Discrete class I molecules on brain endothelium differentially regulate neuropathology in experimental cerebral malaria.

Cerebral malaria is the deadliest complication that can arise from Plasmodium infection. CD8 T-cell engagement of brain vasculature is a putative mechanism of neuropathology in cerebral malaria. To define contributions of brain endothelial cell major histocompatibility complex (MHC) class I antigen-presentation to CD8 T cells in establishing cerebral malaria pathology, we developed novel H-2Kb LoxP and H-2Db LoxP mice crossed with Cdh5-Cre mice to achieve targeted deletion of discrete class I molecules, specifically from brain endothelium. This strategy allowed us to avoid off-target effects on iron homeostasis and class I-like molecules, which are known to perturb Plasmodium infection. This is the first endothelial-specific ablation of individual class-I molecules enabling us to interrogate these molecular interactions. In these studies, we interrogated human and mouse transcriptomics data to compare antigen presentation capacity during cerebral malaria. Using the Plasmodium berghei ANKA model of experimental cerebral malaria (ECM), we observed that H-2Kb and H-2Db class I molecules regulate distinct patterns of disease onset, CD8 T-cell infiltration, targeted cell death and regional blood-brain barrier disruption. Strikingly, ablation of either molecule from brain endothelial cells resulted in reduced CD8 T-cell activation, attenuated T-cell interaction with brain vasculature, lessened targeted cell death, preserved blood-brain barrier integrity and prevention of ECM and the death of the animal. We were able to show that these events were brain-specific through the use of parabiosis and created the novel technique of dual small animal MRI to simultaneously scan conjoined parabionts during infection. These data demonstrate that interactions of CD8 T cells with discrete MHC class I molecules on brain endothelium differentially regulate development of ECM neuropathology. Therefore, targeting MHC class I interactions therapeutically may hold potential for treatment of cases of severe malaria.

Pre-operative vs. post-operative stereotactic radiosurgery for operative metastatic brain tumors: study protocol for a phase III clinical trial.

BACKGROUND AND OBJECTIVES: Almost one third of cancer patients in the United States will develop brain metastases on an annual basis. Surgical resection is indicated in the setting of brain metastases for reasons, such as maximizing local control in select patients, decompression of mass effect, and/or tissue diagnosis. The current standard of care following resection of a brain metastasis has shifted from whole brain radiation therapy to post-operative stereotactic radiosurgery (SRS). However, there is a significant rate of local recurrence within one year of postoperative SRS. Emerging retrospective and prospective data suggest pre-operative SRS is a safe and potentially effective treatment paradigm for surgical brain metastases. This trial intends to determine, for patients with an indication for resection of a brain metastasis, whether there is an increase in the time to a composite endpoint of adverse outcomes; including the first occurrence of either: local recurrence, leptomeningeal disease, or symptomatic radiation brain necrosis - in patients who receive pre-operative SRS as compared to patients who receive post-operative SRS. METHODS: This randomized phase III clinical trial compares pre-operative with post-operative SRS for brain metastases. A dynamic random allocation procedure will allocate an equal number of patients to each arm: pre-operative SRS followed by surgery or surgery followed by post-operative SRS. EXPECTED OUTCOMES: If pre-operative SRS improves outcomes relative to post-operative SRS, this will establish pre-operative SRS as superior. If post-operative SRS proves superior to pre-operative SRS, it will remain a standard of care and halt the increasing utilization of pre-operative SRS. If there is no difference in pre- versus post-operative SRS, then pre-operative SRS may still be preferred, given patient convenience and the potential for a condensed timeline. DISCUSSION: Emerging retrospective and prospective data have demonstrated some benefits of pre-op SRS vs. post-op SRS. This study will show whether there is an increase in the time to the composite endpoint. Additionally, the study will compare overall survival; patient-reported outcomes; morbidity; completion of planned therapies; time to systemic therapy; time to regional progression; time to CNS progression; time to subsequent treatment; rate of radiation necrosis; rate of local recurrence; and rate of leptomeningeal disease. TRIAL REGISTRATION NUMBER: NCT03750227 (Registration date: 21/11/2018).

Treatment outcomes of single-fraction stereotactic radiosurgery for adenoid cystic carcinoma: a case series of 55 patients.

PURPOSE: This study aimed to analyze the treatment outcomes of single-fraction stereotactic radiosurgery (SRS) for adenoid cystic carcinoma patients. METHODS: Retrospective analysis was conducted for 55 patients with 66 lesions. SRS intentions were categorized as definitive, adjuvant, salvage, and palliative. Tumor control was defined as local (within 50% isodose line), marginal (outside 50% isodose line), and distant (metastasis outside head/neck). RESULTS: The median age was 60 years (range 21-85), with 53% males. Tumor origin was head/neck for 88% and trachea/lung for 12%. 61% were recurrent lesions. Median interval from diagnosis to SRS was 14 months. Preceding surgery was performed in 30%. SRS was administered as definitive (30 lesions), adjuvant (13), salvage (19), and palliative (4). SRS was used as a boost to external beam radiation therapy (EBRT) in 39%. Concurrent chemotherapy was administered in 26%. 5-, 10-, and 15-year local control rates were 60%, 33%, and 27%, respectively; local/marginal control rates were 29%, 13%, and 10%. For recurrent lesions treated with SRS without EBRT, 5-year local control rate was 14%, and local/marginal control rate was 5%. For recurrent lesions treated with SRS and EBRT, 5-year local control rate was 100%, and local/marginal control rate was 40%. The rate of distant failure after SRS was 40%. Older age and distant metastasis before SRS were negative factors for overall survival. CONCLUSION: SRS provided a high rate of local tumor control, but marginal failure was frequent. Integrating SRS with added EBRT exhibits potential for enhancing local and local/marginal tumor control, particularly in recurrent cases.

Characterizing T-cell dysfunction and exclusion signatures in malignant peripheral nerve sheath tumors reveals susceptibilities to immunotherapy.

PURPOSE: Malignant peripheral nerve sheath tumors (MPNSTs) are malignant tumors that arise from peripheral nerves and are the leading cause of mortality in Neurofibromatosis Type 1 (NF1). In this study, we characterized whether transcriptomic signatures of T-cell dysfunction (TCD) and exclusion (TCE) that inversely correlate with response to immune checkpoint blockade (ICB) immunotherapy exist in MPNSTs. METHODS: MPNST transcriptomes were pooled from Gene Expression Omnibus (GEO). For each sample, a tumor immune dysfunction and exclusion (TIDE) score, TCD and TCE subscores, and cytotoxic T-cell(CTL) level were calculated. In the TIDE predictive algorithm, tumors are predicted to have an ICB response if they are either immunologically hot (CTL-high) without TCD or immunologically cold (CTL-low) without TCE. TIDE scores greater than zero correspond with ICB nonresponse. RESULTS: 73 MPNST samples met inclusion criteria, including 50 NF1-associated MPNSTs (68.5%). The average TIDE score was + 0.41 (SD = 1.16) with 22 (30.1%) predicted ICB responders. 11 samples were CTL-high (15.1%) with an average TCD score of + 0.99 (SD = 0.63). Among 62 CTL-low tumors, 21 were predicted to have ICB response with an average TCE score of + 0.31(SD = 1.20). Age(p = 0.18), sex(p = 0.41), NF1 diagnosis (p = 0.17), and PRC2 loss(p = 0.29) were not associated with ICB responder status. CONCLUSIONS: Transcriptomic analysis of TCD and TCE signatures in MPNST samples reveals that a select subset of patients with MPNSTs may benefit from ICB immunotherapy.

A Review on the Surgical Management of Insular Gliomas.

The surgical treatment of insular gliomas requires specialized knowledge. Over the last three decades, increased momentum in surgical resection of insular gliomas shifted the focus from one of expectant management to maximal safe resection to establish a diagnosis, characterize tumor genetics, treat preoperative symptoms (i.e., seizures), and delay malignant transformation through tumor cytoreduction. A comprehensive review of the literature was performed regarding insular glioma classification/genetics, insular anatomy, surgical approaches, and patient outcomes. Modern large, published series of insular resections have reported a median 80% resection, 80% improvement in preoperative seizures, and postsurgical permanent neurologic deficits of less than 10%. Major complication avoidance includes recognition and preservation of eloquent cortex for language and respecting the lateral lenticulostriate arteries.

Presentation, imaging, patterns of care, growth, and outcome in sporadic and von Hippel-Lindau-associated central nervous system hemangioblastomas.

OBJECT: Hemangioblastoma is a relatively rare neoplasm occurring mostly in the cerebellum that may arise sporadically or in the context of von Hippel-Lindau (VHL) syndrome. Presentation, imaging, natural history, surgical patterns of care, and outcomes are incompletely defined for this uncommon lesion. We reviewed our large institutional series to help clarify these issues. METHODS: Retrospective analysis of consecutive, neurosurgically managed CNS hemangioblastomas at Mayo Clinic, 1988-2018. RESULTS: Two hundred and eighty five hemangioblastomas were treated in 184 unique patients (115 sporadic, 69 VHL). Compared to sporadic patients, VHL patients were younger (36.7 vs 51.7 years; p < 0.0001), were treated while asymptomatic more commonly (47.3 vs 4.2%; p < 0.0001), had smaller lesions (6.6 vs 13.9 mL; p < 0.0001), and harbored lesions with associated cysts less frequently (51.0 vs 75.0%; p = 0.0002). Macrocystic tumor architecture was associated with larger lesion size and greater symptom severity. Solid lesions later formed cysts at a median 130 months. Growth in both total volume and solid component accelerated after cyst formation (10.6 and 6.0 times median rate prior to cyst emergence). VHL patients died at a younger age (47.9 vs 74.5, p = 0.0017) and were more likely to die of direct disease sequelae. Though treatment-free survival time was significantly longer in sporadic cases, a substantial fraction (> 40%) developed tumor recurrence/progression requiring additional treatment. CONCLUSIONS: Hemangioblastoma presentation varies with etiology and clinical course is more complicated in VHL cases. Nodular lesions often develop cysts over time which is associated with accelerated tumor growth. Sporadic cases have a previously unappreciated but substantial risk of late recurrence/progression requiring treatment.

Pediatric brain tumor cell lines exhibit miRNA-depleted, Y RNA-enriched extracellular vesicles.

BACKGROUND: Medulloblastoma (MB) and diffuse infiltrative pontine glioma (DIPG) are malignant pediatric tumors. Extracellular vesicles (EVs) and their bioactive cargoes have been implicated in tumorigenesis. Most studies have focused on adult tumors, therefore the role of EVs and the noncoding RNA (ncRNA) landscape in pediatric brain tumors is not fully characterized. The overall aim of this pilot study was to isolate EVs from MB and DIPG patient-derived cell lines and to explore the small ncRNA transcriptome. METHODS: EVs from 3 DIPG and 4 MB patient-derived cell lines were analyzed. High-throughput next generation sequencing interrogated the short non-coding RNA (ncRNA) transcriptome. Known and novel miRNAs were quantified. Differential expression analysis, in silico target prediction, and functional gene enrichment were performed. RESULTS: EV secretomes from MB and DIPG patient-derived cell lines demonstrated discrete ncRNA biotypes. Notably, miRNAs were depleted and Y RNAs were enriched in EV samples. Hierarchical cluster analysis revealed high discrimination in miRNA expression between DIPG and MB cell lines and RNA-Seq identified novel miRNAs not previously implicated in MB or DIPG pathogenesis. Known and putative target genes of dysregulated miRNAs were identified. Functional annotation analysis of the target genes for differentially expressed EV-and parental-derived miRNAs revealed significant cancer-related pathway involvement. CONCLUSIONS: This hypothesis-generating study demonstrated that pediatric brain tumor-derived cell lines secrete EVs comprised of various ncRNA cargoes. Validation of these findings in patient samples may provide new insights into the pediatric brain tumor microenvironment and identification of novel therapeutic candidates.

A deep learning model for discriminating true progression from pseudoprogression in glioblastoma patients.

INTRODUCTION: Glioblastomas (GBMs) are highly aggressive tumors. A common clinical challenge after standard of care treatment is differentiating tumor progression from treatment-related changes, also known as pseudoprogression (PsP). Usually, PsP resolves or stabilizes without further treatment or a course of steroids, whereas true progression (TP) requires more aggressive management. Differentiating PsP from TP will affect the patient's outcome. This study investigated using deep learning to distinguish PsP MRI features from progressive disease. METHOD: We included GBM patients with a new or increasingly enhancing lesion within the original radiation field. We labeled those who subsequently were stable or improved on imaging and clinically as PsP and those with clinical and imaging deterioration as TP. A subset of subjects underwent a second resection. We labeled these subjects as PsP, or TP based on the histological diagnosis. We coregistered contrast-enhanced T1 MRIs with T2-weighted images for each patient and used them as input to a 3-D Densenet121 model and using five-fold cross-validation to predict TP vs PsP. RESULT: We included 124 patients who met the criteria, and of those, 63 were PsP and 61 were TP. We trained a deep learning model that achieved 76.4% (range 70-84%, SD 5.122) mean accuracy over the 5 folds, 0.7560 (range 0.6553-0.8535, SD 0.069) mean AUROCC, 88.72% (SD 6.86) mean sensitivity, and 62.05% (SD 9.11) mean specificity. CONCLUSION: We report the development of a deep learning model that distinguishes PsP from TP in GBM patients treated per the Stupp protocol. Further refinement and external validation are required prior to widespread adoption in clinical practice.

Strategies, considerations, and recent advancements in the development of liquid biopsy for glioblastoma: a step towards individualized medicine in glioblastoma.

OBJECTIVE: Glioblastoma (GBM) is a devasting primary brain tumor with less than a 5% 5-year survival. Treatment response assessment can be challenging because of inflammatory pseudoprogression that mimics true tumor progression clinically and on imaging. Developing additional noninvasive assays is critical. In this article, the authors review various biomarkers that could be used in developing liquid biopsies for GBM, along with strengths, limitations, and future applications. In addition, they present a potential liquid biopsy design based on the use of an extracellular vesicle-based liquid biopsy targeting nonneoplastic extracellular vesicles. METHODS: The authors conducted a current literature review of liquid biopsy in GBM by searching the PubMed, Scopus, and Google Scholar databases. Articles were assessed for type of biomarker, isolation methodology, analytical techniques, and clinical relevance. RESULTS: Recent work has shown that liquid biopsies of plasma, blood, and/or CSF hold promise as noninvasive clinical tools that can be used to diagnose recurrence, assess treatment response, and predict patient outcomes in GBM. Liquid biopsy in GBM has focused primarily on extracellular vesicles, cell-free tumor nucleic acids, and whole-cell isolates as focal biomarkers. GBM tumor signatures have been generated via analysis of tumor gene mutations, unique RNA expression, and metabolic and proteomic alterations. Liquid biopsies capture tumor heterogeneity, identifying alterations in GBM tumors that may be undetectable via surgical biopsy specimens. Finally, biomarker burden can be used to assess treatment response and recurrence in GBM. CONCLUSIONS: Liquid biopsy offers a promising avenue for monitoring treatment response and recurrence in GBM without invasive procedures. Although additional steps must be taken to bring liquid biopsy into the clinic, proof-of-principle studies and isolation methodologies are promising. Ultimately, CSF and/or plasma-based liquid biopsy is likely to be a powerful tool in the neurosurgeon's arsenal in the near future for the treatment and management of GBM patients.

Neurosurgical involvement in clinical trials for CNS tumors.

INTRODUCTION: Most clinical trials in neurooncology are led by investigators primarily trained in neurology or medical oncology. While neurosurgeons are trained to be problem-solvers and innovators, research training has historically been focused on laboratory-based discovery approaches and formalized training in prospective clinical trials research is not part of routine graduate training. METHODS: We reviewed literature that demonstrates that innovation and problem-solving are integral to the practice of neurosurgery cite multiple examples of advances in technique and technology that may have had an empirical origin but that led to prospective clinical trials resulting in change in practice. RESULTS: Neurosurgeons have developed and led both traditional (clinical outcome-oriented) and translational prospective clinical trials that have evaluated the best use of currently available therapeutics or tested the ability of novel therapeutics to alter the biology and/or course of disease. CONCLUSIONS: In this review, we focus on a number of the recently developed technologies and therapeutics that were evaluated in clinical trials led or co-led by neurosurgeons. We also highlight some of the barriers that need to be addressed in order to foster neurosurgical participation and leadership in the prospective development of novel therapeutics.

The role of single-fraction stereotactic radiosurgery for atypical meningiomas (WHO grade II): treatment results based on a 25-year experience.

PURPOSE: To clarify the role of stereotactic radiosurgery (SRS) for atypical meningiomas (AM). METHODS: A retrospective analysis of 68 patients with AM having SRS from 1995 until 2019. RESULTS: Nineteen patients (28%) had undergone prior external beam radiation therapy (EBRT) (median dose, 54 Gy). The median follow-up period was 52 months. Eighteen (26%), 17 (25%), and 33 (49%) patients received SRS as an upfront adjuvant (≤ 6 months), early salvage (7-18 months), or late salvage treatment (> 18 months), respectively. The 3-, 5-, and 10-year progression-free survivals (PFSs) were 52%, 35%, and 25%, respectively. The 3-, 5-, and 10-year disease-specific survivals were 85%, 78%, and 61%, respectively. Adverse radiation events (AREs) were observed in 12 patients (18%), with increased or new seizures being the most frequent complication (n = 7). Prior EBRT was associated with reduced PFS (HR 5.92, P < 0.01), reduced DSS (HR 5.84, P < 0.01), and an increased risk of ARE (HR 3.31, P = 0.04). Timing of SRS was correlated with reduced PFS for patients having early salvage treatment compared to upfront adjuvant (HR 3.17, P = 0.01) or late salvage treatment (HR 4.39, P < 0.01). CONCLUSION: PFS for patients with residual/recurrent AM remains poor despite SRS. Prior EBRT was associated with worse tumor control, higher tumor-related mortality, and an increased risk of ARE. Further study on the timing of SRS is needed to determine if upfront adjunctive SRS improves tumor control compared to salvage SRS.

Brain cancer induces systemic immunosuppression through release of non-steroid soluble mediators.

Immunosuppression of unknown aetiology is a hallmark feature of glioblastoma and is characterized by decreased CD4 T-cell counts and downregulation of major histocompatibility complex class II expression on peripheral blood monocytes in patients. This immunosuppression is a critical barrier to the successful development of immunotherapies for glioblastoma. We recapitulated the immunosuppression observed in glioblastoma patients in the C57BL/6 mouse and investigated the aetiology of low CD4 T-cell counts. We determined that thymic involution was a hallmark feature of immunosuppression in three distinct models of brain cancer, including mice harbouring GL261 glioma, B16 melanoma, and in a spontaneous model of diffuse intrinsic pontine glioma. In addition to thymic involution, we determined that tumour growth in the brain induced significant splenic involution, reductions in peripheral T cells, reduced MHC II expression on blood leucocytes, and a modest increase in bone marrow resident CD4 T cells. Using parabiosis we report that thymic involution, declines in peripheral T-cell counts, and reduced major histocompatibility complex class II expression levels were mediated through circulating blood-derived factors. Conversely, T-cell sequestration in the bone marrow was not governed through circulating factors. Serum isolated from glioma-bearing mice potently inhibited proliferation and functions of T cells both in vitro and in vivo. Interestingly, the factor responsible for immunosuppression in serum is non-steroidal and of high molecular weight. Through further analysis of neurological disease models, we determined that the immunosuppression was not unique to cancer itself, but rather occurs in response to brain injury. Non-cancerous acute neurological insults also induced significant thymic involution and rendered serum immunosuppressive. Both thymic involution and serum-derived immunosuppression were reversible upon clearance of brain insults. These findings demonstrate that brain cancers cause multifaceted immunosuppression and pinpoint circulating factors as a target of intervention to restore immunity.

Higher temporal resolution multiband fMRI provides improved presurgical language maps.

PURPOSE: We investigated the hypothesis that increasing fMRI temporal resolution using a multiband (MB) gradient echo-echo planar imaging (GRE-EPI) pulse sequence provides fMRI language maps of higher statistical quality than those acquired with a traditional GRE-EPI sequence. METHODS: This prospective study enrolled 29 consecutive patients receiving language fMRI prior to a potential brain resection for tumor, AVM, or epilepsy. A 4-min rhyming task was performed at 3.0 Tesla with a traditional GRE-EPI pulse sequence (TR = 2000, TE = 30, matrix = 64/100%, slice = 4/0, FOV = 24, slices = 30, time points = 120) and an additional MB GRE-EPI pulse sequence with an acceleration factor of 6 (TR = 333, TE = 30, matrix 64/100%, slice = 4/0, FOV = 24, time points = 720). Spatially filtered t statistical maps were generated. Volumes of interest (VOIs) were drawn around activations at Broca's, dorsolateral prefrontal cortex, Wernicke's, and the visual word form areas. The t value maxima were measured for the overall brain and each of the VOIs. A paired t test was performed for the corresponding traditional and MB GRE-EPI measurements. RESULTS: The mean age of subjects was 42.6 years old (18-75). Sixty-two percent were male. The average overall brain t statistic maxima for the MB pulse sequence (t = 15.4) was higher than for the traditional pulse sequence (t = 9.3, p = < .0001). This also held true for Broca's area (p < 0.0001), Wernicke's area (p < .0001), dorsolateral prefrontal cortex (p < .0001), and the visual word form area (p < .0001). CONCLUSION: A MB GRE-EPI fMRI pulse sequence employing high temporal resolution provides clinical fMRI language maps of greater statistical significance than those obtained with a traditional GRE-EPI sequence.

Salvage Radiosurgery for Recurrent Supratentorial Primitive Neuroectodermal Tumors: A Single Institutional Series and Review of the Literature.

INTRODUCTION: Supratentorial primitive neuroectodermal tumor is a rare, aggressive intrinsic brain tumor with limited treatment options for recurrent disease. SRS as a treatment modality in the recurrent setting was investigated. METHODS: A retrospective review of 8 patients treated with SRS for local or distant recurrence of supratentorial PNET from 1999 to 2014 was conducted. RESULTS: Thirty-six tumors were treated in 15 sessions in 8 patients. The median patient age was 22.5 (interquartile range [IQR], 14.75-43.5 years) with a median 21-month period from diagnosis until SRS (IQR, 16-23.75 months). The median prescription isodose volume was 1.85 cm3 (IQR, 1.85-7.02 cm3); median tumor margin dose was 18 Gy (IQR 14-20 Gy); and median isocenters was 2 (range 1-13). No patients experienced adverse radiation effects. All but 1 patient died, and the median overall survival was 32 months (IQR, 26.75-53.5 months) with median overall survival following SRS of 9.5 months (IQR, 5.25-30 months). Univariate analysis failed to demonstrate a statistically significant association between age, number of gamma knife treatments, interval to gamma knife, and margin radiation dose with overall survival. DISCUSSION/CONCLUSION: This series supports the use of SRS in patients with recurrent supratentorial PNET following multimodal therapy.

Synthetic and systems biology principles in the design of programmable oncolytic virus immunotherapies for glioblastoma.

Oncolytic viruses (OVs) are a class of immunotherapeutic agents with promising preclinical results for the treatment of glioblastoma (GBM) but have shown limited success in recent clinical trials. Advanced bioengineering principles from disciplines such as synthetic and systems biology are needed to overcome the current challenges faced in developing effective OV-based immunotherapies for GBMs, including off-target effects and poor clinical responses. Synthetic biology is an emerging field that focuses on the development of synthetic DNA constructs that encode networks of genes and proteins (synthetic genetic circuits) to perform novel functions, whereas systems biology is an analytical framework that enables the study of complex interactions between host pathways and these synthetic genetic circuits. In this review, the authors summarize synthetic and systems biology concepts for developing programmable, logic-based OVs to treat GBMs. Programmable OVs can increase selectivity for tumor cells and enhance the local immunological response using synthetic genetic circuits. The authors discuss key principles for developing programmable OV-based immunotherapies, including how to 1) select an appropriate chassis, a vector that carries a synthetic genetic circuit, and 2) design a synthetic genetic circuit that can be programmed to sense key signals in the GBM microenvironment and trigger release of a therapeutic payload. To illustrate these principles, some original laboratory data are included, highlighting the need for systems biology studies, as well as some preliminary network analyses in preparation for synthetic biology applications. Examples from the literature of state-of-the-art synthetic genetic circuits that can be packaged into leading candidate OV chassis are also surveyed and discussed.

Short non-coding RNA sequencing of glioblastoma extracellular vesicles.

INTRODUCTION: Like all nucleated cells, glioblastoma (GBM) cells shed small membrane-encapsulated particles called extracellular vesicles (EVs). EVs can transfer oncogenic components and promote tumor growth by transferring short non-coding RNAs, altering target cell gene expression. Furthermore, GBM-derived EVs can be detected in blood and have potential to serve as liquid biopsies. METHODS: EVs were harvested from culture supernatants from human GBM cell lines, purified via sequential centrifugation, and quantified by nanoparticle tracking. RNA was isolated and short non-coding RNA was sequenced. Data was analyzed via the OASIS-2.0 platform using HG38. MirTarBase and MirDB interrogated validated/predicted miRNA-gene interactions respectively. RESULTS: Many short non-coding RNA's were identified within GBM EV's. In keeping with earlier reports utilizing GBM EV micro-RNA (miRNA) arrays, these included abundant micro-RNA's including miR-21. However, RNA sequencing revealed a total of 712 non-coding RNA sequences most of which have not been associated with GBM EV's previously. These included many RNA species (piRNA, snoRNA, snRNA, rRNA and yRNAs) in addition to miRNA's. miR-21-5p, let-7b-5p, miR-3182, miR-4448, let-7i-5p constituted highest overall expression. Top genes targeted by non-coding RNA's were highly conserved and specific for cell cycle, PI3K/Akt signaling, p53 and Glioma curated KEGG pathways. CONCLUSIONS: Next generation short non-coding RNA sequencing on GBM EV's validates findings from earlier studies using miRNA arrays but also demonstrates expression of many additional non-coding RNA sequences and classes previously unassociated with GBM. This may yield important insights into pathophysiology, point to new therapeutic targets, and help develop new biomarkers for disease burden and treatment response.

Adjuvant radiation for WHO grade II and III intracranial meningiomas: insights on survival and practice patterns from a National Cancer Registry.

INTRODUCTION: WHO grades II (atypical) and III (malignant) meningiomas are associated with significant morbidity and mortality. The role of adjuvant radiotherapy (RT) in management remains controversial. The goal of this study was to evaluate the impact of adjuvant RT on 5-year survival in patients with atypical and malignant meningiomas. We secondarily aimed to assess contemporary practice patterns and the impact of sociodemographic factors on outcome. METHODS: We queried the National Cancer Database for patients ≥ 18 years of age with cranial atypical or malignant meningiomas from 2010 through 2015 who underwent surgical resection with or without adjuvant radiotherapy. Subjects with unknown WHO grade or radiation status and those not receiving any surgical procedure were excluded from analysis. RESULTS: The study includes 7486 patients, 6788 with atypical and 698 with malignant meningiomas. Overall 5-year survival was 76.9% (95% CI 75.5-78.3%) and 43.3% (95% CI 38.8-48.2%) among patients with WHO grades II and III meningiomas, respectively. Adjuvant RT correlated with improved survival in a multivariable model in patients with grade II tumors (HR 0.78; p = 0.029) regardless of the extent of resection. Age (HR 2.33; p < 0.001), male sex (HR 1.27; p < 0.001), Black race (HR 1.27; p = 0.011) and Charlson-Deyo Score ≥ 2 (1.35; p = 0.001) correlated with poorer survival whereas private insurance (HR 0.71; p < 0.001) correlated with improved survival. Adjuvant RT was also associated with improved 5-year survival among those with grade III tumors on univariate analysis (log-rank p = 0.006) but was underpowered for multivariable modeling. Utilization of adjuvant radiotherapy was only 28.4% and correlated with private insurance status. Academic institutions (25.3%) and comprehensive community cancer programs (21.4%) had lower radiotherapy utilization rates compared with integrated network cancer programs (30.5%) and community cancer programs (29.7%). CONCLUSIONS: Adjuvant RT may correlate with improved overall survival in patients with grades II and III intracranial meningiomas regardless of the extent of resection. There is poor utilization of adjuvant RT for patients with grades II and III meningiomas likely due to a paucity of quality data on the subject. These findings will be strengthened with prospective data evaluating the role of adjuvant RT.

Glioblastoma Recurrence Versus Treatment Effect in a Pathology-Documented Series.

OBJECTIVE: Patients diagnosed with glioblastoma (GBM) are treated with surgery followed by fractionated radiotherapy with concurrent and adjuvant temozolomide. Patients are monitored with serial magnetic resonance imaging (MRI). However, treatment-related changes frequently mimic disease progression. We reviewed a series of patients undergoing surgery for presumed first-recurrence GBM, where pathology reports were available for tissue diagnosis, in order to better understand factors associated with a diagnosis of treatment-related changes on final pathology. METHODS: Patient records at a single institution between 2005 and 2015 were retrospectively reviewed. Pathology reports were reviewed to determine diagnosis of recurrent GBM or treatment effect. Survival analysis was performed interrogating overall survival (OS) and progression-free survival (PFS). Correlation with radiation treatment plans was also examined. RESULTS: One-hundred-twenty-three patients were identified. One-hundred-sixteen patients (94%) underwent resection and seven underwent biopsy. Treatment-related changes were reported in 20 cases (16%). These patients had longer median OS and PFS from the time of recurrence than patients with true disease progression. However, there was no significant difference in OS from the time of initial diagnosis. Treatment effect was associated with surgery within 90 days of completing radiation. In patients receiving radiation at our institution (n = 53), larger radiation target volume and a higher maximum dose were associated with treatment effect. CONCLUSION: Treatment effect was associated with surgery nearer to completion of radiation, a larger radiation target volume, and a higher maximum point dose. Treatment effect was associated with longer PFS and OS from the time of recurrence, but not from the time of initial diagnosis.

Morbidity and mortality in elderly patients undergoing evacuation of acute traumatic subdural hematoma.

OBJECTIVE: Acute traumatic subdural hematoma (atSDH) can be a life-threatening neurosurgical emergency that necessitates immediate evacuation. The elderly population can be particularly vulnerable to tearing bridging veins. The aim of this study was to evaluate inpatient morbidity and mortality, as well as predictors of inpatient mortality, in a national trauma database. METHODS: The authors queried the 2016-2017 National Trauma Data Bank registry for patients aged 65 years and older who had undergone evacuation of atSDH. Patients were categorized into three age groups: 65-74, 75-84, and 85+ years. A multivariable logistic regression model was fitted for inpatient mortality adjusting for age group, sex, race, presenting Glasgow Coma Scale (GCS) category (3-8, 9-12, and 13-15), Injury Severity Score, presence of coagulopathy, presence of additional hemorrhages (epidural hematoma [EDH], intraparenchymal hematoma [IPH], and subarachnoid hemorrhage [SAH]), presence of midline shift > 5 mm, and pupillary reactivity (both, one, or none). RESULTS: A total of 2508 patients (35% females) were analyzed. Age distribution was as follows: 990 patients at 65-74 years, 1096 at 75-84, and 422 at 85+. Midline shift > 5 mm was present in 72% of cases. With regard to additional hemorrhages, SAH was present in 21%, IPH in 10%, and EDH in 2%. Bilaterally reactive pupils were noted in 90% of patients. A major complication was observed in 14.4% of patients, and the overall mortality rate was 18.3%. In the multivariable analysis, the presenting GCS category was found to be the strongest predictor of postoperative inpatient mortality (3-8 vs 13-15: OR 3.63, 95% CI 2.68-4.92, p < 0.001; 9-12 vs 13-15: OR 2.64, 95% CI 1.79-3.90, p < 0.001; 30% of overall variation), followed by the presence of SAH (OR 2.86, 95% CI 2.21-3.70, p < 0.001; 25% of overall variation) and the presence of midline shift > 5 mm (OR 2.40, 95% CI 1.74-3.32, p < 0.001; 11% of overall variation). Model discrimination was excellent (c-index 0.81). Broken down by age decile group, mortality increased from 8.0% to 15.4% for GCS 13-15 to around 36% for GCS 9-12 to almost as high as 60% for GCS 3-8, particularly in those aged 85 years and older. CONCLUSIONS: The present results from a national trauma database will, the authors hope, assist surgeons in preoperative discussions with patients and their families with regard to expected postoperative outcomes following surgical evacuation of an atSDH.

The T2-FLAIR-mismatch sign as an imaging biomarker for IDH and 1p/19q status in diffuse low-grade gliomas: a systematic review with a Bayesian approach to evaluation of diagnostic test performance.

OBJECTIVE: With the revised WHO 2016 classification of brain tumors, there has been increasing interest in imaging biomarkers to predict molecular status and improve the yield of genetic testing for diffuse low-grade gliomas (LGGs). The T2-FLAIR-mismatch sign has been suggested to be a highly specific radiographic marker of isocitrate dehydrogenase (IDH) gene mutation and 1p/19q codeletion status in diffuse LGGs. The presence of T2-FLAIR mismatch indicates a T2-hyperintense lesion that is hypointense on FLAIR with the exception of a hyperintense rim. METHODS: In accordance with PRISMA guidelines, we performed a systematic review of the Ovid Medline, Embase, Scopus, and Cochrane databases for reports of studies evaluating the diagnostic performance of T2-FLAIR mismatch in predicting the IDH and 1p/19q codeletion status in diffuse LGGs. Results were combined into a 2 × 2 format, and the following diagnostic performance parameters were calculated: sensitivity, specificity, positive predictive value, negative predictive value, and positive (LR+) and negative (LR-) likelihood ratios. In addition, we utilized Bayes theorem to calculate posttest probabilities as a function of known pretest probabilities from previous genome-wide association studies and the calculated LRs. Calculations were performed for 1) IDH mutation with 1p/19q codeletion (IDHmut-Codel), 2) IDH mutation without 1p/19q codeletion (IDHmut-Noncodel), 3) IDH mutation overall, and 4) 1p/19q codeletion overall. The QUADAS-2 (revised Quality Assessment of Diagnostic Accuracy Studies) tool was utilized for critical appraisal of included studies. RESULTS: A total of 4 studies were included, with inclusion of 2 separate cohorts from a study reporting testing and validation (n = 746). From pooled analysis of all cohorts, the following values were obtained for each molecular profile-IDHmut-Codel: sensitivity 30%, specificity 73%, LR+ 1.1, LR- 1.0; IDHmut-Noncodel: sensitivity 33.7%, specificity 98.5%, LR+ 22.5, LR- 0.7; IDH: sensitivity 32%, specificity 100%, LR+ 32.1, LR- 0.7; 1p/19q codeletion: sensitivity 0%, specificity 54%, LR+ 0.01, LR- 1.9. Bayes theorem was used to calculate the following posttest probabilities after a positive and negative result, respectively-IDHmut-Codel: 32.2% and 29.4%; IDHmut-Noncodel: 95% and 40%; IDH: 99.2% and 73.5%; 1p/19q codeletion: 0.4% and 35.1%. CONCLUSIONS: The T2-FLAIR-mismatch sign is an insensitive but highly specific marker of IDH mutation but not 1p/19q codeletion in diffuse LGGs, although there may be significant exceptions. These findings support the utility of T2-FLAIR mismatch as an imaging-based biomarker for positive selection of patients with IDH-mutant gliomas.