survival (OS) in the validation cohort, outperforming WHO grade (5-year LFFR delta-AUC 0.15, 95% CI 0.076-0.229, p=0.001) and DNA methylation grouping (delta-AUC 0.075, 95% CI 0.006-0.130, p=0.01) for LFFR, disease-specific survival, and OS. The biomarker was independently prognostic after accounting for WHO grade, extent of resection, primary versus recurrent presentation, CNV status, DNA methylation group, and Ki67 labeling index, and identified meningiomas benefiting from radiotherapy (interaction p-value=0.0008), suggesting postoperative radiotherapy could be refined in 30.2% of cases. CONCLUSIONS Targeted gene expression profiling of 504 meningiomas improves discrimination of meningioma local recurrence, disease-specific survival, and overall survival, and predicts radiotherapy responses.
2007 Background: Improvements in risk stratification of meningioma are needed to guide post-operative management and application of adjuvant therapy. Although profiling of DNA methylation, copy number variants (CNVs), RNA sequencing, and exome sequencing have better elucidated meningioma biology, these approaches have not revealed clinically tractable biomarkers for radiotherapy responses. In this study, we develop and validate a targeted gene expression biomarker to predict meningioma outcomes and benefit from radiotherapy. Methods: Targeted gene expression profiling was performed on a development set of 173 meningiomas (median follow-up 8.1 years) and a validation set of 331 consecutive meningiomas (median follow-up 6.1 years) treated at independent institutions (70% WHO grade 1, 24% WHO grade 2, 6% WHO grade 3). All patients underwent surgery (n = 504) with or without postoperative radiotherapy (n = 73 with radiation). Regularized Cox regression within the development set resulted in a continuous gene expression risk score for local freedom from recurrence (LFFR). The model (34 genes and 7 housekeeping genes) and thresholds for low, intermediate, and high-risk scores were locked and applied to the validation set. Results: The gene expression risk score outperformed WHO grade (validation 5-year LFFR delta-AUC 0.15, 95% CI 0.076-0.229, p = 0.001) and DNA methylation grouping (delta-AUC 0.075, 95% CI 0.006-0.130, p = 0.01) for LFFR, disease-specific survival, and OS, achieving a negative predictive value for recurrence at 5-years of 93.2%. The biomarker reclassified 35.8% of WHO grade 1 tumors as intermediate or high risk (5-year LFFR/OS 62%/79%), and 18.3% of WHO grade 2-3 tumors as low risk (5-year LFFR/OS 78%/100%). The biomarker was independently prognostic after accounting for WHO grade, extent of resection, primary versus recurrent presentation, CNV status, DNA methylation group, and Ki67 labeling index, and was predictive for LFFR after postoperative radiotherapy, with a hazard ratio of 0.41 for intermediate to high risk propensity-matched meningiomas (95% CI 0.2-0.9, p = 0.0002) versus 0.79 for low risk meningiomas (95% CI 0.1-8.8, p = 0.5182). Conclusions: Targeted gene expression profiling of 504 meningiomas resulted in a biomarker which improved discrimination of meningioma local recurrence, disease-specific survival, and overall survival, and also predicted benefit from radiotherapy.
Abstract BACKGROUND “Diffuse midline glioma, H3 K27M-mutant” is a new tumor entity established in the 2016 WHO Classification of Tumors of the CNS that comprises a set of diffuse gliomas arising in midline structures that is molecularly defined by a recurrent K27M mutation in genes encoding the histone 3 variants H3.3 or H3.1. While this tumor entity is associated with poor prognosis in children, clinical experience in adults remains limited. Given the more frequent origin in the thalamus or spinal cord in adults versus the brainstem in children, gliomas with this mutation may encompass a heterogeneous population of tumor subtypes that vary based on patient age, anatomic site of origin, and concurrent genetic alterations. METHODS The 60 patients included were 18 years or older at initial diagnosis, during the period of 2014-2019 at UCSF. Cases were identified using immunohistochemistry with a H3 K27M-mutant specific antibody and/or next-generation sequencing of histone 3 genes H3F3A, HIST1H3B and HIST1H3C. Targeted NGS was performed on tumors from 21 patients, utilizing an UCSF institutional panel or a variety of commercial sources. RESULTS Patients presented primarily in the 3rd decade of life, and 57% of tumors were located in the thalamus. Genomic profiling revealed p.K27M mutations exclusively in H3F3A and an absence of mutations in HIST1H3B or HIST1H3C, which are present in approximately one-third of pediatric diffuse midline gliomas. Additionally, these adult H3 K27M-mutant diffuse midline gliomas are universally IDH-wildtype, and have frequent mutations in TP53, PPM1D, FGFR1, NF1, and ATRX. The overall survival of this adult cohort is longer than historical averages for both H3 K27M-mutant diffuse midline glioma in children and IDH-wildtype glioblastomas in adults. CONCLUSIONS Together, these findings indicate that H3 K27M-mutant diffuse midline glioma represents a heterogeneous disease with regard to outcomes, sites of origin, and molecular pathogenesis in children versus adults.
Intravascular lymphoma (IVL) is a rare subtype of Non-Hodgkin’s Lymphoma, characterized by the proliferation of neoplastic lymphocytes solely within the lumina of small to medium sized arteries and capillaries, without extension into the surrounding parenchyma. The most common immunotype is diffuse large B-cell, but NK cell and T-cell variants have been described (Ponzoni, 2007). IVL can involve a variety of organs, however there are two main presentations, named for the countries in which these variants predominate. The Western variant typically involves central nervous system (CNS) and skin, while the Asian variant has a predilection for hemophagocytic syndrome and bone marrow involvement. Prognosis is poor overall and while CNS involvement is estimated at approximately 30% of IVL cases, it is also particularly predictive of poor prognosis (Fonkem, 2014; Shimada, 2010). The treatment for IVL is often an anthracycline-based chemotherapy regimen, which has been shown to improve median survival to 13 months, compared to 1.5 months without chemotherapy (Murase 2007). The addition of Rituximab to this regimen has been shown to further increase progression-free and overall survival (Shimada, 2008). However, the standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimens have poor CNS penetrance, and survival may be improved through incorporation of high dose methotrexate and intrathecal cytarabine. Here, we describe three patients with IVL. They presented with focal neurological deficits and radiographic evidence of CNS involvement. All 3 IVL patients were treated with rituximab, cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC). This report will describe clinical presentation, response to treatment, complications, and progression and overall survival of these patients. Their presentations highlight the diagnostic and therapeutic challenge in the management of this occult entity.
Tumor-treating fields (TTF) was approved in 2011 for recurrent glioblastomas then for adjuvant therapy in 2016 given the significant survival benefit shown in recent trials. Since 12/2012, 46 patients were treated with TTF for recurrent or newly diagnosed gliomas at Columbia University. We detail demographics, compliance rates and outcomes in this retrospective cohort. Of 42 treated patients with available compliance data, 16 (38%) were women and 2 (4.8%), 4 (9.5%) and 36 (85.7%) had WHO grade II, III and IV gliomas, respectively. Median age at diagnosis was 56 (23-84) years. TTF was used at recurrence in 33 (79%), with a median of 2 (0-4) prior recurrences, while 9 (21%) were treated at diagnosis. Prior therapies included bevacizumab (18, 43%), surgery [25 (60%) gross total], radiation and temozolomide. Median time to TTF initiation was 15 months, ranging 2.8 months to 17 years, from diagnosis. Median weighted compliance rate was 63% (6-89.4%). Patients were treated a median of 1.8 months, ranging 0.1 to 20.3 months. Concurrent systemic therapy was used in 34 (81%), including temozolomide (12, 29%), nitrosourea (2, 5%), bevacizumab (16, 38%), immunotherapy (23, 55%) or other (6, 14%). Objective response based on RANO was noted in 25 (60%) with combination TTF and systemic therapy. Only 2 (5%) experienced skin toxicity requiring interruptions. Progression free survival was 4.1 months, not significantly different among compliant (11, 26%) versus noncompliant users (median 4.4 vs. 4.1 months, p=0.3005), defined as the use of TTF for >75% of the time. The impact of compliance will be better assessed in multivariable analyses adjusted for potential confounders, especially for the glioblastoma subgroup. In randomized controlled trials, TTF therapy significantly increased survival for patients with glioblastomas. Highly variable and lower than advised compliance rates, however, may limit its benefit, despite the limited toxicities and safety of combination therapy.
I spy great Here's a seek-and-find book that invites youngsters to look at art in a special way - very closely! For each of the 13 paintings reproduced in full colour here, a simple rhyme asks young readers to search for details. All the artworks deal with indoor themes. With major works from the collections of The Metropolitan Museum of Art in New York City, this book offers a close, closer, closest look at works from early Egyptian to 20th-century. Whether children are hunting for four pink shoes, seven blue parasols, a chair in the air, or a man who looks like a rock, they are sure to find a wonderful new way to look at art.
Abstract Meningiomas arising from the meningothelial central nervous system lining are the most common primary intracranial tumors, and a significant cause of neurologic morbidity and mortality1. There are no effective medical therapies for meningioma patients2,3, and new treatments have been encumbered by limited understanding of meningioma biology. DNA methylation profiling provides robust classification of central nervous system tumors4, and can elucidate targets for molecular therapy5. Here we use DNA methylation profiling on 565 meningiomas integrated with genetic, transcriptomic, biochemical, and single-cell approaches to show meningiomas are comprised of 3 epigenetic groups with distinct clinical outcomes and biological features informing new treatments for meningioma patients. Merlin-intact meningiomas (group A, 34%) have the best outcomes and are distinguished by a novel apoptotic tumor suppressor function of NF2/Merlin. Immune-enriched meningiomas (group B, 38%) have intermediate outcomes and are distinguished by immune cell infiltration, HLA expression, and lymphatic vessels. Hypermitotic meningiomas (group C, 28%) have the worst outcomes and are distinguished by convergent genetic mechanisms misactivating the cell cycle. Consistently, we find cell cycle inhibitors block meningioma growth in cell culture, organoids, xenografts, and patients. Our results establish a framework for understanding meningioma biology, and provide preclinical rationale for new therapies to treat meningioma patients.
