bluuebunny/crossref_metadata_2025_split huggingface dataset:
IMMU-08. MICROENVIRONMENT MODULATION BY TIM-3 BLOCKADE IMPROVES THE OUTCOME OF PRECLINICAL DIPG MODELS
Authors: Ausejo-Mauleon Iker , Labiano Sara , Laspidea Virginia , Garcia-Moure Marc , de la Nava Daniel , Puigdelloses Montserrat , Becher Oren J , Jiang Li , Filbin Mariella G , Pastor Fernando , Alonso Marta M 
Published: June 2021

Abstract
Diffuse Midline Gliomas (DMGs), encompassing Diffuse Intrinsic Pontine Gliomas (DIPGs), are the most aggressive pediatric brain tumors. Their meagre survival has not changed despite the combination of radiotherapy with targeted therapies emphasizing the urgent need for effective treatments. Recent research suggested that the DIPG tumor microenvironment is neither highly immunosuppressive nor inflammatory. These analyses showed the lack of infiltrating lymphocytes and the abundance of CD11b+ cells. TIM-3 (HAVCR2) is a member of the T-cell immunoglobulin and mucin domain protein family which is expressed on multiple immune cell types including T cells, Tregs, NK cells, monocytes, dendritic cells and microglia, where it potently regulates not only adaptive immunity but also innate immunity. Therefore, the central hypothesis of this study is that TIM-3 inhibitors could stimulate a cytotoxic immune effect and challenge several components in the tumor microenvironment including microglia, thereby providing a potential effective treatment for DMGs. In silico assessment of TIM-3 expression in a DIPG datasets showed a robust expression of this gene. Moreover, single-cell sequencing analyses of DIPG biopsies uncover its expression on tumor cells, especially in the OPCs compartment. In vivo efficacy studies showed that treatment with anti-TIM-3 antibody significantly increase the overall survival in two DIPG immunocompetent orthotopic animal models (doubling the median), lead to long-term survivors (50%) and showed immune memory. Analyses of CD45+ populations in the tumor microenvironment showed a significant increase in B, NK and CD8+ cells corresponding with a T-cell activate phenotype in treated-mice. The potential therapeutic involvement of NK cells was certified using nude mice and functional studies. Involvement of microglia in currently being analysed. In summary, these data underscore TIM-3 as a potential target DIPGs and uncover the potential involvement of NKs and other immune mechanisms in the efficacy of anti-TIM-3 therapy.
LGG-06. COMPREHENSIVE GENOMIC CHARACTERIZATION AND INTEGRATED CLINICAL ANALYSIS OF LOW-GRADE GLIOMAS IN CHILDREN WITH NEUROFIBROMATOSIS TYPE 1
Authors: Fisher Michael , Jones David , Li Yimei , Guo Xiaofan , Sonawane Poonam , Waanders Angela , Phillips Joanna , Weiss William , Resnick Adam , Gosline Sara , Banerjee Jineta , Guinney Justin , Gnekow Astrid , Kandels Daniela , Foreman Nicholas , Korshunov Andrey , Ryzhova Marina , Massimi Luca , Gururangan Sri , Kieran Mark , Wang Zhihong , Fouladi Maryam , Sato Mariko , Øra Ingrid , Holm Stefan , Markham Stephen , Beck Pengbo , Jäger Natalie , Wittmann Andrea , Sommerkamp Alexander , Sahm Felix , Pfister Stefan , Gutmann David 
Published: June 2021

Abstract

Background
Low-grade gliomas (LGGs) arising in children with neurofibromatosis type 1 (NF1) are usually not biopsied. To identify secondary genetic alterations or molecular features that may contribute to pathogenesis and correlate with clinical behavior, we initiated a comprehensive molecular and clinical analysis of pediatric NF1-LGGs.

Methods
NF1-LGGs were analysed by whole-genome sequencing (31), targeted gene panel sequencing (9), RNAseq transcriptomal profiling (33) and genome-wide DNA methylation analysis (67). Clinical annotation was available for 48 subjects.

Results
Most LGGs harbored bi-allelic NF1 inactivation as the sole genetic abnormality, but 11% had additional alterations (FGFR1 mutation, n=3; PIK3CA mutation, n=2; homozygous 9p21 deletion, n=2; MYB:QKI fusion, n=1; SETD2 mutation, n=1; EGFR amplification, n=1). FGFR1 mutation conferred additional growth advantage in multiple complementary murine Nf1 models. 88% of NF1-LGGs resembled sporadic pilocytic astrocytoma (PA) by methylation, higher than that based on histology. Non-PA methylation patterns included low-grade glial/glioneuronal tumors, rosette-forming glioneuronal tumors, MYB/MYBL1-altered glioma, and high-grade astrocytoma with piloid features (2 tumors histologically diagnosed as LGG). In total, 18% of samples were classified as non-PA and/or harbored an additional non-NF1 mutation. Non-PA methylation class tumors were more likely to harbor an additional non-NF1 mutation (p=0.005). 7.7% of optic pathway hypothalamic gliomas (OPHGs) had other mutations or were not classified by methylation as PA, compared with 20.6% of NF1-LGGs arising elsewhere. There was no difference based on age for the presence of an additional non-NF1 mutation or non-PA methylation class.

Conclusions
Given the overall low occurrence of non-NF1 mutations or non-PA methylation class tumors in this series, routine clinical biopsy of typically-appearing NF1-LGG may not be indicated, particularly for children with OPHG. Biopsy should be considered for non-OPHG tumors refractory to conventional treatment. As additional agents are developed and treatment strategies evolve, the rationale for biopsy of NF1-LGG may become stronger.
LGG-11. BH3-MIMETICS TARGETING BCL-XL SELECTIVELY IMPACT THE SENESCENT COMPARTMENT OF PILOCYTIC ASTROCYTOMA
Authors: Selt Florian , Sigaud Romain , Sievers Philipp , Zaman Julia , Peterziel Heike , Tsai Jessica W , Guiho Romain , Martínez-Barbera Juan Pedro , Pusch Stefan , Schuhmann Martin U , El Damaty Ahmed , Bandopadhayay Pratiti , Pfister Stefan M , Oehme Ina , Sahm Felix , Jones David T W , Witt Olaf , Milde Till 
Published: June 2021

Abstract

Introduction
Pilocytic astrocytoma (PA) is the most common brain tumor in children. Activation of the mitogen-activated protein kinase (MAPK) pathway is a hallmark of PA. Complete remission in non-resectable tumors is infrequently observed with current therapeutic approaches. Most PA tumors cells are in oncogene-induced senescence (OIS), which may explain the benign growth behavior of PAs but also account for resistance to therapy. Therefore, treatment of PA with senolytic agents such as BH3-mimetics is a promising new approach.

Methods
Three patient-derived PA cell lines, DKFZ-BT66, DKFZ-BT308 (both KIAA1549:BRAF-fusion positive) and DKFZ-BT314 (BRAF V600E-mutation positive) were used. Depending on inducible expression or repression of SV40 large T antigen all models can reflect both states of PA, proliferation and OIS. Cells in both states were treated with different BH3-mimetics. Inhibition of metabolic activity was measured after 72 hours. Target expression was assessed by RT-qPCR and Western blot. On-target activity of BH3-mimetics was determined by immunoprecipitation (IP) of Bcl-xL/BAK.

Results
BH3-mimetics with strong binding affinity for Bcl-xL (Navitoclax, A-1131852, A-1155463) showed selectivity for senescent cells in 2/3 models (DKFZ-BT66 and DKFZ-BT314) and acted in nanomolar ranges. IC50s for Navitoclax (Cmax 6600nM in patients) were 40nM (OIS) vs. 200nM (proliferation) and 170nM (OIS) vs. 3700nM (proliferation) in DKFZ-BT66 and DKFZ-BT314, respectively. Target engagement was evident in the Bcl-xL/BAK-IP, and target expression of Bcl-xL was similar in all models studied. The relative resistance of senescent DKFZ-BT308 despite on-target activity is currently being investigated.

Conclusion
Senolytic treatment of PA with BH3-mimetics targeting Bcl-xL is a promising new strategy directly targeting the major senescent part of the tumor in clinically archivable concentrations. However, our data suggests that not all PAs may respond to treatment. The analysis of comparative gene expression analysis and BH3-profiling is ongoing to define predictive biomarkers.
LGG-17. CLINICAL OUTCOME OF PEDIATRIC LOW GRADE GLIOMA WITH POSITIVE BRAF-FUSION TREATED WITH MEK INHIBITOR
Authors: Dennis T L Ku , Liu Anthony P Y , Fu Eric , Luk Chung-Wing , Yau Jeffrey P W , Ling Siu-Cheung , Shing Matthew M K , Chan Godfrey C F 
Published: June 2021

Abstract

Background
Low grade glioma (LGG) is the most common central nervous system (CNS) tumor in children. Some are treated with surgery alone, while chemotherapy is given for unresectable tumor with clinical symptoms or progression. Conventional chemotherapy is effective but 30–40% patients may have reactivation of disease requiring re-treatment throughout lifetime. MEK inhibitor for BRAF-fusion positive LGG is a new treatment option for refractory cases.

Methods
Retrospective search in territory-wide pediatric oncology registry for children diagnosed with LGG from 2010–2020 in Hong Kong. To identify patients with molecular confirmed BRAF-fusion positive LGG and any treatment with MEK inhibitor.

Results
Twelve patients (N=12) were identified with BRAF-fusion positive LGG, male:female was 1:2, age 0.3–15.1yr (median 5.0yr) at presentation. The median follow up duration was 1.8yr. Five patients (42%) had surgical resection only. Seven patients (58%) were given chemotherapy with Carboplatin / Vincristine. Five out of seven (n=7) treated patients (71%) have partial response at their initial treatment. Two patients (29%) had progressive disease during treatment and switched to second-line chemotherapy, vinblastine however without improvement. Three patients required re-treatment as disease reactivation. Total five patients had refractory diseases were treated with MEK inhibitor, Trametinib including one diagnosed NF-1. All of them have adverse skin reaction and raised transaminase with one required dose reduction. They have been taking the MEK inhibitor for 0.1–3.3 yr with sustainable partial response.

Conclusion
Pediatric LGG has overall favourable prognosis. Some of them treated with surgery alone while conventional chemotherapy could also achieve satisfactory disease control. For refractory disease with BRAF-fusion positive, MEK inhibitor is a well tolerated treatment option showing sustainable partial response. However, prolonged medication and disturbing skin reaction are still a major concern for this group of patients. On-going clinical trials to compare conventional chemotherapy versus MEK inhibitor could give us more insight about the clinical benefit, patient selection and treatment duration.
OMIC-03. TRANSLATIONAL CONTROL IN MYC AND MYCN MEDULLOBLASTOMA
Authors: Schmidt Christin , Navickas Albertas , Zindy Frederique , Farmer Dana , Ruggero Davide , Goodarzi Hani , Roussel Martine F , Schwer Bjoern , Weiss William 
Published: June 2021

Abstract
Medulloblastoma has been extensively characterized at the genomic and transcriptional levels, but little is known about how alterations in translational control underlie tumor development. Myc and Mycn are often deregulated in medulloblastoma and play important roles in tumor initiation, maintenance and progression. Although both proteins have similar structures and are functionally redundant in hindbrain development, their amplification in cerebellar granule neural precursor cells leads to different medulloblastoma subtypes. In this project we are employing ribosome profiling on mouse medulloblastoma tumors generated from granule neural precursor cells with enforced expression of Myc or Mycn. Ribosome-protected mRNA sequencing allows us to quantitatively assess the specific transcripts regulated at the level of translation, identify translation regulatory sequences within the mammalian transcriptome, and understand genotype-to-phenotype processes. We discovered that Myc- and Mycn-driven tumors exhibit many more changes at the translational rather than at the transcriptional level. In particular, we found that Mycn-driven medulloblastoma upregulates the translation of Myc target genes, while mRNA levels of those genes show no difference between Myc- and Mycn-driven tumors. Furthermore, we find that the most significant translationally upregulated Myc target genes in the Mycn tumors are transcripts that encode ribosome biogenesis factors. We will further study the role of Myc and Mycn on translational regulation of the medulloblastoma transcriptome using our xenograft model of human iPSC-derived neuroepithelial stem cells overexpressing Myc or Mycn. Our goal is to understand the regulatory function of the translational landscape in Myc- and Mycn-driven medulloblastoma and to decipher the oncogenic signaling cascades leading to different medulloblastoma subtypes.
RARE-04. IMPACT OF LIVE, VIRTUAL EDUCATIONAL SYMPOSIA ON PEDIATRIC NEURO-ONCOLOGIST, NEURO-ONCOLOGIST, AND NEUROSURGEON CONFIDENCE, KNOWLEDGE, AND INTENTION TO EMPLOY TARGETED MEDICAL THERAPIES FOR THEIR PATIENTS WITH NEUROFIBROMATOSIS TYPE 1
Authors: Taylor Bryan , Weaver Rebecca , Gross Andrea , Korf Bruce , Blakeley Jaishri 
Published: June 2021

Abstract
Historical treatment options and management strategies for neurofibromatosis type 1 (NF1) have been limited, with a relative paucity of clinical studies and the traditional paradigm focused on an ineffectual, and possibly even harmful, trimodal combination of radiation, surgery, and surveillance. Fortunately, an emerging preponderance of trial data supporting the use of targeted medical therapies, including MEK inhibitors and multi-kinase TKIs, is expanding the stale treatment paradigm and broadening horizons for patients. Given the profound novelty of this paradigmatic shift in NF1 management, it is imperative that timely, adaptive, and evidence-based educational initiatives be developed and delivered to the interdisciplinary neuro-oncology treatment team in an effort to bridge both learning and practice gaps. With an appreciation of the intrinsically multi-system nature of NF1, which necessitates a longitudinal treatment approach encompassing the totality of the multidisciplinary team, CEC Oncology designed and tailored targeted NF1 educational activities to improve confidence, advance knowledge, and promote enhanced utilization of targeted medical therapies among pediatric neuro-oncologists, neuro-oncologists, and neurosurgeons who manage patients with NF1. We conducted two independent satellite symposia, one at the 2020 Society for Neuro-Oncology (SNO) Annual Meeting and another at the 2020 AANS/CNS Section on Pediatric Neurological Surgery (PNSS), and achieved robust educational outcomes across Moore’s Levels 1–5. There were notable statistical advancements in clinician confidence, knowledge, and intention to employ targeted medical therapies for NF1-related symptomatic, inoperable plexiform neurofibromas from pre-activity to post-activity assessment, and many of these improvements were retained at 6-week follow-up analysis. In conclusion, our outcomes data evidence the critical need for responsive educational activities in the NF1 treatment space, especially as trial data continue to galvanize evolution of this novel pharmacologic armamentarium. Such activities possess the capacity to improve clinician confidence, advance knowledge, and promote utilization of targeted medical therapies in NF1, thereby optimizing patient outcomes.
RARE-07. EFFICACY AND SAFETY OF LAROTRECTINIB IN PEDIATRIC PATIENTS WITH TROPOMYOSIN RECEPTOR KINASE (TRK) FUSION-POSITIVE PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS
Authors: Perreault Sébastien , Doz François , Geoerger Birgit , Nysom Karsten , Øra Ingrid , Boni Valentina , Chisholm Julia , DuBois Steven G , Gerber Nicolas U , Goto Hiroaki , Grilley-Olson Juneko E , Hansford Jordan R , Kang Hyoung Jin , Capra Michael , Schulte Johannes H , Stefanowicz Joanna , Tahara Makoto , Ziegler David S , Norenberg Ricarda , Dima Laura , De La Cuesta Esther , Laetsch Theodore W , van Tilburg Cornelis M 
Published: June 2021

Abstract

Background
NTRK gene fusions are oncogenic drivers in various CNS and non-CNS tumors. Larotrectinib is a highly selective TRK inhibitor approved to treat patients with TRK fusion cancer, with an objective response rate (ORR) of 78% across multiple non-CNS cancers (McDermott et al, ESMO 2020). We report updated data on pediatric patients with TRK fusion-positive primary CNS tumors.

Methods
Patients aged &lt;18 years with primary CNS tumors harboring an NTRK gene fusion enrolled in two clinical trials (NCT02637687, NCT02576431) were identified. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Response was investigator assessed.

Results
By July 2020, 26 pediatric patients with TRK fusion-positive CNS tumors were treated. Tumor histologic subtypes included high-grade glioma (n=13), low-grade glioma (n=7), glioneuronal tumor (n=2), neuroepithelial tumor (n=2), CNS neuroblastoma (n=1), and small round blue cell tumor (n=1). Median age was 7.0 years (range 1.3–16.7). The ORR was 38% (95% CI 20–59%): 3 complete responses, 7 partial responses (including 2 pending confirmation), 14 stable disease, and 2 progressive disease. The ORR in patients with high-grade glioma was 38% (95% CI 14–68%). Nineteen of 21 patients (90%) with measurable disease had tumor shrinkage. The 24-week disease control rate was 77% (95% CI 56–91%). Median duration of response (DoR), PFS and overall survival (OS) were not reached. The 12-month rates for DoR, PFS and OS were 75%, 65%, and 86%, respectively. Duration of treatment ranged from 1.2 to 31.3+ months. Treatment-related adverse events were reported for 15 patients (58%) and were Grade 3–4 in 3 patients (12%), with no discontinuations related to larotrectinib.

Conclusions
In pediatric patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated durable responses, high disease control rate, and good tolerability. These results support testing for NTRK gene fusions in pediatric patients with CNS tumors.
RARE-25. DISSECTING THE CONTEMPORARY EPIDEMIOLOGY OF PRIMARY AND SECONDARY BRAIN TUMORS IN INFANCY THROUGH CHILDHOOD
Authors: Lamba Nayan , Iorgulescu Bryan 
Published: June 2021

Abstract

Introduction
Herein we utilize national registry data to evaluate the epidemiology of primary and secondary pediatric brain tumors according to the WHO2016 classification.

Methods
Pediatric patients (age≤14) presenting between 2004–2017 with a brain tumor were identified by ICD-O-3 and brain metastasis (2010–2017) coding from the National Cancer Database (comprising &gt;70% of newly-diagnosed cancers in the U.S.), and categorized by NICHD age stages: infant (&lt;1yr; n=1,686), toddler (1-2yrs; n=1,732), early- (2-5yrs; n=6,712), middle- (6-11yrs; n=9,175), and late- (12-14yrs; n=5,042) childhood. Patients’ age, sex, race/ethnicity, and overall survival, and tumor location and size were evaluated by WHO2016 tumor type.

Results
24,347 pediatric brain tumor patients were identified. Overall, other astrocytic tumors (24% of females, 20% of males), diffuse astrocytic/oligodendroglial gliomas (23% of females, 21% of males – 64% of which were midline), embryonal (13% of females, 19% of males), and sellar region tumors (12% of females, 8% of males) predominated. Embryonal tumors prevailed in infancy (24%) and toddlerhood (24%), declining to 9% in late childhood; only 40% were female. Ependymal tumors peaked at 15% in toddlerhood (6% overall), whereas choroid plexus tumors peaked at 11% in infancy (1.9% overall). A minority of brain tumors were of neuronal & mixed neuronal-glial (6.1%), germ cell (3.8%), cranial nerve (3.2%), mesenchymal non-meningothelial (2.4%), meningioma (1.6%), pineal (1.1%), hematological/histiocytic (0.5%), and other glioma (0.2%) types. Brain metastases were rare (1.5% overall; from 4.0% in infancy to 0.8% in late childhood; and only 41% were female) – 61% came from adrenal neuroblastoma, 16% from sarcomas, and 6% from malignant rhabdoid tumors/extracranial AT/RT.

Conclusions
Pediatric brain metastases overwhelmingly originate from adrenal neuroblastoma. Although, overall, diffuse astrocytic/oligodendroglial, other astrocytic, embryonal, and sellar region tumors predominate among pediatric brain tumors, together they only comprise 70% of cases and their distribution varies substantially by patients’ age and sex.
EPCT-09. CNS LEVELS OF PANOBINOSTAT IN A NON-HUMAN PRIMATE MODEL: COMPARISON OF BLOOD AND CEREBROSPINAL FLUID PHARMACOKINETIC METHODS AND MALDI MSI
Authors: Warren Katherine , McCully Cynthia Lester , Garcia Rafael Cruz , Stopka Sylwia , Regan Michael , Aye Thet , Zimmerman Sara , Peer Cody , Kramer Josh , Breed Matthew , Figg W Douglas , Agar Nathalie 
Published: June 2021

Abstract

Adequate exposure (effective concentration over time) of a therapeutic agent at its site of action is essential for antitumor efficacy. Given constraints of repeat tissue sampling, non-human primate models predictive of pharmacokinetics in pediatric patients have been utilized to assess central nervous system (CNS) exposure. Assessment of cerebrospinal fluid (CSF) drug levels have been used to extrapolate CNS penetration but the relationship of CSF drug levels with tissue distribution is unclear. Utilizing microdialysis, we previously demonstrated geographic variability of drug permeability across the blood:brain barrier (BBB), but this technique is complex and has a high standard deviation. We, therefore, explored a novel technique, matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI), to compare plasma, CSF, and tissue drug levels in a terminal non-human primate model. Panobinostat, an HDAC inhibitor in clinical trials for DIPG/DMG, was selected for study as it has previously demonstrated poor CNS tissue penetration but suggested modest clinical activity.

Methods
Panobinostat (p.o., dose 1.6 mg/kg) was administered to non-tumor bearing primates (n=2). One hour following administration (Tmax), blood and CSF were collected, the animal euthanized, brain and spinal cord extracted, and immediately frozen at -80. Panobinostat distribution was mapped on ex vivo sagittal tissue sections using MALDI MSI. To provide specificity and degree of permeability, anatomical structures were segmented for analysis to determine drug concentrations. Blood, CSF and tissue levels of panobinostat were measured via LC-MS/MS.

Results
Segmentation analysis revealed quantifiable panobinostat, particularly in the lateral ventricles and choroid plexus, and also in the subventricular zone and brainstem, although the overall panobinostat concentration was below the limit of quantitation in these areas.

Conclusions
Although not reflected in CSF PK, panobinostat is widely distributed in brain tissue. MALDI MSI allows regional assessment of panobinostat penetration and complements CSF pharmacokinetics.