tbuckley/cabot-search huggingface dataset:
NCMP-16. CNS METASTATIC PATTERNS IN BREAST CANCER TREATED WITH CDK4/6 INHIBITORS: PRELIMINARY RESULTS OF A RETROSPECTIVE ANALYSIS
Authors: Danielle A Bazer, Justus Reiss, Mohamed Sherief, Yuan Zhou, Daniel Heinemann Martinez, Amy Parampil, Jordina Rincon Torroella, Antonio C Wolff, Rima Couzi, Vered Stearns, Mary Wilkinson, Danijela Jelovac, Jessica Tao, Jenni Sheng, Jenna V Canzoniero, Cesar Santa-Maria, David O Kamson, Solmaz Sahebjam
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND CDK4/6 inhibitors combined with hormonal therapy or as monotherapy (abemaciclib) play an important role in the management of hormone receptor positive, HER-2 negative breast cancer (BC). To date, these drugs were shown to improve progression-free survival, whereas their comparative effect modulating breast cancer central nervous system metastases (CNSm) has not yet been extensively studied. Here, we present the early findings and analytic plan of our retrospective study to evaluate CNSm patterns and differences among CDK4/6-inhibitors in BC. METHODS In this retrospective chart review study, we queried the Johns Hopkins Electronic Medical Record from 1/1/2014 to 4/25/2024 using the following prescreening criteria: 1) Age ≥18 years; 2) Diagnosis and/or problem list including BC; 3) Palbociclib, abemaciclib, or ribociclib included in the medication list. The identified patients were dichotomized based on the presence/absence of ICD10 codes for CNSm and are currently being chart-reviewed. Patients without longitudinal data or confirmed CNS or with CNSm diagnosed before/within 1 month of CDK-inhibitor initiation were excluded. Population: Prescreening identified 1,419 patients (1,055 palbociclib, 301 abemaciclib, 145 ribociclib) of whom 239, 36, and 19 patients had ICD10 codes for brain metastases, respectively. After exclusion of false positives from this cohort, we confirmed 53 patients with CNSm in the palbociclib, 3 in the ribociclib, and 1 in the abemaciclib group. RESULTS We present the current data from the first-line palbociclib cohort (N=53) where, median time to CNSm on was 24 months (interquartile range 13-46). Fifty-two (98.1%) patients had documented bone, 31 (58.5%) dural, 7 (13.2%) leptomeningeal, and 33 (62.3%) calvarial involvement. Dural and calvarial metastases were strongly associated with each other (pearson-chi2=10.7; p=0.001). CONCLUSIONS This is a work-in-progress, with early preliminary findings showing a high rate of dural and calvarial metastases in this cohort. A more detailed review of the dataset that will also include the CNS-metastasis-free cohort is underway.
CSIG-18. YAP/TAZ TARGET GENES MAY DETERMINE THE SELF-RENEWAL AND SURVIVAL OF GLIOBLASTOMA STEM CELLS
Authors: Mohamed Ishan, Se-Yeong Oh, Elizabeth Young, Zhengang Hu, Renee D Read
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma, a neoplasm arising from neuro-glial stem/progenitor cells, is the most aggressive and lethal form of brain cancer, with a median survival of 14 months. Despite intensive treatments like surgery, radiation, and chemotherapy, recurrence is inevitable, underscoring the urgent need for new treatment strategies. Progress is limited by an incomplete understanding of the biological mechanisms that drive glioblastoma formation and progression, hindering the development of effective therapies. Key molecular pathways, particularly the receptor tyrosine kinases, such as EGFR, and their effector pathways play a critical role in the initiation and maintenance of glioblastoma. Our lab’s research using patient-derived glioblastoma neurospheres and mouse models has shown that the transcriptional co-activators YAP and TAZ are overexpressed downstream of EGFR activity in EGFR-amplified or mutant glioblastoma tumors. YAP/TAZ proteins interact with the TEAD family DNA-binding proteins to promote expression of transcriptional target genes, including SOX2, C-MYC, and EGFR itself in glioblastoma, creating a positive feedback loop that enhances tumor stem cell renewal, proliferation, and survival. Furthermore, our research has demonstrated that inhibiting YAP/TAZ activity with the drug Verteporfin induces apoptosis and promotes growth arrest in patient-derived EGFR-amplified/mutant glioblastoma models. Our findings highlight YAP/TAZ-TEAD as key mediators of glioblastoma stem cell (GSC) self-renewal and survival. Ongoing experiments aim to identify tumor cell-specific YAP/TAZ-TEAD transcriptional target genes predictive of response to YAP/TAZ inhibition in GSCs within EGFR-amplified glioblastomas. Our research seeks to uncover the epigenetic basis of YAP/TAZ dependencies and to determine which genes and cellular processes are critical for tumor stem cell survival, tumor progression, and sensitivity to YAP/TAZ inhibition. These target genes could serve as biomarkers for predicting therapeutic response to YAP/TAZ inhibitors in glioblastoma.
CTNI-78. PNOC008: A PILOT TRIAL TESTING THE CLINICAL BENEFIT OF USING MOLECULAR PROFILING TO DETERMINE AN INDIVIDUALIZED TREATMENT PLAN IN CHILDREN AND YOUNG ADULTS WITH NEWLY DIAGNOSED HIGH-GRADE GLIOMA (EXCLUDING DIFFUSE INTRINSIC PONTINE GLIOMA)
Authors: Lindsay Kilburn, Andrea Franson, Tab Cooney, Cassie Kline, Schuyler Stoller, Alyssa Reddy, Anu Banerjee, Roger Packer, Anne Bendel, Maggie Skrypek, Jane Minturn, Mohamed Abdelbaki, Nicholas Whipple, Priya Chan, John Crawford, Erin Crotty, Angela Waanders, Jennifer Elster, Eric Raabe, Elizabeth George, Soniya Pinto, Nucharin Supakul, Adam Kraya, Michael Prados, Javad Nazarian, David Solomon, Janel Long-Boyle, Annette Molinaro, Sebastian Waszak, Sabine Mueller
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Despite multiple clinical trials in young patients with newly diagnosed high grade gliomas (HGG), survival remains poor. PNOC008 is a single-arm, multi-center pilot trial, investigating the feasibility, toxicity, and efficacy of a molecularly guided individualized treatment approach following radiotherapy. METHODS Patients aged ≤21 years with newly diagnosed, localized, hemispheric HGG (Stratum A) or non DIPG, diffuse midline glioma (DMG) (Stratum B) were eligible. Comprehensive molecular profiling (targeted gene panel, whole exome, and whole transcriptome sequencing) was performed on primary tumor tissue. The molecular data was reviewed by a dedicated tumor board that recommended an individualized treatment plan combining up to four FDA approved drugs. Patients were followed for toxicity and efficacy. Circulating tumor DNA (ctDNA), imaging, and quality of life (QOL) measures were collected at multiple timepoints. RESULTS Fifty-five HGG patients enrolled between 2018 and 2023 (median age 11 years [range 2-20], n=31 female, n=29 Stratum A), including H3K27-altered (n=17), H3/IDH-wildtype diffuse pediatric-type (n=16), and H3G34-mutant diffuse hemispheric glioma (n=12). In 44 patients that followed the recommended treatment, median overall survival (OS) from time of study enrollment was 26.5 months in Stratum A (lower 95% CI: 18.5) and 23.6 months in Stratum B (lower 95% CI: 16.8), and 30 months in H3G34-mutant patients (n=10, lower 95% CI:24.6) with median follow-up of 34.5 months for all patients (lower 95% CI: 32.2). The treatment recommendations most commonly included alkylator with targeted therapy combinations. The often novel drug combinations were generally well tolerated with grade 3 or 4 treatment-related adverse events being mostly hematologic. Central imaging, ctDNA, and QOL analyses are underway. CONCLUSIONS A personalized treatment approach using comprehensive transcriptomic and genomic analysis is feasible and well tolerated with encouraging survival data in children and young adults with HGG. Further analyses of molecular subgroups and correlatives are ongoing.
CTNI-79. ASSESSING SYSTEMIC AND LOCAL LEVELS OF LIDOCAINE DURING SURGERY FOR GLIOBLASTOMA
Authors: Robert Riestenberg, Amir Goodarzi, Dylan Goodrich, Shuai Chen, Yichu Chen, Nina Schloemerkemper, Mirna Lechpammer, Orin Bloch, Kiarash Shahlaie
Journal: Neuro-Oncology (2024)

Abstract The objective of this study is to assess the pharmacokinetics of lidocaine penetration into tumor tissue during glioblastoma surgery. In-vitro studies of glioblastoma have demonstrated co-culture with lidocaine inhibits glioblastoma proliferation via inhibition of TRPM7 channels. TRPM7 is a transmembrane ion channel that modulates proliferation and migration in several human cancers. Scalp block with lidocaine during glioblastoma surgery has been associated with improved survival in human studies. Twelve patients were enrolled in this study. The study group received an intravenous bolus dose of 1.5 mg/kg IBW of lidocaine at induction of anesthesia followed by 2 mg/kg IBW/hr infusion of lidocaine. Craniotomy was performed in the standard fashion. A total of 3 fresh tumor specimens were collected hourly from each patient after confirmation of glioblastoma diagnosis by frozen section. Plasma samples were simultaneously collected for analysis. Lidocaine concentration was measured using mass spectroscopy. The maximum concentration of lidocaine (Cmax), time from bolus to maximum concentration (Tmax), and area under curve from 0-3 hours (AUC) were calculated for each patient. Patients were followed for survival and adverse events. The median tumor specimen Cmax, Tmax, and AUC values were 333 ng/dL (range 226-555), 179 min (range 126-211), and 20665 ng*min/dL (range 8003-55,426), respectively. Peak lidocaine concentration was reached in 6 of 12 cases. Median Cmax and Tmax for plasma samples were 1195 ng/dL (range 951-1475) and 191 min (range 156-211), respectively. Median overall survival was 308 days (range 74-413). Two grade 3 adverse events occurred which were deemed to be unlikely to be related to the study intervention. In conclusion, lidocaine infiltrates tumor tissue when administered intravenously during glioblastoma surgery. Concentrations do not reach levels previously demonstrated to inhibit tumor growth in in vitro studies (roughly 2*108 ng/dL lidocaine). Alternative mechanisms may explain previously observed improved outcomes with lidocaine administration in human studies.
CNSC-33. GROUP3 MEDULLOBLASTOMA WITH BONE MARROW AND ABDOMINAL CAVITY METASTASIS:A CASE REPORT
Authors: Shaoqun Li, Lian Chen, Haojing Kang, Minting Ye, Mingyao Lai, Linbo Cai
Journal: Neuro-Oncology (2024)

Abstract Medulloblastoma is an infratentorial primitive neuro-ectodermal tumour, which is commonly occurring in childhood. It often spreads through the cerebrospinal fluid pathways with a very low rate of systemic metastases. Extra-central nervous system metastases have a poor prognosis in medulloblastoma. Here, we reported a case of Group3 medulloblastoma with bone marrow and abdominal cavity metastasis. A 10-year-old girl complained of headache, dizziness, vomiting and nausea. Magnetic resonance imaging(MRI) of the brain showed a large mass in the fourth ventricle and obstructive hydrocephalus. The surgery was performed to remove the mass and ventriculoabdominnal shunt was performed for obstructive hydrocephalus. Histological verification was proven classic medulloblastoma and next-generation sequencing confirmed molecular group of Gruop3 with MYC amplication. Radiotherapy was subsequently performed one month after the surgery. During the radiotherapy, brain MRI showed metastasis on the surface of the brain, which confer a poor prognosis. After the radiotherapy According to the therapeutic schedule, She would accept chemotherapy one month after the radiotherapy. But She suffered severe bone marrow suppression manifested as anaemia and thrombocytopenia, which can not be improved by medication and blood transfusion. A bone marrow aspiration was subsequently performed, and bone marrow smear showed large numbers of tumor cells at high magnification and was lack of normal hematopoietic cells. The girl was deteriorating rapidly with jaundice, ascites, hepatosplenomegaly and pancreatitis after the bone marrow aspiration. We found a lot of tumor cells in the bleeding tendency ascites and finally confirmed bone marrow and abdominal cavity metastasis concurrently. Eventually, She died less than a month after the metastasis and the overall survival was only 6 months. This typical case demonstrated severe bone marrow suppression of unknown origin should caused alarm and be performed bone marrow aspiration as soon as possible. The prognosis of medulloblastoma with extra-central nervous system metastases is poor and people may die in months.
RADT-30. MANAGEMENT OF PRESUMED PSEUDOPROGRESSION WITH EARLY BEVACIZUMAB IN THE THREE MONTHS AFTER HIGH DOSE RADIATION THERAPY FOR GLIOBLASTOMA
Authors: Michael Back, Benjamin Challis, Patrick Horsley, Marina Kastelan, Nicola Cove, Yim Jackie, James Drummond, Matthew Wong, Adrian Lee, Helen Wheeler
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Optimal management for symptomatic steroid-refractory pseudoprogression (rPsP) following IMRT for Glioblastoma remains poorly defined. This study examined radiological volumetric response and clinical outcomes following use of early Bevacizumab (earlyBEV), defined as commencing during or within 3 months of IMRT. METHODS Consecutive patients managed with Stupp60Gy IMRT between 2016-2023 for Glioblastoma were analysed for those patients receiving earlyBEV for rPsP. Volumetric analysis was performed with sequential MRI T1gd/T2 sequences using preBEV and postBEV scans. Primary endpoint was volumetric reduction of T1gd/T2 volumes at month+2/3 postBEV. Clinical response, overall survival and pattern of relapse, specifically distant failure was assessed. RESULTS Forty-one (14%) of 289 patients received earlyBEV for rPsP, with median follow-up of 9.9months (q1-3:8-25) for survivors. Compared to remaining 248 patient cohort, earlyBEV had worse initial ECOG0,1 (50%vs76%); less near-total resection (5%vs42%); and less MGMT methylation (35%vs46%). Additionally at diagnosis the initial tumours had larger T1gd and T2 volumes. Median time to commencement of earlyBEV was 1.4months postIMRT; including seven patients during IMRT. All patients responded to BEV, with reduction in symptoms, steroid use and radiological volume, though one died pre-assessment. Median T1gd and T2 volumes before earlyBEV were 37cm3 (q1-3:23-63cm3) and 116cm3 (q1-3:90-148cm3) respectively, which were 95% and 78% larger than at diagnosis. Median survival postBEV was 8.1months (95%CI:7.5-8.6). Median volumes postBEV reduced to 16cm3 (q1-3:8-23cm3) and 41cm3 (29-55cm3); which was a percentage reduction for T1gd and T2 of 57% and 65%. Midline shift reduced from 5mm(q1-3:3-8mm) to zero in two-thirds of patients. Patients requiring earlyBEV had worse survival compared to remaining cohort (p&amp;lt;0.001); with median OS 11.9months (95%CI:10.4-13.5) vs 19.9months (95%CI:18.4-21.5). A component of distant relapse was evident in 48% of earlyBEV vs 34% in remaining cohort. One serious adverse event occurred with fatal intracranial haemorrhage day10 after initial BEV dose. CONCLUSION This study data confirms efficacy of earlyBEV for managing steroid-refractory pseudoprogression, but also the worse prognosis of this high-risk cohort.
EPCO-58. INTEGRATIVE PROTEOGENOMIC ANALYSES REVEAL INSIGHTS INTO SUBTYPE-SPECIFIC GLIOMA RISK
Authors: Taishi Nakase, Karl Smith-Byrne, Clinton L Cario, Quinn T Ostrom, Geno A Guerra, Beatrice S Melin, Matilda Rentoft, Margaret Wrensch, John K Wiencke, Robert B Jenkins, Jeanette E Eckel-Passow, Melissa L Bondy, Stephen S Francis, Linda Kachuri
Journal: Neuro-Oncology (2024)

Abstract Gliomas are heterogeneous brain tumors with prognostically-significant subtypes and few risk factors. IDH-wildtype glioblastoma, the most common subtype, carries a dismal prognosis. Using the largest GWAS dataset with histological (11,304 cases, 304,523 controls) and molecular (3,418 cases, 8,156 controls) subtypes, we analyzed the plasma and brain proteome to uncover proteins associated with glioma susceptibility. Using protein quantitative trait loci (pQTL) for 1,776 proteins in brain tissue, we identified 21 candidate proteins, including 9 associations with high probability (&amp;gt;70%) of colocalization (shared causal genetic variants for glioma risk and protein abundance). We confirmed known risk genes such as EGFR (p=1.9×10-35) and D2HGDH (p=1.1×10-5). We also identified novel risk proteins, including ENPP6, a choline phosphodiesterase overexpressed in glioma, for IDH-wildtype glioblastoma (OR=0.62, p=7.6×10-5), and galectin-3, a lectin encoded by a tumor fitness gene in CRISPR screens of glioma proliferation and a clinical drug target, for glioma overall (OR=1.37, p=1.3×10-5). Analyses of the plasma proteome using pQTLs for 1,362 proteins from 3 cohorts (N=88,838) identified 9 colocalized associations in whole blood. Most risk signals were subtype-specific, such as CRELD1 (p=2.5×10-5) for triple-negative glioblastoma. We found three candidate risk proteins for IDH-mutant 1p19q-intact glioma: immunoglobulin glycoprotein BCAM (p=9.6×10-8), neurotrophin receptor SorCS2 (p=3.6×10-5) and immune checkpoint PD-1 (p=1.1×10-5). Interestingly, genetically-predicted PD-1 levels had a larger effect on IDH-mutant 1p19q-intact (OR=2.75, 95% CI=1.61-4.69) than IDH-wildtype (OR=0.73, 95% CI=0.51-1.05) tumors, suggesting germline differences in immune checkpoint mechanisms among subtypes. For all colocalized candidates, genetically-predicted protein abundance was correlated with cis-regulated transcriptional activity in brain tissue. For example, genetically-predicted SORCS2 gene expression in brain tissue was associated with plasma SorCS2 levels (Z=16.1, p=1.1×10-68). Our analysis identified candidate proteins involved in immune response and neuronal proliferation, which may enable prioritization of drug targets and provide insight into disease mechanisms for glioma.
ANGI-01. EXTRANEURAL METASTATIC EPENDYMOMA: DISTANT METASTASIS TO THE PLEURA, LUNGS, LYMPH NODES, AND BONE
Authors: Mina Guirguis, Zhixin Jiang, Chunyu Cai, Michael Youssef
Journal: Neuro-Oncology (2024)

Abstract Ependymomas are neuroepithelial tumors arising from ependymal cells surrounding the cerebral ventricles that account for 1.6-1.8% of primary CNS tumors. They rarely metastasize to extraneural structures, with one study reporting an incidence of 6.2% with a mean time from diagnosis to extraneural metastasis of 75.6 months. This spread, when it does occur, has been reported to occur to the lungs, lymph nodes, liver, and bone. We describe the case of a patient with recurrent WHO Grade III ependymoma, ZFTA::RELA fusion positive, with extraneural metastatic disease to the thoracic spine, lungs, and pelvic bones. He was treated with multiple surgical resections, radiation therapy, and salvage chemotherapy for his extraneural metastasis to the lungs, bone, pleural space, and lymph nodes. His functional and respiratory statuses declined until he ultimately developed pneumonia, status epilepticus, then spontaneous respiratory arrest, which resulted in his passing away. Salvage chemotherapy for ependymoma has unclear mortality benefit and more research must be done to determine how best to treat patients with extraneural metastases, particularly those who fail traditional treatment with resection and radiation therapy.
EPID-33. EPITHELOID SARCOMA IN A LONG-TERM SURVIVOR OF AN ATYPICAL TERATOID / RHABDOID TUMOR WITH RHABDOID TUMOR PREDISPOSITION SYNDROME
Authors: Magimairajan Issai Vanan, Meziane Brizini, Anna Shawyer, Courtney Wilkes, Suyin Lum Min, Camelia Stefanovici, Sate Hamza, Tina Drimes, Catherine Bourne, Patrick McDonald
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Rhabdoid tumor predisposition syndrome (RTPS) predisposes to a high risk of developing Rhabdoid tumors in Brain, kidney; and is defined by a germline mutation in SMARCB1 (rarely SMARCA4) gene. The most frequent pediatric tumor associated with RTPS is atypical teratoid/rhabdoid tumor (ATRT), commonly diagnosed in children &amp;lt; 3 years of age. Epitheloid Sarcoma (ES) is a rare soft tissue sarcoma, arising in any age group and histologically defined by loss of SMARCB1 in tumor cells. METHODS We describe a long- term survivor of ATRT with RTPS presenting 12 years later with ES. Data was collected from medical chart review. RESULTS Our patient was diagnosed with ATRT and RTPS (SMARCB1) at 6 months of age and treated with chemotherapy as per ACNS0333 at diagnosis; by chemotherapy / focal radiation at first relapse and with alisertib on second relapse. At 10yrs of age she presented with multiple firm, skin-colored dermal nodules in both her hands (palms and fingers). She was diagnosed to have palmar warts and treated with topical cantharidin with a waxing and waning course. Subsequently the hand lesions were diagnosed as granuloma annulare and followed up with no therapy. At 12 years of age, lesion in tip of the right thumb increased in size and a punch biopsy was done which revealed ES with IHC showing loss of SMARCB1 in tumor cells. Staging CT of the chest showed multiple bilateral (b/l) small (&amp;lt;1cm) axillary lymph nodes with a negative PET scan. Bilateral axillary lymph node biopsies were negative for ES. She underwent excision of all the hand lesions with negative margins with no further therapy. CONCLUSION Based on our case and single case report in literature, we hypothesize that ES is likely a primary malignancy of RTPS and should be included in the spectrum of malignancies of RTPS.
CSIG-19. IDENTIFICATION AND TARGETING OF TUMOR DRIVER SCHWANN(NF2LOSS) CELLS IN SPORADIC AND NF2-RELATED VESTIBULAR SCHWANNOMAS
Authors: Maxwell Laws, David Asuzu, Ihika Rampalli, Dustin Mullaney, Liyam Laraba, Debjani Mandel, Xiyuan Zhang, Abdel Elkahloun, Bayu Sisay, Dragan Maric, Kory Johnson, Zied Abdullaev, Kenneth Aldape, John Shern, David Parkinson, Prashant Chittiboina
Journal: Neuro-Oncology (2024)

Abstract Vestibular schwannomas (VS) arise from myelinating Schwann cells of CN VIII and are associated with severe morbidity due to local tumor growth. Sporadic and neurofibromatosis type 2 (NF2) associated VS are both characterized by NF2 (merlin) loss but the mechanisms remain unexplored. Using a multiomic approach, we dissected the role of NF2 loss in VS tumor formation and proliferation. We obtained surgical samples from 15 patients undergoing surgery for VS (sporadic, n=4; NF2, n=9), and performed single-cell or single-nucleus RNA sequencing (scRNAseq, n=4; snRNAseq, n=15), transposase-accessible chromatin (snATAC-seq, n=9), whole exome (n=12), and bulk DNA methylation assays (n=15). Transcription factor binding was assayed with ChIPseq. We validated our key findings with immunoblot, ELISA, RNAscope (n=8), and multiplex immunocytochemistry (mIHC; n=8). NF2fl/fl;Periostin-Cre+mice versus their Cre- control littermates treated with novel inhibitors of TEAD auto-palmitoylation (VTs). We mapped the VS transciptome and identified canonical Schwann cells, macrophages, T-cells and endothelial cells. Using the cells that had Chr22 loss (second hit deletions at the NF2 locus), we generated a NF2loss gene signature. We then identified Schwann(NF2loss) cells in all tumors, and found these enriched for YAP1/TAZ-TEAD, NRG1, and HIF-1α signaling pathways. Schwann(NF2loss) cells showed increased TEAD1 expression and chromatin accessibility for TEAD family transcription factor motifs. TEAD1 binding was observed at promoters of genes including VEGFA, EGFR, with strong enrichment for mitogenic pathways. We also found that VEFGA expression was restricted to Schwann(NF2loss) cells, and confirmed this with RNAscope and mIHC. Schwann(NF2loss) cells were key regulators of macrophages (M2-subtype, tissue resident) through M-CSF/IL-34 signaling. NF2fl/fl;Periostin-Cre+ mice showed increased VEGFA expression, and that was reversible by TEAD inhibition in-vivo with VTs. We report that Schwann(NF2loss) cells are key tumor drivers in VS. These cells are highly proliferative (YAP/TAZ-TEAD axis), drive angiogenesis (VEGFA expression), and promote tumor mass accretion (macrophage influx via M-CSF/IL-34 pathway) that can all be targeted via TEAD inhibition.