bluuebunny/crossref_metadata_2025_split huggingface dataset:
IMG-10. IMAGING SUBTYPES OF PEDIATRIC LOW-GRADE GLIOMA ARE ASSOCIATED WITH DISTINCT MOLECULAR CHARACTERISTICS
Authors: Kazerooni Anahita Fathi , Kraya Adam , Rathi Komal S , Kim Meen Chul , Kesherwani Varun , Vossough Arastoo , Familiar Ariana , Khalili Nastaran , Storm Phillip B , Ware Jeffrey B , Song Yuanquan , Foster Jessica , Mueller Sabine , Fisher Michael J , Resnick Adam C , Nabavizadeh Ali 
Published: June 2024

Abstract

BACKGROUND
Pediatric low-grade gliomas (pLGGs) have diverse molecular subtypes with distinct prognoses, necessitating personalized treatments. We aimed to determine whether radiomic features of pLGGs co-segregate with molecular subtypes, establishing a proof-of-concept that distinct molecular aberrations could manifest in differentiable imaging features.

METHODS
Leveraging radiomic, genomic, and transcriptomic data from 201 pLGG patients from the Children’s Brain Tumor Network (CBTN), we identified imaging-based pLGG subtypes through their radiophenotypes. This involved investigating the association of imaging subtypes with 2021 WHO pLGG classifications and profiling transcriptional characteristics distinguishing pLGG clusters. We used principal component analysis and K-Means clustering on 881 radiomic features and incorporated clinical variables (age, sex, tumor location), and derived three imaging subtypes.

RESULTS
BRAF V600E mutations were mainly found in subtype 3, while BRAF::KIAA1549 fusion in subtype 1. To ascertain transcriptome pathways most closely associated with imaging-based subtypes, we applied a supervised machine learning model with elastic net logistic regression using a one-versus-rest strategy for each imaging cluster, considering the top 100 most variable pathways, identified through gene set enrichment and gene co-expression network analyses, molecular subtype, tumor location, age, sex, and race. The predictive accuracy (area under the receiver operating characteristic curve) of the model was 0.86 | 0.72 for imaging subtype 1, 0.93 | 0.71 for subtype 2, and 0.91 | 0.64 for subtype 3 in the training | testing sets. Notably, each imaging subtype exhibited distinct molecular mechanisms; subtype 1 showed up-regulation of oxidative phosphorylation, PDGFRB, and interleukin 4, 10, and 13 signaling, while subtype 3 was linked to histone acetylation and DNA methylation pathways, relating to BRAF V600E pLGGs.

CONCLUSIONS
Our radiogenomics study suggests that intrinsic molecular characteristics of tumors drive distinct imaging subgroups of pLGG, providing a basis for future multi-modal investigations that may better define progression and targetability of the disease.
IMG-16. DECIPHERING THE NEUROIMAGING SPECTRUM OF AT/RT: A PICTORIAL REVIEW OF ATYPICAL TERATOID/RHABDOID TUMORS
Authors: Gonçalves Fabrício G , Goldman-Yassen Adam E , Desai Sandeep , Chauhan Richa S , Rusyn Anastasiia , Carvajal Mario Enrique M , Cardenas Agustin , Cerron-Vela Carmen , Yildiz Harun , Dias Tassiana Cristhina S , Li Rong , Dhall Girish , Johnston James M 
Published: June 2024

Abstract

BACKGROUND
This study presents a detailed pictorial review of Atypical teratoid/rhabdoid tumor (AT/RT), a high-grade central nervous system (CNS) malignancy, emphasizing the relationship between neuroimaging characteristics and clinical, molecular, and histopathological aspects. AT/RT is mainly characterized by the biallelic inactivation of SMARCB1 and occasionally SMARCA4 genes.

METHODS
The review methodically analyzes neuroimaging findings from various imaging techniques, notably MRI. It documents AT/RT appearances in different brain regions, including the cerebellum, cerebellopontine angle cistern, intraventricular, suprasellar, supratentorial, pineal, spinal canal, and cranial nerves. The study integrates these findings with clinical presentation, molecular subtypes (AT/RT-SHH, AT/RT-TYR, and AT/RT-MYC), and pathogenesis, highlighting the connection between imaging features and molecular subtypes.

RESULTS
The results indicate distinctive neuroimaging characteristics of CNS AT/RT, varying with tumor location and molecular subtypes. Common imaging features include contrast enhancement and signal intensity variations on MRI, including subtype-specific variations. Advanced neuroimaging plays a key role in distinguishing AT/RT from other pediatric CNS tumors, aiding in biopsy and treatment planning. Notably, imaging findings are linked with genetic changes, particularly the involvement of SMARCB1 and SMARCA4, affecting tumor appearance and behavior.

CONCLUSIONS
This review underscores the significance of neuroimaging in diagnosing and treating CNS AT/RT. The comprehensive analysis of imaging, combined with molecular and histopathological data, offers valuable insights into AT/RT’s heterogeneous nature. This integrative approach is crucial for a better understanding of AT/RT and for the development of more effective, targeted therapies.
IMG-19. CLINICAL UTILITY OF NON-FDG PET-MRI IN CHILDREN WITH CNS NEOPLASMS: A TERRITORY-WIDE STUDY FROM HONG KONG
Authors: Liu Anthony P Y , Yan Carol L S , Cheng P W , Lo S S M , Chow Terry T W , Fu Eric C H , Yau Jeffrey P W , Lee Vincent , Chan Godfrey C F , Ku Dennis T L , Shing Matthew M K , Siu Deyond Y W 
Published: June 2024

Abstract

INTRODUCTION
Magnetic resonance imaging (MRI) is the gold-standard for neuroimaging, yet details from anatomical scans might be inconclusive in certain scenarios. This study aimed to investigate the utility of amino-acid tracer positron emission tomography-magnetic resonance imaging (PET-MRI) based on a territory-wide Pediatric Neuro-Oncology cohort from Hong Kong.

METHODS
We reviewed the PET-MRI scans of pediatric patients with suspected/confirmed CNS neoplasms co-managed by Hong Kong Children’s Hospital and St. Teresa’s Hospital, Hong Kong from 5/2022-1/2024. Tracers used included C11-MET (n=10, before 5/2023) and F18-FET (n=15, in/after 5/2023). Lesion-to-normal SUVmax ratios (LNRmax) were measured with reference to adjacent or contralateral normal brain structures.

RESULTS
Twenty-five patients were included (M:F=13:12) with a median age of 10 years (range: 1-17). Anatomical sites of interest were the pituitary (n=13), basal ganglia (n=3), cerebellum (n=3), brainstem (n=2), frontal lobe (n=2), cerebellopontine angle (n=1), and spine (n=1). PET-MRI was performed as part of initial diagnostics in 21, to assess post-operative residual in 2, and for possible relapse in 2. Among those evaluated upfront (n=21), median SUVmax and LNRmax were 1.53 (range: 0.87-2.6) and 0.87 (range: 0.45-1.92) respectively in patients with presumed/confirmed low-grade glioneuronal (n=5) or non-oncologic lesions (n=8), versus 4.75 (range: 2.58-9.6) and 3.26 (range: 1.78-4.9) in patients with histologically/biochemically confirmed high-grade lesions (germinoma=6, high-grade glioma=2). Availability of functional PET imaging was deemed useful for scan interpretation in all 25 patients. Specifically, the use of PET-MRI facilitated decision for radiographic surveillance without biopsy/resection in 12 patients, refined tumor grading in 2 patients with discrepant clinical-histologic features, and allowed response-adapted therapy after serial scans in 5 patients.

CONCLUSIONS
Our study demonstrates the potential benefits of PET-MRI in the management of children with CNS pathologies. PET-MRI contributes to the diagnosis, monitoring, and treatment guidance of these patients, providing crucial information for clinical decision-making.
IMG-27. ASSESSMENT OF VARIABILITY OF PEDIATRIC BRAIN TUMOR IMAGING PROTOCOLS ACROSS INSTITUTIONS: ARE WE FOLLOWING RECOMMENDATIONS?
Authors: kotha Apoorva , Yang David L , Aboian Mariam , Nagaraj Usha D , Bhatia Aashim , Goldman-Yassen Adam Ezra 
Published: June 2024

Abstract

BACKGROUND
Evaluating pediatric brain tumors requires imaging children with tailored MRI protocols. Considerable variation in pediatric brain tumor imaging protocols exist across institutions, which can cause inaccuracies in staging. Although recently consensus guidelines for pediatric brain tumor imaging protocols have been established, adherence to these guidelines across institutions is unknown. Institutions may perceive guidelines as applicable for research purposes rather than routine clinical practice. We aim to explore variability in pediatric brain tumor imaging protocols across institutions and determine the factors influencing guideline divergence.

METHODS AND METHODOLOGY
Faculty at institutions routinely imaging pediatric patients with brain tumors were invited to share brain tumor MRI protocols and complete a structured survey. The survey included multiple choice and open-ended queries concerning practice type, the presence of an institutional imaging protocol for pediatric brain tumors and if the protocol was based on specific consensus recommendations. We assessed if protocols included the 7 minimum recommended MRI sequences by the Children’s Oncology Group (COG) guidelines, including slice thickness and gap.

RESULTS
Twenty emails were sent and responses were received from 12 institutions (the data collection is still ongoing). 2 institutions did not have dedicated protocols for pediatric brain tumors. On average, institutions had 5.7 out of the 7 minimum COG-recommended sequences. All 10 institutions included 3D T1 IR-GRE/TSE, DWI or DTI, and SWI sequences in their protocols. 9 (90%) included post-contrast 3D T1 IR-GRE/TSE, 7 (70%) included T2 TSE/FSE, 7 (70%) included either 3D T2 FLAIR or T2 FLAIR TSE/FSE, and 4 (40%) included T1/TSE/FSE. Across all sequences in all protocols, adherence to recommended imaging parameters was 87% for plane, 71% for slice thickness, and 85% for gap.

CONCLUSION
Significant variability in pediatric brain tumor imaging protocols exists across institutions Standardizing imaging protocols through collaboration is vital in ensuring uniformity in care.
IMMU-01. PIONEERING QUAD-TARGETING CAR T CELL THERAPY IN PEDIATRIC CNS TUMORS – ANALYSIS FROM THE INITIAL PATIENTS TREATED ON THE FIRST-IN-HUMAN PHASE 1 TRIAL BRAINCHILD-04
Authors: Ronsley Rebecca , Choe Michelle , Seidel Kristy , Narayanaswamy Prabha , Pattabhi Sowmya , Wendler Jason , Ho On , Rawlings-Rhea Stephanie , Gust Juliane , Huang Wenjun , Crotty Erin , Leary Sarah , Hauptman Jason , Albert Catherine M , Gardner Rebecca A , Park Julie R , Annesley Colleen , Jensen Michael C , Vitanza Nicholas A 
Published: June 2024

Abstract

BACKGROUND
BrainChild-04 is a first-in-human clinical trial of quad-chimeric antigen receptor (CAR) T cell therapy for children and young adults with central nervous system (CNS) tumors. This trial administers repeated locoregional CAR T cells targeting B7-H3, EGFR, HER2, and IL-13Ralpha2 (“quad-CAR T cells”), leveraging multi-antigen targeting to address the tumor heterogeneity of high-grade CNS tumors.

METHODS
The primary endpoints are feasibility and safety, and secondary endpoints are disease response and correlative studies of CAR T cell activity. The trial utilized a Bayesian Optimal Interval (BOIN) design with three dose regimens (DR). There are 2 arms with weekly delivery for 3 weeks of a 4-week cycle:(A) –diffuse intrinsic pontine glioma (DIPG), (B) –non-pontine diffuse midline glioma (DMG) or other relapsed CNS tumors.

RESULTS
Enrolled patients include DMG N=6, DIPG N=5, other CNS tumors N=4. Of the 15 enrolled patients, 7 have been infused with 8 awaiting infusions. A total of 33 intracranial CAR T doses have been delivered, including Arm A DR 1 (N=1), Arm B DR 1 (N=3), DR2 (N=3). The most common adverse events have been grade 1-2 fever (7/7 patients), grade 1-3 headache (6/7), and grade 1-2 nausea/vomiting (6/7). There have been no DLTs and no cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity(ICANS). CTCAE and tumor inflammation-associated neurotoxicity are both being captured. All treated patients are alive with median follow up time post-initial infusion of 93(14-198) days. CAR T cells were detected by flow cytometric analysis of CSF post-infusion in 14/24 CSF samples. Radiographic response, CSF ct-DNA, targeted mass spectrometry, and cytokine analysis will be presented.

CONCLUSIONS
Our preliminary experience suggests tolerability of locoregional quad-CAR T therapy at doses evaluated. The trial remains ongoing and these data support continued evaluation of this product to better assess anti-tumor activity in patients with CNS tumors, including DIPG/DMG.
IMMU-02. MODIFYING CAR T CELL EPIGENETIC PROGRAMS TO IMPROVE THEIR PERSISTENCE AGAINST GROUP 3 MEDULLOBLASTOMAS
Authors: Ward Meghan B , Senaoui Linda , Youngblood Ben A , Roussel Martine F , Krenciute Giedre 
Published: June 2024

Abstract

BACKGROUND
Safe, effective therapies are desperately needed to improve outcomes for patients with medulloblastoma (MB), a malignant pediatric brain cancer. Chimeric antigen receptor (CAR)-T cells are a promising therapeutic option as they target T-cell cytotoxicity exclusively to tumor associated antigens. B7-homolog 3 (B7-H3) is an ideal target for CAR-T cell therapy as all MB subtypes express B7-H3 and healthy tissues do not. However, a roadblock to tumor clearance is the inability of B7-H3 CAR-T cells to persist, suggesting that improving persistence will benefit anti-tumor efficacy. The goal of this study was to compare head-to-head knocking out TET2 or DNMT3A negative epigenetic regulators of CAR-T cell persistence against group 3 MB (G3MB), the most malignant MB subtype.

METHODS
We generated B7-H3 CAR-T cells with CD28ζ signaling domain and performed CRISPR/Cas9 knockout (KO) of TET2, DNMT3A, and AAVS1 as a control. We compared resulting CAR-T cell persistence via repeat stimulation assays in vitro against G3MB cell lines with varying B7-H3 antigen density (D341low, HDMB03mid, and D425high). We further compared KO CAR-T cells in vivo against D341low, HDMB03mid, and D425high orthotopic xenografts.

RESULTS
Our data shows that DNMT3A KO, but not TET2 KO, consistently improves the persistence and expansion of CAR-T cells against G3MB in vitro. In vivo, KO of epigenetic regulators moderately improves CAR-T cell therapy against highly aggressive D341low, HDMB03mid, and D425high but is insufficient to elicit curative responses.

CONCLUSIONS
Our study demonstrates that genetic KO of negative epigenetic regulators of CAR-T cell persistence can improve anti-tumor function against G3MB. We conclude that for the B7-H3.CD28ζ CAR, DNMT3A KO is superior for improving persistence over TET2 KO, but that DNMT3A KO is insufficient in vivo. We believe this is due to the aggressive nature of G3MB and we are optimizing in vivo studies for better representation of CAR-T cell persistence.
IMMU-04. THE ROLE OF CHECK POINT INHIBITORS IN PEDIATRIC PRIMARY DIFFUSE LEPTOMENINGEAL MELANOMATOSIS: REPORT OF TWO CASES
Authors: Oren Liat , Vlodavsky Evgeni , Raz Michal , Yaniv Zoar , Benifla Mony , Constantini Shlomi , Arush Myriam Ben , Campino Gadi Adebe 
Published: June 2024

Abstract

BACKGROUND
Primary diffuse leptomeningeal melanomatosis (PDLM), a subtype of malignant melanomas of CNS, is rare, especially in children. PDLM is defined by diffuse invasiveness of the leptomeninges with or without nodules. Clinical manifestations of PDLM are nonspecific, mimicking the diagnosis of meningitis. As PDLM is neither sensitive to chemotherapy nor radiotherapy, the prognosis is extremely poor. Recently, some new therapeutic aspects like immunotherapy, especially immune check point inhibitors (ICI) are emerging. Cases report: First case: A 13 years old boy presented with 4 months of weakness, dysphasia and vomiting. MRI demonstrated diffuse leptomeningeal enhancement of the brain and spine. Brain biopsy confirmed the diagnosis of PDLM, with low PDL1 stains in immunohistochemistry, without targetable alterations on NGS. PET FDG normal. Treatment with ICI (Nivolumab 1 mg/kg/dose and Ipilimumab 3 mg/kg/dose, 4 courses every 21 days) was started. He developed severe complications after the 1st course (ICI enterocolitis, pancreatitis) and progressive disease after 2 courses. Craniospinal radiotherapy was delivered at a dose of 30 Gy. The disease continued to progress; the patient died nine months after diagnosis. Second case: A 7-year-old boy presented with diplopia, headache and vomiting. MRI demonstrated a cranial leptomeningeal enhancement and hypo-intense T1 and hyper-intense T2 signal at bilateral medial frontal cortex area. PET FDG normal. Brain biopsy confirmed the diagnosis of PDLM, with TMB 1.9, NRAS mutation and wild type BRAF by NGS. He started combination of ICI therapy. Three weeks after 1st course of Ipilimumab-Nivolumab he was admitted to PICU with prolonged status epilepticus. MRI demonstrated progression of leptomeningeal disease. Trametinib was deferred by parents and the child succumbed a year from diagnosis.

CONCLUSIONS
We report two cases of pediatric patients with PDLM treated unsuccessfully by immune check point inhibitors, emphasizing the diagnostic and therapeutic challenges in such a rare disease.
LGG-07. MULTI-OMICS ANALYSIS IDENTIFIES MOLECULAR DRIVERS AND THERAPEUTIC TARGETS IN DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR WITH 1Q GAIN
Authors: Mikkelsen Margit , Li Xiaoyu , Yu Kaiwen , High Anthony , Tran Haiyan , Furtado Larissa V , Leelatian Nalin , Berry Julia D , Mobley Bret C , Dewan Michael C , May Adriana , Kofler Julia , Foster Jessica , Lazow Margot , Boué Daniel R , Qaddoumi Ibrahim , Robinson Giles W , Peng Junmin , Moreira Daniel C , Chiang Jason 
Published: June 2024

Abstract

BACKGROUND
Diffuse leptomeningeal glioneuronal tumors (DLGNT) with 1q gain (1q+) display aggressive clinical behavior. We sought to better describe the clinical characteristics of patients with DLGNT and identify molecular drivers and therapeutic vulnerabilities of DLGNT with 1q+.

METHODS
DLGNTs were collected from multiple institutions, sent for methylome array and if quantity-sufficient, were subjected to RNA-seq, proteome, and phosphoproteome profiling. Wherever available, clinical data was collected.

RESULTS
Twenty DLGNTs (13 with 1q+, 7 without 1q+) were collected. Clinical data was obtained on 15 patients (8 with 1q+, 7 without 1q+). The median progression-free survival (PFS) was 17.5 months for those with 1q+ tumors, compared to 51 months for those without (p=0.058). All with 1q+ tumors (n=4) that received CSI radiotherapy progressed (median 12 months), compared to none without (n=3) (p=0.12). There were no responses (complete or partial) in 1q+ tumors that received chemotherapy (n=8), with 2 progressions on therapy. In tumors without 1q+ that received chemotherapy (n=6), 2 responded (1 complete, 1 partial) and 1 progressed on therapy. For 1q+ tumors that received targeted therapy (n=6), there were no responses and 2 progressions on therapy, compared to 1 response and 1 progression for tumors without (n=3). Gene Set Enrichment Analysis of all differentially methylated regions demonstrated enrichment of genes acting in mRNA processing, transcriptional regulation, p53 signaling, TGF-β receptor signaling, and T cell receptor signaling in 1q+ tumors. It identified genes with transcription factor (TF) binding sites for TFs involved in MAPK, PI3K/AKT/mTOR, WNT, and p53 pathways. Consistent with these results, hypomethylated genes at chromosome 1q in 1q+ tumors are positive regulators of MAPK, PI3K/AKT/mTOR, WNT, and p53 signaling.

CONCLUSIONS
DLGNT with 1q+ were more refractory to current treatment options. We identified putative molecular drivers in 1q+ tumors. Our findings suggest therapy targeting the multiple affected pathways should be considered.
LGG-20. SELUMETINIB IN PEDIATRIC PATIENTS WITH RELAPSED/REFRACTORY OPTIC PATHWAY/HYPOTALAMIC LOW GRADE GLIOMA: A MONOINSTITUTIONAL EXPERIENCE
Authors: Schiavello Elisabetta , Biassoni Veronica , Nigro Olga , Gattuso Giovanna , Puma Nadia , Bergamaschi Luca , Colombo Valeria , Schiariti Marco Paolo , Carrabba Giorgio Giovanni , Massimino Maura Rita 
Published: June 2024

Abstract

BACKGROUND
Pediatric low-grade gliomas (pLGG) are the most common central nervous system tumors in children. The optic pathway and hypothalamic (OPH) frequent localizations are correlated with multiply relapses due to inoperability, thus emphasizing the need for alternative treatments. The results of activation of the BRAF oncogene through a tandem duplication resulting in a KIAA1549–BRAF fusion is the most common genetic aberration. Selumetinib is an oral mitogen-activated protein kinase (MEK) 1/2 inhibitor with promising efficacy and good tolerability on relapsed/refractory pLGG.

METHODS
From January 2021 to January 2024 three patients with refractory OPH-pLGG with KIIA1549-BRAF fusion were treated with Selumetinib 25 mg/sqm/day (compassionate use) all after two lines of chemotherapy. They were males, mean age at diagnosis 8 months, at starting Selumetinib 74 months. All had partial surgery at diagnosis and two of them other debulking surgeries during the treatment. All patients had numerous events of hydrocefalous with need of shunt revision.

RESULTS
Two patients experienced grade-3 stomatitis, one grade 3 nausea-vomiting, one grade 3 gastritis, one grade 1 increased level of CPK (CTCAE-V5.0). For grade 3 toxicity Selumetinib had to be stopped for a maximum of 7 days with clinical benefit. Two of them have completed treatment with Selumetinib, one is ongoing after 20 months, all with radiological stable disease at MRI. Median time of treatment is 26 months (range 20-30 months). All three experienced a trend in reduction of emergency room admission for ventricular-shunt problems. Median PFS at starting Selumetinib was 62 months, median OS is 97 months.

CONCLUSIONS
Selumetinib has a good profile of toxicity, allowing a good quality of life procrastinating radiotherapy and reducing surgery events in a context of heavily pretreated relapsed/refractory patients. Further data are needed on both visual and auxological parameters and late side effects.
LGG-33. NETWORK ANALYSIS INTEGRATING MICRORNAS AND CLINICAL DATA TO DETERMINE PROGNOSTIC OUTCOME IN PEDIATRIC LOW-GRADE GLIOMA PATIENTS
Authors: Catanzaro Giuseppina , Conte Federica , Besharat Zein Mersini , D’Antonio Federica , Spinello Zaira , Carai Andrea , Massimi Luca , Gessi Marco , Figarella-Branger Dominique , Paci Paola , Locatelli Franco , Mastronuzzi Angela , Ferretti Elisabetta 
Published: June 2024

Abstract

BACKGROUND
Low-grade pediatric gliomas (pLGGs) are the most common pediatric brain tumors. Surgical resection, when feasible, represents the standard of care. If complete resection cannot be achieved, disease progression occurs in about 30% of the cases, and these patients receive adjuvant therapy. The identification of predictive biomarkers to predict tumors that will progress after partial resection, requiring systemic treatment (Chemotherapy or target therapy), could support clinicians in the decision-making strategy. MicroRNAs have been related to tumorigenesis and tumor maintenance and can be used as important biomarkers. This study aims to develop a predictive model able to determine prognostic outcomes and to better stratify pLGG patients according to disease progression.

METHODS
MicroRNAs levels have been assessed in 76 human tumor tissue samples. Clinical data have been collected for statistical and network-based analyses. Using a network-based approach, we integrated clinical data and tissue microRNA expression to identify a microRNA signature able to predict disease progression.

RESULTS
Our preliminary microRNA expression analysis displayed new promising signatures correlating with prognostic features, such as disease progression and embryological origin of the tumor.

CONCLUSION
The predictive model we developed integrating biomarkers and clinical data could be crucial to support clinicians in the decision-making strategy and in advancing personalized medicine.