tbuckley/cabot-search huggingface dataset:
NIMG-40. RADIOMICS-BASED DIFFERENTIATION OF GLIOBLASTOMA AND METASTATIC DISEASE: DOES DIFFERENCE IN TYPE OF T1-CONTRAST ENHANCED SEQUENCE MATTER?
Authors: Neetu soni, Camila Zamboni, Amit Agarwal, Nicholas B Larson, Milan Sonka, Girish Bathla
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND To evaluate the radiomics-based model performance for differentiation between glioblastoma (GB) and intracranial metastatic disease (IMD) using magnetization prepared rapid gradient echo (MPRAGE) and volumetric interpolated breath-hold examination (VIBE) T1-contrast enhanced sequences. MATERIALS AND METHODS T1-CE MPRAGE and VIBE sequences acquired in 108 patients (31 GBs and 77 IMD) during the same MRI session were retrospectively evaluated. Post standardized image pre-processing and segmentation, radiomics features were extracted from necrotic and enhancing tumor components. A total of 90 machine learning (ML) pipelines were evaluated using a five-fold cross-validation. Performance was measured by mean AUC, Log-loss, and Brier scores. Pearson correlation analysis of radiomics features from tumor subcomponents was also performed. RESULTS The mean AUC across the top-ten pipelines varied between 0.890-0.851 with T1-CE MPRAGE and 0.907-0.869 with T1-CE VIBE sequence. Top performing models for the MPRAGE sequence commonly used support vector machines, while those for VIBE sequence used either support vector machines or random forest. Common feature reduction methods for top-performing models included linear combination filter and least absolute shrinkage and selection operator (LASSO) for both sequences. Only three of the top ten models used the same combination of feature reduction-ML algorithm pipeline. A feature-wise comparison showed that the radiomic features between sequences were strongly correlated, with the highest correlation for shape-based features. CONCLUSION Radiomics features derived from T1-CE MPRAGE and VIBE sequences may have similar overall classification performance for differentiating GB from IMD, albeit often using different feature selection-ML algorithm pipelines.
NIMG-43. INFARCTION RADIOLOGICALLY MIMICKING INTRA-AXIAL BRAIN TUMORS
Authors: Kyung-Min Kim
Journal: Neuro-Oncology (2024)

Abstract There are several reports of brain lesions that radiologically mimicking the brain tumors. The abscess is representative lesion of resembling the intra-axial tumors in brain MRI. However, cerebral infarction is not a common lesion that resembles a brain tumor and can be easily distinguished from a brain tumor in MRI. Here, we represented the two cases of pathologically diagnosed infarction that radiologically suspected gliomas. A 67-year-old man presented with left side weakness and memory impairment. Brain MRI revealed the rim enhancing lesion radiologically suspected glioma. Navigation guided biopsy was performed and final pathological diagnosis was subacute infarction. A-41-year-old man represented the right side weakness. MRI showed the enhancing nodular lesion with perilesional edema. Surgical excision was performed and pathological diagnosis was infarction. Although advancement of brain imaging techniques, it is difficult to accurately discriminate the intracerebral lesions utilizing the MRI. Further comprehensive study should be executed for more precise differentiation of infarction and brain tumors.
TMOD-07. DEVELOPMENT AND CHARACTERIZATION OF A SPINAL CORD DIFFUSE MIDLINE GLIOMA MODEL
Authors: Reyes Hernandez-Osuna, Andrea Lacalle, Marisol Gonzalez-Huarriz, Javier Marco-Sainz, Daniel Palacios, Sara Nuin, Sandra Morales, Jaime Gallego Perez-Larraya, Ana Patiño-García, Timothy Phoenix, Aurelio Hernandez-Lain, Alvaro Lassaletta, Luis Blasco, Gemma Quincoces, Maria Collantes, Palma Solano, Marta M Alonso, Sara Labiano
Journal: Neuro-Oncology (2024)

Abstract Diffuse midline gliomas (DMGs) are very aggressive central nervous system tumors that occur mainly in children and adolescents. Most DMGs develop in the brainstem, but they can also be found in the thalamus and the spinal cord, the latter comprising 4% of all DMGs. Despite advances in current treatments, the outcome for DMG patients remains extremely poor. The success of immunotherapy in other tumors encourages its translation to DMGs, for which the understanding of the tumor immune microenvironment (TIME) is imperative. The field counts with several murine DMG models in the pontine and thalamic locations. However, there is a paucity of spinal cord models. Thus, in this work, we have generated an orthotopic syngeneic model of H3K27M spinal cord DMG by injecting the tumor cells directly into the spinal cord under the T2 vertebra. We monitored tumor growth by bioluminescence and PET using 18F-FDG and 11C-methionine. As the tumor grew, we observed human-like symptoms in the mice, such as hemiplegia and hemiparesis. TIME characterization showed that this tumor model is mainly infiltrated by macrophages and almost devoid of lymphocytes. We are currently delving into the phenotype of these populations by scRNAseq and spatial transcriptomics. In addition, we are comparing our findings with human samples (n=15) to assess whether our model mimics human disease and can serve as a bonafide model of this tumor location. As a proof of concept, treatment of spinal DMG-bearing mice with a TIM-3 antagonist antibody, previously described as effective in pontine DMG-bearing mice, increased the median overall survival. We showed by microPET imaging that anti-TIM-3 administration into the brain ventricles diffuses to the tumor. These results open a path for the characterization of the spinal cord DMG TIME and for testing preclinical treatments in this new model.
IMMU-38. LEVERAGING INNATE IMMUNE SENSORS TO GENERATE DURABLE ANTI-GLIOMA ADAPTIVE IMMUNE RESPONSES
Authors: Spencer Lea, Hinda Najem, Chao-Hsien Chen, Jun Wei, Ivana William, Shashwat Tripathi, Lisa Hurley, Amy Heimberger, Michael Curran
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma harbors a tumor microenvironment (TME) that is mostly devoid of T cell effector infiltration but is dominated by immune suppressive microglia, macrophages, and myeloid-derived suppresser cells. The innate immune cells in the TME have impaired phagocytosis and antigen presentation and are inadequate for triggering the subsequent immune activating signals needed for anti-tumor effector responses. Phagocytic activity can also be blocked by the upregulation of CD47 on the tumor cells. In the immune checkpoint resistant Qki-/- Pten-/- P53-/- (QPP) glioma model, intratumoral treatment with the synthetic cyclic di-nucleotide STING agonist IACS-8803 (8803) induces global immunological reprogramming and long-term survival resistant to tumor rechallenge. More specifically, in the infiltrating myeloid stroma 8803 increases costimulatory protein CD86 while reducing the expression of suppressive markers CD163 and CD206. Conventional type 1 dendritic cells are increased in both the TME (p&amp;lt;0.05) and the draining cervical lymph node (p&amp;lt;0.01). Intratumoral infiltration of both CD8 T (p&amp;lt;0.05) and NK (p&amp;lt;0.001) cells increases. However, only T cells, but not NK cells, are necessary for 8803 therapeutic activity when assessed with in vivo NK cell depletion studies and treatment in the RAG-/- background. STING activation increases microglial phagocytic capacity, but also induces a compensatory increase in SIRPα expression (p&amp;lt;0.001) – the ligand for CD47. 8803 synergizes with anti-CD47 blockade to enhance microglia phagocytosis of QPP glioblastoma cells in vitro. Finally, the combination of 8803 and anti-CD47 synergizes to extend both median survival and the fraction of long-term survivors in orthotopic QPP-bearing mice (QPP8v; vehicle control MS=39d, anti-CD47 MS=40d, 8803 MS=67d 20% long-term survival, 8803 + anti-CD47 MS=107.5d 40% long-term survival). These data demonstrate that 8803 induces proinflammatory conversion of the glioblastoma TME, generates T cell-dependent survival benefits in QPP-bearing mice, and synergizes with anti-CD47 blockade to enhance microglia phagocytosis of glioblastoma cells and extend survival in QPP-bearing mice.
PATH-58. SEQUENCING OF DNA RECOVERED FROM BRAIN TUMOR BIOPSY SURGICAL WASTE IMPROVES SENSITIVITY OF RAPID IDH/TP53-MUTANT TUMOR DIAGNOSES
Authors: Jack Wadden, Tiffany Adam, Rodrigo Cartaxo, Michael Niculcea, Seongbae Kong, Vishal John, Arushi Tripathy, Cylaina Bird, Javad Nazarian, Jason Heth, Karin Muraszko, Neena Marupudi, Suresh Magge, Hugh Garton, Wajd Al-Holou, Carl Koschmann
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND TP53 and IDH mutations are common in brain tumors and are highly relevant biomarkers for diagnosis and treatment. Thus, biopsy tissue is commonly tested for these mutations via immunohistochemistry (IHC), which is rapid and generally considered highly sensitive. However, IHC only tests for IDH1R132H (80%-90% of IDH mutant disease) and rarer IDH mutations are not covered. p53 nuclear staining is used to identify non-specific p53 upregulation and loss of function but does not test for specific mutations and has a relatively lower overall sensitivity/specificity of ~80%/80-97%. Sequencing can resolve all mutations and improve over IHC, but long turnaround time and high cost prevents this. New advances in rapid sequencing technologies allow same-day, low-cost panel sequencing. However, access to biopsy tissue is zero-sum and obtaining additional tissue for molecular diagnostics confers increased morbidity. We investigate whether tumor DNA recovered from surgical waste (specifically core biopsy needle fluid and non-adherent gauze) is sufficient to diagnose IDH/p53 status of tumors. METHODS Surgeons were instructed to save biopsy needle rinse saline, and/or to recover any non-adherent gauze used in specimen handling. Cell-free DNA was extracted and sequenced using a same-day targeted panel protocol and/or TruSight Oncology 500 panel sequencing. RESULTS 100% of recovered samples yielded enough DNA for targeted sequencing (17/17). In all IDH1R132H IHC positive cases, waste sequencing recapitulated the mutation (4/4). In 7/9 p53 positive cases via IHC (&amp;gt;10% staining), waste sequencing of common hotspot loci was able to identify a specific TP53 mutation. Importantly, sequencing identified alternate IDH mutations in three IHC negative cases (3/13), discovered a rarer TP53 mutation (E286K) in one IHC negative case, and confirmed TP53 negative status in one indeterminate p53 report. CONCLUSIONS Surgical waste is an important diagnostic resource that should be leveraged for rapid diagnostic sequencing. Sufficient DNA can be easily recovered from surgical waste and sequenced within the same time-frame–but with increased sensitivity–to IHC.
CTIM-18. HIGH LEVEL OF MUTATIONAL LOAD AND DIVERSITY OF TUMOR INFILTRATING T LYMPHOCYTES ARE FAVORABLE PROGNOSTIC MARKERS FOR CANCER SURVIVAL IN CHILDREN WITH RECURRENT MEDULLOBLASTOMA DURING ADOPTIVE CELLULAR THERAPY
Authors: Oleg Yegorov, Changlin Yang, Yanina Stratford, Duane Mitchell
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Adoptive cellular therapy (ACT) has shown remarkable efficacy in some patients with solid tumors, resulting in durable complete responses. A key mechanism behind this success is the targeting of neoantigens by T cells. There is culminating evidence that tumor-infiltrating lymphocytes (TILs) have a major effect on the clinical attributes of human cancer and can influence the tumor response to various therapy regimens. We have been sequencing RNA isolated from patient’s tumors to evaluate their mutational burden and identify tumor-specific neoantigens. Additionally, we have identified the entire repertoire of tumor-infiltrating lymphocytes in patients with recurrent medulloblastoma. METHODS Total tumor RNA was extracted from resected brain tumor specimens and after we applied in-house bulk RNA-Seq and TCR-Seq techniques using rapid amplification of cDNA ends (RACE) technology with the addition of a common adapter at the 5’ end. RESULTS &amp; CONCLUSIONS Analysis of the 22 tumor tissues revealed that the frequency of non-synonymous mutations varied dramatically more than 10-fold among patients with recurrent medulloblastoma undergoing adoptive cellular therapy (Re-MATCH protocol, FDA IND BB-14058). Patients with shorter overall survival exhibited non-synonymous mutation frequencies between 0.113 and 0.335 mutations per megabase (Mb). Children with prolonged overall survival had higher mutation frequencies, ranging from 0.6 to 1.1 mutations per Mb. These findings highlight the potential of using mutational burden as a biomarker for patient selection and treatment customization, ultimately aiming to improve outcomes in ACT for recurrent medulloblastoma. Up to 2000 unique TCR clones were found among TIL populations in patients who responded well to ACT. Patients with poor outcomes had significantly lower TCR diversity, with only 10-40 unique TCR clones among TILs. The correlation between TCR diversity among TILs and clinical outcomes in pediatric brain tumors underscores the importance of a diverse T cell repertoire for the success of ACT.
CTIM-20. IDENTIFYING CANDIDATE ANTIGEN TARGETS FOR PEDIATRIC BRAIN TUMOR IMMUNOTHERAPIES THROUGH COMPREHENSIVE IMMUNOGENOMIC ANALYSIS
Authors: Changlin Yang, Vrunda Trivedi, Oleg Yegorov, Duane Mitchell
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Identifying tumor rejection antigens continues to be a significant challenge in the development of effective immunotherapies and their application to pediatric brain tumors. METHODS To identify candidate antigen targets for Medulloblastoma (primary MB, n=170; recurrent MB, n=21), Diffuse Intrinsic Pontine Glioma (DIPG, n=10), and Pediatric High-Grade Astrocytoma (HGA, n=12) for adoptive cellular therapy, we conducted a comprehensive immunogenomic analysis of the transcription profiles of the most aggressive pediatric brain tumors and performed in silico antigen prediction across a wide range of antigen classes. IMPORTANCE OF THE STUDY Pediatric brain tumors are heterogeneous diseases, and current standard treatments do not adequately address this variability. Newer and safer patient-specific treatment approaches are needed for high-risk patients who do not respond to standard therapies. Cellular immunotherapy could be crucial for improving survival and reducing morbidity. For an effective immune response against these brain tumors, appropriate tumor antigens must be targeted. While subgroup-specific genetic mutations in medulloblastoma patients have been reported, the immunogenicity of these genetic alterations remains unknown. Using a custom antigen prediction pipeline, we identified potential tumor rejection antigens with significant implications for the development of cellular therapies for MB, DIPG, and HGA. RESULTS Antigen prediction analysis revealed that most patients express few candidate neoantigen targets that pass all filtering criteria. Overall, the proportion of predicted tumor-associated antigens (TAAs) was higher than that of neoantigens and gene fusions for all molecular subtypes, except for SHH, which exhibited a higher neoantigen burden. Notably, cancer-testis antigens and previously unrecognized neurodevelopmental antigens were found to be expressed in most patients across all medulloblastoma subgroups. Although the absolute immune cell content is predicted to be low, immune gene-signature analysis revealed subgroup-specific differences.
NIMG-50. MULTIPARAMETRIC MRI DISTINGUISHES NEURONAL AND IMMUNE SIGNATURES IN INVASIVE HIGH-GRADE GLIOMA RIM THROUGH GRAPH NETWORK ANALYSIS
Authors: Matthew Flick, Victoria Stevens, Christopher Plaisier, Ramon Barajas, Nhan Tran, Kasthuri Kannan, Leland Hu
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Standard of care surgery for high grade glioma (HGG) employs Magnetic Resonance Imaging to identify the contrast enhancing (CE) core for resection, leaving a non-enhancing (NE) invasive rim of tumor which contributes to recurrence. Multi-parametric MRI (mpMRI) has recently been used to map regional biological heterogeneity of neuronal and immune signatures in HGG, and continues to offer a promising strategy for non-invasive surveillance of tumor progression. Here, we present a graph network analysis relating mpMRI to biological signatures in the NE tumor rim and show the utility of communities of imaging features for discriminating tumor phenotypes. METHODS 53 mpMRI features across 101 spatially-localized RNA-sequenced biopsy samples from 64 patients with IDH-wt HGG were represented as nodes within a Neo4j graph network. Modularity optimization was used to identify communities of densely connected nodes. Communities of nodes representing high proportions of NE samples (one-tailed test) were kept for further analysis. Gene set enrichment analysis (GSEA) on samples within selected imaging communities was analyzed for biological process enrichment using clusterProfiler. Single sample GSEA (ssGSEA) using ssGSEA2 was used to annotate neuronal and immune cell states across samples within selected communities. mpMRI feature selection within each community identified the most relevant imaging features for isolating samples classified into neuronal and immune cell states. RESULTS 11 imaging communities gathered a high proportion of NE samples. Three NE communities showed significant enrichment of neuronal signatures, while one showed significant enrichment of immune pathways. One neuronal-predominant community showed unique upregulation of 14 pathways related to neuronal migration/astrocyte projection. CONCLUSION Network imaging communities can identify clusters of NE glioma samples showing contrasting neuronal and immune signatures, including distinct upregulation of migration and projection pathways. Mapping these imaging feature communities to specific biological processes implicated in glioma progression may aid treatment planning and prognostication for glioma patients.
Probiotics in Health Care: A Critical Appraisal
Authors: Eamonn M. Quigley, Fergus Shanahan
Journal: Annual Review of Medicine (2024)

Consumption of probiotic products continues to increase, perhaps driven by an interest in gut health. However, the field is filled with controversy, inconsistencies, misuse of terminology, and poor communication. While the probiotic concept is biologically plausible and in some cases mechanistically well established, extrapolation of preclinical results to humans has seldom been proven in well-conducted clinical trials. With noteworthy exceptions, clinical guidance has often been derived not from large, adequately powered clinical trials but rather from comparisons of disparate, small studies with insufficient power to identify the optimal strain. The separation of probiotics from live biotherapeutic products has brought some clarity from a regulatory perspective, but in both cases, consumers should expect scientific rigor and strong supporting evidence for health claims.
CTNI-34. A RANDOMIZED PROSPECTIVE TRIAL OF POST-OPERATIVE FLUID RESTRICTION TO DECREASE THE INCIDENCE OF DELAYED HYPONATREMIA AND READMISSION AFTER TRANSSPHENOIDAL SURGERY
Authors: Julie Silverstein, Shinghei Mok, Doriann Klaassen, Jenie Hwang, Sydney Blount, Kelley Williams, Brendan Fong, Chongliang Luo, Albert Kim
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Delayed hyponatremia (hypoNa) is the leading cause of readmission following transsphenoidal surgery (TSS). Some institutions have adopted post-operative fluid restriction (FR) protocols based on retrospective studies. We present results of a prospective randomized controlled trial evaluating post-TSS FR. METHODS 300 participants scheduled for TSS (2016-2023) at a single institution were included. Patients with CKD, CHF, AVP deficiency on postoperative day (POD) 3, chronic hypoNa, untreated adrenal insufficiency/hypothyroidism, and those for whom FR was felt unsafe were excluded. Patients were randomly assigned to control (CON, n=94) or moderate FR (FR1, n=39). Participants in CON group were instructed to drink ad lib. Participants in FR1 were FR to 1.8 liters/day (2 liters/day if &amp;gt; 100 kg) from POD3-14. Based on interim analysis suggesting a trend toward reduced hypoNA, FR was changed to strict FR (FR2, n=62) of 1 liter/day (1.2 liters/day if &amp;gt; 100 kg). Serum sodium (Na) was monitored inpatient and on POD 3, 7, 10, and 14, and readmissions evaluated. Fluid intake and thirst were assessed. RESULTS In the intention-to-treat analysis, incidence of hypoNa (Na &amp;lt; 135 mEq/L) was 31.9% CON, 28.2% FR1, and 21% FR2, and severe hypoNa (Na &amp;lt; 125 mEq/L) 7.4% CON, 5.1% n FR1 and 0% FR2. Readmission for hypoNa occurred in 6.4% (n=6) CON, 7.7% (n=3) FR1 and 1.6% (n=1) FR2. Severe hypoNa occurred more frequently in CON vs. FR2 (P=0.04), and nadir Na was higher in FR2 vs. CON (P=0.02). Although thirst scores were similar among groups, an individual’s thirst score correlated with compliance CONCLUSION Results of this randomized study show a reduction in severe hypoNa and readmission for hypoNa in patients on FR from POD3-14 after TSS vs. patients instructed to drink ad lib. This provides strong evidence that post-TSS FR decreases rate of delayed hypoNa and related readmission.
CTIM-02. PIONEERING QUAD-TARGETING CAR T CELL THERAPY IN PEDIATRIC CNS TUMORS – ANALYSIS FROM THE INITIAL PATIENTS TREATED ON THE FIRST-IN-HUMAN PHASE 1 TRIAL BRAINCHILD-04
Authors: Rebecca Ronsley, Kristy Seidel, Prabha Narayanaswamy, Sowmya Pattabhi, Jason Wendler, On Ho, Stephanie Rawlings-Rhea, Juliane Gust, Wenjun Huang, Erin Crotty, Sarah Leary, Daniel Runco, Jason Hauptman, Rebecca Gardner, Julie Park, Colleen Annesley, Michael Jensen, Nicholas Vitanza
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND BrainChild-04 is a first-in-human clinical trial of quad-chimeric antigen receptor (CAR) T cell therapy for children and young adults with central nervous system (CNS) tumors. This trial administers repeated locoregional CAR T cells targeting B7-H3, EGFR, HER2, and IL-13Ralpha2 (“quad-CAR T cells”), leveraging multi-antigen targeting to address the tumor heterogeneity of high-grade CNS tumors. METHODS The primary endpoints are feasibility and safety, and secondary endpoints are disease response and correlative studies of CAR T cell activity. The trial utilized a Bayesian Optimal Interval (BOIN) statistical design with three planned dose regimens(DR). There are 2 arms with weekly delivery for 3 weeks of a 4-week cycle:(A) –diffuse intrinsic pontine glioma (DIPG), (B) –non-pontine diffuse midline glioma (DMG) or other relapsed CNS tumors. RESULTS Enrolled patients include DMG N=6, DIPG N=5, other CNS tumors N=4. Of the 15 enrolled patients, 7 have been infused with 8 awaiting infusions. A total of 33 intracranial CAR T doses have been delivered, including Arm A DR 1 (N=1), Arm B DR 1 (N=3), DR2 (N=3). The most common adverse events have been grade 1-2 fever (7/7 patients), grade 1-3 headache (6/7), and grade 1-2 nausea/vomiting (6/7). There have been no DLTs and no cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity (ICANS). CTCAE and tumor inflammation-associated neurotoxicity are both being captured. All treated patients are alive with median follow up time post-initial infusion of 93(14-198) days. CAR T cells were detected by flow cytometric analysis of CSF post-infusion in 14/24 CSF samples. Radiographic response, CSF circulating tumor DNA, targeted mass spectrometry, and cytokine analysis will be presented. CONCLUSIONS Our preliminary experience suggests tolerability of locoregional delivery of quad-CAR T cells at doses currently evaluated. The trial remains ongoing and these data support continued evaluation of this product to better assess anti-tumor activity in patients with CNS tumors, including DIPG/DMG.