Typical Central Nervous System Research Articles

TUNEL-n-DIFL Method for Detection and Estimation of Apoptosis Specifically in Neurons and Glial Cells in Mixed Culture and Animal Models of Central Nervous System Diseases and Injuries.

Detection of merely apoptosis does not reveal the type of central nervous system (CNS) cells that are dying in the CNS diseases and injuries. In situ detection and estimation of amount of apoptosis specifically in neurons or glial cells (astrocytes, oligodendrocytes, and microglia) can unveil valuable information for designing therapeutics for protection of the CNS cells and functional recovery. A method was first developed and reported from our laboratory for in situ detection and estimation of amount of apoptosis precisely in neurons and glial cells using in vitro and in vivo models of CNS diseases and injuries. This is a combination of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and double immunofluorescent labeling (DIFL) or simply TUNEL-n-DIFL method for in situ detection and estimation of amount of apoptosis in aspecific CNS cell type. An anti-digoxigenin (DIG) IgG antibody conjugated with 7-amino-4-methylcoumarin-3-acetic acid (AMCA) for blue fluorescence, fluorescein isothiocyanate (FITC) for green fluorescence, or Texas Red (TR) for red fluorescence can be used for in situ detection of apoptotic cell DNA, which is earlier labeled with TUNEL using alkali-stable DIG-11-dUTP. A primary anti-NeuN (neurons), anti-GFAP (astrocytes), anti-MBP (oligodendrocytes), or anti-OX-42 (microglia) IgG antibody and a secondary IgG antibody conjugated with one of the above fluorophores (other than that of ani-DIG antibody) are used for in situ detection of apoptosis in a specific CNS celltype in the mixed culture and animal models of the CNS diseases and injuries.

ApoE—functionalization of nanoparticles for targeted brain delivery—a feasible method for polyplexes?

The blood–brain barrier (BBB) poses a major obstacle in the treatment of all types of central nervous system (CNS) diseases. Small interfering RNA (siRNA) offers in principle a promising therapeutic approach by downregulating disease-related genes via RNA interference. However, the BBB is a formidable barrier for macromolecules such as nucleic acids. In an effort to develop a brain-targeted strategy for siRNA delivery systems formed by electrostatic interactions with cationic polymers (polyplexes (PXs)), we investigated the suitability of the well-known surfactant-based approach for Apolipoprotein E (ApoE)-functionalization of nanoparticles (NPs). The aim of this present work was to investigate if ApoE coating of siRNA PXs formed with cationic branched 25-kDa poly(ethyleneimine) (b-PEI) and nylon-3 polymers without or after precoating with polysorbate 80 (PS 80) would promote successful delivery across the BBB. We utilized highly hydrophobic NM0.2/CP0.8 nylon-3 polymers to evaluate the effects of hydrophobic cyclopentyl (CP) subunits on ApoE binding efficacy and observed successful ApoE binding with and without PS 80 precoating to the nylon-3 but not the PEI polyplexes. Accordingly, ApoE-coated nylon-3 polyplexes showed significantly increased uptake and gene silencing in U87 glioma cells but no benefit in vivo. In conclusion, further optimization of ApoE-functionalized polyplexes and more sophisticated in vitro models are required to achieve more successful in vitro-in vivo translation in future approaches. Graphical abstract

Current status of DNA methylation profiling in neuro-oncology as a diagnostic support tool: A review.

Over the last 2 decades, high throughput genome-wide molecular profiling has revealed characteristic genetic and epigenetic alterations associated with different types of central nervous system (CNS) tumors. DNA methylation profiling has emerged as an important molecular platform for CNS tumor classification with improved diagnostic accuracy and patient risk stratification in comparison to the standard of care histopathological analysis and any single molecular tests. The emergence of DNA methylation arrays have also played a crucial role in refining existing types and the discovery of new tumor types or subtypes. The adoption of methylation data into neuro-oncology has been greatly aided by the development of a freely accessible machine learning-based classifier. In this review, we discuss methylation workflow, address the utility of DNA methylation profiling in CNS tumors in a routine diagnostic setting, and provide an overview of the methylation-based tumor types and new types or subtypes identified with this platform.

Overcoming the blood-brain barrier? - prediction of blood-brain permeability of hydrophobically modified polyethylenimine polyplexes for siRNA delivery into the brain with in vitro and in vivo models

The blood-brain barrier (BBB) is a highly selective biological barrier that represents a major bottleneck in the treatment of all types of central nervous system (CNS) disorders. Small interfering RNA (siRNA) offers in principle a promising therapeutic approach, e.g., for brain tumors, by downregulating brain tumor-related genes and inhibiting tumor growth via RNA interference. In an effort to develop efficient siRNA nanocarriers for crossing the BBB, we utilized polyethyleneimine (PEI) polymers hydrophobically modified with either stearic-acid (SA) or dodecylacrylamide (DAA) subunits and evaluated their suitability for delivering siRNA across the BBB in in vitro and in vivo BBB models depending on their structure. Physicochemical characteristics of siRNA-polymer complexes (polyplexes (PXs)), e.g., particle size and surface charge, were measured by dynamic light scattering and laser Doppler anemometry, whereas siRNA condensation ability of polymers and polyplex stability was evaluated by spectrophotometric methods. The composition of the biomolecule corona that absorbs on polyplexes upon encountering physiological fluids was investigated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and by a liquid chromatography-tandem mass spectrometry (LC-MS-MS) method. Cellular internalization abilities of PXs into brain endothelial cells (hCMEC/D3) was confirmed, and a BBB permeation assay using a human induced pluripotent stem cell (hiPSC)–derived BBB model revealed similar abilities to cross the BBB for all formulations under physiological conditions. However, biodistribution studies of radiolabeled PXs in mice were inconsistent with in vitro results as the detected amount of radiolabeled siRNA in the brain delivered with PEI PXs was higher compared to PEI-SA PXs. Taken together, PEI PXs were shown to be a suitable nanocarrier to deliver small amounts of siRNA across the BBB into the brain but more sophisticated human BBB models that better represent physiological conditions and biodistribution are required to provide highly predictive in vitro data for human CNS drug development in the future.

Chitinase Signature in the Plasticity of Neurodegenerative Diseases.

Several reports have pointed out that Chitinases are expressed and secreted by various cell types of central nervous system (CNS), including activated microglia and astrocytes. These cells play a key role in neuroinflammation and in the pathogenesis of many neurodegenerative disorders. Increased levels of Chitinases, in particular Chitotriosidase (CHIT-1) and chitinase-3-like protein 1 (CHI3L1), have been found increased in several neurodegenerative disorders. Although having important biological roles in inflammation, to date, the molecular mechanisms of Chitinase involvement in the pathogenesis of neurodegenerative disorders is not well-elucidated. Several studies showed that some Chitinases could be assumed as markers for diagnosis, prognosis, activity, and severity of a disease and therefore can be helpful in the choice of treatment. However, some studies showed controversial results. This review will discuss the potential of Chitinases in the pathogenesis of some neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, to understand their role as distinctive biomarkers of neuronal cell activity during neuroinflammatory processes. Knowledge of the role of Chitinases in neuronal cell activation could allow for the development of new methodologies for downregulating neuroinflammation and consequently for diminishing negative neurological disease outcomes.

BCOR expression in paediatric pineoblastoma.

BCOR is expressed in a new brain tumour entity, i.e. 'CNS tumour with BCOR internal tandem duplication' (HGNET BCOR) but not in several other high grade paediatric brain tumours investigated. Immunohistochemical detection of BCOR expression may therefore serve as a potential diagnostic marker. Nevertheless, in rare paediatric glioma cases recurrent EP300-BCOR fusions were detected, which resulted in strong BCOR immunopositivity. We have therefore examined other, not analysed so far, types of central nervous system (CNS) tumours, pineoblastoma and germinoma, to assess a potential involvement of BCOR in these tumours. Levels of BCOR RNA expression were investigated by NanoString nCounter system analysis in a series of altogether 66 high grade paediatric tumours, including four pineoblastoma cases. Immunohistological detection of BCOR was performed in eight pineoblastoma, five germinoma and four atypical teratoid rhabdoid tumours (ATRTs), all located in the pineal region. We detected BCOR expression in all pineoblastomas, at the RNA and protein levels, but not in germinomas and ATRTs. Further analysis of pineoblastoma samples did not reveal the presence of either BCOR internal tandem duplication or BCOR fusion involvement. Positive immunohistological BCOR nuclear reaction in pineoblastoma may therefore differentiate this type of tumour from other high grade tumours located in the pineal region.

The miR-27a-3p/FTO axis modifies hypoxia-induced malignant behaviors of glioma cells.

Glioblastoma multiforme (GBM) is one of the most malignant types of central nervous system (CNS) tumors. N6-methyladenine (m6A) RNA modification is a main type of RNA modification in eukaryotic cells. In this study, we find that the m6A RNA methylation eraser FTO is dramatically downregulated in glioma samples and cell lines, particularly in intermediate and core regions and hypoxia-challenged glioma cells. In vitro, FTO overexpression inhibits the hypoxia-induced capacities of glioma cells to proliferate, migrate and invade, and decreases the percentage of cells with m6A RNA methylation. In vivo, FTO overexpression inhibits tumor growth in the xenograft model and decreases the protein levels of migration markers, including Vimentin and Twist. miR-27a-3p is upregulated within glioma intermediate and core regions and hypoxia-challenged glioma cells. miR-27a-3p inhibits the expression of FTO via direct binding to FTO. miR-27a-3p overexpression promotes hypoxia-challenged glioma cell aggressiveness, whereas FTO overexpression partially diminishes the oncogenic effects of miR-27a-3p overexpression. FTO overexpression promotes the nuclear translocation of FOXO3a and upregulates the expression levels of the FOXO3a downstream targets BIM, BNIP3, BCL-6, and PUMA, possibly by interacting with FOXO3a. Conclusively, FTO serves as a tumor suppressor in glioma by suppressing hypoxia-induced malignant behaviors of glioma cells, possibly by promoting the nuclear translocation of FOXO3a and upregulating FOXO3a downstream targets. miR-27a-3p is a major contributor to FTO downregulation in glioma under hypoxia.

Beneficial Effects of Statins on Seizures Independent of Their Lipid-Lowering Effect: A Narrative Review.

Among the many types of central nervous system (CNS) disorders, seizures and epilepsy severely affect the quality of life and routine daily activity of the sufferers. We aimed to review research studies that investigated the effect of statins on the prevention and treatment of seizures and epilepsy. Both animal models and human studies were included in this review. This article starts with a brief introduction about seizure, its prevalence, treatment, and various animal models of seizures and epilepsy. Next, we discuss statin's mechanism of action, side effects, and effects on neurological disorders with a specific focus on seizures. Finally, the effects of different types of statins on seizures are compared. The present review gives a better understanding of the therapeutic effects of statins on neurological disorders in animal models and human studies. This permits researchers to set up study designs to resolve current ambiguities and contradictions on the beneficial effects of statins on neurological disorders.

FMRP-related retinal phenotypes: Evidence of glutamate-glutamine metabolic cycle impairment

FMRP, the fragile X mental retardation protein coded by the FMR1 gene, is an RNA-binding protein that assists transport, stabilization and translational regulation of specific synaptic mRNAs. Its expression has been found in multiple cell types of central nervous system (CNS) including glial cells where its involvement in glutamate neurotransmitter homeostasis have been shown. Indeed, glutamate homeostasis deficit has been observed in absence of FMRP in-vivo in cortex and hippocampus structures as well as in vitro on astroglial cell culture. Interestingly, the retina which is an extension of the CNS is presenting electrophysiological alterations in absence of FMRP in both human and murine models suggesting neurotransmitter impairments. Therefore, we investigate the consequences of Fmrp absence on Glutamate-Glutamine cycle in whole retinas and primary retinal Müller cells culture which are the main glial cells of the retina. Using the Fmr1-/y mice, we have shown in vivo and in vitro that the absence of Fmrp in Müller cells is characterized by loss of Glutamate-Glutamine cycle homeostasis due to a lower Glutamine Synthetase protein expression and activity. The lack of Fmrp in the retina induces a reduced flow of glutamine synthesis. Our data established for the first time in literature a direct link between the lack of Fmrp and neurotransmitter homeostasis in the retina.

Cerebral Organoids and Antisense Oligonucleotide Therapeutics: Challenges and Opportunities.

The advent of stem cell-derived cerebral organoids has already advanced our understanding of disease mechanisms in neurological diseases. Despite this, many remain without effective treatments, resulting in significant personal and societal health burden. Antisense oligonucleotides (ASOs) are one of the most widely used approaches for targeting RNA and modifying gene expression, with significant advancements in clinical trials for epilepsy, neuromuscular disorders and other neurological conditions. ASOs have further potential to address the unmet need in other neurological diseases for novel therapies which directly target the causative genes, allowing precision treatment. Induced pluripotent stem cell (iPSC) derived cerebral organoids represent an ideal platform in which to evaluate novel ASO therapies. In patient-derived organoids, disease-causing mutations can be studied in the native genetic milieu, opening the door to test personalized ASO therapies and n-of-1 approaches. In addition, CRISPR-Cas9 can be used to generate isogenic iPSCs to assess the effects of ASOs, by either creating disease-specific mutations or correcting available disease iPSC lines. Currently, ASO therapies face a number of challenges to wider translation, including insufficient uptake by distinct and preferential cell types in central nervous system and inability to cross the blood brain barrier necessitating intrathecal administration. Cerebral organoids provide a practical model to address and improve these limitations. In this review we will address the current use of organoids to test ASO therapies, opportunities for future applications and challenges including those inherent to cerebral organoids, issues with organoid transfection and choice of appropriate read-outs.

HGG-27. Understanding the role of PLAG family transcription factors in cortex development and tumorigenesis

Gliomas are the most common type of central nervous system (CNS) tumors in children. Therapy and outcome often reflect the grade of the tumor, with high grade glioma (HGG) leading to a significantly worse survival prognosis than low grade glioma. However, HGG are highly diverse regarding their molecular entities and clinical associations. In some pediatric-type histone 3 K27M mutated HGG, the zinc-finger transcription factor PLAG1 was previously found to be overexpressed, which is also confirmed by patient data from the INFORM program. Further, in a novel type of embryonic CNS tumors without histone mutations, the PLAG1-related genes PLAGL1/PLAGL2 are amplified. However, the consequences of aberrant PLAG gene expression on CNS tumor formation during development are unknown. Especially the understanding of downstream signaling pathways that are commonly altered by this transcription factor family could provide necessary starting points for more specific therapy. We use transgenic mouse models with targeted PLAG1 overexpression in neural stem and progenitor cells to investigate the function of PLAG1 in cerebral cortex development and tumorigenesis. We found that PLAG1 overexpression together with heterozygous loss of p53 activity causes neurological defects and impaired cortex development. Next, to understand how PLAG gene overexpression affects neural specification, we will overexpress the PLAG genes in embryonic neural stem and progenitor cells using in utero electroporation. After FACS isolation of electroporated cells and single nucleus RNA sequencing, we will assess how the overexpression changes the transcriptional trajectories of neural development in mouse cortex stem and progenitor cells. We hypothesize that an early event leads to the constitutive upregulation of PLAG genes, which are usually tightly regulated during development, in patients with pediatric brain tumors harboring aberrant PLAG gene expression. Deciphering the transcriptional downstream pathways of this aberrant expression in neural stem and progenitor cells seems promising to find new potential therapeutic targets.

Radiomics-Based Method for Predicting the Glioma Subtype as Defined by Tumor Grade, IDH Mutation, and 1p/19q Codeletion.

Simple SummaryIn 2016, the World Health Organization (WHO) recommended the incorporation of molecular parameters, in addition to histology, for an optimal definition of the central nervous system (CNS) tumors. Gliomas, being among the most common types of CNS tumors, have distinct clinical outcomes and treatment strategies based on different tumor grades, isocitrate dehydrogenase (IDH) mutation, and 1p/19q codeletion statuses. This paper uses radiomics models to noninvasively predict the glioma subtype with clinical Magnetic Resonance Imaging (MRI) images. Different settings in the radiomics pipeline were investigated to achieve optimal performance, together with a better understanding of the exact role of each setting in the model performance. The characteristics of the radiomic features that best distinguish the glioma subtypes were also analyzed. This paper not only provides a radiomics pipeline which works well for predicting the glioma subtype, but it also contributes to the radiomics model development and interpretability.Gliomas are among the most common types of central nervous system (CNS) tumors. A prompt diagnosis of the glioma subtype is crucial to estimate the prognosis and personalize the treatment strategy. The objective of this study was to develop a radiomics pipeline based on the clinical Magnetic Resonance Imaging (MRI) scans to noninvasively predict the glioma subtype, as defined based on the tumor grade, isocitrate dehydrogenase (IDH) mutation status, and 1p/19q codeletion status. A total of 212 patients from the public retrospective The Cancer Genome Atlas Low Grade Glioma (TCGA-LGG) and The Cancer Genome Atlas Glioblastoma Multiforme (TCGA-GBM) datasets were used for the experiments and analyses. Different settings in the radiomics pipeline were investigated to improve the classification, including the Z-score normalization, the feature extraction strategy, the image filter applied to the MRI images, the introduction of clinical information, ComBat harmonization, the classifier chain strategy, etc. Based on numerous experiments, we finally reached an optimal pipeline for classifying the glioma tumors. We then tested this final radiomics pipeline on the hold-out test data with 51 randomly sampled random seeds for reliable and robust conclusions. The results showed that, after tuning the radiomics pipeline, the mean AUC improved from 0.8935 (±0.0351) to 0.9319 (±0.0386), from 0.8676 (±0.0421) to 0.9283 (±0.0333), and from 0.6473 (±0.1074) to 0.8196 (±0.0702) in the test data for predicting the tumor grade, IDH mutation, and 1p/19q codeletion status, respectively. The mean accuracy for predicting the five glioma subtypes also improved from 0.5772 (±0.0816) to 0.6716 (±0.0655). Finally, we analyzed the characteristics of the radiomic features that best distinguished the glioma grade, the IDH mutation, and the 1p/19q codeletion status, respectively. Apart from the promising prediction of the glioma subtype, this study also provides a better understanding of the radiomics model development and interpretability. The results in this paper are replicable with our python codes publicly available in github.

Novel Insights into Genetic Approaches in Glioblastoma Multiforme Therapy

Glioblastoma multiforme is one of the most common and malignant types of central nervous system (CNS) tumors. Despite the great advances in treatment modalities and the variety of therapeutic options, it remains largely incurable with continuously growth incidence, due to the genomic instability of glioblastoma multiforme cells, their heterogeneity, and their resistance to chemo- and radiotherapies. The aggressive behavior of these brain tumors and their sequestered location behind the blood–brain barrier restricts the role of the immune system. Great success has been made recently in glioblastoma multiforme treatment using genetic based approaches to selectively target cancerous cells and restore tumor suppressor gene expression or silence specific oncogenes to prevent their expression. The use of genetic approaches has attracted more interest and research and has revealed their ability to regulate the expression of glioblastoma multiforme oncogenes without changing the genotype and thus avoiding possible genotoxicity. This review delivers an overview of glioblastoma multiforme cell biology, tumorigenesis, and immune surveillance, and discusses recent advances in genetic based therapies of glioblastoma multiforme.

Neuroimmune and Acute Psychotic Disorders had an Overlapping Immune-Signature in Adolescents and Young Adults; A Case Series

A misguided auto-reactive injury is responsible for diverse types of central nervous system (CNS) conditions. We suspect that, in some of these conditions, the adaptive immune system have a common cellular immune pathogenesis, driven predominantly by T cells, despite variability on the phenotypical clinical presentation.
 Aim: the main goal of this study is to characterize a portion of the adaptive immune response (AIR) on patients presenting with clinical symptoms compatible with monophasic acute neuroimmune disorders (NID) including Psychotic Disorders (PD).
 Methodology: flow cytometry with deep immunophenotyping of T effector (Teff) and T regulatory (Treg) cells was performed on peripheral blood obtained during the acute clinical phase and compared it to the one from an age-matched cohort group [Co).
 Results: our preliminary findings point toward the presence of common “immunosignature” in individuals affected by NID or PD. We also found a shared dysregulation of immune related neurogenes in NID and PD that were not present in normal cohorts.
 Conclusions: this preliminary report gives some insights into the underlying shared pathobiology. If we can improve our capacity for early accurate diagnosis and meaningful disease monitoring of pathogenic T cell subsets, we will both expedite disease detection and may serve as a guide the administration of effective immunotherapeutic agents.

Role of Receptor Protein Tyrosine Phosphatase β/ζ in Neuron-Microglia Communication in a Cellular Model of Parkinson's Disease.

Pleiotrophin (PTN) is a neurotrophic factor that regulates glial responses in animal models of different types of central nervous system (CNS) injuries. PTN is upregulated in the brain in different pathologies characterized by exacerbated neuroinflammation, including Parkinson’s disease. PTN is an endogenous inhibitor of Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ, which is abundantly expressed in the CNS. Using a specific inhibitor of RPTPβ/ζ (MY10), we aimed to assess whether the PTN/RPTPβ/ζ axis is involved in neuronal and glial injury induced by the toxin MPP+. Treatment with the RPTPβ/ζ inhibitor MY10 alone decreased the viability of both SH-SY5Y neuroblastoma cells and BV2 microglial cultures, suggesting that normal RPTPβ/ζ function is involved in neuronal and microglial viability. We observed that PTN partially decreased the cytotoxicity induced by MPP+ in SH-SY5Y cells underpinning the neuroprotective function of PTN. However, MY10 did not seem to modulate the SH-SY5Y cell loss induced by MPP+. Interestingly, we observed that media from SH-SY5Y cells treated with MPP+ and MY10 decreases microglial viability but may elicit a neuroprotective response of microglia by upregulating Ptn expression. The data suggest a neurotrophic role of microglia in response to neuronal injury through upregulation of Ptn levels.

Characterization of the immune response in neuroimmune disorders in children

Background: A misguided auto-reactive injury is responsible for several types of central nervous system (CNS) conditions in pediatrics. We propose that, in some of these conditions, the adaptive immune system has a common cellular immune pathogenesis, driven predominantly by T cells, despite variability on the phenotypical clinical presentation. Methods: We have characterized the CD4+/CD8+ adaptive immune response (AIR) on pediatric patients presenting with clinical symptoms compatible with Neuroimmune Disorders (NID). Flow cytometry with deep immunophenotyping of T cells was performed on peripheral blood obtained during the acute clinical phase and compared to an age-matched cohort group (Co). Results: We found that pediatric patients with confirmed NID, exhibit a pattern of dysregulation of CD4+ lineages associated with autoimmune processes. Discussion: The autoimmune associated CD4+ dysregulation was associated with patients with NID, as compared to healthy controls and patients with non-autoimmune diagnoses. If we can improve our capacity for early accurate diagnosis and meaningful disease monitoring of pathogenic T cell subsets, we can both expedite disease detection and may serve as a guide to the administration of effective immunotherapeutic agents.

An Exploratory Study of the Frequency of Central Nervous System Tumors by Type in the Central Texas Military and Civilian Populations.

Background: The types of central nervous system (CNS) tumors in a patient population with a history of military service were compared to the types of CNS tumors in a similar patient population without a military service history to determine if a relationship exists between military service and CNS tumor type.Methods: This study analyzed data for adult patients diagnosed with an intra- or extra-axial CNS tumor from January 2016 to July 2019. One cohort was constructed of patients who had a history of military service (MIL), and the other cohort was made of patients who did not have a history of military service (NMIL). Appropriate parametric and non-parametric analyses were used to compare frequencies of tumor types between cohorts adjusting for potential confounders.Results: We identified 2001 patients (MIL, n = 190; NMIL, n = 1811). In the MIL cohort, most patients were males, younger, and more racially diverse. In the primary analysis, the MIL cohort showed higher diagnoses of metastatic tumors compared with the NMIL cohort (X2(1)= 3.71, p=.05). The MIL cohort also showed lower diagnoses of meningioma compared to the NMIL cohort. There was no statically significant difference between cohorts or tumors after adjusting for primary source by gender.Conclusions: MIL experience was associated with lower diagnoses of meningioma but higher diagnoses of metastatic cancer, providing support that there may be potential differences in tumor types between patients with a history of military service and those without military history regarding primary CNS tumor frequency.

Pachymeningitis in a Patient With Granulomatosis With Polyangiitis; A Case Report

Introduction: Granulomatosis with polyangiitis (GPA) is a systematic and necrotizing vasculitis with positive autoimmune antibodies. Some studies have reported the prevalence of eye involvement between 40%-50% of cases. Retro orbital granuloma is a rare complication of GPA which should be treated by surgical involvements, while pachymeningitis can be diagnosed by MRI and treated by medical management. In this study, we tried to present a case of GPA with optic neuritis and typical central nervous system (CNS) involvement, while there were no definite features of sinusitis or kidney injuries. Case Presentation: A 15-year-old girl was admitted because of blurred vision in her left eye. She was a known case of GPA three years ago with initial features, including left facial nerve paresis due to pan-sinusitis and pulmonary cavity. Neurologic evaluations, including sensory and motor features, were normal, too. Ophthalmologic examinations showed that visual acuity of the right eye was good, while the visual acuity in the left eye decreased to the point of finger counting at a distance of 20 cm. The left eye Marcus gunn test was positive (3+); anterior and posterior eye segments were normal. The patient was evaluated by brain MRI with gadolinium and a pathologic enhancement in the left cavernous was seen which had a pressure effect on the optic nerve. She was treated by intravenous methylprednisolone followed by rituximab. Conclusion: Reporting orbital mass in a patient who had GPA can be supposed as granuloma which needs a biopsy to confirm a diagnosis. In our case, the imaging manifestation was heterodox for granuloma, while neurosurgical consultation recommended drug treatment for pachymeningitis.

A Murine Ommaya Xenograft Model to Study Direct-Targeted Therapy of Leptomeningeal Disease.

Leptomeningeal disease (LMD) is an uncommon type of central nervous system (CNS) metastasis to the cerebral spinal fluid (CSF). The most common cancers that cause LMD are breast and lung cancers and melanoma. Patients diagnosed with LMD have a very poor prognosis and generally survive for only a few weeks or months. One possible reason for the lack of efficacy of systemic therapy against LMD is the failure to achieve therapeutically effective concentrations of drug in the CSF because of an intact and relatively impermeable blood-brain barrier (BBB) or blood-CSF barrier across the choroid plexus. Therefore, directly administering drugs intrathecally or intraventricularly may overcome these barriers. This group has developed a model that allows for the effective delivery of therapeutics (i.e., drugs, antibodies, and cellular therapies) chronically and the repeated sampling of CSF to determine drug concentrations and target modulation in the CSF (when the tumor microenvironment is targeted in mice). The model is the murine equivalent of a magnetic resonance imaging-compatible Ommaya reservoir, which is used clinically. This model, which is affixed to the skull, has been designated as the “Murine Ommaya.” As a therapeutic proof of concept, human epidermal growth factor receptor 2 antibodies (clone 7.16.4) were delivered into the CSF via the Murine Ommaya to treat mice with LMD from human epidermal growth factor receptor 2-positive breast cancer. The Murine Ommaya increases the efficiency of drug delivery using a miniature access port and prevents the wastage of excess drug; it does not interfere with CSF sampling for molecular and immunological studies. The Murine Ommaya is useful for testing novel therapeutics in experimental models of LMD.

A comparative study for glioma classification using deep convolutional neural networks

Gliomas are a type of central nervous system (CNS) tumor that accounts for the most of malignant brain tumors. The World Health Organization (WHO) divides gliomas into four grades based on the degree of malignancy. Gliomas of grades I-II are considered low-grade gliomas (LGGs), whereas gliomas of grades III-IV are termed high-grade gliomas (HGGs). Accurate classification of HGGs and LGGs prior to malignant transformation plays a crucial role in treatment planning. Magnetic resonance imaging (MRI) is the cornerstone for glioma diagnosis. However, examination of MRI data is a time-consuming process and error prone due to human intervention. In this study we introduced a custom convolutional neural network (CNN) based deep learning model trained from scratch and compared the performance with pretrained AlexNet, GoogLeNet and SqueezeNet through transfer learning for an effective glioma grade prediction. We trained and tested the models based on pathology-proven 104 clinical cases with glioma (50 LGGs, 54 HGGs). A combination of data augmentation techniques was used to expand the training data. Five-fold cross-validation was applied to evaluate the performance of each model. We compared the models in terms of averaged values of sensitivity, specificity, F1 score, accuracy, and area under the receiver operating characteristic curve (AUC). According to the experimental results, our custom-design deep CNN model achieved comparable or even better performance than the pretrained models. Sensitivity, specificity, F1 score, accuracy and AUC values of the custom model were 0.980, 0.963, 0.970, 0.971 and 0.989, respectively. GoogLeNet showed better performance than AlexNet and SqueezeNet in terms of accuracy and AUC with a sensitivity, specificity, F1 score, accuracy, and AUC values of 0.980, 0.889, 0.933, 0.933, and 0.987, respectively. AlexNet yielded a sensitivity, specificity, F1 score, accuracy, and AUC values of 0.940, 0.907, 0.922, 0.923 and 0.970, respectively. As for SqueezeNet, the sensitivity, specificity, F1 score, accuracy, and AUC values were 0.920, 0.870, 0.893, 0.894, and 0.975, respectively. The results have shown the effectiveness and robustness of the proposed custom model in classifying gliomas into LGG and HGG. The findings suggest that the deep CNNs and transfer learning approaches can be very useful to solve classification problems in the medical domain.