bluuebunny/crossref_metadata_2025_split huggingface dataset:
BIOS-02. DIFFERENT GROWTH PATTERN OF VESTIBULAR SCHWANNOMAS IN NEUROFIBROMATOSIS TYPE 2 PATIENTS ACCORDING TO AGE
Authors: Kang Ho , Ji So Young , Hwang Kihwan , Kim Chae-Yong , Han Jung Ho 
Published: November 2024

Abstract
The natural growth pattern of vestibular schwannoma (VS) associated with the rare disease neurofibromatosis type 2 (NF2) has not been sufficiently elucidated, and the rationale for proactive treatment for VS in NF2 is not firmly established. This study aimed to uncover the growth pattern of VS associated with NF2 and identify risk factors for rapid growth. A total of 68 VSs from 41 NF2 patients who were diagnosed in Seoul National University Bundang Hospital from July 2006 to July 2023 were retrospectively reviewed. NF2 was clinically diagnosed according to the Manchester criteria. The mean age was 34±16 years (mean ± standard deviation) at diagnosis. The initial tumor volume was a median of 0.263 cm³ (interquartile range [IQR], 0.053-0.754 cm³), and 51 VSs exhibited serviceable hearing classified as Gardner-Robertson grade 1 or 2. Patients were followed for a median of 45 months (IQR, 30-80 months), during which the median volume increased by 0.145 cm³ (IQR, 0.020-0.783 cm³), representing an annual growth rate of 0.044 cm³/yr (IQR, 0.003-0.202 cm³) or 12.4%/yr (IQR, 2.2-27.5%). Patients younger than 25 years (15 patients with 28 VSs) had significantly smaller initial tumor sizes (0.170 cm³ [IQR, 0.031-0.339 cm³] vs. 0.510 cm³ [0.099-1.399 cm³]) but faster tumor growth rates (annual growth rate; 27.3%/yr [IQR, 11.3-81.4%/yr] vs. 4.7%/yr [IQR, 0.0-16.1%/yr]) compared to those 25 years or older (26 patients with 40 VSs). Among the 51 VSs with serviceable hearing at diagnosis, 40 VSs were followed up for more than 12 months. Among them, 13 (32.5%) experienced unserviceable hearing deterioration at a median of 58 months. The risk of hearing loss significantly increased with faster tumor growth rates. The growth rate of NF2-related VS was higher in patients under the age of 25, which may be helpful in determining indications for proactive treatments like radiosurgery for NF2-related VS.
BIOS-04. THERAPIES FOR LEPTOMENINGEAL DISEASE: A NETWORK META-ANALYSIS
Authors: Suresh Vinay , Panchawagh Suhrud , Muneer Muneeb , Mansouri Alireza , Ozair Ahmad 
Published: November 2024

Abstract

INTRODUCTION
Leptomeningeal disease (LMD) has limited head-to-head comparison of available therapies, including systemic chemotherapy (SysCT), intrathecal (IT) or intraventricular therapy (ITV), whole-brain radiotherapy (WBRT), or cranio-spinal irradiation (CSI). No network meta-analysis (NMA) of randomized controlled trials (RCTs) of LMD has been reported so far.

METHODS
NMA was conducted using published LMD RCTs and reported following PRISMA-NMA guidelines. Primary outcome was survival, assessed using hazard ratios (HRs) and 95% confidence intervals (95%CI). Survival times were converted to HRs under exponential distribution assumption. LogHR standard errors were calculated using deaths per RCT arm. P-scores were used to estimate probability of treatment being superior. Analysis was performed in R using frequentist approach, followed by back-transforming logHRs for indirect and direct comparisons. Incremental effects of individual treatment components were estimated using additive model. Heterogeneity and inconsistency were assessed using tau-squared (τ²), I-squared (I²), and Q-statistics. Analyses were performed separately for main subnetwork with disconnected subnetworks accommodated in additive model.

RESULTS
Seven studies were included, incorporating 7 pairwise comparisons and 9 treatments. 3 subnetworks were identified. Primary subnetwork analysis included 5 studies. Compared to SysCT±RT (reference), logHRs (95%CI) under random effects model were: IT/ITV DepoCyt±SysCT±RT -0.094(-0.468,0.281); IT/ITV methotrexate(MTX)±cytarabine(AraC)±SysCT±RT 0.8567(0.066,1.647). IT/ITV MTX±SysCT±RT 0.318(-0.163,0.798); ITV Thiotepa±SysCT±RT 0.438(-0.294,1.169). Heterogeneity and inconsistency were not detected (τ²=0,I²=0%,Q-statistic=0.57,P=0.45). P-scores were highest for IT/ITV DepoCyt±SysCT±RT (0.894), followed by SysCT±RT (0.769). Disconnected-component-NMA demonstrated incremental logHR: AraC 0.539(-0.347,1.425); IT/ITV DepoCyt 0.052(-0.566,0.670); IT/ITV MTX 0.179(-0.484,0.840); ITV thiotepa 0.298(-0.767,1.362); proton CSI -0.250(-0.726,0.225). No component demonstrated statistically significant incremental benefit, with moderate heterogeneity and adequate fit present (τ²=0.1017,I²=57%,Q-statistic=4.65,P=0.098).

CONCLUSIONS
IT/ITV DepoCyt±SysCT±RT and SysCT±RT were found most effective. Lack of significant incremental benefit warrants evaluating older therapies in contemporary RCTs.
BIOS-08. CISD: A NOVEL, USER-FRIENDLY MULTIFACETED ALGORITHM FOR DETECTING STITCHING ARTIFACTS IN LARGE-SCALE CODEX IMAGING DATASETS
Authors: Jahedi Afrooz , khan Aliya , Gupta Pravesh , Huse Jason , Kannan Kasthuri , Bhat Krishna 
Published: November 2024

Abstract

BACKGROUND
CODEX (CO-Detection by indEXing) imaging has emerged as a pivotal tool in cellular biology, providing unprecedented insights into cellular distributions and interactions within the tissue microenvironment, crucial for advancing computational pathology. Despite its advantages, CODEX is susceptible to stitching errors during the merging of image tiles, which can significantly distort spatial analysis by introducing artifacts that obscure true cellular architecture.

METHODS
Addressing this challenge, we introduce CISD (CODEX Image Stitch Detection), a novel, user-friendly algorithm optimized for the detection of stitching artifacts in large-scale CODEX datasets. Developed and validated using a comprehensive dataset from 7 matched glioblastoma patients—encompassing over 2800 images across 29 immune protein markers—CISD utilizes a combination of image preprocessing, statistical measures, and thresholding to detect stitching errors.

RESULTS
CISD demonstrates robust performance, achieving a median Area Under Curve (AUC) value in the gold standard dataset where 73% of markers exceed 70% AUC, and 17% surpass 90%. Further validation shows that in a secondary dataset, 45% of markers maintain AUC values over 70% with 38% exceeding 90%, validating the algorithm’s consistent efficacy across varied datasets.

CONCLUSION
CISD’s significance lies not only in its computational achievements but also in its accessibility, facilitating high-quality analysis of extensive datasets without complex pattern recognition requirements. This democratizes high-precision computational pathology, enabling more researchers to accurately analyze spatial data. By reducing technical barriers, CISD sets a new benchmark in CODEX imaging, enhancing data reliability and accelerating research discoveries in cellular biology. This innovation stands to substantially refine spatial analysis in digital pathology, ensuring dependable interpretation of complex biological data.
CNSC-01. PEDIATRIC GLIOMAS EXPRESS CIRCADIAN GENES AND DEMONSTRATE CIRCADIAN REGULATION OF TEMOZOLOMIDE SENSITIVITY
Authors: Nettnin Ella A , Garcia Cesar A , Schonfeld Ethan , Mehl Lindsey C , Guinle Maria Isabel Barros , Petritsch Claudia K , Gibson Erin M , Prolo Laura M 
Published: November 2024

Abstract

INTRODUCTION
Pediatric high-grade gliomas (pHGG) are highly invasive brain tumors with dismal survival rates, prompting the need for innovative therapeutic strategies. Previous research in adult glioblastoma patients revealed a correlation between the timing of Temozolomide administration and patient survival. There has, however, been limited exploration into circadian gene expression in pediatric gliomas. In this study, we investigate whether pHGGs exhibit rhythmic expression of circadian genes and whether the timing of drug administration influences Temozolomide sensitivity.

METHODS
A bioinformatics approach, immunocytochemistry and immunoblotting were used to assess key circadian genes in low- and high-grade gliomas. We then used timed qPCR to assess rhythmic expression in BMAL1 and REV-ERBα, two key circadian genes, across 48 hours in our pHGG cells following dexamethasone cell synchronization. Lastly, we used CyQuant Proliferation Assays to examine the effects of Temozolomide applied at peaks versus troughs in BMAL1 expression.

RESULTS
Using data from PedcBioPortal, we found significantly higher expression of BMAL1 in pHGGs compared to pLGGs (0.349 + 1.05 vs 0.0545 + 0.666, p &lt; 0.001). We identified cellular localization of BMAL1 and REV-ERBα in pHGGs along with rhythmic expression of BMAL1 and REV-ERBα in our three pHGGs primary cell cultures across 48 hours (JTK_CYCLE, p &lt; 0.005). Lastly, we demonstrated a chronotherapeutic response to Temozolomide in two of our pHGG cell lines, with significantly decreased proliferation when treatment occurred at trough versus peak BMAL1 expression (p &lt; 0.01).

CONCLUSION
In this study, we found that circadian genes BMAL1 and REV-ERBα are expressed in pHGGs and expression patterns differ between pHGGs versus pLGGs. Circadian gene expression is rhythmic in pHGGs, and pHGGs can have differential Temozolomide-sensitivity based on circadian cycles. These findings suggest that circadian timing of chemotherapy may influence the efficacy of treatment, and next steps will be to explore the mechanisms underlying circadian regulation of Temozolomide sensitivity.
CNSC-05. MAPPING LANGUAGE PROCESSING IN SURGICAL GLIOMA PATIENTS
Authors: Muir Matthew , Noll Kyle , Prinsloo Sarah , Traylor Jeffrey , Liu Ho-Ling , Kumar Vinodh , Prabhu Sujit 
Published: November 2024

Abstract
Previous work from our group has shown that the resection of white matter tracts localized by transcranial magnetic stimulation (TMS) predicts postoperative neurological deficits. Here we use advanced preoperative brain mapping along with formal language evaluations to localize the neuroanatomical underpinnings of language processing in surgical glioma patients. In patients who had TMS tracts resected, the resected portions (“tract-cavity segmentations”) were classified according to the functional outcome (“true positives”-corresponding deficit; “false positives”-no deficit) and normalized to MNI space. For patients who sustained long-term deficits, TMS tracts were segmented according to spatial overlap with normative tracts to create ROIs. Each normalized resection cavity (n=79) was analyzed for overlap with each ROI associated with postoperative deficits (n=8). The percentage of patients who had positive ROI resections that included TMS tracts versus patients who had positive ROI resections irrespective of TMS tracts were analyzed according to the percent who sustained deficits in each group. ROIs from all patients were summed to create a probabilistic atlas of functional white matter. “True positive” tract-cavity segmentations localized into dual anterior/posterior “hubs” and demonstrated significantly higher spatial association with normative tracts across three different measures (p&lt;.05). 92% of patients who underwent ROI resections that included TMS tracts sustained long-term deficits while 34% of patients who underwent ROI resections irrespective of individualized mapping sustained deficits (p&lt;.05). The probabilistic atlas of functional white matter demonstrated significantly higher voxel intensities within the white matter deep to the temporoparietal junction defined by the same posterior “hub” ROI from Figure 1 (p&lt;.001). This study demonstrates that essential language processing localizes to ROIs within normative white matter tracts that require individualized mapping for surgical preservation. The white matter deep to the temporoparietal junction serves as a crucial hub for language-processing circuitry in glioma patients.
CNSC-07. OLIGODENDROGLIAL IMPAIRMENT IN WHITE MATTER TRACTS FOLLOWING NEUROFIBROMATOSIS TYPE 1 (NF1) GERMLINE MUTATION OR CARBOPLATIN TREATMENT
Authors: Aghoghovwia Benjamin Emoefe , Alnassiry Sama , El-Toukhy Hana , Hamblett Ava , Sharafaldin Samer , Harris Momo , Pan Yuan 
Published: November 2024

Abstract
Neurofibromatosis type 1 (NF1) is a cancer predisposition syndrome due to mutations in the NF1 gene. The disease affects 1 in 2500-3000 people worldwide and patients are predisposed to neoplasms such as optic pathway glioma, plexiform neurofibroma. In addition, NF1 patients often experience neurological issues such as learning difficulties. Unfortunately, there is no cure for NF1 yet. Chemotherapy (e.g., carboplatin) remains the first-line treatment for NF1-associated low-grade glioma; while effective in reducing tumor burden, it does not reliably restore neuronal function. In this study, we sought to determine how chemotherapy and Nf1 germline mutations influence neurological function, using genetically engineered mice of NF1. Nf1-heterozygous mice received carboplatin (60 mg/kg/day) or vehicle every other day for one week. Their optic nerves were collected and processed for immunofluorescence and transmission electron microscopy (EM). We found that carboplatin treatment reduces the density of oligodendrocytes in Nf1-heterozygous mice and impairs myelination. Moreover, a similar effect of carboplatin was observed in wild-type mice, suggesting that carboplatin impairs oligodendroglia independent of the NF1 status and the effect of carboplatin should also be evaluated in the non-NF1 context. In another set of experiments, we sought to understand how germline Nf1 mutations influences oligodendroglia. Whereas we did not observe a difference in optic nerve oligodendrocyte density in mice with an engineered mutation targeting the GTPase-activating protein-related domain (GRD) domain of the Nf1 gene, a reduction of oligodendrocyte density was observed in mice harboring a patient-derived mutation (R1809C), which localizes outside of the GRD. A similar effect was observed in the corpus callosum of Nf1+/R1809C mice together with myelin impairment, suggesting a RAS-independent mechanism of Nf1 regulation of oligodendrocytes. Together, these findings indicate that both Nf1 germline mutations and chemotherapy could contribute to oligodendrocyte and myelin deficits in white matter tracts.
CNSC-08. PROGNOSTIC BIOMARKER DISCOVERY THROUGH PROTEOMIC ANALYSIS OF GLIOBLASTOMA MULTIFORME
Authors: Liu Szu-Yuan 
Published: November 2024

Abstract

BACKGROUND
Glioblastoma multiforme (GBM) is an aggressively malignant brain tumor known for its high recurrence rates and dismal survival outcomes. Despite advancements in surgical and therapeutic strategies, the prognosis for GBM patients remains poor. This study applies proteomic analysis to postoperative GBM tumor specimens to identify molecular markers that could enhance prognosis prediction. Through the analysis of protein expression profiles before and after tumor recurrence, we identified significant alterations in protein pathways via Gene Set Enrichment Analysis (GSEA), highlighting potential biomarkers for disease outcome prediction.

METHODS
We employed Sequential Window Acquisition of All Theoretical Fragment Ion Spectra (SWATH-MS) proteomics to analyze protein samples from both primary and recurrent GBM patients. Gene Set Enrichment Analysis (GSEA) was utilized to compare protein expression profiles and discern significantly altered pathways.

RESULTS
Analysis revealed 778 differentially expressed proteins (DEPs), with notable alterations in pathways such as glycolysis, interleukin signaling, and MAPK signaling. Proteins such as TOLLIP, ENO1, and ITGA2B emerged as potential prognostic markers. Validation through an online tumor prognostic analysis platform (ToPP), integrated with The Cancer Genome Atlas (TCGA) data, facilitated the development of a prognostic risk score model. This model effectively categorized patients into high and low-risk groups based on their protein expression profiles, enhancing the prediction of patient outcomes. The proteins and pathways identified offer new insights into the molecular dynamics of GBM postoperatively. The association between protein expression profiles and patient prognosis underscores the potential of these markers in developing customized therapeutic strategies. Additionally, the prognostic risk score model serves as a valuable tool for improving prognostic accuracy and could guide personalized treatment plans.

CONCLUSION
Proteomic profiling of GBM tumors significantly contributes to uncovering the molecular mechanisms driving this aggressive cancer and facilitates the development of dependable prognostic tools. These findings not only affirm the critical role of proteomics in cancer research but also advance personalized medicine strategies in GBM management.
CNSC-09. OTOSYPHILIS MIMICKING A VESTIBULAR SCHWANNOMA
Authors: Nasany Ruham Alshiekh , Blaquier Juan , de la Fuente Macarena , Benjamin Carolina , Mellon Eric 
Published: November 2024

Abstract
Vestibular schwannomas are common nonmalignant primary brain tumors representing up to 80% of the cerebellopontine angle (CPA) tumors. Their diagnosis is made radiographically in most cases with the presence of an enhancing mass along the 8th nerve complex. The United States is experiencing a surge in the number of recorded syphilis cases with an approximate 80% increase since 2018 according to the CDC, after reaching an all-time low in the year 2000. Syphilis can involve the Central Nervous System (CNS) in its early, late, and latent forms, and in its early stages it typically presents in the form of meningitis which can be accompanied by cranial neuropathies especially of the nerves II, VII, and VIII. We present a case of a 35-year-old man who presented with subacute onset unilateral left-sided hearing loss and dizziness that did not respond to prescribed steroids. Magnetic resonance imaging (MRI) revealed an enhancing mass in the left cerebellopontine angle presumed to be a vestibular schwannoma. The patient was subsequently planned for radiosurgery, however, MRI done during the procedure revealed that the mass was of a smaller size. The patient was referred to neuro-oncology and work up included cerebrospinal fluid (CSF) analysis that showed 3 white blood cells, normal protein and glucose, and negative VDRL. Cytology, flow cytometry, and inflammatory markers were negative. However, the Treponema pallidum antibodies were positive confirming otoshyphilis. The patient was treated accordingly with a course of Penicillin G with near resolution of the enhancement of the 8th nerve complex. His hearing remained impaired on his initial follow up, however, his facial weakness near resolved. This case brings up an important diagnostic question in cases of presumed schwannomas where patients would be otherwise treated solely based on the MRI appearance, especially given the re-emergence of syphilis.
CNSC-17. UPREGULATION OF CCL4 AFTER TREATMENT WITH A NOVEL MRNA VACCINE SHIFTS THE PHENOTYPE OF CCR5-EXPRESSING MICROGLIA WITHIN TUMOR MICROENVIRONMENT
Authors: Chauhan Anjali , Thomas Nagheme , Dastmalchi Farhad , McGrath Kyle , Takacs Gregory Pal , Harrison Jeffrey K , Subramaniam Vignesh , Angelini Thomas , Ebrahim Ghaidaa , Tomdio Macaulay Y , Frain Matthew , Mendez-Gomez Hector , Sayour Elias J , von Roemeling Christine , Mitchell Duane A Mitchell A , Rahman Maryam 
Published: November 2024

Abstract

INTRODUCTION
Intra-tumoral immunosuppression is a major cause of treatment failure for patients with glioblastoma (GBM). Our group has developed a proprietary vaccine that combines mRNA encapsulated in lipid nanoparticles with PEG hydrogel and a chemokine (CXCL9). This hydrogel-chemokine-mRNA (HCM) vaccine is delivered subcutaneously (SQ) and results in significant anti-tumor efficacy in syngeneic murine glioma models. The objective of this study was to evaluate the effects of the vaccine on the tumor microenvironment (TME).

METHODS
C57BL/6 mice underwent intracranial implantation of KR158-luc tumor cells and underwent SQ injection of the HCM vaccine using total tumor mRNA. Tumors were collected for analysis at different time points. Q-PCR and flow cytometry were done to evaluate the differential gene expression and CCR5 expression (receptor for CCL4) in the TME following HCM vaccination.

RESULTS
CCL4 was found to be upregulated in tumor-bearing animals treated with HCM vaccine using PCR. In a separate experiment, CCL4 blockade was given prior to HCM vaccination and this resulted in abrogation of the survival benefit of the vaccine. Next, flow cytometry results revealed that microglia in the TME had the highest expression of the CCR5 receptor. Further, QPCR on the isolated microglia from TME revealed significant up-regulation of inflammatory gene CCL5 (25 fold) and down-regulation of anti-inflammatory genes as compared to untreated control and empty hydrogel control.

CONCLUSION
The HCM vaccine results in significant anti-tumor efficacy in murine syngeneic murine glioma which is dependent on upregulation of CCL4 in the TME. The CCL4 exerts its effect through microglia expressing CCR5 in the TME. HCM vaccination shifted the microglia phenotype from immune-suppression to inflammatory state. Further analysis of the effect of CCR5 knock out on the HCM vaccine survival efficacy are under current investigation.
CNSC-20. MONOSYNAPTIC TRACING DEFINES BRAIN-WIDE CIRCUIT CONNECTIVITY OF HUMAN GLIOBLASTOMA
Authors: Sun Yusha , Wang Xin , Zhang Daniel , Zhang Zhijian , Bhattarai Janardhan , Wang Yingqi , Park Kristen , Dong Weifan , Yang Qian , Zhang Feng , Rajamani Keerthi , Mu Shang , Kennedy Benjamin , Hong Yan , Galanaugh Jamie , Sambangi Abhijeet , Kim Sang Hoon , Wheeler Garrett , Goncalves Tiago , Wang Qing , Geschwind Daniel , Kawaguchi Riki , Viaene Angela , Helbig Ingo , Kessler Sudha , Hoke Ahmet , Wang Huadong , Xu Fuqiang , Binder Zev , Chen Isaac , Pai Emily Ling-Lin , Stone Sara , Nasrallah MacLean , Christian Kimberly , Fuccillo Marc , Toni Nicolas , Wu Zhuhao , O’Rourke Donald , Ma Minghong , Ming Guo-li , Song Hongjun 
Published: November 2024

Abstract
Glioblastoma (GBM), a deadly brain cancer, infiltrates the brain and can be synaptically innervated by neurons. Synaptic inputs onto GBM cells identified so far are largely short-range and glutamatergic in nature. The extent of integration of GBM cells into the brain-wide neuronal circuitry is therefore not well understood. We report the application of transsynaptic viral tracing approaches to study the neuronal connectome of GBM. We applied rabies virus-mediated retrograde tracing and herpes simplex virus (HSV)-mediated anterograde tracing approaches to characterize presynaptic partners in vivo in the adult mouse brain and ex vivo with iPSC-derived neurons, cortical organoid-GBM assembloids, and human surgical specimens. After transplantation into adult mice, GBM cells derived from multiple patients rapidly integrated into brain-wide neuronal circuits. GBM exhibited increased connectivity rates compared to transplanted neural progenitor cells, highlighting functional connectivity as a hallmark of malignant cells. Beyond glutamatergic inputs, we identified neuromodulatory inputs across the brain, including cholinergic inputs from the basal forebrain. We validated these long-range cholinergic neuron-to-glioma synapses signaling through the metabotropic CHRM3 receptor by high-resolution microscopy, anterograde monosynaptic HSV tracing, calcium imaging, and patch-clamp electrophysiology. To interrogate the functional effects of acetylcholine (ACh) on GBM, we performed calcium imaging and RNA sequencing analyses, which showed that ACh stimulation induced sustained calcium oscillations and long-lasting transcriptional reprogramming of GBM cells into a more invasive state via CHRM3. Importantly, CHRM3 activation promoted GBM cell invasion, whereas CHRM3 downregulation suppressed GBM cell invasion in vitro and in vivo, suggesting CHRM3 as a potential therapeutic target for this disease. Together, these results reveal the capacity of human GBM cells to robustly integrate into anatomically and molecularly diverse neuronal circuitry in the adult brain. They also support a model wherein rapid synapse formation onto GBM cells may promote a long-lasting increase in tumor cell fitness.