Common Central Nervous System Research Articles

Adipose-derived mesenchymal stem cells ameliorates experimental autoimmune encephalomyelitis via modulation of Th1/Th17 and expansion of Th2/Treg responses.

The most common central nervous system (CNS) inflammatory disease is multiple sclerosis (MS), modeled using experimental autoimmune encephalomyelitis (EAE). Mesenchymal stem cells (MSCs) exhibit potent immunomodulatory capabilities, including the suppression of immune cell functions and anti-inflammatory cytokine production. Female C57BL/6 mice (8-10 weeks old) were divided into three groups: 1. Control, 2. Allogeneic MSCs (ALO) treatment, and 3. Syngeneic MSCs (SYN) treatment. To induce EAE, myelin oligodendrocyte glycoprotein was injected subcutaneously with complete Freund's adjuvant, followed by intraperitoneal pertussis toxin. On Days 6 and 12 postimmunization, the treatment groups received intraperitoneal injections of 2 × 106 MSCs. Daily clinical and weight assessments were performed, and on Day 25, the mice were euthanized. At the end of the period, brain histological analysis was conducted to quantify lymphocyte infiltration. T-cell characteristics were determined usingenzyme-linked immunosorbent assay and Real-time polymerase chain reaction (RT-PCR). The assessment of transcription factor expression levels in the CNS was also performed using RT-PCR. Compared to the control group, both the allogeneic (ALO) and syngeneic (SYN) groups demonstrated significantly reduced disease progression. The maximum clinical scores for the control, ALO, and SYN groups were 4.4 ± 0.1, 2.4 ± 0.2, and 2.1 ± 0.2, respectively (ALO and SYN vs. Control: p < .001). In comparison to the control group, histological studies demonstrated that the allogeneic and syngeneic groups had less lymphocytic infiltration (ALO: 1.4 ± 0.1, SYN: 1.2 ± 0.2, and control: 2.8 ± 0.15; p < .001) and demyelination (ALO: 1.2 ± 0.15, SYN: 1.1 ± 0.1 and control: 2.9 ± 0.1, p < .001). ALO and SYN groups had lower expression of Th1 and Th17 cytokines and transcription factors (IFN-γ: 0.067, 0.051; STAT4: 0.189, 0.162; T-bet: 0.175, 0.163; IL-17: 0.074, 0.061; STAT3: 0.271, 0.253; ROR-γt: 0.163, 0.149, respectively) compared to the control group on Day 25 following EAE induction. Additionally, ALO and SYN groups compared to the control group, expressed more Th2 and Treg cytokines and transcription factors (IL-4: 4.25, 4.63; STAT6: 2.78, 2.96; GATA3: 2.91, 3.08; IL-27: 2.32, 2.46, IL-33: 2.71, 2.85; TGF-β: 4.8, 5.05; IL-10: 4.71, 4.93; CTLA-4: 7.72, 7.95; PD1: 4.12,4.35; Foxp3: 3.82,4.08, respectively). This research demonstrated that MSCs possess the potential to be a therapeutic option for MS and related CNS inflammatory disorders. Their immunomodulatory properties, coupled with the observed reductions in disease severity, lymphocytic infiltration, and demyelination, indicate that MSCs could play a crucial role in altering the course of MS by mitigating inflammatory immune responses and promoting regulatory immune processes. These findings open up new possibilities for the development of MSC-based therapies for MS, and further investigation and clinical trials may be warranted to explore their efficacy and safety in human patients.

Glioblastoma: a comprehensive approach combining bibliometric analysis, Latent Dirichlet Allocation, and HJ-Biplot : Glioblastoma insights and trends: a 49-year bibliometric analysis.

Glioblastoma is a common and aggressive malignant central nervous system tumor in adults. This study aims to evaluate and analyze the scientific results, collaboration countries, main research topics, and topics over time reported about glioblastoma. A bibliometric analysis of glioblastoma publications was performed mainly using R and Multbiplot software for author, journal, and resume. Associated statistic methods Latent Dirichlet Allocation (LDA) and HJ-Biplot. Inclusion criteria were research articles from the PubMed database published in English between 1973 and December 2022. A total of 64,823 documents with an annual growth rate of 8.27% indicates a consistent increase in research output over time. The results for the number of citations and significant publications showed Cancer Res, J Neuro-Oncol, and Neuro-Oncology are the most influential journals in the field of glioblastoma. The countries that concentrated research were the tumor United States, China, Germany, and Italy. Finally, there has been a marked growth in studies on prognosis and patient survival, therapies, and treatments for glioblastoma. These findings reinforce the need for increased global resources to address glioblastoma, particularly in underdeveloped countries. Glioblastoma research's exponential growth reflects sustained interest in early diagnosis and patient survival.

COL8A1 is a potential prognostic biomarker associated with migration, proliferation, and tumor microenvironment in glioma

Glioblastoma (GBM) is a common primary central nervous system tumor. The molecular mechanisms of glioma are unknown, and the prognosis is poor. Therefore, exploring the underlying mechanisms and screening for new prognostic markers and therapeutic targets is crucial. We utilized the weighted gene co-expression network analysis (WGCNA), Differentially Expressed Genes (DEGs), and LASSO-COX analysis to identify three target genes. Next, we constructed and evaluated a prognostic model, screening out COL8A1 as a risk gene. Through a sequence of cellular functional experiments, in vivo studies, and RNA sequencing, we delved into exploring the functional effects and molecular mechanisms of COL8A1 on GBM cells. Finally, the correlation between COL8A1 and tumor immune cells and different inflammatory responses was analyzed. Immunohistochemistry experiments revealed the influence of COL8A1 on macrophage polarization. The COL8A1 expression level was associated with the grade, prognosis, and tumor microenvironment (TME) of glioma. Functional experiments showed that COL8A1 inhibited GBM cell apoptosis and promoted migration, invasion, and proliferation in vitro and in vivo. We also found that COL8A1 promotes the epithelial-mesenchymal transition process and may mediate the activation of the ERK pathway through SHC1. In addition, immune infiltration analysis showed that COL8A1 was closely associated with macrophages in glioma tissues, significantly suppressing the signaling of M1-like -type macrophages and enhancing the signaling of M2-like -type macrophages. COL8A1 was first found to be associated with prognosis, progression, and immune microenvironment of glioma and may serve as a new marker of prognosis and a therapeutic target.

Safranal exerts a neuroprotective effect on Parkinson's disease with suppression of NLRP3 inflammation activation.

Parkinson's disease (PD) is a common central nervous system neurodegenerative disease. Neuroinflammation is one of the significant neuropathological hallmarks. As a traditional Chinese medicine, Safranal exerts anti-inflammatory effects in various diseases, however, whether it plays a similar effect on PD is still unclear. The study was to investigate the effects and mechanism of Safranal on PD. The PD mouse model was established by 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine MPTP firstly. Next, the degree of muscle stiffness, neuromuscular function, motor retardation and motor coordination ability were examined by observing and testing mouse movement behavior. Immunofluorescence staining was used to observe the expression of tyrosine hydroxylase (TH). The dopamine (DA) content of the striatum was detected by High-performance liquid chromatography (HPLC). The expression of TH and NLRP3 inflammasome-related markers NLRP3, IL-1β, and Capase-1 were detected by Real-time Polymerase Chain Reaction (qRT-PCR) and western blotting (WB) respectively. Through behavioral testing, Parkinson's mouse showed a higher muscle stiffness and neuromuscular tension, a more motor retardation and activity disorders, together with a worse motor coordination compared with sham group. Simultaneously, DA content and TH expression in the striatum were decreased. However, after using Safranal treatment, the above pathological symptoms of Parkinson's mouse all improved compared with Safranal untreated group, the DA content and TH expression were also increased to varying degrees. Surprisingly, it observed a suppression of NLRP3 inflammation in the striatum of Parkinson's mouse. Safranal played a neuroprotective effect on the Parkinson's disease and its mechanism was related to the inhibition of NLRP3 inflammasome activation.

Neuroradiological features of patients with bilateral macronodular adrenocortical disease and meningiomas associated or not with genetic variants of ARMC5- a case series.

Meningiomas are the most common primary brain and central nervous system tumors, accounting for approximately 40% of these tumors. The most important exams for the radiological study of meningiomas are computed tomography (CT) and magnetic resonance imaging (MRI). We aimed to analyze the radiological features of patients with meningioma related to the simultaneous presence of bilateral macronodular adrenocortical disease (BMAD), with or without pathogenic variants of ARMC5. This study included 10 patients who were diagnosed with BMAD. All of them had a radiological diagnosis of expansive brain lesions suggestive of meningioma. All patients underwent brain MRI and a neuroradiolgist analyzed the following parameters: number, site and size of lesions; presence of calcification, edema and bone involvement. Eight patients presented with germline variants of ARMC5; the other 2, did not. The most significant result was the incidence of multiple meningiomas, which was 50% in BMAD patients, whereas the average incidence described thus far is lower than 10%. Considering location, the 22 tumors in the BMAD patients were 5 convexity tumors (22.7%), and 17 skull base tumors (77.2%), the opposite proportion of patients without BMAD. A total of 40.9% of the tumors had calcification, 9% had cerebral edema and 40.9% had bone invasion due to hyperostosis. The literature describes meningioma calcification in 25% of patients, bone invasion by tumor hyperostosis in 20%, and cerebral edema in approximately 60%. Relevant results were found considering the rate of multiple meningiomas and tumor location. This finding reinforces the need for further research into the neurological effects caused by genetic variants of ARMC5 in patients with BMAD.

Abstract LB200: Defining the mechanisms of cancer specific transcription factor, tGLI1

Abstract Glioblastoma (GBM) is the most common malignant central nervous system tumor in adults with a five-year survival rate of less than 7%. First identified in GBM, truncated GLI1 (tGLI1), an alternative splicing isoform of GLI1, has emerged as a cancer specific GLI1 variant as tGLI1 is highly expressed in both GBM cell lines and primary specimens but not in normal tissue. Despite an in-frame loss of 41 amino acids, the tGLI1 protein has retained all known GLI1 functional domains and appears to respond to sonic hedgehog in a similar manner as GLI1. However, tGLI1 operates as a gain of function transcription factor with the ability to bind to and activate genes unique from GLI1 to promote invasion, migration, angiogenesis, and stemness in both GBM and breast cancer. Despite the advancements in our understanding of tGLI1, a genome wide DNA binding pattern of tGLI1 has not been established and the mechanism by which tGLI1 gains access to these genes is unknown. To establish a more robust understanding of the differential DNA binding patterns of GLI1 and tGLI1, we carried out ChIP-sequencing (ChIP-seq) and found only 14% of GLI1 and tGLI1 binding sites are shared. These results suggest GLI1 and tGLI1 have even more unique binding pattens across the entire genome that previously thought. However, the underlying mechanism for why GLI1 and tGLI1 bind different regions of the genome remains elusive. To determine whether variations in protein interactions of GLI1 and tGLI1 contribute to the unique binding pattern of tGLI1, we carried out immunoprecipitation (IP) followed by mass spectrometry (mass spec). Results identified 45 GLI1 associated proteins and 52 tGLI1 associated proteins with only a 29% overlap between the two. Furthermore, gene ontology analysis revealed 43% of the tGLI1-specific associated proteins are involved in processes related to RNA binding, processing, and metabolism. From these RNA-related proteins, we validated an interaction between tGLI1 and the protein NONO. NONO, which can bind both RNA and DNA, is involved in a range of molecular processes including paraspeckle formation and transcriptional regulation. In GBM, high NONO expression correlated with poor patient outcomes and the mesenchymal subtype. Interestingly, we observed that NONO, along with another essential paraspeckle component, SFPQ, had a greater interaction with tGLI1 compared to GLI1. Furthermore, co-expressing NONO with tGLI1 significantly increased clonogenic growth as well as CD44 gene transactivation using a luciferase reporter, suggesting it may play a role in tGLI1-driven stem-like properties. Furthermore, co-expression of NONO and tGLI1 increased the nuclear localization of both proteins. Together, these results show NONO may enhance tGLI1 nuclear localization, transcriptional activity, and exacerbate tGLI1-driven phenotypes. These effects of NONO could also contribute to the differential binding pattern between GLI1 and tGLI1. Citation Format: Haddie DeHart, Nolan Gregg, Richard Carpenter. Defining the mechanisms of cancer specific transcription factor, tGLI1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB200.

Molecular characterization and survival analysis of a cohort of glioblastoma, IDH-wildtype

Glioblastoma, IDH-wild type, the most common malignant primary central nervous system tumor, represents a formidable challenge in clinical management due to its poor prognosis and limited therapeutic responses. With an evolving understanding of its underlying biology, there is an urgent need to identify prognostic molecular groups that can be subject to targeted therapy. This study established a cohort of 124 sequential glioblastomas from a tertiary hospital and aimed to find correlations between molecular features and survival outcomes. Comprehensive molecular characterization of the cohort revealed prevalent alterations as previously described, such as TERT promoter mutations and involvement of the PI3K-Akt-mTOR, CK4/6-CDKN2A/B-RB1, and p14ARF-MDM2-MDM4-p53 pathways. MGMT promoter methylation is a significant predictor of improved overall survival, aligned with previous data. Conversely, age showed a marginal association with higher mortality. Multivariate analysis to account for the effect of MGMT promoter methylation and age showed that, in contrast to other published series, this cohort demonstrated improved survival for tumors harboring PTEN mutations, and that there was no observed difference for most other molecular alterations, including EGFR amplification, RB1 loss, or the coexistence of EGFR amplification and deletion/exon skipping (EGFRvIII). Despite limitations in sample size, this study contributes data to the molecular landscape of glioblastomas, prompting further investigations to examine these findings more closely in larger cohorts.

Regulation of CNS pathology by Serpina3n/SERPINA3: The knowns and the puzzles.

Neuroinflammation, blood-brain barrier (BBB) dysfunction, neuron and glia injury/death and myelin damage are common central nervous system (CNS) pathologies observed in various neurological diseases and injuries. Serine protease inhibitor (Serpin) clade A member 3n (Serpina3n), and its human orthologue SERPINA3, is an acute-phase inflammatory glycoprotein secreted primarily by the liver into the bloodstream in response to systemic inflammation. Clinically, SERPINA3 is dysregulated in brain cells, cerebrospinal fluid and plasma in various neurological conditions. Although it has been widely accepted that Serpina3n/SERPINA3 is a reliable biomarker of reactive astrocytes in diseased CNS, recent data have challenged this well-cited concept, suggesting instead that oligodendrocytes and neurons are the primary sources of Serpina3n/SERPINA3. The debate continues regarding whether Serpina3n/SERPINA3 induction represents a pathogenic or a protective mechanism. Here, we propose possible interpretations for previously controversial data and present perspectives regarding the potential role of Serpina3n/SERPINA3 in CNS pathologies, including demyelinating disorders where oligodendrocytes are the primary targets. We hypothesise that the 'good' or 'bad' aspects of Serpina3n/SERPINA3 depend on its cellular sources, its subcellular distribution (or mis-localisation) and/or disease/injury types. Furthermore, circulating Serpina3n/SERPINA3 may cross the BBB to impact CNS pathologies. Cell-specific genetic tools are critically important to tease out the potential roles of cell type-dependent Serpina3n in CNS diseases/injuries.

1235 Using Supervised Machine Learning to Validate a Novel Scoring System for the Prediction of Disease Remission of Functional Adenomas Following Transsphenoidal Resection

INTRODUCTION: Functional pituitary adenomas are common primary central nervous system tumors with potent systemic endocrinological effects. Postoperatively, remission rates range from 65-98%. METHODS: 392 adult patients who underwent primary resection of a functional pituitary adenoma at the three Mayo Clinic between 2006-2022 were retrospectively reviewed. Multivariate logistic regression was performed to identify variables predictive of disease remission. Variables found statistically significant on multivariate analysis were incorporated into our proposed pituitary-SCHEME score. Machine learning models were implemented to compare the accuracy of the pituitary-SCHEME score against the multivariate models. After training (314 patients) and cross-validation of the machine learning models, an independent testing set of 78 patients was performed. SPSS V27 and R4.2.1 were used for statistical analyses. RESULTS: 261 (66.6%) patients achieved post-operative biochemical remission. On multivariate analysis gross-total resection and Knosp-Grade 0,I,II adenomas were predictive of disease remission following resection, while macroadenomas (adenoma &gt; 10mm), male sex, mammosomatotroph and Mixed Growth-Hormone + Prolactin adenomas were predictive of continued disease. In machine learning models, without Pituitary-SCHEME score, the K-Nearest Neighbors (KNN) model achieved the highest accuracy at 75.6% followed by Naive Bayes model. An increase in model sensitivity was achieved with inclusion of Pituitary-SCHEME score with the Linear-Discriminant-Analysis (LDA) model achieving the highest accuracy at 86.9%, followed by the Classification and Regression Trees (CART) model. The random forest model had the largest AUC-ROC among models with and without pituitary-SCHEME score. Model prediction accuracy (with vs. without pituitary-SCHEME score) were found to be statistically different based on Wilcoxon rank sum testing (p &lt; 0.0001). CONCLUSIONS: The novel pituitary-SCHEME score, which incorporates perioperative and endocrinological measures, has promise as a clinical tool to predict patient outcomes following surgical resection of functional adenomas.

Dexamethasone in Patients with Glioblastoma: A Systematic Review and Meta-Analysis.

Glioblastomas are the most common primary central nervous system (CNS) tumors. Although modern management strategies have modestly improved overall survival, the prognosis remains dismal, with treatment side effects often impinging on the clinical course. Glioblastomas cause neurological dysfunction by infiltrating CNS tissue and via perifocal oedema formation. The administration of steroids such as dexamethasone is thought to alleviate symptoms by reducing oedema. However, despite its widespread use, the evidence for the administration of dexamethasone is limited and conflicting. Therefore, we aimed to review the current evidence concerning the use and outcomes of dexamethasone in patients with glioblastoma. We performed a systematic review and meta-analysis according to the PRISMA-P guidelines. We performed a restricted search using the keywords "Dexamethasone" and "Glioblastoma" on PubMed, Web of Science, Cochrane Library, and Academic Search Premier. We included studies reporting on overall survival (OS) and progression-free survival (PFS) in glioblastoma patients receiving higher or lower dexamethasone doses. The risk of bias was assessed using ROBINS-I. We performed a meta-analysis using a random effects model for OS and PFS. Twenty-two retrospective studies were included. Higher doses of dexamethasone were associated with poorer OS (hazard ratio 1.62, confidence interval 1.40-1.88) and PFS (1.49, 1.23-1.81). OS remained worse even when studies corrected for clinical status (1.52, 1.38-1.67). Despite the widespread use of dexamethasone in glioblastoma patients, its use is correlated with worse long-term outcomes. Consequently, Dexamethasone administration should be restricted to selected symptomatic patients. Future prospective studies are crucial to confirm these findings.

302 Targeted Inhibition of the Epigenetically Activated miR-483-5p IGF-2 Pathway as a Novel Therapeutic Strategy for Meningioma

INTRODUCTION: Meningioma is the most common primary central nervous system tumor. These are usually treated by surgical resection with curative intent, however gross total resection is not always feasible and there are many cases of recurrent and refractory disease despite adjuvant radiotherapy. Presently, there is no effective pharmacotherapeutic options for these tumors. METHODS: Small RNA sequencing was performed on meningioma tumor samples to study grade-dependent changes in microRNA expression. Gene expression was analyzed by chromatin marks, qRT-PCR and western blot. miRNA modulation, anti-IGF-2 neutralizing antibodies, and inhibitors against IGF1R were evaluated in a tumor-derived primary cultures of meningioma cells. RESULTS: Meningioma tumor samples showed high, grade-dependent expression of miR-483-5p, associated with high mRNA and protein expression of its host gene IGF-2. Inhibition of miR-483-5p reduced the growth of cultured meningioma cells, whereas a miR-483 mimic increased cell proliferation. Similarly, inhibition of this pathway with anti-IGF-2 neutralizing antibodies reduced meningioma cell proliferation. Small molecule tyrosine kinase inhibitor blockade of the IGF-2 receptor (IGF1R) resulted in rapid loss of viability of cultured meningioma tumor-derived cells, suggesting that autocrine IGF-2 feedback is obligatory for meningioma tumor cell survival and growth. The observed IGF1R-inhibitory IC50 for GSK1838705A and Ceritinib in cell-based assays along with the available pharmacokinetics data predicted that effective drug concentration could be achieved in vivo as a new medical treatment of meningioma. CONCLUSIONS: Meningioma cell growth is critically dependent on autocrine miR-483/IGF-2 stimulation and the IGF-2 pathway provides a new feasible meningioma treatment target.

341 Racial Disparities in Incidence, Treatment, and Survival in Adult Brain Metastases: A 10-Year National Database Analysis

INTRODUCTION: Brain metastases are the most common central nervous system tumors in the United States. It is imperative to understand how prognosis and survival varies demographically to ensure equitable care for vulnerable populations and reduce financial burdens on the healthcare system. METHODS: Using the Surveillance, Epidemiology, and End Result Program (SEER) database, adults with non-primary brain metastases between 2010 and 2019 were identified. The primary outcome measure was all-cause mortality within 5 years. Chi-squared tests of independence and one way analyses of variance were used to compare group differences between White, Black, Asian/Pacific Islander (A/PI), and American Indian/Alaskan Native patients. A Cox proportional hazards model was developed to evaluate the risk of death within 5 years. RESULTS: A total of 65,154 patient records were identified following exclusion based on age (&gt;84 years or &lt;18 years), missing race data, and missing survival data. The incidence of brain metastases increased from 2.53 per 100,000 adults in 2010 to 2.71 per 100,000 in 2019. A/PI patients had the highest population-adjusted incidence, highest population proportion of high income, the longest time from diagnosis to treatment, lowest rate of radiation refusal, and highest rate of chemotherapy treatment. Subsequently, A/PI patients had the highest 5-year survival rate compared to White and Black patients (9.05% vs. 4.15% vs. 3.23% respectively, p &lt; 0.001). Chemotherapy (OR = 0.44) and surgery (OR = 0.51) were the strongest protective factors against death while being widowed (OR = 1.15) and having primary lung cancer (OR = 1.14) strongest risk factors. CONCLUSIONS: A/PI patients also have a significant survival advantage compared to White, Black, and AI/AN patients, potentially due to higher rates of radiation and chemotherapy treatment. Patients of other races are recommended treatment at lower rates than A/PI patients, suggesting a discrepancy in services offered to these patients.

204 Laster Interstitial Thermal Therapy for Primary and Recurrent Meningioma: A Prospective and Retrospective Multi-institutional Study

INTRODUCTION: Meningiomas are a common central nervous system tumor, and a subset are aggressive lesions resistant to standard therapies. Laser interstitial thermal therapy (LITT) has been successfully applied to other brain tumors, but its role in meningioma treatment is understudied. METHODS: Eight United States-based hospitals enrolled patients with meningioma in the prospective multicenter registry and pooled additional retrospective enrollments for this cohort study. Demographics, procedural, safety, and outcomes data were collected and analyzed using standard statistical methods. RESULTS: Twenty adult patients (12 prospective, 8 retrospective) with LITT-targeted meningiomas were accrued. Patients underwent LITT for primary (6 patients) and recurrent tumors (14 patients, ranging from 1st to 12th recurrence). Twenty percent of patients (4/20) had exhausted all other treatment options. Median length of follow-up was 1.3 years. One-third of primary (2/6) and one-half of recurrent meningiomas (7/14) recurred during follow-up. Of those with grading information, grade 2 meningiomas were most common (9/18), followed by Grade 1(5/18), and Grade 3 (4/18). Sixty percent (60%) of patients (12/20) had convexity meningiomas treated with LITT. 2 patients (10%) had post-procedural complications, of which one resolved. One-year estimated local control (LC), progression-free survival, and overall survival were 55.3%, 48.4%, and 86.3%, respectively. In the 10 patients who had 91% ablative coverage, 1-year estimated LC was 64.8%. High grade (Grades 2 and 3) patients (n = 13) treated with LITT had a 1-year LC of 46.3%. CONCLUSIONS: This cohort represents the largest series of patients with meningioma undergoing LITT and supports the safety of the procedure in this tumor type. LITT can offer a much-needed treatment option, especially for those with multiply recurrent meningiomas and where heavy pretreatment limits remaining treatment options. LITT should be considered in the armamentarium of treatment options for meningiomas.

Abstract 1174: Incorporation of multisector analysis into the design of personalized DNA vaccines for patients with newly diagnosed glioblastoma

Abstract Glioblastoma (GBM) is the most common malignant central nervous system (CNS) tumor in adults. Despite multimodality treatment including surgery, radiation, and chemotherapy, patients with GBM have a median survival of less than 2 years. Recent clinical trials have reported promising results using cancer vaccines to stimulate a tumor-directed immune response in several histologies. The majority of trials targeted tumor neoantigens derived from a single tumor sample, which limits the antigen pool in spatially heterogeneous cancers like GBM. Our group previously implemented multisector sequencing into the design of personalized peptide vaccines to increase the candidate pool of targetable neoantigens (NCT03422094). Although the peptide vaccine treatment was successful in stimulating an effector T cell response, it was limited by a long turnaround time from vaccine design to administration and a low peptide production rate. Therefore, we incorporated multisector sampling into the design of a personalized DNA-based GBM vaccine (NCT04015700). An average of 33% of the candidate targetable neoantigens were spatially restricted to a single sampled region, which would have been missed without multisector sequencing. DNA-based vaccines are potentially advantageous over peptide-based vaccines because they enable a higher neoantigen payload and faster manufacturing time with potent immunogenicity. Here, we report the results from 9 subjects enrolled onto the study. Spatially distinct tumor regions were subjected to whole exome sequencing (WES) and RNA-sequencing (RNA-seq), data from which were used to identify neoantigens through the pVACseq algorithm (http://pvactools.org). An average of 32 neoantigens were included in each DNA vaccine, compared to an average of only 9 for the peptide vaccine, and the turnaround time from date of surgery to administration of the DNA vaccine was about half the time. Three subjects had radiographic evidence of tumor progression prior to vaccination, highlighting the aggressive nature of GBM and the need for short manufacturing timeframes. PBMCs pre- and post-DNA vaccination were collected from 7/9 subjects. All subjects presented detectable responses and 6/7 tested revealed a sustained increment in T cell reactivity against tumor neoantigens post-treatment by IFN-γ ELISpot. Intracellular staining showed a neoantigen-specific antitumor CD8/CD4 T cell cytolytic (CD69+, CD107a+) and proliferative (Ki67+) profile. Post-vaccination tumor resections were performed for 2 subjects who also were treated with PD1 blockade upon progression, providing an opportunity to explore vaccine-induced changes in the tumor microenvironment. Herein, we demonstrate the advantages of incorporating multisector sequencing into the development of DNA-based GBM vaccines and provide insights into the resulting immune responses. Citation Format: Elizabeth A. Garfinkle, Katherine E. Miller, Alexandra J. Livingstone, Renzo Perales-Linares, Neil Cooch, Alfredo Perales-Puchalt, Sarah Rochestie, Joann Peters, Niranjan Y. Sardesai, William E. Gillanders, Elaine R. Mardis, Gavin P. Dunn, Tanner M. Johanns. Incorporation of multisector analysis into the design of personalized DNA vaccines for patients with newly diagnosed glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1174.

Naujųjų anti-CD20 monokloninių antikūnų vaidmuo gydant itin aktyvią recidyvuojančiąją remituojančiąją išsėtinę sklerozę: ofatumumabo klinikinis efektyvumas ir saugumas

Multiple sclerosis is the most common chronic demyelinating neurodegenerative central nervous system disease among young adults. Considering its extent in a relatively young population, multiple sclerosis determines a significant socioeconomic burden to the society due to the cost of disease modifying treatment and a lower working capacity of patients and their caregivers. It is important to control neuroinflammation in the central nervous system caused by the pathologic activity of immune cells by considering a high efficacy treatment early in the disease course in order to prevent accumulation of neurological damage and to improve long term outcomes. According to the newest clinical studies, anti-CD20 therapies have proven their effectiveness and safety in active relapsing multiple sclerosis treatment: since 2018, ocrelizumab, and, since 2023, ofatumumab have both been available as treatment options in Lithuania. Because of its high potency and safety, as well as the specific mechanism of action, ofatumumab is effective in lower doses, and, after initial training at a health care facility, it can be self-administered through subcutaneous injection. This article reviews the efficacy, safety data and treatment indications of the latest available anti-CD20 monoclonal antibodies.

Retrospective study of CNS tumors in a tertiary care centre in Western Odisha - A 4 year study

Central nervous system (CNS) tumors comprise nearly 3% of all malignancies world-wide whereas in India it accounts for about 2%. In recent years there has been an increase in CNS tumors with new potential risk factors being observed. The aim of the present study is to highlight the histopathological spectrum of brain tumors in a single tertiary care centre in Western Odisha.This retrospective histopathological analysis of CNS tumors was conducted in the Department of Pathology, VIMSAR, Burla, Odisha, India from October 2016 to September 2020. In the span of 4 years, a total of 94 neurosurgical biopsies were studied. Histopathological examination of routinely processed tissue and hematoxylin and eosin (H&amp;E) stained sections of corresponding cases were thoroughly examined. Immunohistochemistry (IHC) was done whenever required. Thereafter an approach was made to diagnose the cases, based on WHO classification system of 2016.A wide range of histopathological spectrum of CNS tumors was observed and was classified according to the WHO classification system of 2016. The primary CNS tumors were graded from Grade I to Grade IV. The most common CNS tumor in our study we found to be Astrocytic tumors (21 cases, 22.34%) followed by Schwannoma (19 cases, 20.21%) and meningiomas (18 cases, 19.14%). The incidence was more among males (59.51%) as compared to females (40.4%). This study provides an information regarding the prevalence of disease in Western Odisha. Use of modern imaging technique helps to a major extent in making a provisional.

Black Phosphorus Microbubbles Combined with Ultrasound for Treating Parkinson's Disease

AbstractParkinson's disease (PD) is a common chronic central nervous system disorder that reduces quality of life and increases mortality. Currently, the treatment of PD is limited due to the challenge of macromolecular drugs crossing the blood‐brain barrier (BBB). Black phosphorus (BP) has antioxidant and anti‐inflammatory effects and shows potential for neuroprotection. To solve the restriction of the BBB, innovative BP microbubbles (BP@MBs) combined with focused ultrasound (FUS) are constructed to facilitate BBB opening. Additionally, the biocompatibility and safety of BP@MBs with varying dimensions are investigated, including BP quantum dot microbubbles (BPQDs@MBs) and BP nanosheet microbubbles (BPNSs@MBs). The findings indicate that low concentrations of BP have good biosafety and that BPQDs@MBs exhibit better biocompatibility than BPNSs@MBs both in vitro and in vivo at the same concentrations. Moreover, a 6‐hydroxydopamine (6‐OHDA)‐induced PD cell model and an animal model are established to verify the anti‐PD effects of BPQDs@MBs and BPNSs@MBs. The results confirmed that BPQDs@MBs and BPNSs@MBs have antioxidant effects that reduced neuronal apoptosis and improved the motor symptoms of PD in rats. BPQDs@MBs combined with FUS may be a promising option for the clinical treatment of PD.

Surgical outcomes of myelomeningocele repair: A 20-year experience from a single center in a middle-income country

Background and purposeSpina bifida is the second major cause of congenital disorders and the most common central nervous system congenital malformation compatible with life primarily. Herein, we describe the short-term outcome of post-natal Myelomeningocele (MMC) surgical management and predictors of its postoperative complications and mortality. MethodsThis retrospective chart review studies the children who underwent post-natal surgical management for MMC in Namazi hospital, a tertiary referral center, in southern Iran from May 2001 to September 2020. Results248 patients were included in this study. The mean age at the operation was 8.47 ± 8.69 days. The most common site of involvement of MMC was Lumbosacral (86%, n = 204). At the evaluation conducted prior to the operation, cerebrospinal fluid leak was observed in 7% (n=16) of the patients. Postoperatively, 5.7% of the patients expired in the 30-day follow-up after the operation (n = 14), while 24% needed readmission (n = 47). The most common complications leading to readmission were wound dehiscence (n = 10, 42%) and wound purulence (n = 6, 25%). Only the site of the lesion (p-value = 0.035) was associated with postoperative complication. After controlling for potential confounders, the site of the lesion (adjusted odds ratio = 0.146, 95% confidence interval = 0.035–0.610, p-value = 0.008) and age at surgery (adjusted odds ratio = 1.048, 95% confidence interval = 1.002–1.096, p-value = 0.041) were significantly associated with mortality ConclusionsThe age of the patients at the surgery and the site of the lesion are the two factors that were associated with mortality. However, further investigations into preoperative interventions and risk factors to mitigate the risk of complications and mortality are highly encouraged.

Liquid Biopsy for Glioma Using Cell-Free DNA in Cerebrospinal Fluid.

Glioma is one of the most common primary central nervous system (CNS) tumors, and its molecular diagnosis is crucial. However, surgical resection or biopsy is risky when the tumor is located deep in the brain or brainstem. In such cases, a minimally invasive approach to liquid biopsy is beneficial. Cell-free DNA (cfDNA), which directly reflects tumor-specific genetic changes, has attracted attention as a target for liquid biopsy, and blood-based cfDNA monitoring has been demonstrated for other extra-cranial cancers. However, it is still challenging to fully detect CNS tumors derived from cfDNA in the blood, including gliomas, because of the unique structure of the blood-brain barrier. Alternatively, cerebrospinal fluid (CSF) is an ideal source of cfDNA and is expected to contribute significantly to the liquid biopsy of gliomas. Several successful studies have been conducted to detect tumor-specific genetic alterations in cfDNA from CSF using digital PCR and/or next-generation sequencing. This review summarizes the current status of CSF-based cfDNA-targeted liquid biopsy for gliomas. It highlights how the approaches differ from liquid biopsies of other extra-cranial cancers and discusses the current issues and prospects.

The diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) in children

Over the last two decades, immunoglobulin G (IgG) antibodies against myelin oligodendrocyte glycoprotein (MOG), previously thought to be a biomarker of multiple sclerosis (MS), have been shown to cause a distinct disease called MOG antibody-associated disease (MOGAD). MOGAD accounts for approximately one-third of all demyelinating syndromes in children and is the second most common central nervous system (CNS) demyelinating disease after MS. The diagnosis is made by detecting anti-MOG IgG antibodies against the natural MOG antigen, in the presence of compatible clinical and neuroradiological features. However, due to controversies in the methodologies for detecting anti-MOG antibodies and their diagnostic cutoff values, as well as the expanding clinical spectrum, accurate diagnosis may be challenging, at least in a subset of patients. Clinical presentations of MOGAD vary by age; the highest rates are seen in acute disseminated encephalomyelitis in younger children and optic neuritis, myelitis, or brainstem symptoms in older children. Although it was previously thought to be a milder demyelinating disorder and to have a monophasic course in the majority of patients, recent studies have shown that relapses occur in about half of the patients and sequelae develop in a significant proportion of them, especially in those with persistently high antibody titers, leukodystrophy-like magnetic resonance imaging (MRI) lesions, and spinal cord involvement. However, due to the monophasic course in about half of the patients, long-term treatment is not recommended after the first clinical episode but is recommended for patients who experience relapse. Accurate and early diagnosis of MOGAD is essential for proper management and better outcome. This review covers the challenges in the diagnosis of MOGAD in children.