Nervous System Malignancies Research Articles

Survival of pediatric patients with ependymoma in a tertiary cancer center in Rio de Janeiro, Brazil.

Ependymoma is the third most frequent central malignant nervous system tumor in the pediatric age group. There is scarce data in the literature on survival of these patients, especially in upper and lower middle-income countries. We aimed to describe the clinical and demographic characteristics, treatment, and outcome of pediatric patients with ependymoma admitted to a public cancer hospital. Retrospective analysis of medical records of patients with ependymoma, admitted to the Pediatric Oncology department (0-20 years) during the period of 2000-2022. Data on patient, disease characteristics, and treatment were analyzed. Overall survival (OS) was calculated using the Kaplan-Meier method. Seventy-two patients were evaluated; median age at diagnosis was 6.5 years (range: 1-20), 63% were male, 54% of the tumors were in the posterior fossa (PF-EPN), 45% were classified as WHO grade 3, and 68% were operated on in other institutions before referral. Regarding treatment, 72% underwent radiotherapy and 33% of patients underwent chemotherapy. Almost 70% percent of the patients had relapses. The median follow-up time was 5.2 years (Range: 0,1-21,4). The OS in 5 years was 67%. Totally resected tumors had OS in 5 years of 88% (p: 0.028). The results achieved in this series show a survival gap between UMIC and HIC. Relapses occurred mainly in the first ten years and then reached a plateau, with the majority of patients experiencing endocrinological and neurological sequelae.

Seasonality of Deaths Due to Heart Diseases among Cancer Patients.

Background and Objectives: Cancer patients are at increased short- and long-term risk of cardiac toxicity and mortality. It is well-known that cardiac morbidity and mortality follows a seasonal pattern. Here we address the question of whether heart disease-related fatalities among cancer patients also follow a seasonal pattern. Materials and Methods: We performed a retrospective analysis of seasonality of deaths due to heart diseases (n = 503,243) in patients with newly diagnosed cancer reported during the period from 1975 to 2016 in the US's largest cancer registry-the Surveillance, Epidemiology, and End Results (SEER) database. Seasonality was assessed through a classical cosinor model assuming a single annual peak. Results: We identified a significant seasonal peak in the first half of November. A peak with identical features was for all subgroups of patients defined based on demographic characteristics. This was also the case when analysis was performed on subgroups defined by the type of malignancy. Only patients with acute leukemias, pancreatic cancer and nervous system malignancies did not have a seasonal pattern in heart disease-related fatalities. Conclusion: the rate of heart disease-related fatalities after cancer diagnosis follows a seasonal pattern similar to that observed for the general population, albeit with an earlier peak in November. This suggests that close monitoring of the cardiovascular system in cancer survivors must be particularly active from late autumn and during the entire winter period.

Inhibition of human glioblastoma multiforme cells by 10,11-dehydrocurvularin through the MMP-2 and PI3K/AKT signaling pathways

Glioblastoma, formerly known as glioblastoma multiforme (GBM), is a malignant nervous system tumor with high morbidity, recurrence rate, and mortality. Treating glioblastoma is difficult due to complicating factors, and novel therapeutic strategies are required to overcome resistance. In this study, we investigate the glioblastoma inhibitory activity of 10,11-dehydrocurvularin (DCV), a polyketide compound with broad biological activities, despite the fact that its anti-glioma properties and related mechanisms have yet to be studied. We look at how DCV affects glioblastoma cell lines U251 and U87 versus HEB cells. We discover that DCV inhibits glioblastoma cell proliferation, colony formation, migration, and invasion, as well as causing cell apoptosis. DCV treatment inhibits AKT phosphorylation and decreases the level of the PI3K/AKT pathway downstream protein MMP2. Our findings suggest that DCV could be a candidate for developing more potent glioblastoma chemotherapeutic drugs.

Modifiers of and Disparities in Palliative and Supportive Care Timing and Utilization among Neurosurgical Patients with Malignant Central Nervous System Tumors.

Patients with primary or secondary central nervous system (CNS) malignancies benefit from utilization of palliative care (PC) in addition to other supportive services, such as home health and social work. Guidelines propose early initiation of PC for patients with advanced cancers. We analyzed a cohort of privately insured patients with malignant brain or spinal tumors derived from the Optum Clinformatics Datamart Database to investigate health disparities in access to and utilization of supportive services. We introduce a novel construct, "provider patient racial diversity index" (provider pRDI), which is a measure of the proportion of non-white minority patients a provider encounters to approximate a provider's patient demographics and suggest a provider's cultural sensitivity and exposure to diversity. Our analysis demonstrates low rates of PC, home health, and social work services among racial minority patients. Notably, Hispanic patients had low likelihood of engaging with all three categories of supportive services. However, patients who saw providers categorized into high provider pRDI (categories II and III) were increasingly more likely to interface with supportive care services and at an earlier point in their disease courses. This study suggests that prospective studies that examine potential interventions at the provider level, including diversity training, are needed.

Liquid biopsy in CNS tumors: Current status & future perspectives.

Precise classification of central nervous system (CNS) malignancies is vital for the treatment and prognostication. Identification of noninvasive markers can be of importance to guide treatment decisions and in monitoring treatment response. CNS tumors are classified based on morphology with an essential complement of molecular changes, including mutations, amplifications, and methylation. Neuroimaging is the mainstay for initial diagnosis and monitoring tumor response with obvious limitations of imprecise tumor typing and no information on diagnostic, predictive and prognostic markers. Liquid biopsy has evolved as a diagnostic tool in body fluids and is being investigated as a surrogate for tissue biopsy in managing primary and metastatic brain tumors. Liquid biopsy refers to analyzing biological fluids such as peripheral blood, urine, pleural effusion, ascites, and cerebrospinal fluid (CSF); however, peripheral blood remains the primary source of fluid biopsy. The analytes include cell-free DNA (cfDNA) circulating tumor cells (CTCs), circulating micro RNAs (miRNAs), circulating proteins and extracellular vesicles (EVs). Analysis of these components is actively used for early cancer detection, auxiliary staging, prognosis assessment, detection of minimal residual disease (MRD), and monitoring drug resistance in various solid tumors. In recent years, liquid biopsy has been studied in CNS tumors, and analysis of CTCs and cfDNA have become relevant research topics. In the current review, we have explained the clinical potential of liquid biopsy in CNS tumors to assist in diagnosing and predicting prognosis and response to treatment.

METTL7B contributes to the malignant progression of glioblastoma by inhibiting EGR1 expression

Glioblastoma (GBM), a predominant central nervous system (CNS) malignancy, is correlated with high mortality and severe morbidity. Mammalian methyltransferase-like 7B (METTL7B) as a methyltransferase has been identified to participate in cancer progression. However, its function in GBM is elusive. Accordingly, we aimed to explore the effect of METTL7B on GBM. The expression of METTL7B and EGR2 in GBM patients and GBM cells were detected by qPCR, western blots and immunohistochemical staining. Cell viability was assessed by CCK-8 assays. Cell proliferation was determined by EdU, colony formation, and tumor sphere formation assays. METTL7B shRNA was injected into the Balb/c nude mice. The size and weight of isolated tumor was measured. And the expression levels of Ki67, METTL7B and EGR1 were examined by immunohistochemical staining. METTL7B was significantly elevated, while EGR1 was downregulated in clinical GBM tissues. METTL7B upregulation was associated with the low overall survival of GBM patients. Moreover, METTL7B depletion remarkably attenuated GBM cell proliferation. Mechanistically, METTL7B overexpression inhibited EGR1 expression in GBM cells. EGR1 knockdown rescued the inhibitory effect of METTL7B depletion on GBM cell proliferation. Meanwhile, METTL7B depletion arrested more GBM cells at the G0/G1, but fewer cells at the S phase, which EGR1 knockdown reversed these effects. Furthermore, tumorigenicity analysis revealed that METTL7B promotes tumor growth of GBM cells in vivo. METTL7B contributes to the malignant progression of GBM by inhibiting EGR1 expression. METTL7B and EGR1 may be utilized as the treatment targets for GBM therapy.

Routine use of low-dose glucarpidase following high-dose methotrexate in adult patients with CNS lymphoma: an open-label, multi-center phase I study

BackgroundHigh-dose methotrexate (HD-MTX) has broad use in the treatment of central nervous system (CNS) malignancies but confers significant toxicity without inpatient hydration and monitoring. Glucarpidase is a bacterial recombinant enzyme dosed at 50 units (u)/kg, resulting in rapid systemic MTX clearance. The aim of this study was to demonstrate feasibility of low-dose glucarpidase to facilitate MTX clearance in patients with CNS lymphoma (CNSL).MethodsEight CNSL patients received HD-MTX 3 or 6 g/m2 and glucarpidase 2000 or 1000u 24 h later. Treatments repeated every 2 weeks up to 8 cycles.ResultsFifty-five treatments were administered. Glucarpidase 2000u yielded > 95% reduction in plasma MTX within 15 min following 33/34 doses (97.1%) and glucarpidase 1000u yielded > 95% reduction following 15/20 doses (75%). Anti-glucarpidase antibodies developed in 4 patients and were associated with MTX rebound. In CSF, glucarpidase was not detected and MTX levels remained cytotoxic after 1 (3299.5 nmol/L, n = 8) and 6 h (1254.7 nmol/L, n = 7). Treatment was safe and well-tolerated. Radiographic responses in 6 of 8 patients (75%) were as expected following MTX-based therapy.ConclusionsThis study demonstrates feasibility of planned-use low-dose glucarpidase for MTX clearance and supports the hypothesis that glucarpidase does not impact MTX efficacy in the CNS.Clinical trial registrationNCT03684980 (Registration date 26/09/2018).

Epidemiological study of brain cancer in Iran: A systematic review

Introduction: In recent decades, the incidence and mortality rate of brain tumours, especially in adults, has increased. In order to better plan to reduce the burden of this cancer, knowledge of the epidemiological aspects of this disease is essential. Therefore, due to the lack of a comprehensive study on brain cancer in Iran, this study aimed to investigate the epidemiological aspects of this cancer in Iran. Methods: In June 2020, keywords of 'brain tumour', 'nervous system tumours', 'nervous system neoplasm', 'nervous system cancer', 'central nervous system (CNS)' and 'Iran' were searched on Medline/PubMed and Web of Science databases Scopus, Embase, SID, IranMedex, and Google Scholar. The search results were entered Endnotes Version 8; finally, 35 full papers were reviewed and included in the study. Results: The incidence of brain cancer and CNS tumour is lower in children in central Iran. The incidence of CNS cancer was relatively high among children in Golestan province. Furthermore, the standardised incidence of primary CNS tumours in Iran is 5.69 per 100,000, which is lower than in other countries. Nervous system malignancies were more common in men than in women (age-standardized rate 3 versus 2.2 per 100,000 in men and women, respectively). Tehran had the highest incidence of CNS tumours. Meningiomas were the only most common tumour in women. Gliomas were the most common primary brain tumour, and most of the lesions in this subgroup were in low-grade astrocytoma and ependymomas. Brain cancer mortality was higher in men than in women. Age is a potential risk factor, and the incidence of CNS tumours increases with increasing age after 30 years. Conclusion: Nervous system cancers are on the rise in Iran due to lifestyle changes and increased risk factors. Planning to reduce risk factors and early detection of the disease can be helpful in reducing cases and reducing mortality.

Age-specific incidence rate of brain and nervous system malignancy in the world.

Age-specific incidence rate of brain and nervous system malignancy in the world.

Nuclear receptor NR5A2 negatively regulates cell proliferation and tumor growth in nervous system malignancies

Nervous system malignancies are characterized by rapid progression and poor survival rates. These clinical observations underscore the need for novel therapeutic insights and pharmacological targets. To this end, here, we identify the orphan nuclear receptor NR5A2/LRH1 as a negative regulator of cancer cell proliferation and promising pharmacological target for nervous system-related tumors. In particular, clinical data from publicly available databases suggest that high expression levels of NR5A2 are associated with favorable prognosis in patients with glioblastoma and neuroblastoma tumors. Consistently, we experimentally show that NR5A2 is sufficient to strongly suppress proliferation of both human and mouse glioblastoma and neuroblastoma cells without inducing apoptosis. Moreover, short hairpin RNA-mediated knockdown of the basal expression levels of NR5A2 in glioblastoma cells promotes their cell cycle progression. The antiproliferative effect of NR5A2 is mediated by the transcriptional induction of negative regulators of the cell cycle, CDKN1A (encoding for p21cip1), CDKN1B (encoding for p27kip1) and Prox1 Interestingly, two well-established agonists of NR5A2, dilauroyl phosphatidylcholine (DLPC) and diundecanoyl phosphatidylcholine, are able to mimic the antiproliferative action of NR5A2 in human glioblastoma cells via the induction of the same critical genes. Most importantly, treatment with DLPC inhibits glioblastoma tumor growth in vivo in heterotopic and orthotopic xenograft mouse models. These data indicate a tumor suppressor role of NR5A2 in the nervous system and render this nuclear receptor a potential pharmacological target for the treatment of nervous tissue-related tumors.

OTME-11. Characterizing the immunologic context of pediatric brain tumors

Abstract Therapy for pediatric central nervous system (CNS) malignancies can be toxic, and outcomes are suboptimal. Immunotherapy holds promise as a therapeutic avenue, but the poorly understood microenvironment limits its application. The Children’s Brain Tumor Network (CBTN) released the Pediatric Brain Tumor Atlas, containing expression profiles of nearly 700 primary CNS tumors. To study the immune microenvironment, a classification from The Cancer Genome Atlas project is applied. High-grade lesions are predominantly lymphocyte deplete (C4, 81%) or immunologically quiet (C5, 11%). Low-grade lesions are more mixed with 46% C4, 21% C5, and a higher proportion of inflammatory subtype (C3, 31%). For survival parameters, adjusting for tumor grade and extent of resection, the hazard ratio is 2.2 (0.78 – 6.3), p = 0.13) and 2.4 (0.6 – 10.0, p = 0.24) for C4 and C5, respectively. With no events among low-grade tumors, progression-free survival will be another useful metric and released by CBTN in April. Deconvolution of immune cell gene signatures among C4 samples reveals decreased abundance of T cells (OR 0.26, 0.1 – 0.5) yet increasing T-cell abundance is associated with decreased survival time in high-grade samples (HR 3.7, 1.4 – 10.1). Additionally, there are increased macrophage and decreased microglia signatures among high-grade samples and the C4 and C5 subtypes. It is hypothesized that expression of inhibitory immunomodulators contributes to a pro-tumorigenic microenvironment and represent potential therapeutic targets. In lieu of normal tissue in the data set, differential gene expression experiments between disease states reveals upregulated immunomodulators. Conventional immunomodulators, e.g. PDL1 and CTLA4, are expressed in low-grade samples with C3 subtype, which is abundant in craniopharyngioma. Alternative inhibitory immunomodulators, e.g. KDM1A, EZH2, CD276, are significantly expressed in high-grade samples including diffuse midline glioma. Overall, our analysis contributes to the understanding of the immune microenvironment and identifies potential mechanisms of immune escape among pediatric CNS tumors.

Mesenchymal Epithelial Transition Factor Signaling in Pediatric Nervous System Tumors: Implications for Malignancy and Cancer Stem Cell Enrichment.

Malignant nervous system cancers in children are the most devastating and worrisome diseases, specifically due to their aggressive nature and, in some cases, inoperable location in critical regions of the brain and spinal cord, and the impermeable blood-brain barrier that hinders delivery of pharmaco-therapeutic compounds into the tumor site. Moreover, the delicate developmental processes of the nervous system throughout the childhood years adds another limitation to the therapeutic modalities and doses used to treat these malignant cancers. Therefore, pediatric oncologists are charged with the daunting responsibility of attempting to deliver effective cures to these children, yet with limited doses of the currently available therapeutic options in order to mitigate the imminent neurotoxicity of radio- and chemotherapy on the developing nervous system. Various studies reported that c-Met/HGF signaling is affiliated with increased malignancy and stem cell enrichment in various cancers such as high-grade gliomas, high-risk medulloblastomas, and MYCN-amplified, high-risk neuroblastomas. Therapeutic interventions that are utilized to target c-Met signaling in these malignant nervous system cancers have shown benefits in basic translational studies and preclinical trials, but failed to yield significant clinical benefits in patients. While numerous pre-clinical data reported promising results with the use of combinatorial therapy that targets c-Met with other tumorigenic pathways, therapeutic resistance remains a problem, and long-term cures are rare. The possible mechanisms, including the overexpression and activation of compensatory tumorigenic mechanisms within the tumors or ineffective drug delivery methods that may contribute to therapeutic resistance observed in clinical trials are elaborated in this review.

Abstract S12-02: Comprehensive meta-analysis of COVID-19 mortality rates for 22 cancer subtypes from the Reboot: COVID-Cancer Project, an interactive resource with aggregated data from 21,839 cancer patients

Abstract Introduction: The COVID-19 pandemic continues to disproportionately impact people with cancer. Mortality estimates among cancer patients vary and are influenced by numerous factors including cancer type, treatment, disease stage, and patient demographics. To date, attempts to explore these associations have been limited by small cohorts. Methods: Here, we present a meta-analysis of data available through the Reboot: COVID-Cancer Project, a living and freely available resource that includes published clinical studies that report outcomes for cancer patients with COVID-19. Studies were identified using targeted search queries in PubMed, MedRxiv, BioRxiv, and the SSRN eLibrary, followed by rule-based approaches and extensive manual validation and data extraction. The data is updated monthly and can be explored through an interactive dashboard as well as downloaded. Case fatality rates (CFR; the number of deaths per 100 confirmed cases during the study period) were calculated using a random-effects model. Study heterogeneity and sample size bias was assessed using the Egger regression test. Results: As of December 18, 2020, the resource contained 225 publications comprising 21,839 cancer patients with COVID-19. Of these, there was sufficient sample size to quantify CFRs for 22 cancer types across 19,147 patients from 109 publications. The pooled CFR among all cancer patients was 27% (95% CI: 25-30%). For solid tumors and hematological malignancies, the CFRs were 23% (95% CI: 20-25%) and 30% (95% CI: 27-33%), respectively. Within solid tumors, patients with lung (CFR: 32%, 95% CI: 27-36%), prostate (CFR: 30%, 95% CI: 17-43%), and central nervous system (CFR: 27%, 95% CI: 18-36%) malignancies had relatively high CFRs, whereas patients with breast (CFR: 10%, 95% CI: 7-14%) and thyroid (CFR: 5%, 95% CI: 1-11%) malignancies had relatively low CFRs. Among patients with hematological malignancies, CFRs ranged from 10% (95% CI: 3-18%) in patients with chronic myelogenous leukemia to 39% (95% CI: 20-57%) in patients with acute myeloid leukemia. Discussion: We observed significant heterogeneity of COVID-19 CFRs between cancer subtypes. This may in part reflect differences in patient demographics, treatment history, or disease state. Subtype-specific analysis can stratify cancer patients by risk for COVID-19 mortality and advise management strategies. The Reboot: COVID-Cancer Project provides an accessible means to evaluate subtype-specific COVID-19 fatality rates on a by-publication basis. Citation Format: Emily-Claire Duffy, Kelly Fan, Shailesh Advani, Chris Bailey, James R.M. Black, Ellie Strauss, Devon Crittenden, Thomas Bhangdia, Allyson Imbacuan, Emily Yang, Allison Britt, Pradeep Mangalath, Charles Swanton, Laura B. Kleiman, Catherine Del Vecchio Fitz. Comprehensive meta-analysis of COVID-19 mortality rates for 22 cancer subtypes from the Reboot: COVID-Cancer Project, an interactive resource with aggregated data from 21,839 cancer patients [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2021 Feb 3-5. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(6_Suppl):Abstract nr S12-02.

Ongoing Evaluation of Immune-related Response Assessment in Brain Metastases

脑转移瘤是成人恶性神经系统肿瘤最常见的病因。针对这一部分人群，治疗手段有限，预后不佳。近年来，以程序性死亡受体1（programmed cell death protein 1, PD-1）及程序性死亡受体配体1（programmed cell death protein ligand 1, PD-L1）抑制剂为主的免疫治疗，给恶性肿瘤的治疗模式带来了革新。免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）彻底改变了晚期非小细胞肺癌（non-small cell lung cancer, NSCLC）的治疗模式。ICI在某些驱动基因阴性的NSCLC脑转移瘤治疗中，取得了令人鼓舞的结果。然而，针对脑转移瘤患者的临床研究，不仅相应的临床数据有限，其疗效的评价也缺乏统一标准。本文旨在阐述不同的疗效评价标准及其在临床研究中的应用，比较之间的异同，并对未来发展趋势进行展望。

Application and prospect of radiomics in spinal cord and spine system diseases: A narrative review

Spinal cord and spine system diseases are complex and diverse, and prognosis is often poor. Therefore, early diagnosis is essential, especially for spinal system tumors, which are malignant nervous system tumors that have the highest mortality and disability rates. Accurate diagnosis avoids unnecessary operations. Traditional medical imaging diagnosis remains at the level of anatomical morphology, and there is a considerable amount of useful information that can be extracted and utilized. Radiomics is a new method of medical imaging diagnosis that is committed to improving image analysis and is capable of extracting a large number (more than 200 types) of quantitative features from medical images. Numerous studies on the application of radiomics in various systems of the body have been conducted. We reviewed current research on radiomics in spinal cord and spine system diseases and discussed the progress and challenges to provide a basis for improving the diagnosis and identification of spinal cord and spine system diseases and offer evidence-based support for precision medicine.

Craniospinal irradiation in patients diagnosed with glioblastoma with primitive neuronal component prevents distant intracranial and leptomeningeal recurrences.

e14540 Background: Glioblastoma (GBM) is the most common primary central nervous system (CNS) malignancy. In recent years, molecular and histological analyses have identified GBM with primitive neuronal component (GBM-PNC) as a distinct entity with poor regional control and worse overall prognosis. GBM-PNCs are more prone to CNS dissemination and leptomeningeal (LM) metastasis, occurring in up to 40% of patients. Given the concern for distal CNS spread, we hypothesized that craniospinal irradiation (CSI) may be an effective treatment option for GBM-PNC. Methods: We performed a retrospective chart review of patients diagnosed with GBM-PNC treated at a large academic center with institutional review board approval. Clinical, histologic and treatment characteristics, as well as disease outcomes were obtained from the electronic medical record. Results: Ten patients diagnosed with GBM-PNC were identified in the period of 2005-2019. Median follow-up was 17 months. Overall, 80% of patients were men, median age was 49 years (range 20-64) and ECOG 0-1. Fifty percent of patients received CSI as opposed to involved field radiation therapy (IFRT). Four of five patients receiving CSI were treated with proton therapy. All patients, but one received concurrent Temozolomide. Both IFRT and CSI were tolerated well with minimal grade 3-4 toxicities. Patients treated with CSI were more likely to experience transient grade 3-4 lymphopenia (60% vs 0%). Eighty percent of patients experienced a recurrence after treatment with median progression free survival (PFS) of 13 months (range 8-26). PFS did not differ between patients receiving IFRT and CSI (14 vs 12.5 months, p = 0.9). Median overall survival (OS) was 30 months for patients who received IFRT, and median OS was not reached in the CSI group. Of the patients who received CSI as part of their treatment, all recurrences were within the high dose radiation area. On the contrary, 75% of patients who received IFRT experienced multiple recurrences at new intracranial sites and later in the leptomeninges or the spine, requiring multiple treatment courses. Conclusions: This hypothesis generating study demonstrates that CSI may prevent distant intracranial metastasis and LM disease progression. CSI delivered with proton therapy was well tolerated with minimal additional toxicity. A larger study is needed to guide the optimal treatment of patients diagnosed with glioblastoma with primitive neuronal component.

Age‐ and Tissue‐Specific Alternative Splicing of the Neurofibromin Gene in Swine

Neurofibromatosis type 1 (NF1) is one of the most common monogenic disorders that affects 1 in 2,500 children. The disorder manifests in varying, complex phenotypes that include cognitive and learning dysfunction, bone and cardiovascular disorders, and an increased risk of developing benign and malignant nervous system tumors. NF1 is caused by mutations in the neurofibromin gene; over 4,000 different mutations have been clinically identified with very little understanding of genotype‐phenotype association in terms of the clinical presentation of the disorder. The human neurofibromin gene contains 61 exons, of which, four are alternatively spliced (optionally included) to produce isoforms of the protein. Over 50% of the mutations in NF1 patients are thought to produce abnormalities in splicing. Yet, only a handful of studies have examined the role of neurofibromin alternative splicing or acknowledged their potential role in cell biology. Recently, several swine models of NF1 have been developed in hopes that these models will recapitulate the disorder in humans better than existing rodent models and thus offer a more translational platform for the development of novel therapies. In order to assess translatability of swine for NF1, we have characterized the tissue specific expression patterns of neurofibromin in newborn and adult swine. Tissue samples were collected from brain (frontal cortex, cerebellar vermis, amygdala, hippocampus, pituitary body, substantia nigra), nerves (brachial plexus, cranial nerve IV, optic nerve), heart (left ventricle apex), lung (lobe apex), muscle (superior trapezius), gastrointestinal tract (distal ileum, proximal large intestine), and skin (epithelium, adipose) of two‐day old (N=5) and eight‐month old (N=6) swine. The inclusion or exclusion of the four known alternatively spliced exons (ASEs) were determined by RT‐qPCR. Generally, inclusion of ASE 12 was relatively higher in cortical brain and muscle tissue, while inclusion of ASE 31, implicated in regulation of RAS activity, was relatively higher in myelin dense tissue. Inclusion of ASE 57 was significantly higher exclusively in muscle tissue. Interestingly, ASE 13 was not detected in any of the tissue and subsequent sequencing of the exon revealed a significant genomic variation compared to human: ASE 13 in swine contains an additional nucleotide that results in an early stop codon in neurofibromin transcription if this ASE was included. Overall neurofibromin expression was similar between age groups but expression of ASE 31 was overall lower in newborn tissue. Tissues from newborn swine also had lower expression of ASE 12 in brachial plexus, muscle, heart, and lung tissues. This study provides the first characterization of neurofibromin ASE expression in swine.Support or Funding InformationThe research was supported by the Biomedical & Genomic Research Group Discretionary Fund (University of Wisconsin‐Madison), NF North Central, NF Network, and NF Team Foundation.

Superparamagnetic iron oxide nanoparticles drive miR-485-5p inhibition in glioma stem cells by silencing Tie1 expression

Gliomas are highly malignant nervous system tumours. Studies shown that cancer stem cells are one of the main reasons underlying recurrence, metastasis, and poor prognosis in glioma cases. Our previous studies have found that superparamagnetic iron oxide nanoparticles (SPIONs) can act as nucleic acid carriers to drive intracellular overexpression of these nucleic acids. In this study, CD44+/CD133+ glioma stem cells (HuGSCs) were first isolated from surgically resected tissues from patients. qPCR and western blot results showed that Tie1 expression in HuGSCs was significantly higher thanexpression in CD44-/CD133- glioma cells. Bioinformatic analysis and luciferase reporter assays showed that miR-485-5p binds to specific loci on the 3′-UTR of Tie1 mRNA to inhibit Tie1 expression. Subsequently, miR-485-5p/miR-mut and SPION complexes were transfected into HuGSCs. Transmission electron microscopy showed that a highly dense metallic electron cloud is present in HuGSCs. At the same time, in vivo and in vitro studies showed that miR-485-5p@SPIONs can significantly inhibit HuGSC proliferation, invasion, tumourigenicity, and angiogenesis. In-depth analysis showed that Tie1 interacts with neuronal growth factors such as FGF2, BDNF, GDNF, and GFAP. qPCR and western blot results showed that in miR-485-5p@SPIONs-HuGSCs, the expression levels of Tie1 and stem cell markers (Oct4, Sox2, Nanog, CD44, and CD133), and even FGF2, BDNF, GDNF, and GFAP were significantly lower than thelevels in the control group (miR-mut@SPIONs-HuGSCs). Therefore, this study showedthat Tie1 is an important factor that maintains glioma stem cell activity. SPIONs drive miR-485-5p overexpression in cells and inhibit endogenous Tie1 expression to downregulate the protein expression levels of Fgf2/GDNF/GFAP/BDNF and significantly weaken the in vivo and in vitro viability of gliomas.

Targeting Long Non-Coding RNAs in Nervous System Cancers: New Insights in Prognosis, Diagnosis and Therapy.

Long non-coding RNAs (lncRNAs) constitute one of the most broad and diverse classes of cellular transcripts, playing key roles as regulatory molecules in many biological processes. Although the biology of lncRNAs is a new and emerging field of research, several studies have already shown that alterations in the expression of lncRNAs are associated with the development and progression of cancer in different organs and tissues, including central and peripheral nervous system. In this review, we summarize the oncogenic and tumor suppressive roles of lncRNAs in malignant tumors of the nervous system, such as glioma and neuroblastoma, focusing on their functional interactions with DNA, other RNA and protein molecules. We further discuss the potential use of lncRNAs as biomarkers for diagnosis, prognosis and tumor treatment. Gaining insight into the functional association between nervous system malignancies and lncRNAs could offer new perspectives to the development of promising therapeutic tools against cancer.

Ethics consultations in patients with neuro-oncologic diseases.

e13519 Background: In patients with cancer, ethical issues regarding patient autonomy, surrogate decision making, and end-of-life care often arise. Ethics consultation can help clarify perspectives of different stakeholders involved in a patient’s care, facilitate communication, and resolve conflicts. Neurologic manifestations of cancer can cause impairment of cognition, communication, and functional independence. Ethical conflicts in the specific context of neuro-oncologic diseases have yet to be characterized. Methods: In this retrospective study, we reviewed 50 cases where ethics consultation was requested for patients with neurologic malignancies or neurologic complications of cancer treated at Memorial Sloan Kettering Cancer Center (MSK). Results: Of 50 patients (ages 4-76, 56% female) reviewed, 27 had a primary central nervous system (CNS) malignancy, 21 had CNS metastasis, one had a vascular malformation, and one had no clear diagnosis. Neurologic issues contributing to patients’ clinical status included toxic metabolic encephalopathy (14), leptomeningeal disease (10), intracerebral hemorrhage (10), hydrocephalus (9), seizures (6), cord compression (5), and ischemic stroke (3). At the time of ethics consultation, 39 patients lacked decision-making capacity, 47 did not have an advance directive, and 38 did not have a do not resuscitate (DNR) order. Ethical issues identified included surrogate decision making (20), DNR (18), capacity (6), refusal of treatment (5), futility (4), brain death (4), and research ethics (2). Contextual issues included staff-family conflict (22), cultural or religious considerations (10), intra-family conflict (7), intra-staff conflict (6), and physician attitude toward treatment (3). Conclusions: Neuro-oncologic diseases present a unique constellation of ethical conflicts, particularly about end-of-life care. Language and cognitive deficits, impaired decision-making, and sudden neurological decline are factors that shape ethical conflicts in this clinical setting. Further study of ethical issues in neuro-oncology may help patients receive care that is consistent with their goals and values.