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OBJECTIVE The authors’ objective was to examine the safety and efficacy of salvage intracranial cesium-131 brachytherapy in combination with resection of recurrent brain tumors. METHODS The authors conducted a retrospective chart review of consecutive patients treated with intraoperative intracranial cesium-131 brachytherapy at a single institution. Permanent suture-stranded cesium-131 seeds were implanted in the resection cavity after maximal safe tumor resection. The primary outcomes of interest were local, locoregional (within 1 cm), and intracranial control, as well as rates of overall survival (OS), neurological death, symptomatic adverse radiation effects (AREs), and surgical complication rate graded according to Common Terminology Criteria for Adverse Events version 5.0. RESULTS Between 2016 and 2020, 36 patients received 40 consecutive cesium-131 implants for 42 recurrent brain tumors and received imaging follow-up for a median (interquartile range [IQR]) of 17.0 (12.7–25.9) months. Twenty patients (55.6%) with 22 implants were treated for recurrent brain metastasis, 12 patients (33.3%) with 16 implants were treated for recurrent atypical (n = 7) or anaplastic (n = 5) meningioma, and 4 patients (11.1%) were treated for other recurrent primary brain neoplasms. All except 1 tumor (97.6%) had received prior radiotherapy, including 20 (47.6%) that underwent 2 or more prior radiotherapy treatments and 23 (54.8%) that underwent prior resection. The median (IQR) tumor size was 3.0 (2.3–3.7) cm, and 17 lesions (40.5%) had radiographic evidence of ARE prior to salvage therapy. Actuarial 1-year local/locoregional/intracranial control rates for the whole cohort and patients with metastases and meningiomas were 91.6%/83.4%/47.9%, 88.8%/84.4%/45.4%, and 100%/83.9%/46.4%, respectively. No cases of local recurrence of any histology (0 of 27) occurred after gross-total resection (p = 0.012, log-rank test). The 1-year OS rates for the whole cohort and patients with metastases and meningiomas were 82.7%, 79.1%, and 91.7%, respectively, and the median (IQR) survival of all patients was 26.7 (15.6–36.4) months. Seven patients (19.4%) experienced neurological death from progressive intracranial disease (7 of 14 total deaths [50%]), 5 (13.9%) of whom died of leptomeningeal disease. Symptomatic AREs were observed in 9.5% of resection cavities (n = 4), of which 1 (2.4%) was grade 3 in severity. The surgical complication rate was 16.7% (n = 7); 4 (9.5%) of these patients had grade 3 or higher complications, including 1 patient (2.4%) who died perioperatively. CONCLUSIONS Cesium-131 brachytherapy resulted in good local control and acceptable rates of symptomatic AREs and surgical complications in this heavily pretreated cohort, and it may be a reasonable salvage adjuvant treatment for this patient population.

Gliomas arising in the setting of neurofibromatosis type 1 (NF1) are heterogeneous, occurring from childhood through adulthood, can be histologically low-grade or high-grade, and follow an indolent or aggressive clinical course. Comprehensive profiling of genetic alterations beyond NF1 inactivation and epigenetic classification of these tumors remain limited. Through next-generation sequencing, copy number analysis, and DNA methylation profiling of gliomas from 47 NF1 patients, we identified 2 molecular subgroups of NF1-associated gliomas. The first harbored biallelic NF1 inactivation only, occurred primarily during childhood, followed a more indolent clinical course, and had a unique epigenetic signature for which we propose the terminology “pilocytic astrocytoma, arising in the setting of NF1”. The second subgroup harbored additional oncogenic alterations including CDKN2A homozygous deletion and ATRX mutation, occurred primarily during adulthood, followed a more aggressive clinical course, and was epigenetically diverse, with most tumors aligning with either high-grade astrocytoma with piloid features or various subclasses of IDH-wildtype glioblastoma. Several patients were treated with small molecule MEK inhibitors that resulted in stable disease or tumor regression when used as a single agent, but only in the context of those tumors with NF1 inactivation lacking additional oncogenic alterations. Together, these findings highlight recurrently altered pathways in NF1-associated gliomas and help inform targeted therapeutic strategies for this patient population.

Meningiomas are the most common primary intracranial tumors. There are no effective medical therapies for meningioma patients, and new treatments have been encumbered by limited understanding of meningioma biology. Here, we use DNA methylation profiling on 565 meningiomas integrated with genetic, transcriptomic, biochemical, proteomic and single-cell approaches to show meningiomas are composed of three DNA methylation groups with distinct clinical outcomes, biological drivers and therapeutic vulnerabilities. Merlin-intact meningiomas (34%) have the best outcomes and are distinguished by NF2/Merlin regulation of susceptibility to cytotoxic therapy. Immune-enriched meningiomas (38%) have intermediate outcomes and are distinguished by immune infiltration, HLA expression and lymphatic vessels. Hypermitotic meningiomas (28%) have the worst outcomes and are distinguished by convergent genetic and epigenetic mechanisms driving the cell cycle and resistance to cytotoxic therapy. To translate these findings into clinical practice, we show cytostatic cell cycle inhibitors attenuate meningioma growth in cell culture, organoids, xenografts and patients.

Background People with NF1 have an increased prevalence of central nervous system malignancy. However, little is known about the clinical course or pathologic features of NF1-associated gliomas in adults, limiting clinical care and research. Methods Adults (≥18 years) with NF1 and histologically confirmed non-optic pathway gliomas (non-OPGs) at Johns Hopkins Hospital, Memorial Sloan Kettering Cancer Center, and Washington University presenting between 1990 and 2020 were identified. Retrospective data were collated, and pathology was reviewed centrally. Results Forty-five patients, comprising 23 females (51%), met eligibility criteria, with a median of age 37 (18–68 years) and performance status of 80% (30%–100%). Tissue was available for 35 patients. Diagnoses included infiltrating (low-grade) astrocytoma (9), glioblastoma (7), high-grade astrocytoma with piloid features (4), pilocytic astrocytoma (4), high-grade astrocytoma (3), WHO diagnosis not reached (4) and one each of gliosarcoma, ganglioglioma, embryonal tumor, and diffuse midline glioma. Seventy-one percent of tumors were midline and underwent biopsy only. All 27 tumors evaluated were IDH1-wild-type, independent of histology. In the 10 cases with molecular testing, the most common genetic variants were NF1, EGFR, ATRX, CDKN2A/B, TP53, TERT, and MSH2/3 mutation. While the treatments provided varied, the median overall survival was 24 months [2–267 months] across all ages, and 38.5 [18–109] months in individuals with grade 1–2 gliomas. Conclusions Non-OPGs in adults with NF1, including low-grade tumors, often have an aggressive clinical course, indicating a need to better understand the pathobiology of these NF1-associated gliomas.

Meningiomas are the most common primary central nervous system neoplasm. Despite promising recent progress in elucidating the genomic landscape and underlying biology of these histologically, molecularly, and clinically diverse tumors, the mainstays of meningioma treatment remain maximal safe resection and radiation therapy. The aim of this review of meningioma radiotherapy is to provide a concise summary of the history, current evidence, and future for application of radiotherapy in meningioma treatment.

BACKGROUND: Accurate staging of newly diagnosed or recurrent malignancy is essential for effective treatment. An important first step in staging involves the use of PET/CT to identify areas of FDG avidity. PET/CT however has limitations, including false positive FDG uptake from benign causes. In this paper we characterize an uncommon yet clinically important cause of false positive PET/CTs, that of benign anthracotic lymphadenitis (BAL). We examine the clinical, radiographic and histologic characteristics of BAL in patients referred for endobronchial ultrasound (EBUS) guided biopsies and discuss its context in relation to existing literature. METHODS: We performed a retrospective observational case series of 20 patients who were referred for EBUS guided biopsies of PET positive mediastinal and hilar lymph nodes during the work-up or treatment of suspected malignancy. RESULTS: To be included, all patients received PET imaging as well as an EBUS guided biopsy of FDG avid lymph nodes which demonstrated anthracotic pigment as the only histologic abnormality. The key findings were that 90% of patients in this cohort were born outside of the US, 90% had bilateral FDG avid lymph nodes with an average standardized uptake value (SUV) of 7.9±2.2. Most patients, based on their history, had a likely exposure to biomass fuel or urban pollution. CONCLUSIONS: BAL may be an underrecognized cause for PET positive lymph nodes in patients undergoing work-up for malignancy. These findings support the importance of sampling mediastinal and hilar lymph nodes even when SUVs are highly suggestive of malignancy.

Context.— Dedifferentiated chondrosarcoma is a rare adult bone tumor with a dismal prognosis and is composed of a conventional chondrosarcoma juxtaposed to high-grade nonchondrogenic sarcoma. Dedifferentiated chondrosarcomas may represent tumor progression from a differentiated to a primitive histotype. Objective.— To determine the genetic and molecular events that drive progression from a conventional chondrosarcoma to high grade nonchondrogenic sarcoma. Design.— We analyzed the genomic landscape of paired conventional and dedifferentiated components of 11 dedifferentiated chondrosarcoma using targeted next-generation DNA sequencing with immunohistochemical validation. Clinical, radiographic, and pathologic features of tumors were reviewed. Capture-based DNA sequencing targeting the coding regions of 479 cancer genes and select introns was performed. Results.— The tumors arose in the femur (n = 4; 36%), scapula (n = 3; 27%), pelvis (n = 3; 27%), and humerus (n = 1; 9%) of 7 men (64%) and 4 women (36%; median age, 61 years). DNA was adequate for sequencing from all 11 dedifferentiated components (100%) and 9 paired conventional chondrosarcoma components (82%). All tumors (100%) harbored either IDH1 p.R132 or IDH2 p.R172S hotspot mutations. Seven tumors (64%) displayed COL2A1 alterations. TERT promoter mutations were present in 5 of 9 pairs (56%) and 2 (22%) additional unpaired dedifferentiated components. IDH1/2, COL2A1, and TERT mutations were identical in both components of the paired samples. Pathogenic missense or truncating mutations in TP53 and large-scale copy number alterations were more common in dedifferentiated components than in those of matched conventional components. Conclusions.— The results support IDH1/2, COL2A1, and TERT promoter mutations being common in dedifferentiated chondrosarcoma and as likely early events in progression, whereas inactivating mutation of TP53 and high-level copy number alterations may be later events in the dedifferentiated phenotype.

AIMS The aim of this study was to perform a comprehensive retrospective analysis of liver transplant biopsies with parenchymal rejection (PR) at our institution, including histological features, laboratory values and follow-up biopsies, and to compare PR with portal-based acute cellular rejection (ACR). METHODS AND RESULTS Biopsies from 173 patients were evaluated (retrospective database search 1990-2017), including 49 isolated PR, 35 PR with portal ACR (PR/ACR), 34 mild ACR and 52 moderate ACR cases. The rise and fall of serum liver enzymes was calculated as a measure of acute liver injury and response to immunotherapy, respectively. Isolated PR was associated with delayed-onset acute rejection (P

Background Genomic profiling studies of diffuse gliomas have led to new improved classification schemes that better predict patient outcomes compared to conventional histomorphology alone. One example is the recognition that patients with IDH-wildtype diffuse astrocytic gliomas demonstrating lower-grade histologic features but genomic and/or epigenomic profile characteristic of glioblastoma typically have poor outcomes similar to patients with histologically diagnosed glioblastoma. Here we sought to determine the clinical impact of prospective genomic profiling for these IDH-wildtype diffuse astrocytic gliomas lacking high-grade histologic features but with molecular profile of glioblastoma. Methods Clinical management and outcomes were analyzed for 38 consecutive adult patients with IDH-wildtype diffuse astrocytic gliomas lacking necrosis or microvascular proliferation on histologic examination that were genomically profiled on a prospective clinical basis revealing criteria for an integrated diagnosis of “diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV” per cIMPACT-NOW criteria. Results We identified that this diagnosis consists of two divergent clinical scenarios based on integration of radiologic, histologic, and genomic features that we term “early/evolving” and “undersampled” glioblastoma, IDH-wildtype. We found that prospective genomically guided identification of early/evolving and undersampled IDH-wildtype glioblastoma resulted in more aggressive patient management and improved clinical outcomes compared to a biologically matched historical control patient cohort receiving standard-of-care therapy based on histomorphologic diagnosis alone. Conclusions These results support routine use of genomic and/or epigenomic profiling to accurately classify glial neoplasms, as these assays not only improve diagnostic classification but critically lead to more appropriate patient management that can improve clinical outcomes.

Anaplastic meningiomas can have a sarcomatous appearance on histology but true sarcomatous (metaplastic) differentiation is rare. These tumors follow an aggressive clinical course with recurrence and poor clinical outcomes. Due to significant overlap in morphology and immunohistochemical profiles, distinguishing between sarcomatous transformation of a meningioma and a true sarcoma can be challenging. Here, we outline potential diagnostic pitfalls and the utility of ancillary molecular testing in 3 patients diagnosed with sarcomatous meningiomas. We report loss of typical meningothelial markers in sarcomatous meningiomas. Ancillary molecular testing can support the diagnosis of sarcomatous meningioma when a molecular signature consistent with meningioma is seen, such as inactivation of the NF2 gene. Recognition of this rare transformation in meningioma can prevent a misdiagnosis of a primary sarcoma, whether sporadic or radiation-induced from prior treatment of a more classic meningioma.

Advances in molecular profiling of central nervous system tumors have enabled the development of classification schemes with improved diagnostic and prognostic accuracy. As such, the 2016 World Health Organization Classification of Tumors of the Central Nervous System (WHO 2016) introduced a paradigm shift in the diagnosis of brain tumors. For instance, integrated assessment incorporating both histologic features and genetic alterations was introduced into the diagnostic framework of gliomas. IDH1/2 mutation status now represents the most important initial stratifier of diffuse gliomas in adults, although rarer subtypes within the IDH-wildtype category continue to be elucidated. Medulloblastomas and other embryonal neoplasms were also genetically defined and segregated based on molecular subtypes, and 1 molecular subtype of ependymoma was added. In this review, we summarize the rapidly evolving spectrum of recurrent genetic alterations described in central nervous system tumor entities since the publication of the WHO 2016.

OBJECTIVERecurrent meningiomas are primarily managed with radiation therapy or repeat resection. Surgical morbidity after reoperation for recurrent meningiomas is poorly understood. Thus, the objective of this study was to report surgical outcomes after reoperation for recurrent non–skull base meningiomas.METHODSA retrospective review of patients was performed. Inclusion criteria were patients with recurrent meningioma who had prior resection and supratentorial non–skull base location. Univariate and multivariate logistic regression and recursive partitioning analysis were used to identify risk factors for surgical complications.RESULTSThe authors identified 67 patients who underwent 111 reoperations for recurrent supratentorial non–skull base meningiomas. The median age was 53 years, 49% were female, and the median follow-up was 9.8 years. The most common presenting symptoms were headache, weakness, and seizure. The WHO grade after the last reoperation was grade I in 22% of cases, grade II in 51%, and grade III in 27%. The tumor grade increased at reoperation in 22% of cases. Tumors were located on the convexity (52%), parasagittal (33%), falx (31%), and multifocal (19%) locations. Tumors involved the middle third of the sagittal plane in 52% of cases. In the 111 reoperations, 48 complications occurred in 32 patients (48%). There were 26 (54%) complications requiring surgical intervention. There was no perioperative mortality. Complications included neurological deficits (14% total, 8% permanent), wound dehiscence/infection (14%), and CSF leak/pseudomeningocele/hydrocephalus (9%). Tumors that involved the middle third of the sagittal plane (OR 6.97, 95% CI 1.5–32.0, p = 0.006) and presentation with cognitive changes (OR 20.7, 95% CI 2.3–182.7, p = 0.001) were significantly associated with complication occurrence on multivariate analysis. The median survival after the first reoperation was 11.5 years, and the 2-, 5-, and 10-year Kaplan-Meier survival rates were 91.0%, 68.8%, and 50.0%, respectively.CONCLUSIONSReoperation for recurrent supratentorial non–skull base meningioma is associated with a high rate of complications. Patients with cognitive changes and tumors that overlap the middle third of the sagittal plane are at increased risk of complications. Nevertheless, excellent long-term survival can be achieved without perioperative mortality.

Giant cell myositis (GCM) is a rare inflammatory myopathy associated with myasthenia gravis and thymoma. Here, we report on a woman in her late 50s with a history of myasthenia gravis, systemic lupus erythematosus and stage IV thymoma with pleural metastases, who presented with proximal weakness, neuromuscular respiratory failure and hypercalcaemia. She was diagnosed with GCM via muscle biopsy and screened for myocarditis but showed no evidence of myocardial involvement. Her hypercalcaemia was consistent with a granulomatous process, likely driven by her GCM. Her strength gradually improved, and her hypercalcaemia did not recur after treatment with high dose steroids, intravenous immune globulin and plasma exchange. Her course was complicated by several opportunistic infections in the setting of her immunosuppression. Despite the high morbidity associated with GCM, she demonstrated clinical improvement after initiating immunosuppressive therapy and continues to be managed in the outpatient setting.

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.

BackgroundPrognostic markers for meningioma are needed to risk-stratify patients and guide postoperative surveillance and adjuvant therapy.ObjectiveTo identify a prognostic gene signature for meningioma recurrence and mortality after resection using targeted gene-expression analysis.MethodsTargeted gene-expression analysis was used to interrogate a discovery cohort of 96 meningiomas and an independent validation cohort of 56 meningiomas with comprehensive clinical follow-up data from separate institutions. Bioinformatic analysis was used to identify prognostic genes and generate a gene-signature risk score between 0 and 1 for local recurrence.ResultsWe identified a 36-gene signature of meningioma recurrence after resection that achieved an area under the curve of 0.86 in identifying tumors at risk for adverse clinical outcomes. The gene-signature risk score compared favorably to World Health Organization (WHO) grade in stratifying cases by local freedom from recurrence (LFFR, P

Primary central nervous system lymphoma (PCNSL) is a rare form of extranodal non-Hodgkin lymphoma that primarily arises in the brain, spinal cord, leptomeninges, and vitreoretinal compartment of the eye. The term is sometimes used interchangeably with primary central nervous system diffuse large B-cell lymphoma (PCNS DLBCL) because DLBCL comprises a great majority (90–95%) of PCNSL. Although rare, other types of lymphomas can be seen in the central nervous system (CNS), and familiarity with these entities will help their recognition and further workup in order to establish the diagnosis. The latter is especially important in the case of PCNSL where procurement of diagnostic specimen is often challenging and yields scant tissue. In this review, we will discuss the most common types of primary lymphomas that can be seen in the CNS with emphasis on the diagnostic histomorphologic, immunophenotypic, and molecular genetic features. The differential diagnostic approach to these cases and potential pitfalls will also be discussed.

SUMMARYMeningiomas 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 ofNF2/Merlin. Immune-enriched meningiomas (group B, 38%) have intermediate outcomes and are distinguished by immune cell infiltration,HLAexpression, 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.

BACKGROUND Meningioma treatments are limited due to incomplete understanding of meningioma biology. To address this, we performed multiplatform molecular profiling on 565 meningiomas with comprehensive clinical data to define genomic drivers and identify therapeutic vulnerabilities. METHODS DNA methylation profiling was performed on meningiomas from UCSF (n=200, discovery) and Hong Kong University (n=365, validation). Median follow-up was 5.6 years, and there were 388/142/35 WHO grade I/II/III meningiomas. Copy number variants (CNVs) were calculated for all meningiomas, and RNA sequencing was performed on UCSF meningiomas. Cell type deconvolution, metagenomics, CRISPR, and pharmacology were used for mechanistic and functional validation. RESULTS Unsupervised hierarchical clustering of differentially methylated DNA probes revealed that meningiomas were comprised of 3 epigenetic subgroups associated with good, intermediate, and poor outcomes, with representation from all WHO grades in each subgroup. Meningiomas from the subgroup with the best outcomes (52% WHO grade I) were distinguished by recurrent gain of Chr5. Meningiomas from the subgroup with intermediate outcomes (31% WHO grade II) were distinguished by genomic stability, enrichment of innate immune genes, and immune infiltration in the setting of endogenous retroviral gene re-expression, a mechanism of immune recruitment. The most aggressive subgroup of meningiomas (57% WHO grade III) was distinguished by genomic instability, including recurrent loss of Chr22q harboring NF2, and decreased immune infiltration. Consistently, NF2 suppression in primary meningioma cells derived from immunogenic meningiomas decreased expression of innate immune genes critical for immune recruitment, suggesting a novel immunostimulatory function of NF2. The most aggressive subgroup of meningiomas were further distinguished by activation of the mitogenic FOXM1 transcriptional program, and recurrent loss of Chr9p harboring CDKN2A/B, which rendered primary meningioma cells from this subgroup susceptible to CDK4/6 inhibitors. CONCLUSIONS Meningiomas are comprised of 3 epigenetic subgroups defined by genetic mechanisms driving immune infiltration in the tumor microenvironment and meningioma cell proliferation.

The FGFR1 gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma (PA), dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activating FGFR1 alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with TACC1 as the partner, or hotspot missense mutations within the tyrosine kinase domain (either p.N546 or p.K656). However, the specificity of these different FGFR1 events for the various LGNET subtypes and accompanying genetic alterations are not well defined, nor are the histopathologic features of pilocytic astrocytomas with FGFR1 alterations versus those harboring the more common BRAF mutations or fusions. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with FGFR1 alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with FGFR1 alterations, and is uniquely characterized by FGFR1 kinase domain hotspot missense mutations in combination with either PIK3CA or PIK3R1 mutation, often with accompanying NF1 or PTPN11 mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized by FGFR1-TACC1 fusion as the solitary pathogenic alteration. Additionally, DNT and PA are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying NF1 or PTPN11 mutation, but lacking the accompanying PIK3CA or PIK3R1 mutation that characterizes RGNT. The glial component of LGNET with FGFR1 alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with FGFR1 alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with BRAF mutation or fusion. Together, this analysis refines the classification and histopathologic spectrum of LGNET with FGFR1 alterations.

Background Malignant peripheral nerve sheath tumor (MPNST) is an aggressive and poorly understood malignant neoplasm. Even in the setting of multimodal therapy, the clinical course of MPNST is frequently marked by metastatic conversion and poor overall prognosis, with optimal treatment paradigms for this rare tumor unknown. Methods We reviewed the medical records and histopathology of 54 consecutive patients who were treated at University of California San Francisco between 1990 and 2018. Results Our cohort consisted of 24 male and 30 female patients (median age 38 years). Fédération Nationale des Centres de Lutte Contre Le Cancer (FNCLCC) sarcoma grading criteria segregated patients into groups with differences in overall survival (OS) (P = .02). Increasing Ki-67 labeling index was associated with poor OS (hazard ratio [HR] 1.36 per 10%, P = .0002). Unsupervised hierarchical clustering-based immunohistochemical staining patterns identified 2 subgroups of tumors with differences in H3K27me3, Neurofibromin, S100, SOX10, p16, and EGFR immunoreactivity. In our cohort, cluster status was associated with improved locoregional failure-free rate (P = .004) in response to radiation. Conclusions Our results lend support to the FNCLCC sarcoma grading criteria as a prognostic scheme for MPNST, although few cases of grade 1 were included. Further, we identify increased Ki-67 labeling as a strong predictor of poor OS from MPNST. Finally, we identify a subset of MPNSTs with a predictive immunohistochemical profile that has improved local control with adjuvant radiotherapy. These data provide insights into the grading and therapy for patients with MPNST, although further studies are needed for independent validation.

TheFGFR1gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activatingFGFR1alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often withTACC1as the partner, or hotspot missense mutations within the tyrosine kinase domain (either at p.N546 or p.K656). However, the specificity of these differentFGFR1events for the various LGNET subtypes and accompanying genetic alterations are not well defined. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET withFGFR1alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET withFGFR1alterations, and is uniquely characterized byFGFR1kinase domain hotspot missense mutations in combination with eitherPIK3CAorPIK3R1mutation, often with accompanyingNF1orPTPN11mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized byFGFR1-TACC1fusion as the solitary pathogenic alteration. Additionally, DNT and pilocytic astrocytoma are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanyingNF1orPTPN11mutation, but lacking the accompanyingPIK3CAorPIK3R1mutation that characterizes RGNT. The glial component of LGNET withFGFR1alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas withFGFR1alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas withBRAFmutation or fusion. Together, this analysis improves the classification and histopathologic stratification of LGNET withFGFR1alterations.

In this review, we describe Schwann cell development from embryonic neural crest cells to terminally differentiated myelinated and nonmyelinated mature Schwann cells. We focus on the genetic drivers and signaling mechanisms mediating decisions to proliferate versus differentiate during Schwann cell development, highlighting pathways that overlap with Schwann cell development and are dysregulated in tumorigenesis. We conclude by considering how our knowledge of the events underlying Schwann cell development and mouse models of schwannoma, neurofibroma, and malignant peripheral nerve sheath tumor can inform novel therapeutic strategies for patients with cancers derived from Schwann cell lineages.

Objectives Foramen magnum meningiomas (FMM) are complex lesions because of their proximity to the brain stem and posterior cerebrovasculature. The objective of this study is to report surgical outcomes and complications after resection of FMM. Methods A retrospective chart review was conducted on patients with FMM from 1998 to 2015. Univariate logistic regression and recursive partitioning analysis were used to identify risk factors associated with complications and extent of resection (EOR). Results We identified 28 patients with FMM. Median follow-up was 5.9 years. Tumors were World Health Organization grade I (92.9%) or grade II (7.1%). The vertebral artery was completely encased (25%), partially encased (11%), or not encased (64%). Median size was 11.9 cm3. EOR was gross total (39%) and subtotal (61%). The observed recurrence rate was 4% (n = 1). There were 38 complications in 12 patients (43%), and 6 patients (21%) had complications requiring additional surgery. Complications included cerebrospinal fluid leak/hydrocephalus (n = 7, 25%), weakness (n = 4, 14%), numbness (n = 4, 14%), and cranial nerve deficits: IX, X (n = 4, 14%), XI (n = 2, 7%), XII (n = 5, 18%). Medical complications included pneumonia (n = 1, 4%) and meningitis (n = 1, 4%). Tumor volume greater than 14 cm3 (odds ratio [OR] = 21.7, p = 0.0010), any vertebral artery encasement (OR 6.1, p = 0.0386), and subtotal resection (OR 6.4, p = 0.0398) were significantly associated with complications. Tumor volume greater than 14 cm3 was also significantly associated with subtotal resection (OR 8.3, p = 0.0201). Conclusions Resection of FMM carries perioperative morbidity that increases with larger tumor size. Despite the morbidity, long-term recurrence-free survival is achievable with maximal safe resection and adjuvant radiation.

BACKGROUND Malignant peripheral nerve sheath tumor (MPNST) is an aggressive neoplasm associated with neurofibromatosis type 1 (NF1). Despite multimodal therapy, clinical outcomes remain poor. To elucidate markers of MPNST treatment response, we retrospectively reviewed the medical records of MPNST patients at a single institution and performed histopathological and immunohistochemical (IHC) analysis for predictive and prognostic features. METHODS We identified 54 consecutive patients treated at University of California San Francisco between 1990 and 2018 that met diagnostic criteria for MPNST on pathologic review with sufficient tissue available for histology and immunohistochemistry (IHC) assays. IHC was performed for Ki-67, EGFR, p53, H3K27me3, neurofibromin, S100, p75NTR, SOX10, p16, and SOX2. Overall survival (OS), metastasis free survival (MFS), and locoregional failure free rate (LFFR), were estimated using the Kaplan-Meier method. Log-rank test, Cox Proportional Hazards regression, and hierarchical clustering were performed in R. RESULTS With a median follow up of 19.2 months, the 5-year OS, MFS, and LFFR were 58%, 68%, and 66%, respectively, with no significant differences between NF1 associated (n=32) and sporadic tumors (n=22). Radiation therapy significantly improved 5-year LFFR (80% versus 49%, p=0.05), but not OS or MFS. Tumor grade was associated with worse OS by Fédération Nationale des Centres de Lutte Contre Le Cancer (FNCLCC) grading (p=0.02). Furthermore, elevated Ki-67 index was associated with worse 5-year OS (39% versus 73% for Ki-67 index ³ 60 and Ki-67 index < 60, p=0.01). Finally, hierarchical clustering of IHC data identified a predictive signature defined by elevated Ki-67 and EGFR expression associated with improved responses to radiation therapy (5-year OS 86% versus 10%, p=0.004). CONCLUSIONS Our data provide insights into the diagnosis and treatment of MPNST. Additional investigation is needed to understand the biologic mechanisms and generalizability of the signatures uncovered in our analysis.

BACKGROUND Clinical biomarkers for identifying patients at risk for recurrence after resection of meningioma are lacking and are needed for guiding adjuvant therapy. The aim of this study was to identify a prognostic gene expression signature for meningioma. METHODS Targeted gene expression analysis was performed on a discovery dataset of 96 meningiomas with suitable tissue identified from a retrospective institutional biorepository. Recurrence was dichotomized based on the median time to local recurrence (TTR). With median follow-up of 6.4 years, the discovery dataset was enriched for clinical endpoints of local recurrence (58%), mortality (42%), and disease-specific mortality (49% of deaths). A 266 gene expression panel was used to interrogate the discovery dataset, and a prognostic gene signature and risk score was generated using prediction analysis for microarrays (PAM) and elastic net regression. The risk score was validated using gene expression data (GSE58037) from 56 meningiomas resected at an independent institution (20% local recurrence, 18% mortality, median follow-up 5.4 years). RESULTS A 36-gene signature was identified achieving an AUC of 0.86 for TTR faster than the median in the discovery cohort. A risk score between 0 and 1 based on this signature was strongly associated with shorter TTR (F-test, P< 0.0001), and on multivariate Cox regression (MVA), was independently associated with recurrence (RR 1.56 per 0.1 increase, 95% CI 1.30–1.90, P< 0.0001) and mortality (RR 1.32 per 0.1 increase, 1.07–1.64, P=0.01) after adjusting for WHO grade, age, extent of resection, and sex. Similarly, in the validation dataset, the gene risk score was correlated with shorter TTR (P=0.002) and associated with mortality on MVA (RR 1.86 per 0.1 increase, 1.19–2.88, P=0.005) after adjustment for WHO grade. CONCLUSIONS The prognostic meningioma gene expression risk score presented here could be useful in identifying patients at higher risk of progression after resection.

OBJECTIVES: Chordoid meningiomas are a rare histologic variant that follow an aggressive clinical course. Here, we examine histopathologic and radiologic features of chordoid meningiomas to identify risk factors for recurrence. METHODS: Retrospective chart reviews were performed on 11 patients with chordoid meningioma and 15 patients with meningioma with focal chordoid features (

OBJECTIVE: Extracranial meningioma metastases are rare, and patients with meningiomas are not routinely screened for systemic metastases. We report our experience with meningioma metastases and screening for metastases in select patients with recurrent meningiomas. METHODS: All patients undergoing surgical resection or stereotactic radiosurgery for primary or recurrent meningioma from 2009 to 2017 at a single center were retrospectively reviewed. Indications for metastasis screening were patients with recurrent meningioma after 2 prior resections and radiation therapy or symptoms concerning for metastasis. Screening was performed with CT chest/abdomen/pelvis, FDG PET-CT, or somatostatin receptor specific (DOTATATE) PET-CT. RESULTS: Of 1203 patients treated, 929 (77.2%) had WHO grade 1 meningioma by surgical pathology or imaging, 234 (19.5%) had grade 2 and 35 (2.9%) had grade 3 meningioma. A total of 298 meningiomas (24.8%) recurred, with a mean of 1.6 recurrences per patient. Screening for metastases was performed in 28 patients; one (3.6%) had a grade 1 tumor, 16 (57.1%) were grade 2, and 11 (39.3%) were grade 3. Five patients (17.9%) were screened because of systemic symptoms. Of the patients screened, 27 (96.4%) had recurrent meningioma, with a mean 3.2 recurrences. Ten patients (35.7%) had suspicious extracranial lesions by imaging. On biopsy, 8 were meningioma metastases, 1 was a non-meningioma malignancy, and 1 was lost to follow-up. Biopsy-confirmed metastases occurred in: liver (5), lung (3), mediastinum (1) and bone (1). The overall incidence of metastases was 0.67% (n=8). Incidence increased to 2% of WHO grade II tumors and 8.6% of grade 3. Using our indications, the number needed to screen to identify one patient with biopsy-confirmed malignancy was 3.1. CONCLUSIONS: Screening of patients with multiply recurrent meningioma or symptoms concerning for metastasis may identify extracranial metastases in a significant proportion of patients and can inform decision making for additional treatments.

OBJECTIVEExtracranial meningioma metastases are uncommon, occurring in less than 1% of patients diagnosed with meningioma. Due to the rarity of meningioma metastases, patients are not routinely screened for distant disease. In this series, we report their experience with meningioma metastases and results of screening for metastases in select patients with recurrent meningiomas.METHODSAll patients undergoing resection or stereotactic radiosurgery for primary or recurrent meningioma from 2009 to 2017 at a single center were retrospectively reviewed to identify patients who were diagnosed with or underwent imaging to evaluate for systemic metastases. Imaging to evaluate for metastases was performed with CT scanning of the chest, abdomen, and pelvis or whole-body PET/CT using either FDG or 68Ga-DOTA-octreotate (DOTATATE) tracers in 28 patients. Indications for imaging were symptomatic lesions concerning for metastasis or asymptomatic screening in patients with greater than 2 recurrences being evaluated for additional treatment.RESULTSOf 1193 patients treated for meningioma, 922 (77.3%) patients had confirmed or presumed WHO grade I tumors, 236 (19.8%) had grade II tumors, and 35 (2.9%) had grade III tumors. Mean follow-up was 4.3 years. A total of 207 patients experienced recurrences (17.4%), with a mean of 1.8 recurrences. Imaging for metastases was performed in 28 patients; 1 metastasis was grade I (3.6%), 16 were grade II (57.1%), and 11 were grade III (39.3%). Five patients (17.9%) underwent imaging because of symptomatic lesions. Of the 28 patients screened, 27 patients had prior recurrent meningioma (96.4%), with a median of 3 recurrences. On imaging, 10 patients had extracranial lesions suspicious for metastasis (35.7%). At biopsy, 8 were meningioma metastases, 1 was a nonmeningioma malignancy, and 1 patient was lost to follow-up prior to biopsy. Biopsy-confirmed metastases occurred in the liver (5), lung (3), mediastinum (1), and bone (1). The observed incidence of metastases was 0.67% (n = 8). Incidence increased to 2% of WHO grade II and 8.6% of grade III meningiomas. Using the proposed indications for screening, the number needed to screen to identify one patient with biopsy-confirmed malignancy was 3.83.CONCLUSIONSSystemic imaging of patients with multiply recurrent meningioma or symptoms concerning for metastasis may identify extracranial metastases in a significant proportion of patients and can inform decision making for additional treatments.