bluuebunny/crossref_metadata_2025_split huggingface dataset:
HGG-18. SINGLE CELL RNA-SEQ ANALYSIS OF PEDIATRIC HIGH-GRADE GLIOMA PATIENT SAMPLES IDENTIFIES COMMON GLIAL AND IMMUNE CELL TYPES THAT HELP TO EXPLAIN HETEROGENEITY AND TUMORIGENESIS
Authors: DeSisto John , Donson Andrew , Griesinger Andrea , Fu Rui , Levy Jean Mulcahy , Foreman Nicholas , Vibhakar Rajeev , Green Adam 
Published: June 2023

Abstract

BACKGROUND
Pediatric high-grade gliomas (PHGG) are aggressive, undifferentiated central nervous system (CNS) tumors. PHGG comprises subtypes that differ phenotypically, histologically and by cellular composition. Despite intensive research, overall survival rates have remained for decades around 2% for diffuse midline glioma (DMG) and 20% for non-DMG PHGG. We hypothesized that PHGG’s heterogeneity, a key difficulty in devising therapies, results from functional and lineage differences in tumor cell types.

METHODS
Using 19 PHGG samples from our institution’s pediatric brain tumor bank, we constructed a single-cell RNA-Seq (scRNA-Seq) dataset that included tumor and immune cells, generated predicted cell types by mapping the scRNA-Seq data onto known cell types, and performed differential gene expression and geneset enrichment analyses. We acquired bulk RNA-Seq and DNA methylation data to characterize overall tumor properties.

RESULTS
Samples consisted of several principal tumor cell types, including cells with astrocyte characteristics, oligodendrocyte progenitor cell (OPC) characteristics, and cells that expressed OPC markers but had slight enrichment in mesenchymal and inflammatory gene expression (OPC-like/Mes cells). We also found a potential stemlike population that expressed neural stem cell markers. The predicted astrocytes, OPCs and OPC-like/Mes cells differed in their gene expression profiles, pathway enrichment, and tendency to proliferate as assessed from expression of cell cycle genes. A combined microglia/macrophage population, strongly enriched in mesenchymal and inflammatory gene expression, may serve to induce inflammatory gene expression in tumor cells. Key conclusions from the scRNA-Seq analysis were validated using multi-channel immunofluorescence staining.

CONCLUSIONS
PHGG comprises a small stemlike population and varying proportions of proliferating glial lineage tumor cells. CNS-resident microglia/macrophages may trigger mesenchymal gene expression in PHGG. We will use our results to investigate the roles of PHGG’s diverse tumor cell populations in resistance to radiotherapy and to develop treatments to target individual cell types comprising PHGG.
HGG-28. INTERIM ANALYSIS OF THE GCC1949 PHASE 2 TRIAL USING INDOXIMOD-BASED CHEMO-IMMUNOTHERAPY FOR PATIENTS WITH PEDIATRIC BRAIN TUMORS
Authors: Johnson Theodore S , Pacholczyk Rafal , Aguilera Dolly , Berrong Zuzana , Castellino Robert C , Chi Susan , Creager Julianne , Eaton Bree R , Fangusaro Jason R , Huang Chenbin , Hummel Trent , Ingerski Lisa , Kennedy Eugene P , Ring Eric , Sadek Ramses F , Satpathy Sarthak , Schniederjan Matthew , Thomas Beena E , Yeo Kee Kiat , Bhasin Manoj , MacDonald Tobey J , Munn David H 
Published: June 2023

Abstract
Brain tumors are the leading cause of cancer-related death in children. We report interim results of an ongoing multi-institutional phase 2 trial (NCT04049669) of the IDO pathway-inhibitor indoximod utilized in a chemo-immunotherapy regimen for patients 3-21 years of age with either recurrent malignant brain cancer or newly-diagnosed diffuse intrinsic pontine glioma (DIPG). Patients are treated with oral indoximod (38.4 mg/kg/day, divided BID) plus oral temozolomide (200 mg/m2/day for 5 days) in 28-day cycles. Patients for whom radiation therapy is planned as standard-of-care receive indoximod during the up-front radiation regimen. During treatment, palliative radiation, surgery, or dexamethasone are allowed as needed for clinical management. To date, 53 patients have been treated. Estimated median follow-up time was 23 months (range 0.2-35.5 months), and indoximod-based therapy was well tolerated. Estimated median overall survival (OS) was 15 months for the entire mixed population (n= 53, 95%-C.I. 11.5-23.2 months); 23.8 months for recurrent ependymoma (n=26); 13.5 months for recurrent medulloblastoma (n=12); 5.8 months for recurrent glioblastoma/diffuse midline glioma (GBM/DMG, n=9, excludes DIPG); and 9.6 months for newly-diagnosed DIPG (n=6). For the 39 response-evaluable patients to date (those with measurable disease and at least one follow-up MRI on-therapy), objective response in any single lesion by pediatric RANO criteria occurred in 20/39 patients (9/17 ependymoma, 9/11 medulloblastoma, 0/6 GBM/DMG, 2/5 DIPG). Lesion response was associated with significantly better overall survival (estimated median OS 23.2 months, n=20) compared to patients without lesion response (median OS 6.6 months, n=19) (p=0.0005). Single-cell RNA sequencing of serial peripheral blood samples allowed identification of expanded T cell clones, which was correlated with survival. Updated results from the first 53 patients will be presented. These data are replicating results of the preceding phase 1 study (NCT02502708) and provide preliminary evidence of anti-tumor activity in pediatric brain tumors.
IMG-08. VOLUMETRIC MEASUREMENT OF TUMOR SIZE OUTPERFORMS STANDARD TWO-DIMENSIONAL METHOD IN EARLY PREDICTION OF TUMOR PROGRESSION IN PEDIATRIC GLIOMA
Authors: Khalili Nastaran , Kazerooni Anahita Fathi , Bagheri Sina , Familiar Ariana , Viswanathan Karthik , Anderson Hannah , Haldar Debanjan , Ware Jeffrey B , Vossough Arastoo , Nabavizadeh Ali 
Published: June 2023

Abstract

BACKGROUND
Pediatric brain tumors (PBTs) are the leading cause of cancer-related death in children. Currently, based on the RAPNO guidelines, two-dimensional (2D) measurements are used to detect progression. However, due to the complex radiographic appearance of many PBTs, 2D measurements may not accurately reflect tumor growth. Here, we compared 3D, 2D, and qualitative radiologists’ interpretations in a group of PBTs to determine tumor progression.

METHODS
Six PBT patients (5 low-grade glioma, 1 ependymoma, age range at the time of baseline scan: 23-191 months) with an average of 5 imaging time points who had at least one episode of progression with subsequent surgery were included. Segmentation was performed on either T1 post-contrast or FLAIR, whichever that best identified the tumor. For 2D measurements, the two largest perpendicular diameters in a section that included the largest tumor component were measured. For the volumetric assessment, the tumors were manually segmented, and the volume was computed using the ITK-SNAP software. In multifocal tumors, only the tumor component that showed progression and underwent resection was included. A 25% and 41% increase in tumor size was considered as progression on 2D and 3D measurements, respectively. The time to progression (TTP) based on 2D vs 3D assessment as well as the official pediatric neuroradiologist interpretation based on the electronic health record report was compared.

RESULTS
In three of six patients, volumetric segmentation detected tumor progression at an earlier time point compared to 2D measurements and radiologists’ interpretation (median TTP: 134 compared to 503 for 2D and radiologist interpretation). For these three patients, the TTP based on 3D vs 2D assessment was: 252 vs 1299 days, 134 vs 503 days, and 80 vs 255 days.

CONCLUSION
Volumetric measurements can determine tumor progression earlier than the current standard method of 2D measurements and qualitative interpretation of radiologists in PBTs.
IMG-10. MAGNETIC RESONANCE FUNCTIONAL IMAGING BIOMARKER FOR DISTINGUISHING HIGH GRADE FROM LOW GRADE PEDIATRIC BRAIN TUMORS
Authors: Kelly Teresa Gross , Schmainda Kathleen , Prah Melissa , Jeffrey Knipstein , Maheshwari Mohit , Lew Sean , Baker Marjorie Bessette 
Published: June 2023

Abstract
This study aims to show that the ratio between perfusion MRI (RCBV) and diffusion MRI (ADC - apparent diffusion coefficient) is more effective in distinguishing low-grade from high-grade pediatric brain tumors than either parameter (RCBV or ADC) alone. After IRB approval was obtained, an initial pilot prospective study was performed that included 38 patients (newborn - 18 years) (22 females and 16 males). All MRI exams were performed on a 1.5 T or 3.0 T scanner. Surgically resected tumors were classified as low grade (WHO I, II) or high grade (WHO III, IV). ROIs were selected using tumor boundaries delineated on the FLAIR sequence, excluding perilesional edema. Both standardized and normalized perfusion RCBV (sRCBV, nRCBV) as well as diffusion (ADC) mean values were acquired. Then sRCBV/ADC ratios were calculated. Statistical analysis included the Wilcoxon-Mann-Whitney t-test using an alpha=0.05 as the level of significance. The results of this preliminary study revealed that the sRCBV/ADC ratio calculations were more effective at separating high grade from low grade tumors than were RCBV or ADC values alone. As a result of this original pilot study, the calculated sRCBV/ADC ratio has occasionally been used as a clinical tool at our institution. In order to validate the results from this original pilot study, we have collected additional retrospective data to increase sample size. We plan to share the results of this additional data in order to validate that the sRCBV/ADC ratio is an easy-to-use imaging biomarker that can effectively separate high grade from low grade pediatric brain tumors. This information is useful for patient care in that it can potentially help predict prognosis which is essential for parental counseling, and potentially reduce the need for invasive tests and biopsies.
LGG-12. CLINICAL AND MOLECULAR FEATURES OF DISSEMINATED PEDIATRIC LOW-GRADE GLIOMA
Authors: Levine Adrian , Li Cyril , Haizel-Cobbina Joseline , Nobre Liana , Bennett Julie , Dewan Michael , Tabori Uri , Hawkins Cynthia 
Published: June 2023

Abstract
Although most pediatric LGG (PLGG) have excellent long-term survival, there is a subset of cases that disseminate throughout the neuraxis (DLGG) that have very poor outcomes. The reason for this aggressive behavior is unknown but we hypothesize that distinct and specific biological mechanisms underlie the metastatic ability. The methylation-based class of diffuse leptomeningeal glioneuronal tumor (DLGNT) is characterized by MAPK pathway activating fusions with chromosome 1p loss, 19q loss, and/or 1q gain. However, it is unknown what proportion of DLGG match the DLGNT group, and which other methylations classes are at risk of metastasis. To improve our understanding of this rare patient population, we created an international DLGG consortium. Data from the first 68 cases shows a broad age distribution and no sex predilection. As expected, DLGG has much worse prognosis than the overall PLGG population. Virtually all DLGG progress at 5 years, compared to a quarter of other PLGG, and DLGG are 5-times more likely to die at 10 years. We observe three patterns of dissemination – 35% present with a localized mass and have secondary dissemination, 50% with disseminated tumor and a clear dominant mass, and 15% with disseminated disease without a dominant mass. In 47 patients with molecular testing, BRAF fusions accounted for 64% of driver alterations. Additional alterations were identified less frequently, including BRAF V600E (9%), FGFR1 alterations (9%), and KRAS mutations (4%). In 25 patients with methylation profiling, 10 (40%) successfully classified with a calibrated score above 0.8, illustrating that many cases do not fit a defined methylation group. The most common methylation classification was pilocytic astrocytoma (5 patients), and surprisingly only two patients classified as DLGNT. In sum this study illustrates the variable clinical behaviour associated with metastasis in PLGG and expands the range of molecular driver alterations, including ones previously unreported in DLGNT.
LGG-17. EPIGENETICALLY DEFINED ANGIOCENTRIC GLIOMAS MAY LACK ANGIOCENTRIC GROWTH AND INSTEAD SHOW A VARIETY OF GROWTH PATTERNS
Authors: Stegat Lotte , Rohwer Jenny L , Stichel Damian , Schrimpf Daniel , Coras Roland , Pagès Mélanie , Tauziède-Espariat Arnault , Varlet Pascale , Hans Volkmar H , Meyer Jochen , Schittenhelm Jens , Staszewski Ori , Cheesman Edmund , Glatzel Markus , Schmid Simone , Wesseling Pieter , Korshunov Andrey , Sexton-Oates Alexandra , Schüller Ulrich , Kõrgvee Lenne-Triin , Mueller Sabine , Olar Adriana , Snuderl Matija , Schweizer Leonille , Aronica Eleonora , Sahm Felix , von Deimling Andreas , Blumcke Ingmar , Jones David T W , Capper David , Wefers Annika K 
Published: June 2023

Abstract
Angiocentric glioma mainly occurs in children and young adults. It is associated with a good prognosis (CNS WHO grade 1). Molecularly, most angiocentric gliomas have a MYB-QKI fusion. Histologically, angiocentric gliomas were initially defined by an angiocentric growth of the tumor cells. However, we noticed that epigenetically defined angiocentric gliomas often get different diagnoses based on their histology as they may lack this angiocentric growth pattern. We collected 48 epigenetically defined angiocentric gliomas from 46 patients with sufficient tissue for histological and molecular analyses (DNA methylation analyses; RNA sequencing of a subset; 37 supratentorial and 11 infratentorial cases). The classification was done using unsupervised hierarchical cluster analyses from DNA methylation data and the brain tumor classifiers v11b4 and v12.5 (www.molecularneuropathology.org). Angiocentric gliomas were epigenetically distinct from the diffuse astrocytomas, MYB- or MYBL1-altered. A MYB-QKI fusion was detected in 69% (n = 18/26) of angiocentric gliomas, confirming the diagnosis. Other fusions detected were fusions of MYB with intergenic sites, mainly close to QKI (19%; n = 5/26), and MYBL1-QKI (8%; n = 2/26). We then did a histological workup of these cases. Only 75% showed the typical angiocentric growth pattern that often was not very pronounced. Many angiocentric gliomas displayed an unspecific growth while others resembled pilocytic astrocytoma or ependymoma. Hence, about 59% of angiocentric gliomas were initially misdiagnosed without molecular analyses (supratentorial 50%, infratentorial 100%). We obtained similar results expanding the cohort with further epigenetically defined angiocentric gliomas for which no tissue for a histological re-evaluation was available (total 68 cases; 50 supratentorial, 12 infratentorial; 65 patients). In this expanded cohort, 54% of cases were initially misdiagnosed (45% of supratentorial and 100% of infratentorial cases). In summary, we show that angiocentric glioma often does not show the typical angiocentric growth pattern. Thus, molecular analyses are needed for a reliable diagnosis.
MDB-05. HUMAN FETAL CEREBELLAR CELL ATLAS INFORMS MEDULLOBLASTOMA ORIGIN AND ONCOGENESIS
Authors: Luo Zaili , Lu Richard 
Published: June 2023

Abstract
Medulloblastoma (MB) is the most common malignant childhood brain tumor, yet the origin of the most aggressive subgroup-3 form remains elusive, impeding development of effective targeted treatments. Previous analyses of mouse cerebella or human counterparts from frozen tissue nuclei5 have not fully defined the compositional heterogeneity of MBs. Here, we undertook an unprecedented single-cell profiling of freshly-isolated human fetal cerebella to establish a reference map delineating hierarchical cellular states in MBs. We identified a unique transitional cerebellar progenitor connecting neural stem cells to neuronal lineages in developing fetal cerebella. Intersectional analysis revealed that the transitional progenitors were enriched in aggressive MB subgroups, including group-3 and metastatic tumors. Single-cell multi-omics revealed underlying regulatory networks in the transitional progenitor populations, including transcriptional determinants HNRNPH1 and SOX11, which are correlated with clinical prognosis in group-3 MBs. Genomic and Hi-C profiling identified de novo long-range chromatin-loops juxtaposing HNRNPH1/SOX11-targeted super-enhancers to cis-regulatory elements of MYC, an oncogenic driver for group-3 MBs. Targeting the transitional progenitor regulators inhibited MYC expression and MYC-driven group-3 MB growth. Our integrated single-cell atlases of human fetal cerebella and MBs reveal potential cell populations predisposed to transformation and regulatory circuitries underlying tumor cell states and oncogenesis, highlighting hitherto unrecognized transitional progenitor intermediates predictive of disease prognosis and potential therapeutic vulnerabilities.
MDB-36. SONIDEGIB, GANT61, AND VELIPARIB TREATMENT BOTH ALONE AND IN COMBINATION INCREASES RADIATION SENSITIVITY IN PEDIATRIC SONIC HEDGEHOG MEDULLOBLASTOMA
Authors: Price Laura , Lau Bonnie 
Published: June 2023

Abstract
Medulloblastoma is the most common malignant brain tumor in children, accounting for 20-25% of all pediatric brain tumors. The current standard of care includes both craniospinal and focal radiation therapy which lead to negative long term consequences in the pediatric population such as bone and tissue hypoplasia, decreased neurocognitive functioning, as well as an increased risk for secondary radiation induced cancers. Thus, there is a need for novel approaches to radiation therapy that can effectively target and kill tumor cells while minimizing radiation toxicity in healthy tissue. Here, we investigate a new approach to radiation therapy relying on two classes of therapeutic agents, Sonic Hedgehog (SHH) inhibitors and Poly (ADP-ribose) Polymerase (PARP) inhibitors. The dysregulation and constitutive activation of the SHH signaling pathway accounts for ~30% of all medulloblastomas. In addition to playing a role in tumorigenesis, the SHH pathway is known to play a role in the radiation sensitivity of various cancer types. PARP1 is known to play a key role in DNA damage repair, and it has previously been shown to affect the radiation sensitivity of pediatric brain cancers including high grade glioma, medulloblastoma, and ependymoma. We hypothesize that both inhibiting the SHH pathway at Smoothened (Smo) or Gli1 and inhibiting PARP1 will enhance medulloblastoma tumor cell killing following radiation therapy. We found that in vitro treatment with Sonidegib, GANT61, and Veliparib alone without radiation was sufficient to decrease tumor cell viability and self-renewal. When followed by radiation, pre-treatment with Sonidegib, GANT61, and Veliparib, both alone and in combination, resulted in further decreased tumor cell viability and self-renewal. These data suggest that inhibition of Smo, Gli1, or PARP1 alone or in combination is a promising therapeutic strategy for increasing the radiation sensitivity of pediatric SHH medulloblastoma.
TRLS-10. ROVER: A PHASE 1/2 STUDY OF AVAPRITINIB IN PEDIATRIC PATIENTS WITH SOLID TUMORS DEPENDENT ON KIT OR PDGFRA SIGNALING
Authors: Koschmann Carl , Hoffman Lindsey M , Kramm Christof M , Plant-Fox Ashley , Abdelbaki Mohamed S , Bui Ashley , Casanova Michela , Morgenstern Daniel A , Swamy Preethi , Shi Hongliang , Hong Janet , Rinne Mikael L , Chi Susan N 
Published: June 2023

Abstract
Pediatric patients with advanced relapsed/refractory (R/R) solid (including central nervous system [CNS]) tumors have poor prognoses. KIT alterations are common in germ cell tumors and high-grade glioma (HGG); platelet-derived growth factor receptor alpha (PDGFRA) alterations are common in sarcoma and HGG. Diffuse midline gliomas with H3K27-altered (DMG-H3K27-altered) depend on PDGFRA signaling for tumor growth. However, no KIT-/PDGFRA-targeted therapies are currently approved for pediatric patients with R/R solid or CNS tumors, including DMG-H3K27-altered. The selective KIT and PDGFRA inhibitor avapritinib has demonstrated potent activity against KIT activation-loop (exon 17) and juxtamembrane (exon 11) mutants (IC50&lt;2 nM), and PDGFRA activation-loop (D842V) mutants (IC50=0.24 nM). Cellular IC50 of wild-type PDGFRA was 95 nM. CNS penetration in preclinical models (steady-state brain-to-plasma ratios from 0.74–1.00) indicates potential for CNS antitumor activity. Avapritinib is approved to treat adults with advanced systemic mastocytosis in the USA, and in Europe after ≥1 prior systemic therapy. Avapritinib is also approved for the treatment of adults with unresectable/metastatic gastrointestinal stromal tumors harboring PDGFRA exon 18 mutations (including D842V) in the USA, and PDGFRA D842V mutations in Europe. ROVER, a 2-part phase 1/2, multicenter, open-label study (NCT04773782), is investigating avapritinib in pediatric patients aged 2 to &lt;18 years with R/R solid tumors dependent on KIT or PDGFRA signaling, including DMG-H3K27-altered. Objectives include safety, efficacy, and pharmacokinetics. Part 1 will enroll ≥12 patients; the primary endpoint is to determine the recommended Part 2 dose (RP2D). Part 2 will enroll ≥25 patients at the RP2D; the primary endpoint is objective response rate per RECIST v1.1 for solid tumors and Response Assessment in Neuro-Oncology for CNS tumors. Avapritinib once daily will be administered in continuous 28-day cycles. Study enrollment is planned at 26 sites in 9 countries, including North America, Europe, and Asia/Pacific.
TRLS-11. A PHASE 1 STUDY OF SAVOLITINIB IN RECURRENT, PROGRESSIVE, OR REFRACTORY MEDULLOBLASTOMA, HIGH-GRADE GLIOMA, DIFFUSE INTRINSIC PONTINE GLIOMA, AND CENTRAL NERVOUS SYSTEM (CNS) TUMORS HARBORING MET ABERRATIONS: A PEDIATRIC BRAIN TUMOR CONSORTIUM TRIAL
Authors: Salloum Ralph , Huang Jie , Stewart Clinton F , Fuller Christine , Smolarek Teresa , Lenzen Alicia , Waanders Angela J , Baxter Patiricia , Lindsay Holly , Robison Nathan , Pillay-Smiley Natasha , Partap Sonia , Fangusaro Jason , Onar-Thomas Arzu , Fouladi Maryam , Dunkel Ira J 
Published: June 2023

Abstract
Aberrant mesenchymal epithelial transition receptor (MET) activation leads to neoplasia, promotes invasive tumor growth, angiogenesis, and metastasis. Deregulation of MET signaling pathway is frequently observed in pediatric CNS tumors making MET inhibition a potential therapeutic target in this patient population. A phase 1 first-in-children trial of the MET inhibitor savolitinib was performed in children with recurrent, progressive or refractory medulloblastoma, high-grade glioma (HGG), diffuse intrinsic pontine glioma (DIPG), and other CNS tumors harboring MET aberrations. The study sought to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of savolitinib using a Rolling-6 design given orally once daily continuously, and to describe its toxicity profile and pharmacokinetics (PK). Once the MTD was established, a PK expansion cohort was opened to enrollment. This will be followed by an efficacy expansion cohort for patients whose tumors harbor activating genomic MET aberrations. Tumor tissue and blood were collected as part of correlative studies in consenting subjects. Twenty-eight patients enrolled (median age:12 years; range: 6-21); one patient was deemed ineligible, and 22 patients were evaluable for dose finding. The MTD/RP2D was 350 mg/m2 (dose level 3). Two dose limiting toxicities were reported in 2 subjects and consisted of grade 3 fatigue and grade 3 ALT elevation. The most common grade 3/4 toxicities were: neutropenia (7.7%) and lymphopenia (7.7%). One partial response was observed in a patient with recurrent HGG on dose level 1 (150 mg/m2). As of the most recent data freeze, the patient had completed 35 treatment courses. Sustained stable disease was experienced by 3 other patients with recurrent DIPG who remained on treatment for a median of 9 cycles (range: 4-24). Correlative studies are ongoing and will be presented. Savolitinib was well-tolerated in children with recurrent CNS tumors with an MTD/RP2D of 350 mg/m2. Antitumor activity was observed.