bluuebunny/crossref_metadata_2025_split huggingface dataset:
IMG-29. IMPLICATIONS OF IMAGE HARMONIZATION FOR BRAIN TUMOR CLINICAL TRIALS
Authors: Parida Abhijeet , Jiang Zhifan , Anwar Syed Muhammad , Stence Nicholas , Foreman Nicholas , Packer Roger J , Fisher Michael J , Avery Robert A , Linguraru Marius George 
Published: June 2024

Abstract

BACKGROUND
Clinical trials for rare pediatric conditions like optic pathway gliomas associated with NF1 (NF1-OPGs) require numerous sites that utilize different MRI scanners and protocols. These MRIs must be harmonized for reliable comparison using machine learning tools. We propose a deep-learning based MRI harmonization that enables reproducible data analysis across multiple sites and MRI platforms.

METHODS
One-hundred eighty clinical T1-weighted-MRIs of pediatric NF1-OPG subjects were acquired from three sites [Children’s National Hospital (site A, N=60), Children’s Hospital Colorado (site B, N=60), and Children’s Hospital of Philadelphia (site C, N=60)] using different MR scanners (GE, Phillips, and Siemens, respectively). MRIs from A and B were used to train a branched neural network and C were used for testing. Using unsupervised learning, the neural network identified differences in imaging protocols and harmonized data to a chosen protocol, e.g., that of site A, while preserving the patient anatomy. The harmonization was evaluated using Wasserstein distance (nWD), which measured similarity between two gray scale appearances of MRI intensity histograms. Anatomy preservation metric (AP) measured relative volume changes in gray matter (GM) segmented using Freesurfer, before and after harmonization. For both metrics, 100% means the best possible harmonization was achieved.

RESULTS
Before harmonization, nWD between grayscale appearance of MRIs from sites A and B was 27.3±3.1%. After harmonization, the similarity became 94.2±2.0% with a GM volume error of 3.11±0.56ml which corresponded to AP of 93.1±4.7%. For the test data, nWD similarity post harmonization improved from 38.2±3.9% to 93.4±2.2% with GM volume error of 4.12±0.47ml which corresponded to AP of 90.3±3.5%.

CONCLUSIONS
Our approach enables MRI harmonization while preserving anatomy for precise analysis using machine learning tools. It scales to new sites to support multisite clinical trials that utilize imaging outcomes for brain tumors and other rare diseases.
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: Ibanez Jorge , Meehl Michaela , Ward Meghan B , Ocasio Jennifer , Baker Suzanne , Krenciute Giedre 
Published: June 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.
IMMU-13. 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 J , Davidson Tom Belle , Prolo Laura , Batchelor Tracy T , Campen Cynthia J , Davis Kara L , Gust Juliane , Lim Michael , Majzner Robbie G , Park Julie R , Partap Sonia , Ramakrishna Sneha , Richards Rebecca , Schultz Liora , Vitanza Nicholas A , Wang Leo D , Mackall Crystal L , Monje Michelle 
Published: June 2024

Abstract

BACKGROUND
Immunotherapies are increasingly being explored as potential therapeutic modalities for the treatment of central nervous system (CNS) tumors and have unique toxicity profiles. Toxicity syndromes such as cytokine release syndrome (CRS) and immune effector-cell associated neurotoxicity (ICANS) were identified through experiences with chimeric antigen receptor (CAR) T-cell therapies for B cell malignancies; the creation of grading scales for these toxicities standardized the reporting and enabled management.

METHODS
From our collective experiences in treating patients with immunotherapies for CNS tumors, we have identified a localized neurotoxicity syndrome, distinct from the systemic toxicities of CRS and ICANS, termed tumor inflammation-associated neurotoxicity (TIAN).

RESULTS
TIAN develops secondary to localized inflammation at the tumor site. From a mechanistic perspective, we identified two types of TIAN: 1) type 1 TIAN arises in the setting of mechanical space constraints when peritumoral edema results in tissue shifts and increased intracranial pressure, which if untreated, can lead to a life-threatening herniation syndrome and 2) type 2 TIAN occurs when local neuronal dysfunction causes transient worsening/new neurological deficits. Whereas type 1 TIAN encompasses the concept of “pseudoprogression,” type 2 TIAN can occur in the absence of edema when neural-immune interactions disrupt local neural function. Patients can have both type 1 and type 2 TIAN simultaneously; understanding the type of TIAN can inform management. To facilitate the uniform reporting and management of TIAN, we created a TIAN grading scale that applies to both types of TIAN. Although, type 1 TIAN is generally associated with higher-grade toxicity, high-grade type 2 TIAN can occur when local inflammation compromises respiratory or autonomic functions.

CONCLUSIONS
Recognizing TIAN as a distinct, local neurotoxicity syndrome is critical to guiding clinical management and prognostication when treating patients with CNS tumors with immunotherapies.
LGG-16. BRAFV600K LOW-GRADE GLIOMA EMERGENCE DURING THERAPY FOR BRAFV600E HIGH-GRADE GLIOMA
Authors: Proctor Luke , Smith Amy , Aguilar-Bonilla Ana 
Published: June 2024

Abstract

BACKGROUND
BRAFV600E mutations are prevalent in pediatric brain tumors, constituting 20% of low-grade and 5% of high-grade gliomas. Other single-nucleotide substitutions in BRAF are described in adult cancers but rarely in pediatric brain tumors. Our case sheds light on a unique scenario—a patient with a BRAF-mutated high-grade spinal glioma who later developed slowly progressive intracranial low-grade glioma, subsequently undergoing rapid high-grade transformation.

METHODS
Case Report

RESULTS
Our patient initially presented as a thirteen-year-old male with a two-month history of progressive bilateral hand weakness/paresthesias. Spine MRI revealed a fusiform expansile intramedullary neoplasm from C3-T2, brain MRI was negative. Biopsy showed an anaplastic astrocytoma with BRAFV600E mutation and MYC-N amplification. Initial treatment included proton radiation and a 2-year course of Dabrafenib/Trametinib, maintaining disease stability. After four months off therapy, he developed local progression, and re-staging brain MRI showed new cerebellar/supratentorial lesions. Dabrafenib/Trametinib was re-started until progression two years later. He developed hydrocephalus and underwent ETV and brain tumor biopsy, which revealed a low-grade glioma with BRAFV600K mutation. At this point, Dabrafenib/Trametinib continued for another 1.5 years; he exhibited slow progression of the brain tumors before a cerebellar lesion developed rapid progression. He had GTR of the rapid-growing lesion, and pathology reported a Grade 4 invasive astrocytoma harboring BRAFV600E, two VUS MTOR mutations, and MGMT promoter methylation. Current treatment involves radiation therapy concurrent with temozolomide.

CONCLUSIONS
While combinatorial Dabrafenib/Trametinib is effective in glioma therapy, resistance and progression challenges persist. Our case presents a unique manifestation—a patient with a spinal high-grade glioma with BRAFV600E who developed a secondary low-grade glioma with BRAFV600K in the brain, which, after several years, transformed into a high-grade glioma. Future research is crucial for comprehending the intricate role of BRAF mutations in pediatric gliomas, paving the way for improved patient outcomes.
LGG-51. SYSTEMIC IMMUNE TOXICITY OF BRAF AND MEK-INHIBITORS IN CHILDREN: A PAN-CANADIAN SERIES
Authors: McKeown Tara , Renzi Samuele , Larouche Valerie , Yeung Rae , Hawkins Cynthia , Bartels Ute , Ramaswamy Vijay , Bouffet Eric , Tabori Uri , Bennett Julie , Das Anirban 
Published: June 2024

Abstract

BACKGROUND
BRAF/MEK-inhibitors have been transformative for pediatric gliomas with RAS/MAPK pathway aberrations. The RAS/MAPK pathway has a complex role in immune regulation. Though well-known in adults, the systemic immune-related adverse effects (irAE) of BRAF/MEKi in children are not widely reported.

METHODS
We performed a retrospective chart review for irAE following BRAF/MEKi in children treated at SickKids between 2016-2023. Additional patients were included through a pan-Canadian survey.

RESULTS
136 patients on BRAF/MEKi were included (MEKi: 74%, BRAFi: 13%, BRAF+MEKi: 13%); irAE was reported in 6/136 (4.5%). One additional patient was included through the national survey. Median age was 14 years (range: 7-16). Male:female was 3:4. Three patients were on BRAFi, and two each on MEKi, and BRAF+MEKi. Early events developing within weeks of drug initiation included hyper-immune systemic inflammatory responses in three children on BRAFi and one child on MEKi. There was no evidence of any concomitant infection. Two children needed intensive care and showed evidence of multi-organ dysfunction. Delayed irAE developing after months to years on therapy included multi-systemic sarcoid-like reaction, parasympathetic dysautonomia (both on BRAF+MEKi) and brachial neuritis/Parsonage-Turner syndrome (MEKi). Management included drug holidays, dose reductions, and immunosuppressive treatment with steroids. Long-term steroids were needed in two of these seven patients.

CONCLUSIONS
Pediatric oncologists need to be aware of rare yet possibly under-reported systemic immune toxicity in children treated with BRAF/MEKi. They can present acutely, or while on chronic therapy. Management may be challenging in view of issues with rebound tumor growth on stopping some of these drugs, with select patients needing concomitant, long-term immunosuppressive therapy. Genetic susceptibility and biomarkers may need to be systematically studied in future clinical trials of novel RAS/MAPK inhibitors. Continued surveillance and reporting are needed for the marketed compounds, especially for children on long-term use of these inhibitors.
LGG-55. DIFFERENTIAL TOXICITY PROFILE OF INDIVIDUAL MEK INHIBITORS: A MULTI-INSTITUTION RETROSPECTIVE REVIEW
Authors: Shin Jimin , Zhang Anthony , Meyer Ashley , Ogle Andrea , Shatara Margaret , Cluster Andrew , Abdelbaki Mohamed S , Navalkele Pournima , Faigenbaum Erica , Brosius Stephanie , Kotch Chelsea , Cantor Evan , Brossier Nicole 
Published: June 2024

Abstract

BACKGROUND
Most pediatric low-grade gliomas (pLGGs) are driven by molecular aberrations in the mitogen-activated protein kinase pathway (MAPK), which can be targeted by novel agents such as MEK inhibitors (MEKi.) However, MEKi use is accompanied by a varied side effect profile, with the most severe dose-limiting effects involving dermatologic, cardiac, and ophthalmic toxicities.

METHODS
Multi-institutional retrospective chart review of patients less than 25 years of age who underwent MEKi monotherapy between 2015-2022 was conducted. Data was collected from 4 sites, including Connecticut Children’s, St. Louis Children’s Hospital, Cardinal Glennon Children’s Hospital, and Children’s Hospital of Philadelphia.

RESULTS
Ninety-six patients were included in the analysis; 54 (56.4%) with brain tumors and 56 (58.3%) with germline mutation in NF-1. Forty-nine (51%) received trametinib, 42 (43.8%) selumetinib, 5 (5%) binimetinib. Of 42 patients with skin toxicity data available, 35 (83%) had cutaneous toxicity, with the most prevalent being acneiform rash (40.0%), followed by maculopapular rash (28.6%) and eczematous dermatitis (11.4%). The mean number of cutaneous skin toxicities was 2.4 (trametinib group = 2.2, selumetinib group = 2.6). Eighteen of 96 (18.8%) patients experienced cardiac toxicity, of which 11 (61.1%), experienced reduction in left ventricular ejection fraction (6 trametinib, 5 selumetinib), 4 (22.2%) developed pericardial effusions. 10 of 96 (10.4%) patients experienced ophthalmic toxicities, most commonly blurred vision (30.0%). Other toxicities included elevated CK (36, 37.5%), anemia (32, 33.3%), and eosinophilia (17, 17.7%).

CONCLUSION
There was not an observable clinically relevant difference in toxicities between MEKi, with skin toxicity the most prevalent. The prevalence of cardiac toxicity in the patient cohort reinforces the need for appropriate monitoring via echocardiography. MEKi remain an excellent option for therapy for LGG but with the need for continued supportive care and monitoring.
MDB-26. GENE REGULATORY NETWORK LANDSCAPE OF GROUP 3/4 MEDULLOBLASTOMA
Authors: Joshi Piyush , Stelzer Tamina , Okonechnikov Konstantin , Sarropoulos Ioannis , Sepp Mari , Pour-Jamnani Mischan V , Rademacher Anne , Yamada-Saito Tetsuya , Schneider Céline , Schmidt Julia , Schäfer Philipp , Leiss Kevin , Bortolomeazzi Michele , Mallm Jan-Philipp , da Silva Patricia B G , Statz Britta , Wittmann Andrea , Schramm Kathrin , Blattner-Johnson Mirjam , Fiesel Petra , Jones Barbara , Milde Till , Pajtler Kristian , van Tilburg Cornelis M , Witt Olaf , Rippe Karsten , Korshunov Andrey , Jones David T W , Hovestadt Volker , Northcott Paul A , Thongjuea Supat , Jäger Natalie , Kaessmann Henrik , Pfister Stefan M , Kutscher Lena M 
Published: June 2024

Abstract
Intra-tumor heterogeneity in brain cancers contributes to therapy resistance and relapse through positive selection of resistant tumor cell populations. Resolving the molecular mechanisms driving intra-tumor heterogeneity will uncover tumor-specific vulnerabilities and advance effective treatment strategies. Group 3/4 medulloblastomas, the most common embryonal cerebellar tumor subgroup, are highly heterogeneous tumors with high frequency of relapse which are almost certainly fatal. Here, we generated and analyzed a comprehensive single-cell multi-omic Group 3/4 medulloblastoma atlas, comprising 355,295 cells from 38 tumor patients representing eight Group 3/4 molecular subtypes. We identified transcription factor gene regulatory networks driving intra- and inter-tumor heterogeneity in Group 3/4 medulloblastoma, and determined the common regulatory framework that drives this heterogeneity. We show that Group 3/4 tumor diversity stems from differential enrichment of cell-states along four molecular identity axes: photoreceptor, MYC, precursor, and unipolar brush cell-like. Further, we show that intermediate subtype I/VII tumors exhibit a unique biology where a tumor exhibits dual Group 3 and Group 4-like tumor cell-states in a single tumor, and for a subset of these tumors, we identified a potential role of PAX6 in driving the observed dual trajectory. Altogether, our study demonstrates how oncogenic events together with key lineage determinants hijack normal developmental programs and drive Group 3/4 tumor identity away from the normal cerebellar unipolar brush cell-lineage.
MDB-35. DEVELOPMENT OF DUAL LUCIFERASE ASSAY FOR 3D-COMPATIBLE HIGH THROUGHPUT SCREENING IN MEDULLOBLASTOMA
Authors: Ajongbolo Aderonke O , Sperle Karen , Zheng Haozhe , Pochan Darrin J , Langhans Sigrid A 
Published: June 2024

Abstract

BACKGROUND
Medulloblastoma is the most common malignant pediatric brain tumor, originating from the cerebellum, a part of the brain that controls balance, coordinated movement and other non-motor behaviors. 2D cell cultures are commonly used for testing of new compounds in high throughput screening (HTS) targeting this cancer, largely because there are numerous highly optimized assays available for analyzing this cell culture model. However, they have significant limitation in mimicking in vivo conditions of the tumor microenvironment. 3D cell-culture methods have been embraced to enhance the modeling of in vivo tissue, replicating the multicellular architecture and the characteristics of the extracellular matrix. Presently, there are efforts to integrate 3D cell-culture with HTS to yield more clinically relevant results. However, one of the requirements for this is a 3D-compatible cell-based assay suitable for HTS. We developed such an assay which measures the activity of YAP/TAZ, a central molecule of Hippo-signaling pathway, and has been implicated in medulloblastoma. It plays a crucial role in maintaining tissue balance by coordinating proliferation, apoptosis, and differentiation.

METHODS
We cloned 8xGTIIC-NlucP, a brighter and more sensitive luciferase (Nanoluciferase) reporter plasmid that detects YAP/TAZ activity. Responsiveness to YAP/TAZ activity, and its inhibition were detected using a dual luciferase assay in the medulloblastoma cell lines after transfection. A normalization plasmid with a constitutive promoter for firefly luciferase was used in this assay to differentiate compounds that affect YAP/TAZ activity specifically as opposed to those that are toxic to the cells.

RESULTS
A robust signal for YAP/TAZ activity, and its reduction when cells were treated with inhibitor, was seen in the three medulloblastoma cell lines used, which further validates the result.

CONCLUSION
In conclusion, we were able to develop a 3D-compatible cell-based assay with Nanoluciferase which can be a foundation for HTS targeting medulloblastoma using 3D cultures.
MDB-39. HOW DO TUMOUR DERIVED EXTRACELLULAR VESICLES INTERACT WITH THE DEVELOPING NERVOUS SYSTEM AND LEAD TO ALTERED PAIN PROCESSING IN CANCER SURVIVORS?
Authors: Jackson Hannah K , Grabowska Anna , James Victoria , Dajas-Bailador Federico , Coyle Beth , Hathway Gareth 
Published: June 2024

Abstract

BACKGROUND
Childhood cancer-related pain and its treatment lack sufficient clinical attention due to limited understanding of the underlying mechanisms. While chemotherapy-induced peripheral neuropathic pain (CIPN) mechanisms in adults have been extensively studied, those in early life remain unexplored. In the CIPN literature there is a growing body of evidence for tumour derived factors altering pain processing. Our study aims to understand how tumour derived extracellular vesicles (EVs) interact with the developing nervous system and impact pain processing in childhood brain tumour survivors.

METHODS
We determined dose-response curves and IC50 values for several medulloblastoma (MB) cell lines using standard-of-care chemotherapy drugs: vincristine, etoposide, cisplatin, and lomustine. EVs were isolated via size exclusion chromatography and characterised through western blotting, flow cytometry and electron microscopy. We quantified the effects of chemotherapy on EV release using ZetaView analysis. We then tested whether EVs from relevant MB cell lines could influence axon development in primary mouse embryonic day 16.5 dorsal root ganglion (DRG) neurons in vitro after pre-treatment with chemotherapy-treated EVs.

RESULTS
EVs from chemotherapy-treated and untreated cells exhibited similar size and shape. However, a combination of vincristine, etoposide, and cisplatin at low concentrations significantly increased EV secretion by MB cell lines. Moreover, 24-hours following treatment with chemotherapeutic exposed EVs there was complete cell death of embryonic DRG neurons compared to the PBS or control EV treated neurons.

CONCLUSION
Standard chemotherapy drugs substantially enhanced EV release from MB cells, and co-culture of embryonic DRG neurons with chemotherapy exposed EVs resulted in neuronal death. Our next step is to investigate whether administering these selected EVs in healthy animals alters pain responses and pain maturation. We also aim to study the biodistribution of these EVs within the nervous system and body, after infusion into the cerebrospinal fluid as well as how EV cargo is altered by chemotherapeutics.
MDB-43. SHARED DECISION-MAKING (SDM) REGARDING RADIATION-AVOIDING (RA) THERAPY IN YOUNG CHILDREN WITH MEDULLOBLASTOMA (MB)
Authors: Kugelmann Andrew R , Gross Naina L , Srinivasan Anand , McNall-Knapp Rene Y 
Published: June 2024

Abstract

BACKGROUND
Standard treatment for MB in patients age ≥ 3 years includes craniospinal radiation with tumor bed boost and chemotherapy. Radiation carries substantial risk of long-term issues, particularly in the youngest patients: second malignancy, neurocognitive issues, vasculopathy and endocrinopathies. Numerous trials have attempted to decrease or avoid the use of radiation by intensifying chemotherapy, some using high dose chemotherapy with autologous hematopoietic stem cell rescue (HDC). One of the most successful RA protocols, Children’s Oncology Group ACNS0334 enrolled children age &lt; 36 months and treated with 3 cycles of induction (+/- high dose methotrexate) and 3 cycles HDC without planned radiation. Since 2012, we offer SDM with caregivers regarding treatment of their children ages 3-7 years with MB. Caregivers may choose standard radiation and chemotherapy (SRC) or the RA treatment above.

OBJECTIVE
Describe patient and disease characteristics and outcomes in patients aged 3-7 years treated for MB with SDM regarding the use of radiation.

METHODS
Retrospective analysis of diagnosis, treatment and clinical outcomes in all children &lt;8 y.o. who completed treatment for MB between 2012 and 2023.

RESULTS
There were 16 patients offered SDM (all gross total resection without metastases) 7 chose RA and 9 SRC. The SRC group was enriched with molecularly high-risk patients (4 MYC or MYCN amplification, 1 SHH with P53 mutation). In the RA group, relapse occurred in 14% (n=1 of 7). In the SRC group, 44% relapsed (n=4 of 9). One patient developed high-grade glioma in the radiation boost field 10 years later. There was 1 death in the RA group due to disease progression and 5 deaths in the SRC group, 1 due to second malignancy.

CONCLUSIONS
We report excellent survival with RA therapy for appropriately selected young children (age 3-7 years) when SDM is used with families to determine the best treatment for their child.