bluuebunny/crossref_metadata_2025_split huggingface dataset:
IMG-09. DETERMINING OPTIMAL IMAGING SCHEDULE FOR PLGG AND PHGG PATIENTS OFF-THERAPY
Authors: Patel Krupesh , Moshe Maua , Amankwah Ernest , Holloway Leah , Stapleton Stacie 
Published: June 2023

Abstract
To this point there is no standard imaging schedule across all institutions in the surveillance of pediatric low-grade gliomas (pLGG) and pediatric high-grade gliomas (pHGG) after therapy completion. We at our institution use the Children’s Oncology Group (COG) protocols ACNS1831/ACNS1833 to guide our surveillance of pLGG. The MRI schedule is every 3 months for year 1 (after therapy), every 6 months for years 2 and 3, and annually for years 4 and 5. For pHGG we do MRI imaging every 3 months for year 1, every 4 months for year 2, every 6 months for years 3-5, and annually for years 6-10. It is uncertain if this imaging schedule is optimal in terms of tracking tumor evolution post-treatment. pLGG are a diverse group of tumors but generally tend have a slower progression rate when compared to pHGG. Studies have shown a 5-year progression-free survival (PFS) of 45% to 65% for residual tumor of any size for pLGG. 3-year PFS for pHGG at best is 18%. When possible, spacing imaging, decreasing sedations, and decreasing gadolinium-based contrast agents that can deposit in the body are key drivers in imaging schedules. Through retrospective analysis we are establishing if imaging schedules should be adjusted based on disease progression or recurrence.
IMMU-05. TUMOR INFLAMMATION-ASSOCIATED NEUROTOXICITY (TIAN): A TOXICITY SYNDROME IN PATIENTS TREATED WITH IMMUNOTHERAPY FOR CENTRAL NERVOUS SYSTEM TUMORS
Authors: Mahdi Jasia , Dietrich Jorg , Straathof Karin , Roddie Claire , Scott Brian , Davidson Tom Belle , Prolo Laura , Batchelor Tracy , Campen Cynthia , Davis Kara , Gust Juliane , Lim Michael , Majzner Robbie , Park Julie , Partap Sonia , Ramakrishna Sneha , Richards Rebecca , Schultz Liora , Vitanza Nicholas , Wang Leo , Mackall Crystal , Monje Michelle 
Published: June 2023

Abstract
Immunotherapies have transformed the therapeutic landscape for various cancer indications; currently several preclinical and clinical studies are exploring immune-based therapies for the treatment of central nervous system (CNS) tumors. The recognition of toxicity syndromes and establishment of toxicity grading scales for cytokine release syndrome (CRS) and immune effector-cell associated neurotoxicity syndrome (ICANS) have improved the administration and management of chimeric antigen receptor (CAR)-based therapies for B cell malignancies. We have observed a localized neurotoxicity syndrome, distinct from CRS and ICANS, in patients treated with immunotherapies for CNS tumors, which we term tumor inflammation-associated neurotoxicity (TIAN). TIAN arises secondary to localized inflammation at the tumor site causing local neuronal dysfunction and/or local inflammation-induced edema leading to tissue shifts and increased intracranial pressure (ICP). Although TIAN can be associated with inflammation-induced tumoral edema and may share similarities with “pseudoprogression,” TIAN can also occur in the absence of edema due to neural-immune interactions causing primary local neural dysfunction. We distinguish two types of TIAN:1) type 1 TIAN occurs when tumor inflammation-induced edema leads to mechanical space constraints and results in increased ICP, hydrocephalus, and if unmanaged, may cause a herniation syndrome 2) type 2 TIAN reflects inflammation-induced local neural electrophysiological dysfunction resulting in transient worsening/development of new neurological symptoms. In order to facilitate the safe administration of immunotherapies for CNS tumors and standardize reporting and clinical management, we have proposed a TIAN grading scale that encompasses both types of TIAN. Even though type 1 TIAN typically consists of higher-grade toxicities than type 2 TIAN, high-grade toxicities can also be seen in type 2 TIAN when tumor inflammation affects critical cardiopulmonary functions. As the promise of immunotherapies for the treatment of CNS tumors materializes, recognizing TIAN as a distinct, local neurotoxicity syndrome will be essential for patient safety and clinical management.
IMMU-10. PILOCYTIC ASTROCYTOMAS SHOW EVIDENCE OF INTRINSIC IMMUNE SURVEILLANCE AND ACTIVATION WITHIN THE TUMOR MICROENVIRONMENT
Authors: Najem Hinda , Tripathi Shashwat , McCortney Kathleen , Horak Victoria Jane , Leonard Kaethe , Steffens Alicia , Walshon Jordain , Horbinski Craig M , Wadhwani Nitin R , James Charles David , Lam Sandi , Lesniak Maciej S , Burks Jared K , Heimberger Amy B , DeCuypere Michael G 
Published: June 2023

Abstract

PURPOSE
To clarify the immunoreactivity and potential immunotherapeutic targets of pediatric low- and high-grade gliomas (HGG).

METHODS
Spatial sequential immunofluorescence (seqIFTM) of 24 protein markers, NanoString analysis of 770 immune genes, and scRNA sequencing were used to profile and characterize the tumor microenvironment (TME) of 13 newly diagnosed WHO grade 1 pilocytic astrocytomas (PA), 6 pediatric HGG, and 3 normal brain (NB) samples.

RESULTS
Relative to NB, HGGs were enriched with T cells, cancer-associated fibroblasts (CAF), CD11c+ antigen-presenting cells, and CD163+ macrophages. In contrast, PA showed more CD11c+P2RY12+ microglia and CD11c+CD205+ dendritic cells (DCs). TMEM119+ microglia were present in NB and brain adjacent to PA but were rare within the TME of all gliomas regardless of histology. PA uniquely contained naïve CD45RO-FoxP3-PD-1-TIM-3-LAG-3- T cells forming immunological synapses, as visualized by Lck+ expression at the membrane interfaces, during interaction with either microglia or DCs. This finding was not encountered in HGG. TIM-3 was the most frequently expressed immune modulatory target on all the myeloid populations, regardless of tumor histology. PD-L1 expression, especially on microglia, was more frequent in PA than in HGG. NanoString analysis revealed the pro-inflammatory and enabler of diapedesis IL-1 pathway genes (IL1RAP, TICAM2, and IRAK4) were upregulated in PA relative to the matched adjacent brain using unsupervised hierarchical clustering.

CONCLUSIONS
Based on multiple orthogonal analysis strategies, PAs display a more pro-inflammatory phenotype, in comparison to HGG, suggesting immunological surveillance that may be driven by IL-1, as a baseline feature at presentation.
IMMU-18. TARGETING GD2 IN THALAMIC DIFFUSE MIDLINE GLIOMA WITH TRANSIENT MRNA CAR T CELLS
Authors: Foster Jessica , Madsen Peter , Harvey Kyra , Patterson Luke , Griffin Crystal , Stern Allison , Storm Phillip , Resnick Adam 
Published: June 2023

Abstract
Chimeric antigen receptor (CAR) T cells targeting the disialoganglioside GD2 have shown promise as a therapeutic for diffuse midline glioma (DMG). However, thalamic tumors have been excluded from clinical trials due to prior studies showing neurotoxicity and fatality when using virally transduced CAR T cells. We hypothesized repeated dosing of transient GD2-directed mRNA CAR T cells could be employed for safe and effective treatment of thalamic DMG. GD2-directed CAR T cells were created using mRNA and first tested against the murine thalamic DMG xenograft 7316-6349 via locoregional delivery with an indwelling catheter for repeated dosing. The previously reported fatal neurotoxicity observed in mice using lentiviral CAR T cells could be recapitulated with aggressive dosing. Four doses of 5x106 mRNA CAR T cells delivered intratumorally twice a week resulted in median overall survival of 9 days for GD2-treated mice compared to &gt;30 days for CD19-treated controls (p&lt;0.01). This toxicity could be avoided by decreasing the dose and timing of infusions to 2x106 mRNA CAR T cells delivered once weekly. Bioluminescent imaging showed regression of tumor in GD2-treated mice compared to CD19-treated controls (radiance fold change -3x106 versus +20x106 p/sec/cm2/sr, p&lt;0.01). To assess survival before the onset of graft-versus-host disease, we utilized the aggressive hypermutant thalamic DMG model 7316-3058, treating with 2x106 CAR T cells intratumorally once weekly. Overall survival was significantly prolonged for 7316-3058 mice treated with GD2-directed mRNA CAR T cells compared to CD19-directed controls (median OS 48 days versus 33 days, p=0.03). Notably, non-tumor bearing mice treated with GD2-directed CAR T cells developed fatal neurotoxicity within 14 days, suggesting a very narrow therapeutic window in the brain. These data highlight the utility of titratable mRNA-based CAR T cell therapy for CNS tumors and establish GD2-directed mRNA CAR T cells as a safe and effective method for treating thalamic DMG.
LGG-02. DRUG-CLASS SPECIFIC GENE-BASED MAPK SENSITIVITY SCORES (MSS) PREDICT SENSITIVITY TO MAPK INHIBITORS AND IDENTIFY IMMUNE INFILTRATION AS PUTATIVE TARGET IN PEDIATRIC LOW-GRADE GLIOMAS
Authors: Sigaud Romain , Albert Thomas K , Heß Caroline , Hielscher Thomas , Winkler Nadine , Walter Carolin , Münter Daniel , Selt Florian , Usta Diren , Ecker Jonas , Brentrup Angela , Hasselblatt Martin , Thomas Christian , Varghese Julian , Capper David , Thomale Ulrich W , Driever Pablo Hernáiz , Simon Michèle , Horn Svea , Herz Nina Annika , Koch Arend , Sahm Felix , Hamelmann Stefan , Andrade Augusto Faria , Jabado Nada , Schouten-van Meeteren Antoinette Y N , Hoving Eelco , Brummer Tilman , van Tilburg Cornelis M , Pfister Stefan M , Witt Olaf , Jones David T W , Kerl Kornelius , Milde Till 
Published: June 2023

Abstract

INTRODUCTION
Pediatric low-grade gliomas (pLGG), the most common brain tumors in children, are driven by alterations in the MAPK pathway. Several clinical trials have shown the potential for MAPK inhibitors (MAPKi) treatment in pLGG. However, the range of response is broad, even within entities sharing the same driving genetic MAPK alteration. A predictive stratification tool is needed to identify patients that will be more likely to benefit from MAPKi therapy.

METHODS
We generated gene-expression-based MAPKi sensitivity scores (MSS) for each MAPKi class (BRAFi, MEKi, ERKi), based on MAPK-related genes differentially regulated between MAPKi sensitive and non-sensitive cell lines from the Genomics of Drug Sensitivity in Cancer (GDSC) dataset. Single sample Gene Set Enrichment Analysis (ssGSEA) was used to measure and validate our MSSs in the GDSC dataset and an independent PDX dataset (XevaDB). The validated signatures were tested in a pLGG-specific background, using gene expression data from PA cell lines and primary pLGG samples.

RESULTS
Our MSS could differentiate MAPKi sensitive cells in the GDSC dataset, and significantly correlated with MAPKi response in the XevaDB PDX dataset. The MSS were able to differentiate glioma entities with differing MAPK alterations from non-MAPK altered entities, and showed the highest scores in pLGG. The MSSs were heterogeneous within pLGG entities with a common MAPK alteration, as observed in MAPKi clinical studies. Intriguingly, a strong correlation between our MSS and the predicted immune cell infiltration rate, as determined by the Estimate score, was observed and confirmed in a pLGG scRNA sequencing dataset.

CONCLUSION
These data demonstrate the relevance of gene-expression signatures to predict response to MAPKi treatment in pLGG, and will be further investigated in a prospective manner in upcoming clinical trials. In addition, our data could suggest a role of immune infiltration in the response to MAPKi in pLGG that warrants further validation.
LGG-04. CLINICALLY RELEVANT MODELING OF FUSION-DRIVEN PEDIATRIC LOW GRADE GLIOMAS USING DROSOPHILA MELANOGASTER
Authors: Jung Geena , Jain Payal , Liang Zizhuo , Li Feng , Rathi Komal , Chen Xin , Straka Joshua , Koptyra Mateusz , Sanchez-maldonado Stephanie , Fathikazerooni Anahita , Familiar Ariana , Nabavizadeh Ali , Waanders Angela , Huang Xi , Resnick Adam , Song Yuanquan 
Published: June 2023

Abstract
Pediatric low-grade gliomas (PLGGs) are the most common brain tumors in children, with varying degrees of brain invasion. Recent whole-genome sequencing has identified a rare gene fusion involving RAF1, a RAF isoform. Unlike other RAF fusions, RAF1 fusions are resistant to existing RAF inhibitors. Therefore, aside from surgical resection with adjuvant chemotherapy and radiation therapy, there are few targeted therapeutic alternatives for RAF1-fusion-driven PLGGs. Despite the prevalence and challenges this disease presented, our understanding of PLGGs was limited by a lack of genetic models. We ultimately picked Drosophila melanogaster as our model organism due to the conservation of major signaling pathways between flies and humans. Furthermore, this connection between humans and flies, coupled with other technical advantages associated with this model organism, like short generation cycle and its powerful genetic toolbox, makes Drosophila melanogaster an ideal organism to study the genesis and progression of PLGGs. With the help of the GAL4/UAS system, we established four fusion-driven PLGG fly genetic models and found that glial overexpression of QKI-RAF1, a fusion gene in pilocytic astrocytomas, induces an invasion-like phenotype with aberrant glial migration. This migration defect was suppressed by glial overexpression of repulsive guidance signaling receptors Robo2 or PlexA/B, indicating the dysregulation of repulsive guidance signaling pathways. Immunostaining coupled with quantitative analysis revealed that Robo2 expression is downregulated in migrating tumor cells in flies, which is recapitulated in mouse astrocytes overexpressing QKI-RAF1 and PLGG patients with RAF fusions. We further broaden our findings by profiling the tumor transcriptomes, revealing potential downstream effectors, including the G protein-coupled receptor GPR180/CG9304, and inhibition of which suppresses tumor invasion in flies. Taken together, we present the PLGG fly model system, leading to the discovery of Robo2, Plexins, and GPR180/CG9304 as potential therapeutic targets.
LGG-06. DEVELOPMENT OF A WEB-BASED MOBILE DEVICE CALCULATOR APPLICATION FOR PREDICTING SHORT- AND LONG-TERM SURVIVAL IN PEDIATRIC OPTIC PATHWAY GLIOMA: A POPULATION-BASED DATABASE ANALYSIS
Authors: Brown Nolan , Kuo Cathleen , Gendreau Julian 
Published: June 2023

Abstract
Optic pathway gliomas (OPG) are low-grade lesions arising from the astrocytes of the visual pathway and diencephalon. For most patients, observation appears to be the treatment of choice, but it remains unclear how frequently serial imaging should be obtained and at what point lesions can be deemed to have become quiescent. There is therefore an ongoing need for prognostication tools that can accurately predict the behavior of OPG to help identify those lesions meriting therapeutic intervention. In the present study, we leverage population-level data from the Surveillance, Epidemiology, and End Results program (SEER) database to develop a predictive calculator for overall survival (OS) in pediatric OPG. Accordingly, we extracted all available patient-level data from the SEER database. Training and testing datasets were established. Cox proportional hazards regressions were then used to identify independent predictors of survival, and model validation was performed. A total of 1,052 pediatric patients met inclusion criteria. Most were between 5 to 9 years old (45.7%), males (51.6%), white (85.6%), non-Hispanic (82.1%), and 232 patients (22.1%) came from houses with a median income less than $54,999, while 111 patients (10.6%) lived in a rural county. Nearly 90% of patients did not undergo surgical debulking. Twenty-three patients (2.2%) received radiotherapy and 294 (27.9%) received chemotherapy. Additionally, univariate and multivariate analyses were performed to identify variables associated with OS. Median household income and subtotal resection were found to be predictors of OS on univariate analysis. Furthermore, on multivariate analysis, median household income greater than $55,000 and subtotal resection were predictive of higher OS. Age at diagnosis, sex, rural versus urban setting, benign versus malignant behavior, and use of chemotherapy or radiotherapy did not appear to affect OS. Finally, we created a calculator (https://spine.shinyapps.io/optic_glioma/) using our model to estimate 5-,10-, and 1-year OS probability and other survival outcomes.
LGG-09. CLINICAL ACTIVITY OF PAN-RAF INHIBITOR TOVORAFENIB IN THE REGISTRATIONAL PEDIATRIC LOW-GRADE GLIOMA ARM OF THE PHASE 2 FIREFLY-1 (PNOC026) STUDY
Authors: Kilburn Lindsay , Khuong-Quang Dong-Anh , Nysom Karsten , Landi Daniel , Ziegler David , Driever Pablo Hernáiz , Leary Sarah , Bailey Simon , Van der Lugt Jasper , Perreault Sebastien , Waanders Angela , Baxter Patricia , Witt Olaf , Hargrave Darren , McCowage Geoffrey , Zhao Xin , Da Costa Daniel , Cox Michael , Manley Peter , Hansford Jordan 
Published: June 2023

Abstract
Genomic alterations of BRAF are common oncogenic drivers in pediatric low-grade glioma (pLGG). Tovorafenib is an investigational, oral, selective, brain-penetrant, small molecule, type II panRAF inhibitor. FIREFLY-1 (NCT04775485) is a multicenter phase 2 study evaluating the efficacy and safety of tovorafenib monotherapy in patients with BRAF-altered cancers. Registrational arm 1 includes patients 6 months-25 years of age with recurrent or progressive LGG previously treated with ≥1 prior line of systemic therapy. Tovorafenib 420 mg/m2 (≤600 mg) is administered weekly, in 28-day cycles, (tablet or liquid suspension formulation) until progression. The primary endpoint of arm 1 is ORR, as defined by RANO criteria and determined by blinded independent review. As of September 28, 2022, arm 1 had enrolled 77 patients and is fully accrued. All patients had ≥6 months of follow-up. Median age at enrollment was 8 years (range 2-21). Patients had received a median of 3 prior lines of systemic therapy (range: 1-9); 60% had received prior MAPK pathway-targeted agents. The most common tumor site was optic pathway (51%). Sixty-four patients harbored a tumor BRAF fusion/rearrangement (83%) and 13 (17%) a V600E mutation. Median duration of tovorafenib treatment is 8.4 months (range 0.7-16.8); 59 patients (77%) remained on treatment at data cutoff. ORR in 69 RANO-evaluable patients was 64%, [3 CR, 41 PR (10 unconfirmed) and 19 SD] with a clinical benefit rate of 91%. The most common treatment-related adverse events (TRAEs) of any grade were hair color changes (75%), increased creatine phosphokinase (64%), anemia (46%), fatigue (42%) and maculopapular rash (42%). Two patients (3%) discontinued tovorafenib due to TRAEs. Updates from a longer follow-up on the 77 patients in arm 1 will be presented. Tovorafenib was generally well tolerated and showed encouraging evidence of antitumor activity in children and young adults with refractory BRAF-altered LGG.
LGG-11. COGNITIVE, ACADEMIC, AND QUALITY OF LIFE OUTCOMES IN SURVIVORS OF PEDIATRIC LOW-GRADE GLIOMA: CHALLENGING THE ‘BENIGN TUMOR’ PERCEPTION
Authors: Nagabushan Sumanth , Hamayun Mashaal , Fardell Joanna E , Donoghoe Mark , Bland Elizabeth , Bye Ann , Jacobson Erica , Manoharan Neevika , Ziegler David S , McLoone Jordana K , Johnson Alexandra M , Cohn Richard J 
Published: June 2023

Abstract
High survival rates in pediatric low-grade gliomas (pLGG) may overshadow potentially significant long-term toxicities and functional impact. Chemo-radiation sequelae are well documented, in contrast to those who undergo surgical resection or observation alone. We performed a retrospective cohort study from 2000-2015, assessing cognitive, academic, and quality of life (QoL) impact on 45 eligible pLGG survivors aged 0-16 years at diagnosis, at a median 7.4 years post-treatment. A multidisciplinary panel oversaw proxy questionnaires for young children (&lt;7 years), proxy and self-reported for adolescents (8-15 years) and self-reported for young adults (&gt;15 years). Data included demographics; tumor and treatment; early school (young child) progress; academic and occupation achievement (adolescents and young adults); health; and lifestyle issues. The incidence of abnormalities in the domains studied were compared to published population statistics. 16% of survivors underwent observation alone, and 84% surgery (58% complete resection). 57% of survivors experienced cognitive deficits. Young children (50%) and adolescents (42%) had low cognitive functioning scores, correlating with poor academic (p &lt; 0.01) and standardised school educational tests’ performance. 42% of mainstream school attendees required learning support; 33% examination assistance; 50% completed secondary education and 22% a tertiary degree, but had attention (young child and adolescent), and memory (young adult) issues. 65.9% of survivors had at least one neurological concern, highest in adolescents (70%). Language deficits (42.9%), pain, fatigue, and hearing loss (28.6 %) in young children; and vision/sleep difficulties (35%); fatigue (30%) and mobility (25%) in adolescents were reported. Young adults suffered headaches (47.1%) and fatigue (29.4%). Young children (57%) suffered more emotional disturbance than adolescents (16%). Anxiety (23%) and depression (14%) reflected poor QoL on Emotion Thermometer scales in all survivors. These findings challenge the ‘benign’ label of pLGG and highlights the importance of close psychosocial surveillance in helping survivors achieve their best emotional and educational potential.
LGG-23. OUTCOMES UTILIZING BRAF INHIBITION MONOTHERAPY IN BRAFV600E MUTATED PEDIATRIC LOW GRADE GLIOMAS
Authors: McThenia Sheila , Reddy Kartik , Goldman-Yassen Adam E , Gray Rachel , Connelly Erin , Patteson Brooke , Aguilera Dolly , Castellino Robert Craig , Fangusaro Jason Ronald , Janss Anna , Mazewski Claire , MacDonald Tobey 
Published: June 2023

Abstract

BACKGROUND
Pediatric low-grade glioma (pLGG) tumorigenesis is driven by activation of the RAS/RAF/MAPK pathway. pLGGs have an overall survival over 95%; however, patients harboring a BRAFV600E alteration may have worse outcomes. Combined BRAF/MEK inhibition following incomplete resection demonstrated improved outcome in pLGG compared to combined carboplatin/vincristine chemotherapy. We evaluated efficacy and tolerability of single agent BRAF inhibitor treatment in our single institution pLGG cohort.

METHODS
We performed a single institution retrospective analysis, (2013-2023) at Children’s Healthcare of Atlanta on patients 0-21 years old with new or progressive BRAFV600E mutated pLGG, who were treated off-study with BRAF inhibitor monotherapy. We evaluated 2-year Progression Free Survival (PFS) and Objective Response (CR+PR). All toxicities were evaluated and described.

RESULTS
We identified fifteen patients with BRAFV600E mutated pLGGs treated with BRAF inhibitor monotherapy. Median age of diagnosis: 5.8 years (0.20–18.0). Histologic diagnosis: pilocytic astrocytoma (PA)(N=3); atypical PA (N=1); ganglioglioma (N=3); atypical ganglioglioma (N=3); pleomorphic xanthoastrocytoma (PXA)(N=2); LG neuroepithelial tumor (N=1); infiltrating glioma (N=1); and LGG (NOS)(N=1). Tumor location: hypothalamus/optic chiasm (N=5); third ventricle/thalamus (N=3); parietal/temporal lobe (N=3); brainstem (N=2); and cervicomedullary junction/spinal cord (N=2). Mean therapy duration: 30.7 months (3.9-74.6). Median follow-up: 32.6 months (16-78.1). Two-year PFS: 80% (12/15). Objective Response(OR) for 14 evaluable patients at 1-year on initial BRAF inhibitor therapy: 43% (0/14 CR+6/14 PR). Patients tolerated treatment with Grade 1 rash being the most common toxicity. Three of 15 patients (20%) discontinued therapy due to toxicities, including rashes, arthralgias/myalgias (Grade 2), and one corneal lesion.

CONCLUSIONS
In our small cohort of incompletely resected BRAFV600E mutated pLGGs, BRAF inhibition monotherapy was effective and well tolerated with an OR comparable to published outcomes of dual MEK/BRAF inhibitor therapy. This promising treatment should be further studied in prospective clinical