bluuebunny/crossref_metadata_2025_split huggingface dataset:
HGG-23. DECIPHERING THE RELATIONSHIP OF MICROSATELLITE-INSTABILITY AND MUTATIONAL BURDEN IN HIGH-GRADE GLIOMA PATIENTS WITH CONSTITUTIONALLY IMPAIRED DNA DAMAGE RESPONSE
Authors: Blattner-Johnson Mirjam , Sturm Dominik , Jones Barbara C , Previti Christopher , Sievers Philipp , Jäger Natalie , Hirsch Steffen , Dikow Nicola , Sahm Felix , Kramm Christof M , Witt Olaf , Pfister Stefan M , Jones David T W 
Published: June 2023

Abstract
Multiple large-scale genomic studies across pediatric tumors have reported an overall frequency of ~6-10% of patients with constitutional pathogenic variants, but associations of cancer predisposition with distinct tumor types vary between zero and 100%. We analyzed sequencing and DNA methylation data from 363 patients to explore the landscape of cancer predisposition in pediatric high-grade gliomas (pedHGG). Almost all pedHGG with constitutional alterations resulting in DNA mismatch repair deficiency (MMRD) were classified to IDH-mutant or pedRTK1a DNA methylation classes. Conversely, 70% of pedRTK1a and nearly 60% of IDH-mutant pedHGG (&lt;18 years) arose in patients with either Lynch or cMMRD syndromes. Biallelic MMR inactivation (cMMRD) was found almost exclusively to affect the exchangeable part of the mismatch repair machinery complex (MSH6/PMS2; 75%), while heterozygous loss affected non-exchangeable core members MLH1 or MSH2 (93%). IDH-mutant MMRD tumors showed substantially lower overall tumor mutational burden (TMB &lt; 40), less microsatellite instability, and frequent MSH6 mutation (60%), while pedRTK1-MMRD tumors often harbored additional alterations in POLE, leading to an ultra-mutator phenotype (TMB &lt; 100), had higher microsatellite instability burden, and more often linked to PMS2 or MSH2 loss. Both IDH-mutant- and pedRTK1-MMRD tumors were associated with poor outcome, with MMRD-associated IDH-mutant pedHGG resulting in significantly shorter survival compared with sporadic IDH-mutant tumors (p=0.0015). We observed a nonlinear correlation between increasing numbers of point mutations, InDels and microsatellite instability. Exemplary, patients with pathogenic constitutional variants in MSH6 showed a significantly lower number of InDels compared with overall TMB, which might be due to repair ability of the replacement protein MSH3. As newer studies point towards an important role of InDels in antigen presentation and therefore as a potential biomarker for immune checkpoint inhibition, further exploration of these detailed molecular associations in conjunction with clinical outcome and response data is warranted.
HGG-24. A NOVEL ONCOGENIC ROLE FOR MENIN IN GLIOMA
Authors: Yang Yanhong , Saito Yuhki , Goldberg Elena , Mrad Zaki Abou , Larsen Alexandra Giantini , Ghita Greta , Tabar Viviane 
Published: June 2023

Abstract
High-grade gliomas (HGGs) represent the most common subtype of primary malignant tumors from brain or spinal cord. With about 18 months overall survival time, HGGs is the leading cause of death from primary brain tumor. Survival outcomes have not improved significantly over the past two decades despite major research and therapeutic discovery efforts. Previous work from our lab suggested a role for menin in initiation and maintenance of pediatric high-grade glioma. Here we describe a critical oncogenic role of menin (encoded by the MEN1 gene) in maintaining HGGs proliferation. Using a panel of early passage HGG lines harboring diverse genomic alterations, we demonstrate that silencing of MEN1 blocks proliferation (60%-80%) of a subset (8/12) of HGGs, independent of their genomic alteration profile. An oncogenic role of menin has been described in MLL-rearrangement leukemia, where menin complexes with MLL to affect H3K4 trimethylation and activate leukemogenic genes. However, we found that the menin-MLL interaction is not associated with glioma. Instead, our mechanistic studies suggest that menin plays a critical role in maintaining H3K27 acetylation marks across the genome. Using immunoprecipitation and mass spectrometry, we identified HMGN1 (high mobility group nucleosome-binding domain 1 protein) as a putative novel menin partner. HMGN1 is a chromatin remodeling protein associated with chromatin accessibility and H3K27 acetylation. Transcriptional studies of patient-derived HGGs revealed that knockout of MEN1 and silencing of HMGN1 both resulted in broad repression of genes associated with proliferative tumor progenitor clusters. Ongoing work is aimed at therapeutic targeting by novel menin inhibitors. Our work demonstrates the role of epigenetic remodeling in controlling glioma proliferation and identifying novel therapeutic targets.
IMG-03. HARNESSING COMPUTATIONAL IMAGING, SCALABLE CLOUD-BASED WORKFLOWS, AND MULTI-MODAL DATA ANALYTICS WITH INTEROPERABLE SOFTWARE PLATFORMS IN PEDIATRIC NEURO-ONCOLOGY; THE ROAD AHEAD FOR CHILDREN’S BRAIN TUMOR NETWORK (CBTN)
Authors: Nabavizadeh Ali , Familiar Ariana , Kazerooni Anahita Fathi , Viswanathan Karthik , Kim Meen Chul , Lubneuski Alex , Heath Allison P , Vossough Arastoo , Storm Phillip B , Resnick Adam C 
Published: June 2023

Abstract
Neuroimaging is acquired as part of the clinical standard of care for treatment of brain tumor patients. Capitalizing on this data and integration of imaging with other data types to perform predictive analytics is an increasing need. Here, we review the efforts at CBTN in the past couple of years to establish user-friendly workflows to support the entire imaging data lifecycle and to bridge access to multi-modal datasets with scalable analytics scale, to empower researchers to make breakthrough discoveries that will advance patient care. An automated deep learning-based brain extraction and tumor subregion segmentation model based on a multi-institutional dataset was developed that can reliably segment the MRI scans of children across a variety of brain tumor histologies. This model was subsequently integrated into an end-to-end imaging pipeline for collecting, managing, and analyzing clinically acquired radiology exams of the CBTN consortium with processing of 12,500 exams to date. A public website was also created to allow users to search and explore the dataset based on sequence labels, and clinical and imaging attributes. In addition, we established a scalable workflow and processes for de-identification, ingestion, quality control, and management of digital pathology slides on CBTN (over 8,000 slides to date). Finally, we established interoperability between imaging (Flywheel) and molecular (CAVATICA) platforms deployed in cloud ecosystems which allows streamlined, user-friendly workflows to ingest and harmonize files, perform cohort selection, prepare data using standard processing packages and cloud resources, and conduct analysis on extracted multi-modal feature sets. The described workflow lays the foundation for broad use of imaging studies and access to multi-modal datasets and analytics, with the goal of empowering researchers to make breakthroughs in patient care. The next step is to apply these tools in the context of clinical trials.
IMG-05. A MULTI-INSTITUTIONAL AND MULTI-HISTOLOGY PEDIATRIC-SPECIFIC BRAIN TUMOR SUBREGION SEGMENTATION TOOL: FACILITATING RAPNO-BASED ASSESSMENT OF TREATMENT RESPONSE
Authors: Kazerooni Anahita Fathi , Khalili Nastaran , Haldar Debanjan , Viswanathan Karthik , Familiar Ariana , Bagheri Sina , Anderson Hannah , Arif Sherjeel , Madhogarhia Rachel , Kim Meen Chul , Mahtabfar Aria , Storm Phillip B , Resnick Adam , Ware Jeffrey B , Davatzikos Christos , Vossough Arastoo , Nabavizadeh Ali 
Published: June 2023

Abstract
Current response assessment in pediatric brain tumors (PBTs), as recommended by the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group, relies on 2D measurements of changes in tumor size. However, there is growing evidence of underestimation of tumor size in PBTs using 2D compared to volumetric (3D) measurement approach. Accordingly, automated methods that reduce manual burden and intra- and inter-rater variability in segmenting tumor subregions and volumetric evaluations are warranted to facilitate tumor response assessment of PBTs. We have developed a fully automatic deep learning (DL) model using the nnUNet architecture on a large cohort of multi-institutional and multi-histology PBTs. The model was trained on widely available standard multiparametric MRI sequences (T1-pre, T1-post, T2, T2-FLAIR) for segmentation of the whole tumor and RAPNO-recommended subregions, including enhancing tumor (ET), non-enhancing tumor (NET), cystic components (CC), and peritumoral edema (ED). As a prerequisite step for accurate tumor segmentation, we also generated another DL model based on DeepMedic for brain extraction from mpMRIs. The models were trained on an institutional cohort of 151 subjects and independently tested on 64 subjects from the internal and 29 patients from external institutions. The trained models showed excellent performance with median Dice scores of 0.98±0.02/0.97±0.02 for brain tissue segmentation, 0.92±0.08/0.90±0.17 for whole tumor segmentation, 0.76±0.31/0.87±0.29 for ET subregion, and 0.82±0.15/0.80±0.28 for segmentation of non-enhancing components (combination of NET, CC, and ED) in internal/external test sets, respectively. The automated segmentation demonstrated strong agreement with expert segmentations in volumetric measurement of tumor components, with Pearson’s correlation coefficients of 0.97, 0.97, 0.99, and 0.79 (p&lt;0.0001) for ET, NET, CC, and ED regions, respectively. Our proposed multi-institutional and multi-histology automated segmentation method has the potential to aid clinical neuro-oncology practice by providing reliable and reproducible volumetric measurements for treatment response assessment.
IMMU-08. SALVAGE IMMUNOTHERAPIES FOR REPLICATION REPAIR DEFICIENT (RRD) HIGH-GRADE GLIOMA FAILING ANTI-PD1 MONOTHERAPY: AN IRRDC REPORT
Authors: Das Anirban , Fernandez Nicholas R , Levine Adrian , Bianchi Vanessa , Stengs Lucie , Edwards Melissa , Nobre Liana , Pugh Trevor J , Tsang Derek S , Ertl-Wagner Birgit , Morgenstern Daniel A , Bouffet Eric , Hawkins Cynthia , Tabori Uri 
Published: June 2023

Abstract

BACKGROUND
Although the initial response to immune-checkpoint inhibition (ICI) for patients with DNA replication-repair deficient high-grade glioma (RRD-HGG) is encouraging, the role of immune-based salvage approaches for those progressing on anti-PD1 monotherapy is unknown.

METHODS
We performed an international registry study of patients managed using central molecular, genomic, radiological review and treatment recommendations between 2015-2021. Post-progression treatment included re-irradiation where feasible, and continuation of anti-PD1 with anti-CTLA4 (ipilimumab), or a MEK-inhibitor (MEKi). Outcomes included radiological response (iRANO), toxicity, second progression-free (PFS2) and overall survival (OS2). Companion biomarkers were performed centrally.

RESULTS
Among 75 patients with RRD-HGG receiving PD-1 blockade, 20 are progression-free at a median follow-up of 44.6-months. For 55 patients with relapsed/progressive tumors, continuation of ICI (n=38) resulted in median OS2 of 11.6-months (51% alive) versus 1.2-months when ICI was discontinued (n=17; no survivors, p&lt;0.001).
The combination of ipilimumab/nivolumab (n=24) resulted in response/stable disease in 75% with median OS2 of 12.1-months but high autoimmune toxicities (54%). The addition of MEKi led to response in 3/5 patients with prolonged survival. The addition of re-irradiation improved median OS2, especially in tumors with lower mutation burden (p=0.002), and those who received ipilimumab (median OS2=33-months).
Several biological insights were gained. Early radiological ‘flare’ in 33% of RRD-HGG on combined immunotherapy and radiation were associated with immunogenic radiation induced signatures. MEKi responses were associated with reinvigoration of peripheral immune response. Finally, delayed, sustained responses were observed in ultra-hypermutant RRD-HGG exhibiting changes in somatic mutational spectra.

CONCLUSION
These data suggest that the continuous mutagenesis renders hypermutant RRD-HGG susceptible to checkpoint inhibitors beyond initial progression. The combination with re-irradiation and additional immune/targeted agents can maximize survival in these children and young adults. Future research should focus on biology-driven rational immunotherapy combinations that also result in lower toxicity to maximize patient benefit.
IMMU-09. DISSECTING THE INTERPLAY BETWEEN THE ENDOGENOUS IMMUNE RESPONSE AND ONCOLYTIC VIRUS THERAPY IN PEDIATRIC BRAIN TUMORS
Authors: Hoare Owen , Jung Jangham , Inagaki Akihito , Yu Bohyeon , Collins Sara , Chuntova Polly , Barcova Maria , Patel Trishna , Kasahara Noriyuki , Müller Sabine , Diaz Aaron 
Published: June 2023

Abstract
Oncolytic virus (OV) elicits an antitumor immune response in addition to tumor-cell killing. However, it is unknown if a pre-existing antitumor immune response aids or hinders OV therapy. To study the interplay between the endogenous immune response and OV we profiled tumors from immunocompetent intracranial models of medulloblastoma and glioblastoma treated with measles virus (MV) and retrovirus (Toca-511), using single-cell and bulk-RNA sequencing. For both models, we assayed specimens from two treatment groups, a mid-treatment group where mice were sacrificed upon observation of treatment response, and a post-treatment group where treatment-resistant mice were sacrificed when they had succumbed to their disease. As controls, we included a cohort treated with heat-inactivated virus and a cohort treated with PBS. Both MV and Toca-511 OV therapies significantly improve survival compared to controls. From each of the MV and Toca-511 treatment/control groups, 3 mice per group were profiled via RNA sequencing. Additionally, tumors from 5 mice treated with MV alone and 4 mice treated with MV and anti-PD1 immune-checkpoint blockade (ICB) were subjected to single-cell RNA sequencing (scRNA-seq). ScRNA-seq generated 38,491 cells after filtering for quality control and successfully captured both endogenous and viral RNAs. We found that in samples treated with both OV and ICB there were higher rates of virally infected cells, depletion of M2-polarized myeloid infiltrates, and depletion of endothelial cells, compared to controls. Comparing virally infected tumor cells to non-infected controls we observed a down-regulation of translation initiation-complex genes and an upregulation of markers of oxidative phosphorylation. Infected cells from treatment-resistant tumors upregulate antigen presentation and myeloid chemotaxis genes. These studies show that OV enhances survival and anti-brain-tumor immunity. They support MV and ICB as potentially being synergistic. They suggest translation control and perturbation of the myeloid compartment as strategies for enhancing intracellular MV proliferation and infection efficiency, respectively.
IMMU-12. T CELL SEQUESTRATION IN POSTERIOR FOSSA TUMORS
Authors: Wilson Zach , Fecci Peter 
Published: June 2023

Abstract

INTRODUCTION
T cell dysfunction contributes to immune escape in patients with cancer and is particularly severe in CNS tumors. T cell sequestration is a contributing mechanism of T cell lymphopenia and lymphoid organ contraction occurring in treatment naive patients and mice with Glioblastoma. Our group demonstrated that this phenomenon is mediated by loss of S1P1 surface expression on T-Cells within the bone marrow. We demonstrated in murine models that reversing T cell sequestration via stabilization of surface S1P1 licenses T cell activating therapies. As pediatric brain tumors much more commonly involve the posterior fossa and brainstem, the present work set out to assess whether T cell sequestration also occurs in tumors located in the cerebellum (medulloblastoma, high grade glioma).

METHODS
CT2A murine glioma cells were orthotopically implanted into the posterior fossa of C57BL/6 mice. Blood, spleen, and bone marrow were analyzed when tumors became sizable (Day 18-21). Flow cytometry was utilized to measure total, CD4+, and CD8+ T cell counts, as well as the proportion of T cells expressing surface S1P1.

RESULTS
Compared with mice injected with methylcellulose, mice bearing cerebellar CT2A tumors demonstrated significantly decreased splenic weight, increased total, CD4, and CD8 T cell counts in the bone marrow, and a decreased proportion of surface S1P1 expressing T cells within the bone marrow.

CONCLUSIONS
T cell sequestration within the bone marrow associated with loss of surface S1P1, as previously demonstrated in high grade tumors of the forebrain, also occurs with tumors implanted into the cerebellum, suggesting that the genesis T cell sequestration is independent of location within the brain. Future work on this project will add additional tumor histology to our analysis as well as measuring the effects of S1P1 stabilization on response to T cell activating therapies in these models of cerebellar tumors.
IMMU-17. DEVELOPMENT OF AN INTRACRANIAL CANNULA IMPLANTATION SYSTEM FOR SERIAL LOCOREGIONAL CAR T CELL INFUSIONS IN MICE
Authors: Harvey Kyra , Madsen Peter , Smith Tiffany , Griffin Crystal , Patterson Luke , Vitanza Nicholas , Storm Phillip , Resnick Adam , Foster Jessica 
Published: June 2023

Abstract
Pediatric CNS tumors are responsible for the majority of cancer-related deaths in children. As many tumors lack efficacious treatments, there is a crucial need to develop more promising therapeutic options, such as immunotherapies. Of particular interest is the use of chimeric antigen receptor (CAR) T cell therapy. Current clinical trials are ongoing targeting the cell surface molecules HER2, EGFR, B7-H3, IL13RA2, and the disialoganglioside GD2. While the majority of trials deliver CAR T cells into the cerebral spinal fluid with repeated doses, this has not been completed in preclinical models due to difficulty performing multiple stereotactic surgeries. To evaluate repeated locoregional delivery of CAR T cells in preclinical murine models, we established an indwelling catheter system that recapitulates indwelling catheters currently being used in human clinical trials. Following orthotopic injection and engraftment of tumor cells in mice, intratumoral placement of a fixed guide cannula is completed on a stereotactic apparatus and secured with screws and acrylic resin. Treatment cannulas are then inserted through the fixed guide cannula for repeated CAR T cell delivery. With this system, we tested novel CAR T cells directed against glypican 2 (GPC2), resulting in significant tumor regression in medulloblastoma model 7316-4509 (p&lt;0.01), as well as significantly prolonged survival in thalamic diffuse midline glioma 7316-3058 (p&lt;0.05). Stereotactic placement of the guide cannula can be adjusted to deliver CAR T cells directly into the lateral ventricle or other locations in the brain. This platform offers a reliable mechanism for preclinical testing of repeated intracranial infusions of CAR T cells and other novel therapeutics, offering a superior preclinical model for translation to clinical trials.
IMMU-19. NIVOLUMAB-INDUCED CNS DEMYELINATION IN A 15-YEAR-OLD WITH CLASSIC HODGKIN LYMPHOMA
Authors: Ramirez Alejandra , Jonokuchi Alexander , Hijiya Nobuko , Gomes William , Wesley Sarah , Kaur Gurcharanjeet 
Published: June 2023

Abstract

INTRODUCTION
Nivolumab associated neurologic immune-related adverse events (irAEs) have been reported in less than 1% of patients and mainly in the adult population. Here we present a pediatric case of nivolumab related CNS demyelination. Case description: 15-year-old male with nodular sclerosis stage III classic Hodgkin lymphoma was enrolled to receive chemotherapy following SWOG S1826 protocol. Eight weeks after the first dose of nivolumab, he had a single episode of seizure. Prolonged EEG showed no epileptiform discharges. Levetiracetam was initiated. Initial MRI showed a non-enhancing T2 hyperintense focal cortical thickening in the left primary motor cortex. CSF studies were significant for mild lymphocytic pleocytosis. One dose of nivolumab was held with subsequent doses given. Levetiracetam was continued and follow-up EEGs were normal. Repeat MRI done three months later showed multiple new parenchymal hyperintense lesions including in the anterior temporal lobe with central curvilinear enhancement, and faintly enhancing lesions in the left fusiform gyrus, juxtacortical white matter of the right middle temporal gyrus, and left superior cerebellar peduncle, findings consistent with CNS demyelination. At this time, CSF showed 9 WBCs (94% lymphocytes) and oligoclonal bands with negative cytology and flow cytometry making CNS lymphoma highly unlikely. The last two doses of nivolumab were held and he was started on methylprednisolone. The most recent MRI ten weeks after the last dose of nivolumab showed resolution of the abnormal findings.

DISCUSSION
There is limited published literature about neurologic complications of immune checkpoint inhibitors (ICPis) in the pediatric population. CNS demyelination and other neurologic irAEs should be suspected in patients presenting with new neurologic symptoms who started any ICPi within the past three months and after other causes including disease progression, metastasis, metabolic or infectious disorders have been ruled out. Treatment varies depending on severity but includes discontinuation of the ICPi and steroids.
IMMU-22. ALLOGENEIC NK CELLS SECRETING IL15 AND RESISTANT TO TGF-β Show Antitumor Activity Against Gliobastoma
Authors: Muniraj Nethaji , Chaudhry Kajal , Terao Joshua , Barron Luke , Suri Vipin , Bollard Catherine , Cruz Conrad Russell 
Published: June 2023

Abstract

INTRODUCTION
High grade brain cancers, like most solid tumors, often relapse and are resistant to current therapies. Limited efficacy to cell therapy may be related to intratumoral heterogeneity and the suppressive tumor microenvironment. Hence, we aimed to modify allogeneic natural killer (NK) cells, which can recognize expressed tumor stress ligands, to resist TGF-β and secrete IL15.

METHODS
Cord blood-derived NK cells were expanded and modified to express IL15 and a dominant negative receptor (DNR) against TGF-β. NK cell product activity against the GBM cell line U87MG were evaluated in vitro and in vivo. The behavior of these cells were also analyzed ex vivo, to evaluate the impact (including potential toxicity) of increasing the potency of this allogeneic NK cell product.

RESULTS
While animals injected with NK cells secreting IL15 and expressing DNR successfully cleared tumors 6 days after T cell infusion, we did not observe significant differences in survival between the groups (no treatment control mice vs treated with mock-transduced NK cell vs DNR-transduced NK cells vs IL-15/DNR-transduced NK cells). Therefore, we sought to determine whether cytokine-related toxicity was responsible for death in the setting of tumor clearance. We compared no treatment control mice vs mice treated with mock-transduced or IL-15/DNR-transduced NK cell products. Elevated levels of IL-15 were detected in the plasma of mice treated with IL-15/DNR-transduced NK cells. These elevated IL-15 levels corresponded with NK cell persistence in the brain measured by ddPCR. However, no other cytokines were upregulated.

CONCLUSIONS
We observed improved tumor clearance when NK cells were both protected against immune suppressive TGF-β and were capable of secreting the stimulatory cytokine IL15. We are currently performing additional experiments to determine whether toxicity from IL15 secretion occurs. To potentially mitigate this toxicity we plan to engineer a suicide gene into these constructs.