tbuckley/cabot-search huggingface dataset:
MDB-25. ESTABLISHING A NOVEL CEREBELLAR ORGANOID MODEL FOR INVESTIGATING HEREDITARY PREDISPOSITION TO CHILDHOOD BRAIN CANCER
Authors: Frederik Manz, Luca Bianchini, Alexander Atamian, Paul Northcott, Giorgia Quadrato, Lena Kutscher
Journal: Neuro-Oncology (2024)

Abstract During the development of the central nervous system, pools of progenitor cells undergo proliferation and subsequent differentiation into mature neurons, establishing a functional neuronal network. However, an imbalance in these processes, characterized by excessive proliferation and loss of differentiation, can lead to tumor formation in pediatric patients. In the developing cerebellum, medulloblastomas of the Sonic Hedgehog (SHH) group arise from excessive proliferation of granule neuron progenitor cells (GNPs) driven by SHH signaling, accompanied by hindered differentiation into mature granule neurons. Genetic predisposition accounts for nearly 40% of all pediatric SHH-medulloblastomas, but the development of humanized models to study these predisposition genes has been lacking. To address this gap, we created an ATOH1-driven EGFP reporter iPSC line to generate reliable cerebellar organoids focused on the development of the granule cell lineage. Our cerebellar organoid protocol yielded homogeneous organoids with robust activation of the ATOH1-EGFP reporter around day 30. Through bulk transcriptomics analysis at day 30, we observed pronounced expression of GNP markers, followed by increased expression of markers associated with mature granule neurons by day 60. Furthermore, by aligning the single-nuclei RNA sequencing (snRNAseq) data of day 60 cerebellar organoids with our human cerebellar development snRNAseq atlas, we identified various cerebellar cell types, including GNPs, mature granule neurons, Purkinje cells, interneurons, as well as glutamatergic and GABAergic neurons. Using this protocol, we examined the development of cerebellar organoids in models of hereditary predisposition to childhood cancer. Using a Gorlin syndrome model, we found that PTCH1HET organoids are larger in size than their isogenic control counterparts, while a model for ELP1HET hereditary predisposition showed no change in size compared with control organoids. These organoid models will allow us to uncover novel molecular mechanisms of hereditary predisposition using human cells.
IMMU-03. DELETION OF RASA2 IN CAR T CELLS OVERCOMES DYSFUNCTIONAL IMMUNE SYNAPSE FORMATION AGAINST DIPGS, ENHANCING IN VITRO AND IN VIVO ANTITUMOR RESPONSE
Authors: Jorge Ibanez, Michaela Meehl, Meghan B Ward, Jennifer Ocasio, Suzanne Baker, Giedre Krenciute
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse intrinsic pontine gliomas (DIPGs) are highly lethal pediatric brain tumors and a leading cause of cancer-related death in children. There is currently no cure for DIPG, highlighting an urgent need for novel therapeutics. Chimeric antigen receptor (CAR)-T-cell therapy offers great promise for DIPG treatment; however, several limitations need to be addressed. The goal of this study is to identify why CAR T cells are ineffective against DIPG and overcome this roadblock by improving the immune synapse (IS), or the interaction between tumor and CAR T cells. METHODS In this study, we targeted the tumor associated antigen B7-H3 by generating B7-H3 specific CAR T cells with CD28z signaling domain. We compared in vitro and in vivo antitumor response of CAR T cells against patient derived DIPGs and non-DIPG brain tumors. We contrasted the IS quality in DIPGs against other brain tumors by confocal microscopy. We further generated IS-enhanced CAR T cells by knocking out RASA2 and compared their performance against control KO in terms of IS-quality, killing kinetics, expansion, cytokine secretion, and in vivo tumor control. RESULTS Our data shows that CAR T cells have potent in vitro antitumor activity but fail in vivo against DIPGs which correlates with the formation of deficient IS, reflected by small synapses and poor calcium flux and cell polarity. RASA2 deletion in CAR T cells resulted in improved IS quality evidenced by bigger synapses, increased calcium flux, and CAR clustering upon antigen activation. In concordance, RASA2 KO CAR T cells elicited increased expansion, cytokine secretion, and in vivo antitumor activity against DIPGs compared to control KO. CONCLUSIONS This study shows that poor IS formation contributes to CAR T cell failure against DIPGs. Enhancing the IS formation in CAR T cells improves antitumor activity against DIPGs and should be considered for clinical translation.
Evaluation of the 2021 <scp>ESC</scp> recommendations for family screening in hereditary transthyretin cardiac amyloidosis
Authors: Steven A. Muller, Belén Peiró‐Aventin, Giulia Biagioni, Giacomo Tini, Giulia Saturi, Christina Kronberger, Anouk Achten, Stephan Dobner, Wouter P. te Rijdt, Alessio Gasperetti, Anneline S.J.M. te Riele, Guerino G. Varrà, Alberto Ponziani, Alexander Hirsch, Aldostefano Porcari, Manon G. van der Meer, Mattia Zampieri, Pim van der Harst, Andreas Kammerlander, Elena Biagini, J. Peter van Tintelen, Emanuele Barbato, Folkert W. Asselbergs, Silvia Menale, Christoph Gräni, Marco Merlo, Michelle Michels, Christian Knackstedt, Christian Nitsche, Simone Longhi, Beatrice Musumeci, Francesco Cappelli, Pablo Garcia‐Pavia, Marish I.F.J. Oerlemans
Journal: European Journal of Heart Failure (2024)

The 2021 European Society of Cardiology (ESC) screening recommendations for individuals carrying a pathogenic transthyretin amyloidosis variant (ATTRv) are based on expert opinion. We aimed to (i) determine the penetrance of ATTRv cardiomyopathy (ATTRv-CM) at baseline; (ii) examine the value of serial evaluation; and (iii) establish the yield of first-line diagnostic tests (i.e. electrocardiogram, echocardiogram, and laboratory tests) as per 2021 ESC position statement.
MDB-27. OUTCOMES FOR CHILDREN TREATED FOR MEDULLOBLASTOMA USING A RADIATION-SPARING APPROACH: A REPORT FROM THE CHILDREN’S BRAIN TUMOR NETWORK
Authors: Rebecca Ronsley, Erin E Crotty, Nicholas A Vitanza, Jeffrey Stevens, Hannah Goldstein, Bonnie Cole, Ralph Ermoian, Sarah E S Leary
Journal: Neuro-Oncology (2024)

Abstract OBJECTIVE To describe real-world outcomes in children with medulloblastoma treated with radiation-sparing chemotherapy in the USA. METHODS Clinical and molecular data were obtained from the Children’s Brain Tumor Network (CBTN), a multi-institutional collaboration to collect and freely share biological samples and longitudinal clinical data from consented patients. Patients with medulloblastoma treated with radiation-sparing regimens were included. Clinical data included patient demographics, stage, extent of resection, treatment regimen, and survival. Three-year overall survival (OS3) was calculated from diagnosis to death from any cause or last follow-up with log-rank p-value. RESULTS Eighty-one patients (56% male, median age 2.51 [range 0-7.44] years) with medulloblastoma (32% metastatic) were included. Molecular group was available for 36 (44%). Patients were treated according to protocols CCG99703 (n=26), ACNS0334 Arm A (n=13), ACNS0334 Arm B (n=30), PBTC026 (n=10), and ACNS1221 (n=2). Only 29 (36%) were enrolled on a therapeutic study. Seventy-two patients had median follow-up of 2.7 years (range 0.3-13 years). OS3 was 79+6; OS3 by molecular group was 90+9 in SHH (n=14), 55+14 in Group 3 (n=16), 56+25 in Group 4 (n=6). OS3 was 92+5 for 55 patients with localized disease versus 53+12 for 26 with metastasis (p=0.001); 86+6 for 55 patients with gross total resection versus 62+11 in 26 with partial resection or biopsy (p=0.03). OS3 was not associated with upfront radiation, 80+7 for 54 patients who received no radiation before relapse versus 78+9 for 27 who received radiation before relapse (21 focal, 6 craniospinal). OS3 was 87+8 for 30 patients on a methotrexate-containing regimen versus 74+7 for 51 without methotrexate (p=0.27). Five patients developed second malignancy. CONCLUSIONS CBTN data report real-world survival for young children treated with radiation-sparing approaches, most not enrolled on studies. Ongoing molecular characterization of the CBTN cohort will facilitate additional analysis to improve risk stratification and therapy selection for young children.
OTHR-16. HYPERACTIVATION OF THE INTEGRATED STRESS RESPONSE VIA PROTEASOME INHIBITION KILLS DMG AND ATRT WHILE SPARING NORMAL IPSC BRAIN ORGANOIDS
Authors: Orlandi V Novak, Alyssa Wu, Charles Eberhart, Eric H Raabe
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND H3K27-altered diffuse midline glioma (DMG) and atypical teratoid/rhabdoid tumor (ATRT) have increased baseline activation of the integrated stress response (ISR), an evolutionarily conserved system that enables cells to tolerate stress. This activation is manifested by elevated levels of ATF4. Transient or low-level expression protects cells from stress, while persistent, high-level activation leads to cell death. Ixazomib is an orally bioavailable proteasome inhibitor that causes endoplasmic reticulum stress, which is a major upstream activator of the ISR. We hypothesized that the high baseline level of ATF4 in DMG and ATRT would make these tumors susceptible to ISR activators such as ixazomib. METHODS After determining the IC50, DMG and ATRT cell lines were treated with increasing concentrations of ixazomib. To evaluate if ixazomib selectively kills DMG and ATRT, we treated iPSC brain organoids in parallel with tumor cells. Combination treatment of ixazomib and idarubicin, a brain-penetrant anthracycline, was conducted to assess synergy. RESULTS Ixazomib significantly induced apoptosis and suppressed proliferation in multiple cell lines, as shown by western blots for cleaved PARP and phospho-Rb expression as well as cleaved caspase-3 and BrdU immunofluorescence (DMSO vs. 25nM p&amp;lt;0.0001 by ANOVA). Additionally, western blots detected elevated ATF4 and CHOP expression in ixazomib treated cells, indicating activation of the ISR. CC3 immunofluorescence and western blot for cleaved PARP showed significantly increased apoptosis in DMG and ATRT cell lines treated with ixazomib (JHHDIPG1 and CHLA06 – DMSO vs. 25nM p&amp;lt;0.0001 by ANOVA), while iPSC brain organoids were not affected. Synergy testing of ixazomib and idarubicin showed an overall zero-interaction-potency (ZIP) synergy score of 23.464 in CHLA06 and 19.084 in HSJD007 (scores of 10 or above indicate synergy). CONCLUSIONS By over-activating the ISR, ixazomib kills DMG and ATRT cells without impacting normal iPSC brain organoids. This effect may potentially be enhanced with the addition of idarubicin.
OTHR-18. IMPACT OF COVID-19 ON CLINICAL TRIAL ENROLLMENT IN THE DEPARTMENT OF PEDIATRIC HEMATOLOGY ONCOLOGY AT WASHINGTON UNIVERSITY SCHOOL OF MEDICINE/ST. LOUIS CHILDREN’S HOSPITAL FROM 2017 TO 2023
Authors: Heather Roemerman, Mohamed Abdelbaki, Alison Barnwell, Sally Jones, Meili Hollingsworth, Lisa Murray, Brittany Tackett
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND COVID-19 had a significant impact on clinical research within the healthcare system worldwide. However, there are only limited reports on its effects on clinical trials in pediatric cancer, specifically in brain tumors. We reviewed the impact of COVID-19 in the Department of Hematology and Oncology in St. Louis Children’s Hospital (SLCH). We analyzed the number of clinical trials open at our center from 2017 to 2023. We hypothesized that in 2020 there would be a significant drop in study participant enrollments at our site overall. METHODS We analyzed data from our online tracking system from 2017 to 2019, pre-pandemic, and 2020-2023, post pandemic. We will also perform a literature review of the impact COVID-19 had on clinical trial enrollment involving childhood cancers in the United States. We will compare these findings to our experience at SLCH. RESULTS In 2020, while non-therapeutic trial enrollments declined to about half of all enrollments compared to 2019, enrollments in therapeutic trials significantly increased to almost three-fold. Overall, when combining non-therapeutic and therapeutic enrollments from 2017-2020, there was a significant decrease in 2020. By 2023, total enrollments nearly recovered to pre-pandemic levels. CONCLUSIONS COVID-19 negatively impacted non-therapeutic studies at SLCH as many trials permanently closed; however, the negative effect on therapeutic studies was minimal.
HGG-50. LOW GRADE GLIOMA CAUGHT IN TRANSFORMATION: UTILITY OF COMPREHENSIVE GENOMIC PROFILING IN PEDIATRIC LI FRAUMENI SYNDROME ASSOCIATED HIGH-GRADE GLIOMA
Authors: Sumanth Nagabushan, Noemi Fuentes-Bolanos, Loretta M S Lau, Megan Rumford, Meera Warby, Eliza Courtney, Andrew Grant, Michael Rodriguez, Annalisa Solinas, David S Ziegler, Stewart J Kellie, John Heath, Mandy Ballinger, Katherine Tucker
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse paediatric-type high-grade glioma (HGG), H3-wildtype (WT) and IDH-WT have been recognised as a distinct subgroup in the 5th edition of the World Health Organization (WHO) Classification of Tumours of the Central Nervous System (CNS) (2021). METHODS We describe two patients with LFS with conflict between histological and molecular findings. They underwent integrated multi-omics to guide personalised therapy. RESULTS The first patient is a 10-year-old female with a left thalamic diffuse astrocytoma, histologically at least CNS WHO grade 2, with H3K27M, BRAFV600E and IDH1R132H negativity by immunohistochemistry (IHC) and retained H3K27me3, prompting initial management as a low-grade glioma. ZERO2 multi-omics profiling demonstrated no DNA methylation match, (v11b4 and 12.5), but loss of TP53 function (heterozygous germline mutation with tumour whole copy chromosome 17 loss); single copy chromosome X loss with BCOR mutation, and NF1 and FGFR1 mutations. However, tumor aneuploidy, IDH-WT status, co-segregated NF1 alteration and LFS suggested malignant transformation, leading to HGG treatment. The second patient is a 6-year-old boy with LFS, detected on cascade testing, after his brother’s diagnosis of bithalamic diffuse paediatric-type HGG MYCN, following cancer surveillance through Surveillance Study in Multi-organ Cancer Prone Syndrome (SMOC-Junior). Baseline whole-body MRI identified an asymptomatic bithalamic glioma, histopathologically compatible with low-grade astrocytoma except for mosaic loss of H3K27me3. DNA methylation matched (0.99) to diffuse pediatric-type HGG MYCN-subtype, with multiple copy number aberrations, EGFR amplification/overexpression, NF1 mutations and TP53 loss of heterozygosity, without MYCN-alteration or increased expression. He received HGG-specific radiation therapy and is on an NF1-targeted maintenance therapy with trametinib, a MEK inhibitor. In both cases, molecular features suggested early transformation. CONCLUSIONS These patients highlight that integrated multi-omic diagnostic approaches can identify transformation in TP53-altered low grade gliomas and inform development of personalised management guidelines for patients and families with Li Fraumeni syndrome.
LGG-18. BEVACIZUMAB: GOOD FOR EYES AND MRI’S! A NATIONAL UK ASSESSMENT OF VISUAL AND RADIOLOGICAL OUTCOMES OF BEVACIZUMAB THERAPY IN PAEDIATRIC LOW-GRADE GLIOMA (PLGG)
Authors: Katie L Green, Paraskevi Panagopoulou, Felice D’Arco, Patricia O’Hare, Richard Bowman, Bronwen Walters, Mette Jorgensen, Olga Slater, Rehana Ahmed, Simon Bailey, Fernando Carceller, Elizabeth Corley, Martin English, James Hayden, Ahmed Kamal, J P Kilday, Stephen Lowis, Blanche Lumb, Erika Pace, Susan Picton, Barry Pizer, Ayad Shafiq, Lena Uzunova, Shaun Wilson, Harriet Wayman, Darren Hargrave, Enrico Opocher
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Bevacizumab (BEV) is increasingly used for PLGGs in varying manners despite limited evidence. The potential for BEV to preserve or rescue vision in OPGs has not yet been explored. We performed a nationwide UK evaluation of BEV use for PLGG to provide large cohort safety &amp; efficacy (radiological &amp; visual) data. METHODS A retrospective UK multi-centre analysis of patients treated with BEV for PLGG 2009-2020. Clinical patient, tumour, treatment and toxicity data were analysed from medical records. Age-adjusted LOGMAR visual acuity and radiological MRI assessments (RANO) were reviewed from initiation of BEV until latest follow-up. Standardized radiological &amp; visual criteria assessed efficacy and clinical–radiological correlation. RESULTS 88 PLGG patients from 11 PTCs received BEV either 3rd-line with irinotecan (85%) or alongside 1st/2nd line chemotherapy (15%) at median age 6 years (0.65-17). Median duration from diagnosis to BEV was 38 months. PLGGs included:15% Non-OPGs, 85% OPGs. Cohort OS 92% at median follow-up 34 months(3-106). Toxicity was limited and minimal. 8% stopped BEV for CTCAE grade 2+ toxicities, &amp; 3 patients had SAEs (2 intracranial haemorrhages, 1 thrombosis) after stopping BEV without obvious alternative cause. Overall radiological response (SD/PR/CR) was 88%; median duration to best response 3 months. Overall visual response (stable/improved) was 72%; median duration to best response 3-6 months. Superior visual outcomes were seen in NF1-OPGs (p=0.02). Concordance between visual and radiological responses was 36%; 48% using best eye only visual responses. 65% patients with treatment response had tumour progression (all-cause) within 8 months of BEV cessation. Visual responses endured significantly longer than radiological responses (p0.03). CONCLUSIONS BEV is a generally safe and effective treatment for PLGG. Most patients demonstrated on-treatment radiological and visual response. Preservation of response after BEV was limited, though visual responses endured better than radiological responses. BEV may have a unique role as a sight-saving strategy in OPG.
LGG-21. IMMUNE MICROENVIRONMENT PROFILING OF BRAF-FUSION PILOCYTIC ASTROCYTOMA: DIRECTIONAL PRIORITIZATION OF IMMUNOTHERAPEUTIC TARGETS
Authors: Shashwat Tripathi, Hinda Najem, Amy Heimberger, Michael DeCuypere
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The immune microenvironment of pediatric gliomas is relatively understudied despite being a leading cause of childhood mortality. Pilocytic astrocytomas (PA) are the most common pediatric glioma and surgical resection is often curative. However, PAs are not always amenable to surgery and can have significant long-term morbidity and mortality. The ten-year progression-free survival for PA patients with significant residual tumor is less than 50% and other non-surgical treatment options are frequently necessary. METHODS To identify PA patients that may be responsive to immune checkpoint inhibitors and to guide prioritization of available immunotherapeutic treatments, orthogonal immune profiling strategies were used to identify patients that may benefit from the next generation of immune therapeutics. Because the KIAA1549-BRAF fusion is expressed in 70% of PA, we prospectively collected patients to comprehensively characterize the unique immune biology of these tumors using nanostring profiling, scRNASeq, and SeqIF™ multiplex staining. RESULTS The tumor microenvironment of BRAF-fusion PA was notable for antigen presentation and the interaction of CD11c+ cells with T cells through Lck+ immunological synapses. PA CD11c+CD206+ dendritic cells localized to vessel walls and were positive for TIM3 expression, an immune checkpoint marker. A unique highly activated microglia subcluster was identified that morphologically resembled T cells expressing TNF and TIM3. Our results are consistent with others that suggest potential benefit in targeting tumors with elevated MAPK activity. Finally, the expression of other immune checkpoints such as Lag-3, PD-1, and TIGIT are minimally co-expressed, suggesting that T cells are not in a state of exhaustion, as seen in adult high-grade gliomas. CONCLUSIONS Analysis of BRAF-fusion PA identified a unique highly activated P2RY12+ microglia population dispersed throughout the tumor microenvironment, active antigen presentation between a CD11c+ antigen presenting cells and T cells, and a unique therapeutic opportunity for targeting TIM3.
NURS-17. SHOULD EVERY CENTRE HAVE A TARGETED THERAPY CLINIC?
Authors: J Ryles, T Arif, A Connor, G Halliday, R M Hill, S Leech, R Rennison, T Thornton, S Bailey
Journal: Neuro-Oncology (2024)

Abstract There is increased use of targeted therapies for children with Central Nervous System (CNS) tumours both at presentation and at relapse. Eighteen months ago, a dedicated CNS targeted therapy clinic was set up at The Great North Children’s Hospital in Newcastle upon Tyne. Referrals are accepted from all major centres in the north of the UK. Within our monthly clinic, five targeted therapies have been used so far including Selumetinib and Tovorafenib with an average of eight children per clinic. General practitioners are asked to carry out all blood investigations forty-eight hours prior to clinic. This has been audited and initial analyses show we have successfully reduced the time children spend in hospital from four hours to one hour. Having blood results prior to clinic means treatment can be prescribed and dispensed promptly. Furthermore, obtaining bloods in the community has reduced the workload for our oncology day unit. The side effect profile of targeted therapies differ from those of standard chemotherapy and requires specific expertise from members of the multidisciplinary team. We are able to predict trends in symptoms and manage them successfully and efficiently. We have direct access to the ophthalmology and Neurofibromatosis team at each clinic. We offer skin care management prior to beginning treatment and will refer to the dermatology team for a same day review where needed. Finally, this clinic has enabled us to offer informal peer support for children and their families, which enhances their overall hospital experience. In summary, our Targeted Therapy Clinic, with the invaluable input of many members of the MDT, has improved the quality of care for children being treated on targeted agents. Given these benefits, we are keen to support other Primary Treatment Centres to develop similar clinics, especially with the increased use of targeted treatments across CNS tumours.