tbuckley/cabot-search huggingface dataset:
INNV-24. CONGENITAL EMBRYONAL TUMOR WITH MULTILAYERED ROSETTES AND TREATMENT IN A NEWBORN
Authors: Jessica Casey, Sarina Raman, Joseph Lasky, Sumit Gupta
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Embryonal Tumor with Multilayered Rosettes (ETMR) is a rare but deadly pediatric brain tumor with no standard of care treatment. We present a unique case of congenital ETMR and treatment strategy using intrathecal topotecan and no radiation therapy. Case report: A term baby was admitted to NICU at 12 hours of life with respiratory arrest requiring intubation. CT of the brain revealed a 4.2x3.9x3.5cm left posterior fossa hyperdense hemorrhagic mass with moderate hydrocephalus. She underwent posterior fossa craniotomy for biopsy and evacuation at two days of life. Pathology was consistent with an ETMR. MRI brain after first resection was not concerning. She underwent re-resection at 3 months of age due to re-growth (2x3x3cm). She was then treated as per Head Start 4 chemotherapy regimen with vincristine, cisplatin, etoposide, cyclophosphamide, and methotrexate, followed by consolidation with three tandem auto-hemopoietic stem cell transplants (HSCT) with carboplatin and thiotepa conditioning. Maintenance treatment consisted of intrathecal topotecan every four weeks (0.2mg per dose &amp;lt;1 year old, 0.25mg per dose when ≥1 year old) for 12 doses. She also received oral vorinostat (100mg PO QD) and isotretinoin (80mg/m2 divided BID) during maintenance for 1 year. No radiation was given. The treatment course was complicated by mucositis, febrile neutropenia, pseudomonas sepsis and an episode of respiratory arrest secondary to choking from epistaxis. The patient is currently doing well and continues to remain in remission for over seven months after end of treatment. CONCLUSION We present a case of congenital ETMR with a unique treatment option and strategy using Head Start 4 therapy with three tandem auto-HSCT as consolidation, followed by 12 months of maintenance therapy with intrathecal topotecan, oral vorinostat, and isotretinoin, without any radiation, leading to sustained remission.
BIOM-31. MOLECULAR ANALYSIS OF RESECTED BREAST CANCER BRAIN METASTASES REVEALS CEREBELLAR LOCATION AND TRIPLE NEGATIVE SUBTYPE ARE NEGATIVE PROGNOSTIC FACTORS
Authors: Laura Huppert, Mia Salans, Kelsey Kuwahara, Maggie Zhou, Lauren Boreta, Steve Braunstein, Michelle Melisko, Manish Aghi, Ramin Morshed, Harish Vasudevan
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Brain metastases (BMs) are a significant cause of morbidity and mortality in metastatic breast cancer (MBC), yet prognostic and predictive biomarkers remain poorly understood. STUDY DESIGN 90 consecutive patients with breast cancer BMs who underwent surgical resection from 2006-2022 were retrospectively identified. Review of the electronic medical record and institutional cancer registry were completed to identify baseline clinical parameters and outcomes. BM mutation analysis was performed using a CLIA-certified targeted DNA mutation sequencing assay as part of routine clinical care. RESULTS All patients were female, median age at first BM resection was 57.9 years (range 27.0-81.3 years), and receptor subtypes included HR+/HER2- (n=27, 30.0%), HER2+ (n=33, 36.7%), and triple negative BC (TNBC; n=30, 33.3%). At time of first BM resection, most patients had a solitary BM (n=55, 61.1%), with anatomic locations including cerebellar (n=29, 32.2%), frontal (n=26, 28.9%), and parietal (n=17, 18.9%) sites. BM DNA mutation analysis (n= 20) revealed pathogenic alterations in TP53 (n=17, 85.0%), ERBB2 amplification (n=7, 35.0%), PIK3CA (n=4, 20.0%), BRCA1 (n=3, 15.0%), and BRCA2 (n=2, 10.0%). Most patients received postoperative radiation (n=82, 90.8%) and/or systemic therapy (n=67, 82.7%). Cerebellar location was significantly associated with the risk of developing leptomeningeal disease compared to other BM resection sites (HR = 2.75, p=0.02). Among all patients, median overall survival (OS) from first BM resection was 27.8 months (range 0.1-196.6 months). HR+/HER2- (median 37 months) or HER2+ (median 36 months) MBC was associated with significantly increased OS compared to TNBC (14.4 months) (p&amp;lt;0.01, log-rank test). CONCLUSIONS Patients with breast cancer BMs exhibited a median OS of &amp;gt;2 years following BM resection, and patients with TNBC had a significantly worse prognosis. Targetable mutations were observed in 40% of resected BM specimens, supporting the utility of molecular analysis of resected BMs to help guide clinical management.
RADT-39. CENTRAL NERVOUS SYSTEM BRIDGING RADIOTHERAPY (CNS-BRT) ACHIEVES RAPID CYTOREDUCTION PRIOR TO CAR T-CELL THERAPY FOR AGGRESSIVE B-CELL LYMPHOMAS
Authors: Gustav Cederquist, Javin Schefflein, Sean Devlin, Gunjan Shah, Roni Shouval, Harper Hubbeling, Kathryn Tringale, Beatrice Fregonese, Carla Hajj, Alexander Boardman, Parastoo Dahi, Richard Lin, Paola Ghione, Gilles Salles, Miguel-Angel Perales, M Lia Palomba, Lorenzo Falchi, Michael Scordo, Christian Grommes, Joachim Yahalom, Brandon Imber
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND CAR T-cell therapy (CART) for central nervous system lymphoma (CNSL) is a promising strategy, yet responses are frequently not durable. Bridging radiotherapy (BRT) is used for extra-cranial lymphoma to improve CART outcomes through cytoreduction of high-risk lesions. We hypothesized that CNS-BRT would achieve similar, significant cytoreduction prior to CART for CNSL. METHODS We analyzed CNSL patients with non-Hodgkin B-cell lymphomas who received CNS-BRT prior to commercial CART. Best CNS response post-CART was evaluated using the International Primary CNS Lymphoma Collaborative Group (IPCG) or RANO for parenchymal or leptomeningeal lesions, respectively. Cytoreduction from CNS-BRT was calculated as change in lesion size prior to CART. RESULTS Twelve patients received CNS-BRT, with median follow up of 11.8m (IQR: 8.5–21.9). Ten had CNSL (9 secondary, 1 primary) and 2 patients had epidural disease (evaluable for toxicity). All ten CNSL patients had progressive disease at the time of CNS-BRT. RT targets included whole brain (n=3), involved site (partial) brain (n=4), involved site spine (n=4), and orbits (n=1) with median dose 24Gy (range: 15-33). 1/12 patients experienced grade ≥3 cytokine release syndrome (CRS), and 3/12 patients experienced grade ≥3 immune effector cell-associated neurotoxicity syndrome (ICANS). CNS-BRT achieved a 74.0% (95%CI: 62.0–86.0) mean reduction in lesion size from baseline (p=0.014) at a median of only 12d from BRT completion and pre-CART infusion. Best CNS response included 8 complete responses (CR), 1 partial response (PR), and 1 progressive disease (PD). Three patients experienced CNS relapse outside the BRT field for a 12-month estimated risk of CNS progression post-CART of 20.0% (95%CI: 3–49). CONCLUSIONS Early data suggest CNS-BRT achieves rapid cytoreduction and favorable CNS response. The rates of severe CRS/ICANS were similar to comparison series of CNSL patients treated with CART without BRT suggesting an acceptable safety profile. Our data support further study of BRT as a bridging strategy for CNSL-directed CART.
BIOS-01. MACHINE LEARNING-BASED PREDICTION OF INPATIENT CARE COSTS FOR PATIENTS WITH BRAIN METASTASES: A REAL-WORLD ANALYSIS
Authors: Ahmad Ozair, Chixiang Chen, Graeme Woodworth, Debraj Mukherjee
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Brain metastases (BMs) are increasingly a cause of significant cancer-related morbidity, mortality, and economic burden. While BM-related healthcare costs have been previously described, predictive analytics based on contemporary cohorts, particularly for inpatient care, remain unavailable. This study sought to evaluate inpatient care costs (IPCC) and associated reimbursements for patients with BMs and perform predictive modeling through supervised machine learning (sML) using a contemporary, commercial US claims database. METHODS This retrospective study, reported following STROBE and TRIPOD+AI reporting guidelines, included adult patients (aged 18-65 years) in the United States (US) with BMs included in the MarketScan Commercial Claims and Encounters Database who received inpatient care during January 2016 to December 2021. Eligible patients were identified using ICD-10 codes. IPCC measures were adjusted using the Medical Care component of the 2023 Consumer Price Index. The primary study outcome was total IPCC, represented by adjusted gross total payments. After log-transformation performed due to data skew, sML was carried out using Random Forest algorithm with 1000 iterations with a 70:30 training-test data split, followed by residual analysis and evaluation of predictive performance using root-mean-squared error (RMSE), out-of-bag error (OOBE), and calibration curve. Multivariable linear regression was carried out for sensitivity analyses. RESULTS A total of 25117 unique inpatient admissions across 13477 BM patients were included, with median (IQR) age of 57 years (51-61). Gross median (IQR) CPI-medical-care-adjusted values per admission were: total payments $28,119.51 (16847.45-55111.67); hospital payments $24,678.74 (14601.66-47864.84); and payments to principal physician $884.80 (441.07-2434.15), being 3.6% (IQR 1.9-6.8) of total payment. Median inpatient length of stay was 4 days (IQR 2-8). ML model had an OOBE of 0.61 and, using test data, RMSE of 0.85, indicating robust performance. No major deviations were found on residual analysis. CONCLUSIONS Contemporary IPCCs for BM patients in US are substantial but driven minimally by payments to principal physician. sML may be utilized to successfully predict IPCC for BM patients.
RADT-28. THE ROLE OF CRANIAL RE-IRRADIATION IN EGFR MUTANT LUNG CANCER PATIENTS WITH BRAIN METASTASES
Authors: Raymond Luke, Hani Ashamalla, Kathryn Beal, Jonathan Knisely, Jonathan Lee, Christine Garcia, Bahaa Mokhtar, Anthony Panariti, Silvia Formenti
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Re-irradiation with stereotactic radiosurgery (SRS) or whole-brain radiotherapy (WBRT) may be used for treating recurrent brain metastases. Here, we are reporting on the rate of cranial re-irradiation based on our institutional experience in patients with mutated Epidermal Growth Factor Receptor Non-Small Cell Lung Cancer (mEGFR-NSCLC). METHODS This is a retrospective review of patients from three NYP-WCM hospitals with brain metastases treated with radiotherapy and Tyrosine Kinase Inhibitors (TKIs) from December 2012 to May 2023. RESULTS Ninety-eight patients (60.5%) out of 162 with brain metastases from mEGFR-NSCLC were treated with radiation. Twenty-seven patients (27.5%) were treated with WBRT. Among 71 patients treated with SRS, 10 (14.1%) patients underwent surgical resection of the dominant brain lesion followed by fractioned SRS (FSRS) to the surgical bed. Sixty-one (85.9%) patients received SRS for intact brain lesions ranging from single fraction 16-20Gy to FSRT with 24Gy –30Gy in 3-5 fractions based on the size and eloquence of the brain site of the brain metastasis. In the SRS group, fifteen (21.1%) patients required at least one more course of cranial irradiation. The mean duration of local intracranial control between the first and the second course of radiation was 19.6 months [range from 2.0- 56.7 months], while from the start of TKI to the first intracranial failure was 11.3 months [0.8m-45.3 months]. In the WBRT group, two patients (7.4%) were treated with another course of WBRT 20Gy in 5 fractions. These two patients started TKI simultaneously with their first course of WBRT; the mean duration of intracranial local control was 12.8 months [range from 11.6-14.1 months]. Both patients suffered significant cognitive declines. CONCLUSION In the Tyrosine Kinase Inhibitor era, patients with brain metastases from mEGFR-NSCLC have protracted progression-free survival. Multiple courses of cranial re-irradiation may be needed. Stereotactic radiotherapy should be preferred for the best results in preserving cognitive functions.
CNSC-22. GLIOBLASTOMA CELLS EXHIBIT NEURON-LIKE EXCITABILITY IN BOTH ACUTE AND ORGANOTYPIC HUMAN BRAIN SLICES
Authors: Tong Tong, Kirstine Juul Elbæk, Jens Eschen, Attila Ozsvar, Søren Ole Stigaard Cortnum, Ann Kathrine Sindby, Bjarne Winther Kristensen, Kaare Meier, Nikola Mikic, Jens Christian Hedemann Sørensen, Marco Capogna, Jonathan Ting, Wen-Hsien Hou, Anders Rosendal Korshøj
Journal: Neuro-Oncology (2024)

Abstract Glioblastomas (GBM) are known for their significant intratumor heterogeneity, featuring a variety of plastic cell types that make effective treatment challenging. Recent studies have shown that neuronal-progenitor-like transcriptomic cell states at the leading edge of the tumor receive synaptic input from nearby neurons, which drives disease proliferation. However, the excitability of GBM cells remains controversial, with observations ranging from non-excitable to neuron-like excitability, complicating our understanding of their pathophysiology. In this study, we developed a novel experimental approach to study glioblastoma cells in both acute and cultured brain slices infiltrated with cancer from GBM patients. Using an adeno-associated virus for gene delivery, we selectively expressed fluorescent proteins in specific cell types. Fluorescence-guided whole-cell patch-clamp recordings were then used to analyze the electrophysiological properties of GBM cells and neurons within the tumor microenvironment. Our findings show that GBM cells have distinct electrophysiological properties, including a depolarized resting membrane potential (-31.95 ± 2.18 mV, n = 55 cells) and high membrane resistance (1.27 ± 0.19 GΩ, n = 62 cells). Approximately 56% of GBM cells at the tumor’s leading edge exhibited neuron-like excitability, generating aberrant action potentials (aAPs) upon depolarization. Collectively, our study provides direct evidence of the intrinsic excitability of GBM cells and a detailed characterization of their electrophysiological properties in the cancer-infiltrated human cortex. These insights shed new light on tumor heterogeneity and cell-cell interactions in glioblastoma, potentially guiding the development of targeted therapies.
NCMP-22. CO-OCCURRENCE OF MULTIPLE SCLEROSIS AND HODGKIN LYMPHOMA. IS THERE A COMMON PATHOPHYSIOLOGY?
Authors: Ipshita Garg, Paunel Agyei, Néstor Gálvez-Jiménez, Surabhi Ranjan
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Multiple sclerosis (MS) and Hodgkin lymphoma (HL) share common epidemiology, genetics and immunological factors. Both affect immune activation, cell proliferation and lymphocyte-mediated immunity. However, occurrence of these two distinct clinical conditions is rare. We present a case of a woman with transverse myelitis fulfilling criteria for MS with synchronous HL. CASE REPORT A 37-year-old woman presented to the emergency room with bilateral leg weakness, numbness and urinary retention. A contrasted MRI of the brain and thoracic spine showed non-specific, non-enhancing white-matter lesions in the brain, and patchy areas of peripheral contrast-enhancement with T2-hyperintensity in the thoracic cord. Treatment with steroid infusion resulted in mild improvements of leg weakness and numbness. Cerebrospinal fluid (CSF) demonstrated oligoclonal bands (OCB) and increased IgG index. Serum was positive for JCV antibody. Due to the atypical MRI findings, namely the peripheral nature of thoracic contrast-enhancement, we were concerned for other inflammatory or autoimmune etiologies. A computed tomography of the chest, abdomen and pelvis revealed a large mediastinal mass and enlarged lymph nodes. A biopsy revealed classic HL. Three-months later, a follow-up MRI brain showed worsening contrast-enhanced lesions. A repeat CSF study revealed normal OCBs and IgG index. CSF was negative for malignant cells and JC virus DNA. To rule out a rare possibility of central nervous system HL, a biopsy of an enhancing brain lesion was obtained, which showed focal gliosis and focal perivascular lymphocytic infiltrates. No malignant cells were observed. She was diagnosed with multiple sclerosis and started systemic chemotherapy (doxorubicin, bleomycin, dacarbazine and vinblastine) for HL. CONCLUSIONS We report a case of an atypical transverse myelitis with HL. Although familial genetic clustering has been described, other potential common risk-factors between MS and HL are Epstein-Barr Virus infection and immunologic overlap, particularly in the context of lymphocyte-mediated immunity.
NIMG-16. ASSESSMENT OF RESPONSE TO LOMUSTINE-TEMOZOLOMIDE CHEMOTHERAPY IN ADDITION TO RADIOTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA USING FET PET
Authors: Jan-Michael Werner, Michael M Wollring, Caroline Tscherpel, Elena K Rosen, Garry Ceccon, Isabelle Stetter, Philipp Lohmann, Johannes Weller, Gabriele Stoffels, Christian Baues, Eren Celik, Felix M Mottaghy, Roland Goldbrunner, Ulrich Herrlinger, Gereon R Fink, Karl-Josef Langen, Norbert Galldiks
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND We examined the value of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET for early response assessment in patients with newly diagnosed glioblastoma and methylated O6-methylguanine-DNA methyltransferase promoter treated with lomustine-temozolomide chemotherapy in addition to radiotherapy. METHODS Thirty-one patients (29-74 years) were treated according to the CeTeG/NOA-09 phase-3 trial. FET PET and anatomical MRI were performed at baseline and follow-up after the third cycle. We obtained mean and maximum tumor-to-brain ratios (TBR) and metabolic tumor volumes (MTV). Thresholds derived from FET PET were defined using receiver operating characteristic analyses to predict progression-free survival (PFS) of ≥12 months. The predictive value of FET PET parameters was subsequently evaluated using univariate and multivariate survival estimates. MRI response assessment was based on the RANO 1.0 criteria. FET PET data were also used to estimate response according to the PET RANO 1.0 criteria. RESULTS Patients received a median number of 6 cycles of lomustine-temozolomide chemotherapy (3-6 cycles). After treatment initiation, the median follow-up was 17.2 months (7.2-59.4 months). As of April 2024, we confirmed tumor progression according to the RANO 1.0 criteria in 24 patients (77%). After three cycles of lomustine-temozolomide chemotherapy, a reduced mean TBR value by ≥10% predicted a significantly longer PFS (31.0 vs. 10.4 months; P=0.039). In contrast, changes in maximum TBR values, MTV, the RANO 1.0 criteria, and the PET RANO 1.0 criteria were not predictive for response (P&amp;gt;0.05). Multivariate survival analysis revealed that changes in mean TBR values predicted a significantly prolonged PFS independent of age, the extent of resection, and the Karnofsky Performance Status (P=0.036; HR, 3.892; 95% CI, 1.242-17.230). CONCLUSION Our results suggest that FET PET is clinically valuable for identifying responders to lomustine-temozolomide chemotherapy in addition to radiotherapy early after treatment initiation. The evaluation of FET PET’s value in predicting a significantly longer overall survival is ongoing.
CNSC-29. CIRCADIAN SIGNALING IN GLIOBLASTOMA SYNCHRONIZES TUMOR DAILY RHYTHMS AND REGULATES TUMOR PROGRESSION
Authors: Maria Gonzalez-Aponte, Anna Damato, Tatiana Simon, Nigina Aripova, Joshua Rubin, Erik Herzog
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is the most common primary brain tumor in adults with a poor prognosis despite aggressive therapy. A recent, retrospective clinical study found that administering Temozolomide in the morning increased patient overall survival by 6 months compared to evening. Previous work has shown that murine and human models of GBM have cell-intrinsic circadian rhythms in expression of the core clock genes Bmal1 and Per2. This suggests that GBM has circadian rhythms that entrain to the hosts’ central clock. Understanding the mechanisms underlying circadian entrainment and tumor growth in GBM is essential to determine whether regulation of tumor biology and susceptibility to therapies varies with time of day. Here, we tested the hypothesis that daily host signaling regulates tumor growth and synchronizes circadian rhythms in GBM. We found that GBM cells transduced with luciferase reporters to record clock gene expression have intrinsic circadian rhythms, with Bmal1 peaking 8-12 h before Per2 in murine and human cell lines in vitro and in vivo. Further, intrinsic circadian rhythms in clock gene expression in GBM entrain to the host through glucocorticoid signaling, regardless of tumor type or host immune status. We found daily glucocorticoids (i.e., Dexamethasone) promoted or suppressed GBM growth depending on time of day of administration and on the clock gene, Bmal1. Blocking circadian signals, like VIP or glucocorticoids, dramatically slowed GBM growth and disease progression. Our results suggest that GBM tumors entrain to the circadian circuit of the brain and depend on clock-controlled cues like VIP and glucocorticoids to grow at specific times of day. This work may inform personalized circadian medicine to improve individual GBM patient outcomes.
DDEL-01. ENGINEERING MRNA THERAPIES FOR BRAIN TUMORS
Authors: Saigopalakrishna Yerneni, Juliana Hofstatter Azambuja, Daria Strelkova-Petersen, Brendan Gallagher, Julie Shin Kim, Namit Chaudhary, Yongxin Zhao, Peter Lucas, Linda McAllister-Lucas, Norbert Pardi, Drew Weissman, Kathryn Whitehead
Journal: Neuro-Oncology (2024)

Abstract Safe delivery of mRNA to the brain will revolutionize the treatment of brain tumors. While lipid nanoparticles (LNPs) are clinically most advanced non-viral delivery vehicles for therapeutic mRNA, LNP-mediated mRNA delivery to the brain remains challenging. We hypothesized that rationally designed LNPs based on extracellular vesicle mimicry would enable efficient delivery of RNA therapeutics to brain cells without undue toxicity. We engineered LNPs consisting of four components similar to the formulation used in the mRNA COVID-19 vaccines (Moderna and Pfizer-BioNTech): ionizable lipid, cholesterol, helper lipid and polyethylene glycol (PEG)-lipid. We screened ten classes of helper lipids based on lipids enriched in extracellular vesicles to engineer biomimetic LNPs and tested their GFP mRNA delivery efficacy in SIM-A9 mouse microglia cell line. Several unique LNP formulations with potent delivery efficacy (&amp;gt;90% cells transfected) and stable GFP expression kinetics (5 days) were identified. LNP formulations with high transfection efficacy were then tested in vivo for luciferase mRNA delivery via intrathecal injection in C57BL/6 mice. Luciferase expression in vivo confirmed widespread mRNA delivery in the brain. We then tested Cre recombinase mRNA delivery in Ai9 mouse to identify LNP-targeted cells via flow cytometry and histology. Flow cytometry and expansion microscopy confirmed Cre recombinase mRNA delivery to a variety of brain cells, including microglia (75-90%), neurons (31-40%), neural stem cells (39-62%), oligodendrocytes (70-90%), and astrocytes (44-76%). LNPs were further evaluated for Cas9 mRNA and CD81 sgRNA delivery in C57BL/6 mouse brains to assess brain-targeted gene editing. Sanger sequencing showed that CRISPR-Cas9 editing was successful in ~40% of cells in the mouse brain. In summary, we engineered extracellular vesicle-based LNP library that can deliver RNA therapeutics to a variety of brain cells in vivo. With further development, this technology could potentially enable genetic and epigenetic therapies targeting drivers of brain tumors.