bluuebunny/crossref_metadata_2025_split huggingface dataset:
TRLS-16. RESULTS FROM SJDAWN: A ST JUDE CHILDREN’S RESEARCH HOSPITAL PHASE 1 STUDY EVALUATING MOLECULARLY DRIVEN DOUBLET THERAPIES FOR ALL CHILDREN WITH REFRACTORY OR RECURRENT CENTRAL NERVOUS SYSTEM (CNS) MALIGNANT NEOPLASMS AND YOUNG ADULTS WITH SHH MEDULLOBLASTOMA
Authors: Robinson Giles W , Orr Brent A , Dhanda Sandeep K , Lin Tong , Sabin Noah D , Han Katie , Kostecka Anna , Onar-Thomas Arzu , Roussel Martine F , Stewart Clinton , Gajjar Amar , Northcott Paul A 
Published: June 2024

Abstract

BACKGROUND
Pediatric CNS tumors have recurring molecular aberrations that modulate the cell cycle. We hypothesized that ribociclib, a brain-penetrant CDK4/6 inhibitor, given in doublet combinations could benefit patients with CNS malignancies. SJDAWN (NCT03434262) was launched to determine the recommended phase 2 dose (RP2D), safety, pharmacokinetics, and early efficacy of doublets.

METHODS
Patients &gt;1 and &lt;40 years with recurrent/refractory CNS malignancy were stratified into 3 strata. Escalating dose-levels in 28-day cycles were evaluated in each stratum by rolling-6 design with an expansion cohort at the highest tolerated dose-level. RP2D was declared if ≤3 dose-limiting toxicities (DLTs) occurred in 12 patients. Stratum A evaluated ribociclib/gemcitabine in group3/group4 (Grp3/4) MB and ependymoma (EPN). Stratum B evaluated ribociclib/trametinib in malignancies not eligible for stratum A or C. Stratum C evaluated ribociclib/sonidegib in skeletally mature patients with SHH-MB, TP53 wildtype with chr9q loss and/or PTCH1 mutation. Tumor, blood, and CSF samples were analyzed.

RESULTS
From 2018-2022, 68 patients enrolled: 33 in A (22 Grp3/4-MB, 11 EPN); 28 in B (15 HGG, 13 other); 7 SHH-MB in C. The RP2D was gemcitabine 1250mg/m2 IV day 1, 15 and ribociclib 350mg/m2 PO 1-21 days for A; trametinib 0.025mg/kg PO days 1-14 and ribociclib 280mg/m2 PO days 7-21 for B; and not established for C. DLTs included neutropenia (A), thrombocytopenia (B), mucositis (B), and rash (C). The 6-, 12-, and 24-month progression-free survival (PFS) was 42%(26%-58%), 18%(8%-33%), and 12%(4%-26%) in A, 18%(7%-34%), 4%(1%-15%), and 0% in B, 71%(30%-92%), 43%(13%-73%), and 0% in C. PFS beyond 2-years was observed in 3 Grp3/4-Subgroup3 MBs and 1 EPN. Amplification of CDK6, CCND2, and MYCN in serial CSF samples suggested a mechanism of resistance.

CONCLUSIONS
Ribociclib doublets are tolerated, and the lengthy survival of some patients suggests a selective benefit.
ETMR-06. PNOC031 - INTERNATIONAL TRIAL FOR EMBRYONAL TUMOR WITH MULTILAYERED ROSETTES
Authors: Hanson Derek , Chi Susan , Braunstein Steve , Elhalawani Hesham , Kool Marcel , Filbin Mariella , Gojo Johannes , Plasschaert Sabine , Von Hoff Katja , Margol Ashley , Kline Cassie , Molinaro Annette , Prados Michael , Mueller Sabine 
Published: June 2024

Abstract
Embryonal tumors with multilayered rosettes (ETMR) are aggressive central nervous system neoplasms with unfavorable prognosis, exhibiting rapid disease progression and frequent post-therapeutic relapse. The rarity of ETMR necessitates global collaboration to advance therapies. Radiotherapy (RT) has been associated with improved survival outcomes in ETMR with case series revealing that nearly half of ETMR patients treated without RT relapse within six months of diagnosis. However, RT is often withheld due to young patient age and neurodevelopmental considerations. This high-rate of on-treatment relapse is unique to ETMR and suggests that radiation-sparing regimens may be suboptimal. PNOC031 is an international collaboration, establishing a global clinical trial to innovate and improve therapeutic interventions for children with ETMR. Eligible patients with newly-diagnosed ETMR are stratified into three cohorts: Cohort 1 - gross total resection/RT-eligible patients to receive early focal radiotherapy (RT); Cohort 2 – gross total resection/not RT-eligible to receive high-dose chemotherapy with autologous stem cell rescue; and Cohort 3 – less than gross total resection or with metastatic disease to receive RT or high-dose chemotherapy per RT eligibility, based on age and tumor location. Cohort 1 will test the hypothesis if early RT improves outcomes in a pilot cohort of 20 patients. Patients will receive six weeks of induction chemotherapy, followed by focal irradiation and an additional six weeks of chemotherapy. Six-month progression-free survival will be assessed to determine the impact of radiotherapy on the rate of early relapse. Cohorts 2 and 3 will allow collection of uniform prospective clinical data using a common treatment backbone, to inform future clinical trial design for ETMR. Incorporating a myriad of correlative studies, including next-generation sequencing, cerebrospinal fluid analyses, microbiome profiles, and evaluations of social determinants of health alongside cognitive outcomes, will enhance comprehensive understanding of clinical responses and advance therapeutic options for this high risk disease.
ETMR-07. OVEREXPRESSION OF THE PLAG-GENE FAMILY MEMBER PLAG1 DURING MURINE BRAIN DEVELOPMENT LEADS TO ABERRANT EXPRESSION OF IMPRINTED GENES AND THE FORMATION OF MIDLINE BRAIN TUMORS
Authors: Vaillant Jan , Keck Michaela-Kristina , Wittmann Andrea , Hofmann Nina , Sievers Philipp , Chen Angela , Rozowsky Jacob S , Filbin Mariella G , Beroukhim Rameen , Bandopadhahay Pratiti , Jones David T W , Kutscher Lena M 
Published: June 2024

Abstract

BACKGROUND
The transcription factor PLAG1, ordinarily active during development, has been identified as overexpressed in several pediatric brain tumor entities, including H3 K27-altered diffuse midline glioma. Additionally, our group recently identified a novel type of embryonic CNS tumors with amplification of the related genes PLAGL1 and PLAGL2. How this aberrant PLAG family gene activation drives tumor formation is unknown. We hypothesize that aberrant activity of these transcription factors impedes normal differentiation, thereby fostering neoplastic transformation.

METHODS
To investigate this, we utilize transgenic mouse models engineered to exhibit targeted PLAG1 overexpression and loss of Trp53 during brain development. Following, we use bulk and single-cell RNA-seq to examine underlying mechanisms and are working on whole genome CRISPR-Cas9 screens to detect genetic dependencies in derived tumorsphere cultures.

RESULTS
We found that transgenic mice develop brain tumors in the midline. RNA-seq of these tumors suggests the activation of developmental (homeobox transcription factors) and imprinted genes e.g. H19 and Dlk1, the latter being similarly activated in pediatric CNS tumors with PLAGL1/2 amplification. Using single-cell RNA-seq of the resultant tumors, we compared the gene expression profiles of the tumor cells to a developmental mouse brain atlas. Tumor cells best correlated to radial glia stem cells and glioblasts, supporting the hypothesis of a developmental block caused by PLAG1 overexpression. A subpopulation of the tumor cells seemed to escape the radial glia cell state but were then ultimately locked in the OPC state. A similar mechanism was observed in H3 K27M diffuse midline gliomas.

CONCLUSION
Collectively, we provide evidence that PLAG1 overexpression drives pediatric brain tumor formation by inhibiting normal cellular differentiation. The ongoing CRISPR screen in PLAG1 and PLAGL1 overexpressing murine cell lines, ChIP-seq analysis of the murine tumors, and comparisons with human data and hNSC models aims to unveil the specific molecular mechanisms underlying tumor progression.
ETMR-10. DEVELOPMENT AND CHARACTERIZATION OF A NOVEL IMMUNOCOMPETENT ORTHOTOPIC MOUSE MODEL FOR THE STUDY OF EMBRYONAL TUMORS WITH MULTILAYERED ROSETTES (ETMRS)
Authors: Hervás-Corpión Irati , Zalacain Marta , González-Huarriz Marisol , Largaespada David A , Alonso Marta M 
Published: June 2024

Abstract

BACKGROUND
ETMRs are highly aggressive CNS embryonal tumors with a median survival of &lt;12 months. They are characterized by the presence of multilayered rosettes, amplification of the C19MC microRNA cluster, and high expression of LIN28A; all which are used as diagnostic markers of ETMR. To understand more deeply the mechanisms involved in ETMR pathogenesis, as well as to test immune therapies, it is necessary to develop appropriate immunocompetent murine models that resemble human ETMRs, which are currently scarce. Thus, the aim of our study is the generation and characterization of a novel preclinical ETMR mouse model.

METHODS
The murine PNET cell line DF1-MYC, produced using a MYC overexpressing RCAS model on a C57BL/6J background, and corresponding allografts were implanted into the supratentorial region of 4-week-old NSG and immunocompetent NTV-a p53floxed mice. Mice were monitored and sacrificed. For efficacy studies, the survival curves were plotted according to the Kaplan-Meier method. For tumor histological analysis and immunohistochemistry, FFPE brain sections were stained with H&E or antibodies against Ki67, c-Myc and Lin28a. Transcriptional profile was characterized by RNA-seq.

RESULTS
DF1-MYC-bearing NP53 mice did not develop tumors except one mouse that showed a small tumor with multilayered rosettes. With the goal of achieving complete penetrance, we injected DF1-MYC cells orthotopically in NSG mice and allografts subsequently in NP53 mice. Specifically, our MYC384 allograft ETMR mouse model show a penetrance of 70% with a median survival of 36 days. Importantly, the MYC384 allograft model recapitulates histopathologic features of human ETMR, including the presence of highly proliferative undifferentiated cells with multilayered rosettes. Moreover, we are working on overexpressing Lin28a and c-Myc in MYC384 to create a more realistic molecular model of ETMR while allowing us to achieve 100% penetrance.

CONCLUSION
We describe MYC384 as a potential relevant immunocompetent mouse model of ETMR with almost complete penetrance.
ETMR-13. MARROW-ABLATIVE CONSOLIDATION CHEMOTHERAPY WITH AUTOLOGOUS HEMATOPOIETIC PROGENITOR CELL RESCUE (HDCT) DECREASES THE DEVELOPMENT OF CHOROID PLEXUS CARCINOMA (CPC)-SPECIFIC RELAPSE IN HIGH-RISK TP53-MUTATED (GERMLINE OR SOMATIC) YOUNG CHILDREN WITH NEWLY DIAGNOSED CPC
Authors: Yankelevich Maxim , Ozorio Diana S , Zaky Wafik , Lafay-Cousin Lucie , Margol Ashley , Toll Stephanie , Prados Michael , Gardner Sharon L , Hanson Derek , Quiroz Lina , Fox Javier E , Mueller Sabine , Finlay Jonathan L 
Published: June 2024

Abstract

BACKGROUND
CPC are childhood cancers in which the loss of TP53 function defines unfavorable disease. CPC-free survival rates have remained poor in patients with TP53 mutations and recent data revealed CPC-free survival of 29% with a non-marrow-ablative chemotherapy strategy. Previously reported results of the “Head Start” (HS) HDCT approach were limited by small patient numbers and incomplete TP53 mutation data. Consequently, the role of HDCT in TP53-mutated CPC remains unclear.

METHODS
We have analyzed data on TP53 status, CPC-free survival and second cancers from the largest cohort of patients who received initial therapy with the intent of undergoing HDCT.

RESULTS
Twenty-seven children with CPC received HS-like induction chemotherapy and 23 completed HDCT consolidation. Somatic or germline TP53 mutations were identified in 17 patients, 4 exhibited TP53 wild type (TP53wt); TP53 status remained untested in 6. Five-year CPC-free survival was 66% for patients with TP53 germline mutations (n=12), 40% for those with somatic tumor TP53 mutations (n=5) and 50% with confirmed TP53wt (n=4). Among patients with germline TP53 mutations, only 4/12 experienced CPC recurrences, 4 died from secondary cancers and 4 are currently alive. The 5-year CPC-free survival for 23 patients who underwent HDCT was 52%. All six survivors with TP53 mutations had undergone HDCT, and 5/6 avoided irradiation. Eight/12 patients with TP53 germline mutations and Li-Fraumeni Syndrome (LFS) developed second malignancies, including 6 patients in HDCT group and the remaining 2 patients who did not undergo consolidative HDCT.

CONCLUSIONS
Our data indicate that HDCT consolidation is associated with improved CPC-free survival compared with historical reports in children with TP53 mutated CPC. The ultimate development of second cancers affects outcomes for those with LFS, irrespective of HDCT treatment. These data justify the inclusion of HDCT in the prospective international trial under development for young children with newly diagnosed TP53 mutated CPC.
ETMR-17. CLINICAL DESCRIPTION OF PEDIATRIC CHOROID PLEXUS PAPILLOMAS FOR IDENTIFICATION AND VALIDATION OF HIGH-RISK CHARACTERISTICS
Authors: Fiedler Christian , Kordes Uwe , Thomas Christian , Hasselblatt Martin , Bison Brigitte , Behrens Lars , Kortmann Rolf-Dieter , Timmermann Beate , Pietsch Torsten , Rutkowski Stefan , Obrecht-Sturm Denise 
Published: June 2024

Abstract

BACKGROUND
Choroid plexus papilloma (CPP) and atypical CPP (aCPP) have an excellent prognosis. However, some CPP/aCPP relapse and may qualify for postoperative treatment.

METHODS
Patients from the International CPT-SIOP Registry with CPP/aCPP recruited in Germany between 2011–2023 were included and analysed according to initial staging (postoperative residual tumor [R+], meningeosis [M+]), biology, postoperative treatment and outcome.

RESULTS
Ninety-three patients were identified (male: n=53, female: n=40). Median age at diagnosis was 1.9(0.1–17.6) years. Initial staging was R0/M0 in n=63, R+/M0 in n=21, R0/M+ in n=5 and R+/M+ in n=4. aCPP was diagnosed in n=38. Methylation subtype was available for n=34:”adult” n=3, “pediatric-A” n=19 and “pediatric-B” n=12 (6/12 aCPP). Median follow-up was 5.5(±0.99) years. Twelve tumors relapsed: R0/M0 n=4, R+/M0 n=7, R+/M+ n=1. Two relapsed patients died. Eleven patients initially received ≥1 surgery. Most patients did not receive postoperative treatment (watchful waiting, n=86). Seven patients (R0/M0 n=3, R+/M0 n= 1, R0/M+ n=2, R+/M+ n=1) received chemotherapy. None was irradiated during first-line treatment. Histology and biology had no impact on PFS (5y-PFS: CPP 88.6±4.9%, aCPP 82.7±6.5%, pPFS=0.3; “adult” 33.3±27.2%, “pediatric-A” 93.8±6.1%, “pediatric-B” 72.9±13.5%, pPFS=0.08). Patients with R0/M0-status had better 5y-PFS than those with R+ and/or M+ (90.4±4.1% vs. 77.7±8.1%, p=0.05). Neither incomplete resection alone, nor meningeosis alone did relate to inferior PFS in CPP/aCPP separately analysed (R+: p=0.07/p=0.07, M+: p=0.5/p=0.4). In the whole cohort, R+ was associated with inferior survival (5y-PFS R+ 72.2±9.8% vs. R0 91.3±3.7%, p=0.009). It remains unclear if R+-patients benefit from chemotherapy (5y-PFS watch-and-wait vs. chemotherapy 75.1±9.8% vs. 50.0±35.4% pPFS=0.7).

CONCLUSION
Incomplete resection appears to have impact on the risk for relapse in CPP/aCPP. It remains unclear whether those patients benefit from postoperative chemotherapy.
ETMR-19.BCOR/L1-ALTERATIONS REWIRE HISTONE REGULATION TO INDUCE ONCOGENIC PATHWAYS IN PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS
Authors: Bruckner Katharina , Lötsch-Gojo Daniela , Gabler Lisa , Wang Shanzheng , Kirchhofer Dominik , Labelle Jenna , Madlener Sibylle , Senfter Daniel , Schmitt-Hoffner Felix , Federico Aniello , Koster Jan , Dorfer Christian , Tauziède-Espariat Arnault , Pahnke Jens , Hovestadt Volker , Beck Alexander , Schueler Julia , Haberler Christine , Berger Walter , Filbin Mariella G , Kool Marcel , Gojo Johannes 
Published: June 2024

Abstract

BACKGROUND
Central nervous system (CNS) tumors with BCOR internal tandem duplication (ITD) or BCOR/L1 fusions are recently described tumor types with distinct molecular characteristics and poor clinical outcome. BCOR and its homologue BCORL1 are essential components of the non-canonical polycomb repressor complex (PRC) 1.1 thereby acting as epigenetic regulators exerting a profound impact on central cellular mechanisms. However, the influence of BCOR/L1-alterations on the functionality of PRC1.1 in pediatric CNS tumors remains understudied.

METHODS
We performed bulk as well as single-cell/nucleus RNA sequencing (scRNA-Seq) and chromatin immunoprecipitation sequencing (ChIP-Seq) of CNS tumor tissue harboring BCOR-ITD or BCOR/L1 fusions. Additionally, BCOR/L1-altered, patient-derived cell models were used for downstream in vitro analyses.

RESULTS
ChIP-Seq analysis demonstrated binding of both KDM2B and mutant BCOR/L1 at PRC1.1 target genes whereas PRC1/2-mediated histone modifications H3K27me3 and H2AK119ub were absent. In addition, PRC1.1 target gene loci were characterized by high H3K27ac levels indicating increased transcriptional activity in BCOR/L1 mutant samples. Indeed, PRC1.1 targets such as FGFR1, GATA6, and ERBB3 were found to be upregulated in bulk transcriptome (n=37) analyses. Using scRNA-seq (n=10), we resolved a transcriptionally distinct cell population, specific for BCOR/L1-driven CNS tumors, which expressed high levels of PRC1.1 target genes. Besides PRC1.1 target genes, the targetable receptor tyrosine kinases PDGFR/FGFR(1/3), and IGF1R were found to be upregulated in pediatric BCOR/L1-altered CNS cancers. Accordingly, drug screens of patient-derived cell models revealed sensitivity towards small molecule inhibitors targeting the respective pathways. This translated well in anti-tumor effects of the FGFR/PDGFRA inhibitor nintedanib in BCORL1::NUTM2HP-fused patient-derived xenograft bearing mice.

CONCLUSIONS
Our data demonstrate for the first time that BCOR/L1-altered CNS tumors are driven by dysfunction of PRC1.1 histone modifications inducing profound transcriptomic changes ultimately activating oncogenic pathways. We further identified first feasible therapeutic targets including FGFR and PDGFR which may be leveraged for improved therapy of patients suffering from this aggressive tumor type.
ETMR-25. UNRAVELING THE ROLE OF SHH SIGNALING PATHWAY IN RETINOBLASTOMA
Authors: Liu Xiao , Zhang Jiao , Xu Zhenhua , Dlugosz Andrzej , Frank Stephan , Meyer Peter , Suzuki Hiromichi , Nakashima Taakuma , Pei Yanxin 
Published: June 2024

Abstract

BACKGROUND
Retinoblastoma (RB) is a pediatric cancer affecting the retina, often requiring surgical removal of one or both eyes due to the limited effectiveness of current treatments. There is an urgent need for advanced therapeutic strategies capable of effectively eliminating tumors, thereby obviating the need for surgical removal of eyes in affected children. Achieving this goal requires a deeper understanding of the cellular and molecular mechanisms governing RB initiation and progression.

METHODS
Using a transgenic mouse model, we identified the crucial role of the Shh signaling pathway in Rb1 mutation-induced tumorigenesis, highlighting its potential as a novel therapeutic target for RB treatment.

RESULTS
We have observed frequent overexpression of Shh signaling proteins (SHH, GLI1, and GLI2) in human RB, correlating with aggressive clinicopathological features. GLI2 overexpression is necessary for Rb1 deletion-induced RB tumor initiation in mouse retinal progenitor cells (RPCs). These mouse intraocular tumors accurately replicate human RB at both cellular and molecular levels. Additionally, Shh pathway activation extends to normal retinal cells adjacent to human RB tumors, suggesting the involvement of Shh signaling in RB-microenvironment interactions. Importantly, our studies have identified a novel small molecular inhibitor targeting the Shh pathway, effectively inhibiting RB growth in vitro and in vivo by targeting both tumor cells and the tumor microenvironment (TME).

CONCLUSIONS
The proposed research aims to provide unprecedented insights into the role of SHH signaling pathway in RB initiation and progression and the supporting communication network between RB tumors and TME. These outcomes have the potential to treat RB effectively while improving the well-being of young individuals with RB and those at risk of RB.
ETMR-32. SUPRATENTORIAL NEUROEPITHELIAL TUMOR WITH PLAGL1 FUSION: A CASE REPORT
Authors: Rocco Abbey , Beck Mary , McHugh Michele , Lampe Ashley , Meyer Ashley , Ogle Andrea , Cluster Andrew , Brossier Nicole M , Dahiya Sonika , Abdelbaki Mohamed S , Perkins Stephanie , Roland Jarod , Shatara Margaret 
Published: June 2024

Abstract

BACKGROUND
Supratentorial neuroepithelial tumor with PLAGL1 fusion has emerged as a novel subgroup within pediatric brain tumors. Despite its recent identification, critical aspects such as optimal clinical characteristics and management strategies remain elusive. This case report aims to contribute essential insights to the growing body of literature surrounding this enigmatic tumor entity, providing a detailed exploration of its clinical presentation and histopathological features.

METHODS
A retrospective chart review was conducted, and relevant data were analyzed.

RESULTS
An 11-year-old female presented with a two-week history of headaches, vomiting, lethargy, and decreased oral intake. Neuroimaging revealed a left frontal lesion with conspicuous mass effect and midline shift, prompting urgent craniotomy due to sudden onset altered mental status. Histopathological analysis revealed a hypercellular glial neoplasm characterized by perivascular pseudorosettes, scattered microcalcifications, microcysts, and areas of necrosis. Immunohistochemical staining revealed GFAP positivity in a substantial subset of tumor cells, rare dot-like positivity for EMA, and diffuse membranous and focal dot-like positivity for D240. Olig2 was mostly negative, indicating the absence of Oligodendrocyte lineage differentiation. The tumor exhibited an elevated Ki-67 proliferation index (approximately 20-30%). Fluorescence in situ hybridization (FISH) studies were negative for RELA, YAP1, and C19MC rearrangements. Targeted next-generation sequencing unveiled an EWSR1-PLAG1 fusion and methylation profiling classified the tumor as “Neuroepithelial tumors, PLAG1-fused” with high confidence. Given the morphological resemblance to anaplastic ependymoma, the therapeutic recommendation included focal irradiation (54 Gy) with proton therapy. The patient, now 12 months post-therapy, is showing favorable clinical outcomes.

CONCLUSION
This case report underscores the clinical and histopathological intricacies of supratentorial neuroepithelial tumors with PLAGL1 fusion. The identification of EWSR1-PLAG1 fusion and associated molecular alterations informs diagnostic considerations and treatment strategies for this novel entity, emphasizing the importance of continued research to enhance our understanding of its clinical behavior and optimal management approaches.