tbuckley/cabot-search huggingface dataset:
TMIC-13. INTEGRATING SNRNASEQ AND SPATIAL TRANSCRIPTOME (ST) SHOWS DIVERSE TRANSCRIPTOMIC LANDSCAPE FOR TUMOR MICROENVIRONMENT (TME) IN INTRACRANIAL GERMINOMAS
Authors: Na Lin, Anthony Pak-Yin Liu, Kay Ka-Wai Li, Queenie Hoi-Wing Wong, Rui Ryan Yang, Danny Tat-Ming Chan, Xiaofan Ding, Ho-Keung Ng
Journal: Neuro-Oncology (2024)

Abstract The incidence of intracranial germ cell tumors is 5-8 times higher in East Asia and histologically, germinoma is well known to show intense lymphocytic infiltrates. In spite of germinoma’s well known immune infiltration, there have only been a few studies on its tumor micro-environment (TME). There has been no study using the recent and comprehensive techniques of single nucleus sequencing or spatial transcriptomics to study its TME. In this study, we studied snRNAseq (Chromium 10X) of FFPE tissues of 24 intracranial germinomas, and spatial transcriptomes (STs) (Visium Spatial) from fresh tissues from ten matched cases. For the TME, in contrast to common belief, macrophages and fibroblasts were equally represented as T- and NK-cells as immune cells. Clinical stage correlated with a lesser proportion of fibroblasts and T- and NK-cells. There was no correlation with proportion of tumor cells with either focal vs bifocal disease or clinical stage. Common gene modules (non-negative matrix factorization) were epithelial-mesenchymal transition (complete and partial), cell cycle and immune cells. Cell interaction analysis showed strong interaction between germ cells and macrophages involving CXCL, MIF and MK pathways. By ligand-receptor analysis, MIF combined with CD74 might promote tumor development. For ten cases, we studied STs with fresh tissues and integrated the results with snRNSeq, deconvoluting the spots for ST using snRNAseq cell types as reference (SPOTight) and achieved integrated single cell expression atlases of the STs (Seurat package). STs revealed a similar CNV plot pattern as those derived from snRNAseqs. Multimodal Intersection Analysis integrated significant genes based on snRNAseq and different regions’ significant genes based on STs. There was correlation between the expression of the four gene modules for tumor and immune cells for cell neighborhood. In conclusion, we showed in details the heterogenous expression landscape of TME of germinomas.
NIMG-70. COMPARISON OF VOLUMETRIC AND CROSS-SECTIONAL MEASUREMENTS IN DIFFUSE MIDLINE GLIOMAS: RETHINKING RESPONSE ASSESSMENT
Authors: Neda Khalili, Nastaran Khalili, Deep Gandhi, Andrea Franson, Paarth Jain, Hannah Anderson, Wenxin Tu, Shuvanjan Haldar, Ariana Familiar, Phillip Storm, Jeffrey Ware, Adam Resnick, Arastoo Vossough, Ali Nabavizadeh, Anahita Fathi Kazerooni
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The Response Assessment in Pediatric Neuro-Oncology (RAPNO) criteria, which are based on bidimensional or cross-sectional product (CP) measurements of tumor size, are the standard for assessing treatment response in diffuse midline glioma (DMG). This study aims to investigate the correlation between CP and volumetric measurements in progressive disease (PD) and compare their prognostic impact in pediatric patients with DMG. METHODS We retrospectively reviewed clinical and imaging data from 27 subjects with newly diagnosed DMG, encompassing 16 subjects from the PNOC003 and PNOC007 clinical trials and 11 subjects from the Children’s Hospital of Philadelphia. Tumors were segmented using a pretrained pediatric-specific autosegmentation model followed by manual revisions. Tumor volume and CP measurements were automatically derived from the outlined tumor. Cox regression analysis was used to compare the performance of CP and volumetric measurements in predicting overall survival (OS). The correlation between CP and volumetric thresholds for PD was assessed by linear regression. Comparison of survival of patients classified as PD versus non-PD by CP and volumetric measurements at 7 months post-baseline scan was performed using log-rank analysis. RESULTS Cox regression analysis demonstrated that volumetric measurements were significantly associated with OS (p=0.04), whereas CP measurements were not a significant predictor (p=0.07). An approximate 55% increase in segmented volume corresponded to a 25% increase in CP, which is the definition of PD according to RAPNO criteria (R2 = 0.71). At 7 months, volumetric classification of PD more accurately predicted survival than the CP method (p=0.06 for volumetric vs 0.14 for CP). CONCLUSION Our study showed that volumetric measurements are better predictors of survival compared to bidimensional measurements. We are extending this analysis to a larger sample size, examining survival at additional time points, and incorporating other factors influencing OS, such as treatment approaches.
NCMP-05. CLINICAL AND RADIOGRAPHIC IMPROVEMENT WITH REPLACEMENT OF FOLATE METABOLITES IN A PATIENT WITH INTRATHECAL METHOTREXATE-INDUCED MYELOPATHY
Authors: Hannah Kim, Jasmine L May, Niccoló E Mencacci, Karan S Dixit
Journal: Neuro-Oncology (2024)

Abstract Methotrexate (MTX)-induced myelopathy is a rare but serious adverse effect of intrathecal (IT) MTX, which may mimic subacute combined degeneration (SCD). MTX disrupts the normal synthesis of methionine, which plays an important role in maintaining myelin sheath integrity, resulting in degeneration of the dorsal columns. This degeneration does not respond to classic treatment with vitamin B12 and folate supplementation, unlike SCD. Here, we describe a case of a 45-year-old woman with Philadelphia-positive B-cell acute lymphoblastic leukemia treated with hyperCVAD regimen with ponatinib, who after 14 doses of prophylactic IT MTX, developed progressive lower extremity weakness, paresthesias, gait instability, saddle anesthesia, and bowel/bladder dysfunction. Her neurologic exam was also notable for diffuse hyporeflexia. The onset of symptoms followed a diarrheal infection, and an initial MRI spine showed no evidence of abnormal enhancement. She was initially treated with intravenous immunoglobulins for presumed acute inflammatory demyelinating polyneuropathy. She then re-presented one week later with progressively worsening symptoms. A repeat MRI spine revealed a new longitudinally extensive T2 hyperintense signal within the dorsal columns from T7 to T12. CSF results were notable for mild pleocytosis and increased myelin basic protein; the latter of which is often seen in MTX-induced myelopathy. The patient received high-dose administration of key metabolites of the methyl-transfer pathway including S-adenosylmethionine (PO 400mg three times daily), folinate (IV 20mg four times daily), cyanocobalamin (PO 1000mcg once daily) and methionine (PO 5mg once daily) for 7 days. This treatment regimen resulted in both clinical and radiographic improvement. Subsequent MRI spine demonstrated complete resolution of the abnormal signal in the thoracic cord. This case highlights (1) the diagnostic complexity of IT MTX-induced myelopathy (2) the role response to treatment plays in uncovering this diagnosis, and (3) how the replacement of folate metabolites facilitates both radiographic and clinical improvement in IT MTX-induced myelopathy.
CNSC-48. DIFFERENTIAL GENE EXPRESSION UNDERLYING EPILEPTOGENICITY IN PATIENTS WITH GLIOMAS
Authors: Armin Mortazavi, Anas Khan, Edwin Nieblas-Bedolla, Ujwal Boddeti, Muzna Bachani, Alexander Ksendzovsky, Kory Johnson, Kareem Zaghloul
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Seizures are a common sequela for patients suffering from gliomas. Molecular properties are known to influence the initiation of seizures that may influence tumor growth. Different levels of gene expression associated with seizures related to gliomas remain unclear. We analyzed RNA sequencing of gliomas to further probe these differences. METHODS Total RNA sequencing was obtained from The Cancer Genome Atlas - Lower Grade Glioma project, comprised of 2021 WHO classification low grade gliomas, including IDH-mutant and IDH-wild type, to distinguish differential expression in patients who did and did not experience seizures. Utilizing QIAGEN Ingenuity Pathways Analysis, we identified canonical and functional pathways to further characterize differential expression. RESULTS Of 289 patients with gliomas, 83 (28.7%) had available information regarding seizure occurrence prior to intervention and other pertinent variables of interest. Of these, 50 (60.2%) were allocated to the seizure group. When comparing the level of RNA expression from these tumors between the seizure and non-seizure groups, 52 genes that were significantly differentially regulated were identified. We found canonical pathways that were altered, most significantly RhoGDI and Semaphorin Neuronal Repulsive signaling. Functional gene analysis revealed tumors that promoted seizures had significantly increased functional gene sets involving neuronal differentiation and synaptogenesis. CONCLUSIONS In the setting of gliomas, differences in tumor gene expression exist between individuals with and without seizures, despite similarities in patient demographics and other tumor characteristics. There are significant differences in gene expression associated with neuron development and synaptogenesis, ultimately suggesting a mechanistic role of a tumor-neuron synapse in seizure initiation.
NCOG-28. SERUM PROTEIN BIOMARKERS LINKED TO NEURODEGENERATIVE PROCESSES ARE ELEVATED IN GLIOMA PATIENTS AND ASSOCIATED WITH SEVERITY OF NEUROLOGIC SYMPTOMS
Authors: Emory Hsieh, Tito Mendoza, Dhaivat Raval, McKenzie C Kauss, Kaitlynn Slattery, Michelle L Wright, Tara S Davis, Ann Choi, Kimberly Reinhart, Hope Miller, Elizabeth Vera, Marta Penas-Prado, Mark R Gilbert, Terri S Armstrong, Vivian A Guedes
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioma patients frequently report neurologic symptoms, adding to the complexity of cancer management and negatively impacting quality of life. However, mechanisms associated with the development of neurologic symptoms in glioma patients remain unclear. Pathological changes in the brain of glioma patients might result in elevated peripheral blood levels of proteins previously linked to central nervous system (CNS) damage and neurodegeneration, including neurofilament light chain (NfL), tau, and glial fibrillary acidic protein (GFAP). Here, we tested the hypothesis that the circulating levels of these proteins in blood are elevated in glioma patients and associated with the severity of neurologic symptoms. METHODS Patients (n=73) were enrolled in a natural history study (NCT02851706, PI T. Armstrong). Healthy subjects (n=39) were recruited by the National Institutes of Health Clinical Center Blood Bank. Neurologic symptom severity and walking interference were assessed using MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT). Serum proteins were analyzed using ultrasensitive assays (Meso Scale Discovery). RESULTS Participants were predominantly white (patients 74%, healthy subjects 67%) and male (patients 58%, healthy subjects 54%). The median age was 44 (range=24,74) for patients and 49 (range=19,78) for healthy volunteers. No significant differences in age, sex, or race were observed between patients and healthy subjects. Serum levels of NfL (p&amp;lt;0.0001), GFAP (p&amp;lt;0.0001), and tau (p&amp;lt;0.0001) were higher in glioma patients when compared to healthy subjects. Patients with walking interference had higher levels of GFAP (p=0.003), NfL (p=0.003), and tau (p=0.004), and those who reported numbness had higher levels of GFAP (p=0.012). CONCLUSIONS These findings suggest that serum levels of protein markers of neurodegeneration are elevated in glioma patients and associated with the presence of neurologic symptoms. Blood-based biomarkers have the potential to shed light on the mechanisms underlying symptoms and offer a non-invasive alternative for monitoring CNS damage that impact patient outcomes.
SURG-34. NEURO ENDOSCOPIC VS CRANIOTOMY APPROACH IN SUPRATENTORIAL HYPERTENSIVE INTRACEREBRAL HEMORRHAGE: AN UPDATED META-ANALYSIS
Authors: Abdul Haseeb, Muhammad Ashir Shafique, Muhammad Saqlain Mustafa, Ajeet Singh, Sadaf Iftikhar, Burhanuddin Sohail Rangwala, Anzah Imtiaz Waggan, Tagwa Kalool Fadlalla Ahmad, Brandon Lucke Wold
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Intracerebral hemorrhage (ICH) is a serious medical condition associated with high mortality and disability rates. Surgical interventions, including neuro-endoscopic surgery (NES) and craniotomy, are employed to manage ICH and improve patient outcomes. This meta-analysis compares the effectiveness of NES versus craniotomy in treating ICH. METHODS A systematic literature search was conducted to identify relevant studies comparing NES with craniotomy for ICH. Inclusion criteria encompassed primary or secondary results from randomized controlled trials (RCTs) or observational studies (OSs) with confirmed supratentorial ICH. Data were extracted, and methodological quality was assessed using appropriate tools. Statistical analysis was performed using Comprehensive Meta-Analysis. RESULTS Twenty-six studies (n=3237 patients) were included in the analysis. NES was associated with significantly lower mortality compared to craniotomy (OR: 0.45, 95% CI 0.33 to 0.60, p &amp;lt; 0.00001). Hematoma evacuation rates were higher with NES (SDM: 1.505, 95% CI 0.835 to 2.160, p &amp;lt; 0.00001). NES also showed better functional outcomes (OR: 3.31, 95% CI 1.78 to 6.17, p = 0.0002) and reduced blood loss (SDM: -3.06, 95% CI -3.979 to -2.141, p = 0.000). Additionally, NES was associated with shorter hospital and ICU stays, shorter operative times, and fewer complications such as infection and rebleeding. CONCLUSION NES emerges as a promising alternative to craniotomy for treating ICH, offering advantages in terms of mortality reduction, improved functional outcomes, and fewer complications. Future studies should explore advancements in neuro-endoscopic techniques to optimize patient outcomes further.
EXTH-06. DEVELOPMENT OF ANTISENSE OLIGONUCLEOTIDE THERAPY AGAINST ZFTA-RELA EPENDYMOMA
Authors: Nicholas Laboe, David Gee, Kelsey Bertrand, Sameer Agnihotri, Stephen Mack
Journal: Neuro-Oncology (2024)

Abstract Treatment for ependymoma (EPN), the third most common pediatric brain tumor, has not changed in the last 30 years, consisting of surgery and radiotherapy. When EPNs relapse, there are very limited therapeutic options, thus highlighting a dire need for more effective treatment for these tumors. Over 95% of supratentorial EPN are driven by ZFTA fusion oncoproteins, the most common variant being ZFTA-RELA. ZFTA fusion oncoproteins (FO) alone are sufficient to drive tumors in murine models. We hypothesize that: these tumors continue to depend on ZFTA-RELA expression, and that the FO represents a lead target for therapeutic development. RESULTS To assess this dependency, we utilized CRISPR-Cas9 mediated knockout (KO) of ZFTA-RELA oncoproteins from a series of patient derived cell lines as compared to control cells. We found that ZFTA FO driven patient models were dependent upon ZFTA FO expression, and KO led to impaired cellular proliferation. To determine whether a reduction in FO protein levels would also be sufficient to reduce tumor growth, we screened a series of antisense oligonucleotides (ASOs) for ZFTA FO knockdown efficiency in patient-derived cell lines. We quantified knockdown efficiency by western blot and selected the top-performing ASOs targeting a functionally important zinc finger domain of ZFTA. Top-performing ASOs reduced tumor cell proliferation in single dose experiments by 50%, while a non-targeting ASO treated population was unaffected. Repeated ASO doses over 96 hours saw a 75% reduction compared to a 10% reduction in the non-targeting group. CONCLUSION Our findings suggest that ZFTA-RELA drives tumor initiation and continued maintenance and proliferation of EPN. Tumor proliferation can be slowed by reducing FO levels below a required threshold. ASO therapy, potentially in combination with translation inhibitors, is one promising route for targeted treatments in this aggressive EPN subtype and could be expanded against other EPN driver proteins such as EZHIP.
TMOD-27. RECURRENT GLIOBLASTOMA AFTER LASER ABLATION OF THE PRIMARY TUMOR IN A PRECLINICAL ORTHOTOPIC MODEL EXHIBIT INCREASED GENETIC SIGNATURES OF CELL CYCLE AND CELL MOTILITY
Authors: Tavarekere Nagaraja, Ian Lee
Journal: Neuro-Oncology (2024)

Abstract Image-guided laser interstitial thermal therapy (LITT) is a minimally invasive tumor cytoreductive treatment for recurrent gliomas and tumors in eloquent loci. We have adapted this technique to develop an image-guided glioblastoma (GBM) ablation model, its recurrence and have tested the efficacy of imaging biomarkers in evaluating tumor ablation and recurrence. The cytopathology and molecular signatures of the primary and recurrent tumors were compared. Immune-compromised female rats were implanted with U251N tumor cells in one brain hemisphere (n=20). Tumor growth was monitored using magnetic resonance imaging (MRI). When tumors reached about 4 mm in diameter, they were ablated using a clinical LITT system (Visualase®), under MRI guidance. Five other rats implanted with U251N tumors were used as unablated controls. MRI data were acquired at 24 h post-LITT, and at 2 and 4 weeks. Rats were sacrificed for histopathology at 2 and 4 weeks, and brain sections stained for hematoxylin and eosin, human major histocompatibility complex, Ki67, a cell proliferation marker and sex determining region Y)-box 2 (SOX2), a stem cell transcription factor. An additional cohort of rats with primary (n=4) and post-LITT recurrent (n=4) U251N tumors were used for analysis of their molecular composition using RNA-Seq approach. In the treated groups, MRI showed little tumor tissue at 24 h, evidence of recurrence at 2 weeks and significant tumor tissue at 4 weeks. Tumor DCE-MRI parameters showed elevated intra-tumoral vascular permeability (i.e., Ktrans) values at pre-LITT imaging, that shifted to peri-ablation periphery at 24 h. A trend of progressive decrease in Ktrans was seen until 1-week post-ablation. Increasing Ktrans values at 2 weeks and after 4 weeks coincided with tumor recurrence. RNA-Seq data showed that cell cycle, cellular movement and inflammatory disease genes were the most differentially expressed genes in the recurrent tumors suggesting increased infiltration may primarily underlie treatment resistance.
PATH-50. AI-POWERED AUTOMATED TISSUE SEGMENTATION IMPROVES OUTCOME STRATIFICATION IN GLIOBLASTOMA
Authors: Georges Ayoub, Dina Elharouni, Connor Bossi, Constantin Möller, Seth Malinowski, Julia Japo, Anurag Jayant Vaidya, Andrew Zhang, Muhammad Shaban, Andres Santos, Drew Williamson, David Meredith, Faisal Mahmood, Keith Ligon
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma displays morphological heterogeneity on routine H&amp;E whole slide images, with conflicting evidence on the reliability of morphological features in predicting tumor behavior and treatment response. However, current standards for assessing morphology and disease status rely on nonquantitative manual evaluation by pathologists, which are prone to inherent variation. We sought to (1) expand the tools available for quantitative assessment and (2) evaluate the utility of this approach in identifying valuable biomarkers. We trained a deep learning-based algorithm using DenseNet on HALO AI platform for automated segmentation of six tissue classes (heavy infiltration, mild infiltration, mesenchymal tissue, geographic necrosis, palisading necrosis, and hemorrhage) on 3232 labeled annotations from 100 whole slide images. Manual pathologists’ estimations from clinical records showed strong correlation with corresponding digital quantifications (p&amp;lt;0.001), and further pixel-wise validation on 828 separate annotations showed high overlap between predicted and ground truth segmentations (precision=0.88, recall= 0.85, F1-score=0.87). We then identified a longitudinal cohort of 115 newly diagnosed glioblastoma tissue paired with the recurrence post-treatment (RT/TMZ), including all 827 H&amp;E whole slide images scanned at 40x. The quantification of longitudinally paired tissue showed a relative increase in geographic necrosis (+62%) and mild infiltration (+110%) and a relative decrease in palisading necrosis (-54%) and heavy infiltration (-35%) between the two timepoints. Patients with rapid clinical progression had more areas of large geographic necrosis (p=0.002), and mesenchymal tissue increase was associated with worse overall survival (p=0.016). Digitally quantified heavy infiltration as a predominant tissue on recurrence outperformed corresponding pathologist estimation of tumor as a predominant tissue on recurrence in stratifying overall-survival (p=0.005 vs p=0.640). Collectively, our AI-powered classifier enables an automated objective quantification of glioblastoma tissue, identifies markers of clinical response, and offers a potential adjunct to enhance routine pathologic reporting of glioblastoma.
BIOM-06. NOGGIN CONTRIBUTES TO BRAIN METASTATIC COLONIZATION OF LUNG CANCER CELLS
Authors: Seung Ho Yang
Journal: Neuro-Oncology (2024)

Abstract Brain metastasis is a common complication among patients with lung cancer, yet the underlying mechanisms remain unclear. In this study, we aimed to investigate the pathogenesis of brain metastasis in lung cancer. We established highly colonizing metastatic lung cancer cells, A549-M2, through multiple implantations of A549 human lung cancer cells in the carotid artery of athymic nude mice. Compared to parental cells (M0), M2 cells demonstrated slower growth in culture plates and soft agar, as well as lower motility and higher adhesion, key characteristics of mesenchymal-epithelial transition (MET). Further analysis revealed that M2 cells exhibited decreased expression of epithelial-mesenchymal transition markers, including ZEB1 and Vimentin. M2 cells also demonstrated reduced invasiveness in co-culture systems. RNA sequencing and gene set enrichment analysis confirmed that M2 cells underwent MET. Intriguingly, depletion of Noggin, a BMP antagonist, was observed in M2 cells, and replenishment of Noggin restored suppressed migration and invasion of M2 cells. In addition, Noggin knockdown in control M0 cells promoted cell attachment and suppressed cell migration, suggesting that Noggin reduction during brain colonization causes inhibition of migration and invasion of metastatic lung cancer cells. Our results suggest that lung cancer cells undergo MET and lose their motility and invasiveness during brain metastatic colonization, which is dependent on Noggin.