bluuebunny/crossref_metadata_2025_split huggingface dataset:
IMG-31. DEUTERIUM METABOLIC IMAGING OF RESPONSE TO PRECISION THERAPY IN BRAF-V600E MUTANT GLIOMAS
Authors: Batsios Georgios , Udutha Suresh , Gillespie Anne Marie , Petritsch Claudia , Mueller Sabine , Viswanath Pavithra 
Published: June 2024

Abstract

BACKGROUND
Oncogenic BRAF-V600E mutations are frequently observed in low- and high-grade gliomas in children. BRAF transduces signals from receptor tyrosine kinases to downstream effectors such as MEK1/2 and ERK, which regulate metabolism and proliferation. The combination of the BRAF-V600E inhibitor dabrafenib and the MEK1/2 inhibitor trametinib (Dab/Tra) improves patient survival. However, there is considerable variation in response durability, underscoring the need for early biomarkers of treatment response. Magnetic resonance imaging (MRI), which is the gold standard for patient management, does not reliably assess response to therapy. Since the BRAF/MEK pathway regulates metabolism, the goal of this study was to determine whether Dab/Tra induces alterations in glucose metabolism that can be leveraged for non-invasive imaging of response to therapy.

METHODS
We performed gene expression profiling, in vivo metabolomics, stable isotope tracing, and deuterium metabolic imaging in patient-derived and syngeneic BRAF-V600E mutant models (AM38, 2341).

RESULTS
Our studies indicate that Dab/Tra downregulates glucose metabolism to lactate in AM38 and 2341 cells. In vivo infusion with [U-13C]-glucose in mice bearing intracranial AM38 tumors confirmed that Dab/Tra downregulates 13C-lactate production in the tumor. Mechanistically, Dab/Tra destabilizes hypoxia inducible factor-1a and downregulates glycolytic genes, including SLC2A1, HK2, PFKFB3, and LDHA. Importantly, deuterium metabolic imaging using [6,6’-2H]-glucose, which is a clinical stage method of imaging glycolysis, shows a reduction in lactate production within 48h of treatment with Dab/Tra in AM38 tumor-bearing mice.

CONCLUSIONS
Our studies mechanistically link BRAF/MEK inhibition with reduced glycolysis and identify [6,6’-2H]-glucose as a novel, non-invasive agent for imaging early response to therapy. Since [6,6’-2H]-glucose is a safe, orally administered agent, our studies can be rapidly translated to the clinic, where they will provide physicians with a much-needed tool to determine whether patients are responding to therapy at an early timepoint that predicts extended survival.
IMMU-07. COMBINED PD1 AND LAG3 INHIBITION IN PRECLINICAL MODELS AND PATIENTS WITH DNA REPLICATION REPAIR DEFICIENT GLIOBLASTOMA (RRD-GBM): AN IRRDC STUDY
Authors: Das Anirban , Crump Owen , Kos Olha , Stengs Lucie , Li Amanda , Levine Adrian , Nakano Yoshiko , Stein Alexander , Abebe-Campino Gadi , Bronsema Annika Eva Charlotte , Bianchi Vanessa , Edwards Melissa , Zacharoulis Stergios , Ertl-Wagner Birgit , Morgenstern Daniel , Pugh Trevor J , Ohashi Pamela S , Bouffet Eric , Hawkins Cynthia , Dirks Peter , Tabori Uri 
Published: June 2024

Abstract

BACKGROUND
RRD-GBM harbour high tumor mutation burden (TMB) and respond to anti-PD1 immune checkpoint inhibition (ICI). However, the majority ultimately progress, highlighting the need for combinatorial therapies for sustained immune-surveillance.

METHODS
We performed transcriptomic analyses of human RRD-GBM specimens for immune checkpoint expression, and accordingly, tested combined ICI in immunocompetent murine models. Based on these preclinical data, we treated refractory patients using a combination of anti-PD1 and anti-LAG3 through single-patient trials/ compassionate access. Complimentary immuno-genomic biomarker analyses including circulating tumor DNA (ctDNA) were performed to study mechanisms and track responses.

RESULTS
Human RRD-GBM (n=80) demonstrated high LAG3 expression, providing a strong rationale for targeting. We tested combined anti-PD1 and anti-LAG3 inhibition in three immunocompetent RRD-GBM murine models. In the anti-PD1-responsive (Nestin-Cre-MSH2LoxP/LoxP-POLES459F/+) model, combined inhibition resulted in universal tumor response and survival. In the anti-PD1 resistant models (Mlh1-/-/Nestin-Cre+/Trp53LoxP/LoxP and therapy-induced hypermutant ENU/Trp53-/- gliomas), the combination improved survival despite a lack of response to anti-PD1 monotherapy. Biologically, high LAG3 expression and exhaustion was observed in CD8 T-cells after treatment with anti-PD1, which was subsequently ablated by the addition of anti-LAG3. Serially transplanted mice showed response and improved survival to the combination, suggesting that resistance to anti-PD1 could be abrogated by the combination. Four patients with RRD-GBM who had failed anti-PD1 treatment were treated using the combination, resulting in objective radiological responses and prolonged ongoing survival in patients with RRD-GBM and high LAG3 expression. Tolerability was better than a previous study of combined CTLA4 and PD1 inhibition for similar patients. Correlation with paired immuno-genomic tumor analyses, flow-cytometry, T-cell receptor clonotype and CSF ctDNA are ongoing prospectively.

CONCLUSION
LAG3 is an effective target in refractory RRD-GBM. Combined inhibition with anti-PD1 inhibition demonstrated radiological response, prolonged survival and manageable toxicities in patients, and will be tested in future clinical trials.
IMMU-16. LOCOREGIONAL DELIVERY OF MRNA CAR T CELL THERAPY INTO THE CEREBROSPINAL FLUID IN PRECLINICAL MODELS OF DIFFUSE MIDLINE GLIOMA
Authors: Harvey Kyra , Al-atrache Zein , McManus Olivia , Dickson Conor , Patterson Luke , Beaubien Ezra , Wilson Cullen , Hajeebu Sreehita , Keil Samantha , Braun Molly , Meechan Michael , Vitanza Nicholas A , Iliff Jeff , Madsen Peter , Foster Jessica 
Published: June 2024

Abstract

BACKGROUND
GD2-directed Chimeric Antigen Receptor (CAR) T cell therapy is a promising immunotherapeutic modality for diffuse midline glioma (DMG). We developed mRNA CAR T cells as a safe alternative to virally transduced CAR T cells and have shown that intra-tumoral (IT) infusions of mRNA GD2-directed CAR T cells result in significant tumor regression with improved toxicity in murine DMG models. For clinical translation, we sought to determine the optimal route and trafficking patterns of CAR T cells administered into the cerebrospinal fluid (CSF).

METHODS
NSG mice engrafted with DMG xenograft SU-DIPG13P* in the pons were treated with 5x106 mRNA CAR T cells either into the lateral ventricle (LV) or into the cisterna magna (CM), with brains harvested after 24 hours for analysis using confocal microscopy.

RESULTS
Both LV and CM treated mice showed higher GD2-directed CAR T cell migration to tumors compared to CD19-directed controls, with higher accumulation of GD2-directed CAR T cells in the parenchyma for LV treated mice compared to CM (p&lt;0.001). To evaluate efficacy of delivery in the CSF, NSG mice engrafted with DMG xenograft 7316-6349 in the pons were treated with 5x106 mRNA CAR T cells IT, LV, or CM twice a week for 3 weeks totaling 6 doses. Mice were imaged weekly to monitor bioluminescent tumor signal, showing that mice treated with GD2-directed CAR T cells IT had significantly decreased tumor burdens compared to LV and CM GD2 CAR treated groups (p &lt; 0.05 and p &lt; 0.01 respectively), as well as compared to CD19 controls (p &lt; 0.01).

CONCLUSIONS
Despite local infiltration, mRNA CAR T cells delivered into the CSF did not fully reduce tumor burden, and thus, future work is aimed at evaluating potential routes of priming tumors to attract subsequent cellular therapy doses delivered intra-ventricularly.
LGG-01. PROGNOSTIC UTILITY AND CHARACTERISTICS OF MIB-1 LABELING INDEX AS A PROLIFERATIVE ACTIVITY MARKER IN CHILDHOOD LOW-GRADE GLIOMA: A RETROSPECTIVE OBSERVATIONAL STUDY
Authors: Gorodezki David , Zipfel Julian , Thomas Nägele , Ebinger Martin , Schuhmann Martin U , Schittenhelm Jens 
Published: June 2024

Abstract

BACKGROUND
The prognostic utility of MIB-1 labeling index (LI) in pediatric low-grade glioma (PLGG) has not yet conclusively been described. We assess the correlation of MIB-1 LI and tumor growth velocity, aiming to contribute to the understanding of clinical implications and the predictive value of MIB-1 LI as an indicator of proliferative activity and progression-free survival (PFS) in pediatric low-grade glioma.

METHODS
MIB-1 LI of a cohort of 172 pediatric low-grade gliomas were comprehensively characterized. Correlation to tumor growth velocity, assessed by sequential MRI-based three-dimensional volumetric analyses, and PFS was analyzed.

RESULTS
Mean MIB-1 LI accounted for 2.7 % (range: &lt;1 – 10) and showed a significant decrease to 1.5 % at secondary surgery (p =.0013). A significant difference of MIB-1 LI in different histopathological types and a correlation to tumor volume at diagnosis could be shown. Linear regression analysis showed a correlation between MIB-1 LI and preoperative TGV (R² =.55, p &lt;.0001), while correlation to tumor growth velocity remarkably decreased after incomplete resection (R² =.08, p =.013). Log-rank test showed no impact of MIB-1 LI on 5-year PFS after incomplete (MIB-1 LI &gt; 1 vs ≤ 1%: 48 vs 46 %, p =.73) and gross-total resection (MIB-1 LI &gt; 1 vs ≤ 1%: 89 vs 95 %, p =.75).

CONCLUSIONS
This data confirms a correlation of MIB-1 LI and radiologically detectable tumor growth velocity in PLGG for the first time. Compared to preoperative tumor growth rates, a crucially decreasing correlation of MIB-1 LI and tumor growth velocity after surgery may result in limited prognostic capability of MIB-1 LI in pediatric low-grade glioma.
LGG-10. RECOMBINANT HUMAN ENDOSTATIN IN COMBINATION WITH CHEMOTHERAPY FOR PEDIATRIC LOW-GRADE GLIOMAS
Authors: Zhang Jun-ping , Ge Jing-jing , Liu Ya-jing 
Published: June 2024

Abstract

BACKGROUND
Pediatric low-grade gliomas (pLGGs) entail highly effective treatment regimens. In this study, we aimed to examine the efficacy and safety of recombinant human endostatin (rh-ES) combined with chemotherapy for pLGGs.

METHODS
We collected the clinical data of pLGG patients treated with carboplatin and vincristine (CV) plus rh-ES in the Department of Neuro-oncology, Sanbo Brain Hospital Capital Medical University, Beijing, China, from July 2015 to October 2019 and retrospectively analyzed the effectiveness and safety of this regimen.

RESULTS
A total of 41 eligible patients were enrolled. Median age at diagnosis was 4 years. Median follow-up lasted for 22.7 months (range 8-73.4 months). Six patients achieved complete response, 7 attained partial response, 4 had minor response, the disease was stable in 3 cases, and in 1 the condition progressed. The objective response rate was 90.2% and complete response rate was 14.6%. The median time to response was 4.1 months. The duration of response was 28.1 months. The progression rate within 6 months of treatment completion was 6.9%. 5-year rates were 74% for progression-free survival and 92% for overall survival. The main toxicities included myelosuppression and carboplatin allergy. No serious rh-ES-related toxicities were observed.

CONCLUSIONS
Rh-ES in combination with CV in pLGG patients was effective and safe and could achieve rapid and lasting responses.
LGG-15. DEEP LEARNING ENABLES LONGITUDINAL RISK PREDICTION FOR PEDIATRIC LOW-GRADE GLIOMAS AFTER SURGERY
Authors: Tak Divyanshu , Garomsa Biniam Amsalu , Zapaishchykova Anna , Ye Zezhong , Vajapeyam Sridhar , Mahootiha Maryamalsadat , Pardo Juan Carlos Climent , Familiar Ariana , Liu Kevin , Bandopadhayay Pratiti , Nabavizadeh Ali , Mueller Sabine , Aerts Hugo , Haas-Kogan Daphne , Poussaint Tina Young , Kann Benjamin Harris 
Published: June 2024

Abstract

BACKGROUND
Disease progression is challenging to predict following surgery for pediatric low-grade glioma (pLGG), and early progression indicators on MRI surveillance imaging would help guide management. Longitudinal surveillance imaging data may capture subtle temporal tumor changes and patterns that could inform recurrence risk but are difficult to synthesize clinically. We applied deep, self-supervised learning to longitudinal surveillance MRI to predict short-interval event-free-survival (EFS) risk from time-of-scan.

METHODS
We retrospectively collected data from 278 patients (2,174 scans) who underwent surgical resection for pLGG at Dana-Farber Cancer Institute/Boston Children’s Hospital (DFCI/BCH) from 1990-2022. A deep-learning model was pretrained with T2-FLAIR sequences to determine the chronological scan order for each patient (temporal pretraining). The model was fine-tuned to predict 1-year EFS from point-of-scan using a subset of scans from DFCI/BCH and then validated on a hold-out dataset (511 scans, 67 patients). Separately, the model was fine-tuned on an external dataset from the Children’s Brain Tumor Network (CBTN) and validated on a hold-out set (204 scans, 61 patients). Results were compared to a model trained without temporal pretraining.

RESULTS
Median follow-up and interval between scans were 73 and 6.3 months for DFCI/BCH and 20 and 5.8 months for CBTN. Temporal pretraining improved performance for 1-year EFS, for DFCI/BCH (AUC: 0.83 [0.71-0.90] vs. 0.78 [0.62-0.91]; F1-score: 0.80 vs. 0.67), and CBTN hold-out sets (AUC: 0.75 [0.58-0.90] vs. 0.53 [0.35-0.70], p=0.01; F1-score: 0.65 vs. 0.55). Increasing the number of longitudinal scans available to the model incrementally improved performance up to 7 scans/patient for DFCI/BCH and 10 scans/patient for CBTN.

CONCLUSIONS
Deep-learning with temporal pretraining improves the predictive analysis of tumor growth patterns in postoperative pLGG surveillance MRI, enabling accurate short-interval EFS prediction. This model could help inform patients and clinicians regarding surveillance regimen and initiation of adjuvant therapy.
LGG-19. SLIPPED CAPITAL FEMORAL EPIPHYSIS (SCFE): A RARE ADVERSE EVENT ASSOCIATED WITH FGFR TYROSINE KINASE INHIBITOR THERAPY IN A CHILD
Authors: Brizini Meziane , Drimes Tina , Bourne Catherine , Streilein Jessica , Drapeau Annie , Wrogemann Jens , Archer Lori Anne , Bigio Marc Del , Vanan Magimairajan Issai 
Published: June 2024

Abstract

BACKGROUND
FGFR tyrosine kinase inhibitors (FGFR-TKIs) are being increasingly used off-label in children with hard-to-treat tumors harboring specific FGFR alterations. We report a case of Slipped Capital Femoral Epiphysis (SCFE), an on target skeletal toxicity of a pan-FGFR TKI inhibitor, erdafitinib.

METHODS
Data was extracted from chart review of the patient and literature search for the use of FGFR-TKIs in children and their side effects.

RESULTS
A 13-year-old boy was diagnosed to have a optic pathway/ hypothalamic glioma with signs of increased intracranial pressure and obstructive hydrocephalus requiring placement of ventriculo-peritoneal (VP) shunt. Sequencing of the tumor showed FGFR1-Tyrosine kinase domain internal tandem duplication (FGFR1-KD-ITD) and was negative for BRAF mutation/ fusion. Two weeks later, he was treated for a VP shunt infection (surgical revision and 6 weeks antibiotics). He developed hypothalamic obesity with rapid weight gain and BMI &gt;30. After a four-month delay from the initial diagnosis, he was started on erdafitinib a pan-FGFR1-4 inhibitor, through a special access program. At 12 weeks of treatment, he developed persistent knee pain. X-ray of the hips showed slipped capital femoral epiphysis (SCFE) of the right hip. Erdafitinib was discontinued and he underwent surgery with in-situ pinning of the right hip and prophylactic pinning of the left hip. MRI at the time of stopping the medication showed a 30% decrease in the size of the tumor, which has remained stable at 6 months follow up.

CONCLUSIONS
Based on our experience and literature review of pediatric patients who are treated with pan-FGFR TKIs, we recommend: a) monitoring both rate of weight gain/ BMI for obesity and growth velocity while on therapy and b) update the drug toxicity profile of FGFR TKIs to include skeletal toxicities and inform parents/ patients of these toxicities at the time of consent for therapy.
LGG-29. BEYOND MAPK SIGNALING - GENOME-SCALE CRISPR/CAS9 SCREENS REVEAL NEW TARGETS FOR TREATMENT OF KIAA1549::BRAF-DRIVEN PEDIATRIC LOW-GRADE GLIOMA
Authors: Borgenvik Anna , Misek Sean , Zhang Alexander , Fekade Ruth , Ragnoni Timothy , Fultineer Aaron , Zhou Kevin , Bondeson Daniel , Novikov Dana , Bahadur Sher , Choi Seung (Riley) H , Goodale Amy , Condurat Alexandra L , Cordero Carolina Ortiz , Persky Nicole , Kiessling Laura , Root David , Eck Michael , Boehm Jesse , Jones David , Beroukhim Rameen , Bandopadahayay Pratiti (Mimi) 
Published: June 2024

Abstract
Since the KIAA1549::BRAF fusion was discovered as the most common driver of pediatric low-grade glioma (pLGG), it has been hypothesized that the fusion induces oncogenicity through BRAF activation as a result of KIAA1549 replacing the BRAF negative regulatory N-terminus. This led to the rapid translation of MAPK pathway inhibitors into the clinical setting. Despite most tumors exhibiting promising initial responses, some tumors are not sensitive and about half of responsive tumors grow back after treatment cessation. Therefore, strategies that result in sustained tumor responses are desperately needed. We have recently performed genome-scale CRISPR/Cas9 screens across isogenic neural stem cell models transduced to express pLGG-associated oncogenes (KIAA1549::BRAF, BRAFV600E, and multiple FGFR1 and MYB family alterations) to generate a dependency map of genetic vulnerabilities associated with expression of these oncogenes. We also included normal neural stem cells to allow identification of genetic dependencies specifically induced by the expression of each oncogene. Surprisingly, through these efforts, we have discovered KIAA1549::BRAF expressing cells to harbor striking and specific dependency on multiple members of an enzymatic complex that exerts its activity outside of the MAPK signaling axis*. Interestingly, this enzymatic complex has been described to modify only a few substrates, including KIAA1549, suggesting specificity. We have now validated this dependency across other isogenic models of KIAA1549::BRAF-expressing cells. Finally, our KIAA1549::BRAF-expressing models exhibit preferential sensitivity to a tool compound that targets our novel enzyme, suggesting novel therapeutic potential for KIAA1549::BRAF. These findings highlight a MAPK pathway-independent avenue for therapeutically targeting the most frequent genomic alterations in pediatric brain tumors. Consequently, we also propose that the fusion partner KIAA1549 is instrumental for the aberrant BRAF signaling driving pLGGs. (* we are currently in the process of working with our IP offices to ensure that we can disclose the names of the genes and proteins at the ISPNO meeting)
LGG-30. CLINICAL CHARACTERIZATION OF PEDIATRIC LOW-GRADE GLIOMAS REQUIRING MULTIPLE ANTI-TUMOR TREATMENTS
Authors: Rijsdijk Tiago P J , Lammers Julie A S , Kranendonk Mariëtte E G , Meijer Lisethe 
Published: June 2024

Abstract

BACKGROUND
In pediatric low-grade gliomas (pLGG), central nervous system World Health Organization grade 1-2 tumors, the majority of patients achieve favorable outcomes. However, a significant minority requires multiple anti-tumor treatments. The objective of this study is to identify the clinical characteristics of patients requiring multiple anti-tumor treatments, enabling early detection and the subsequent adjustment of treatment strategies

METHODS
Data was retrieved on tumor location, age at diagnosis, gender, NF1 status, extent of resection, and number and type of anti-tumor treatments of 282 patients from our institution. Patients were categorized into a single (STG) and multi-treatment group (MTG). Multi-treatment was defined as tumor progression after initial anti-tumor treatment requiring additional treatment, including more than a 3-month waiting period between initial surgery and subsequent treatment.

RESULTS
The median follow-up was 3 years. Optic pathway glioma was more prevalent in the MTG vs the STG, 62% vs 22%, respectively. Patients in the MTG were younger at diagnosis vs the STG (4.9 vs 8.5 yrs, P &lt; 0.001). There was no significant difference in NF1 prevalence or gender between both groups. The predominant characteristic of patients in the MTG was carboplatin and vincristine as initial treatment, with a tumor in the optic pathway and a mean age at diagnosis of 4.9 yrs. In addition, the patients in the MTG mostly underwent partial resection (PR) and never gross total resection (GTR).

CONCLUSIONS
Our results indicate that a younger age at diagnosis, a tumor in the optic pathways and not undergoing GTR are prognostic factors for multi-treatment. The goal of anti-tumor treatment is to achieve senescence. Our results show that in the MTG, this is not attainable with the current treatment strategies. Therefore, exploring alternative treatment strategies is essential to diminish morbidity and mortality and enhance the quality of life for these patients.
LGG-45. LOW DOSE CARBOPLATIN – ETOPOSIDE REGIMEN IN PEDIATRIC PATIENTS WITH LOW GRADE GLIOMA
Authors: Tellini Marco , Nicola Marco Di , Fonte Carla , Castelli Barbara , Guidi Milena , Giordano Flavio , D’Incerti Ludovico , Balducci Federico , Censullo Maria Luigia , Scagnet Mirko , Genitori Lorenzo , Buccoliero Anna Maria , Bianchi Benedetta , Sardi Iacopo 
Published: June 2024

Abstract

INTRODUCTION
Chemotherapy remains the cornerstone in case of incompletely resected pedatric Low Grade Glioma (pLGGs) and for recurrent tumors in unfavorable locations. Based on previous cisplatin etoposide regimen (INT Milan strategy), we tried to reduce toxicity and achieve a similar tumor control using a modified regimen composed of CBCDA-etoposide.

METHODS
From August 2012 to December 2023 we treated 79 pLGGS (45 F (57%), 34 M (43%)) with carboplatin (400 mg/m2 day 1) and etoposide (100 mg/2 day 1-3) at 4-6 weeks interval with 10 cycles in one year or until disease progression. Median age at diagnosis is 7 years. Seventeen patients were affected by neurofibromatosis type 1 (21.5%). 28 pLGGS affected visual pathway (35.4%). Treatment was delivered for clinical symptoms and/or radiological evidence of progression.

RESULTS
According to RAPNO criteria, on brain magentic resonance imaging (MRI) at the end of treatment 40 patients had stable disease (50.6%), 10 had partial response (12.7%), 7 had major response (8.9%), 5 had minor response (6.3%), 2 presented complete remission (2.5%), 13 patient had disease progression (16.5%). 2 patients are undergoing treatment (2.5%). Acute toxicity was unremarkable. During follow up (median time 59,5 months) 9 children (11,4%) developed audiological alterations but 2 of them also received radiotherapy. 14 patients presented hematological toxicity CTCAE grade 3 or 4 (17,7%). During follow up 30 patients developed a progressive disease (38%) and require further treatments and only one patients died because of progressive disease. Overall survival was 98,7% (78/79).

CONCLUSIONS
The combination of low doses CBCDA-etoposide seems equally effective with a lower hematological and audiological toxicity compared to other regimens.