bluuebunny/crossref_metadata_2025_split huggingface dataset:
BIOM-14. UTILITY OF MIRNA-BASED LIQUID BIOPSY AND RADIOGRAPHIC IMAGING IN PEDIATRIC BRAIN TUMOR PATIENTS
Authors: Arif Shehbeel , Madsen Peter , Familiar Ariana , Rathi Komal , Coyle Anne , Foster Jessica , Naqvi Ammar , Nabavizadeh Ali , Storm Phillip B , Hollawell Madison , Koptyra Mateusz , Resnick Adam C 
Published: June 2024

Abstract

BACKGROUND
MRI is the current gold standard imaging technique for diagnostic evaluation and monitoring of pediatric CNS tumors; however, MRI measures can only provide inference into tumor biology and molecular stratification. miRNAs are an abundant and stable nucleic acid found circulating in blood and cerebrospinal fluid (CSF) and can be utilized as a tumor biomarker.

METHODS
We hypothesized that correlating miRNA biomarkers with radiological tumor measurements may provide improved diagnostic and monitoring for patients with pediatric brain tumors. Using a cohort of 54 pediatric brain tumors including low grade glioma, ependymoma, germ cell tumor, medulloblastoma, atypical teratoid rhabdoid tumor and high-grade glioma we attempted to combine MRI findings and circulating miRNA data. The miRNA expression was profiled in 33 CSF and 52 plasma samples using the HTG EdgeSeq platform. Clinically acquired, multi-parametric MRI scans at time-points close to liquid biopsy collection were collected retrospectively and used to generate volumetric tumor segmentations. Machine learning methods were implemented to evaluate combinatory features.

RESULTS
We identified unique miRNA targets that significantly correlated with MRI features, clinical findings, and patient outcomes. In both CSF and plasma, miRNA expression was found to correlate with diagnosis and clinical features including tumor grade and disease burden (p &lt; 0.05). In CSF, miRNA expression was correlated with MRI features including cystic core presence, edema, leptomeningeal disease and tumor location (p &lt;0.05). In plasma, differences in miRNA expression were related to MRI measurements including cystic core volume, location, and leptomeningeal disease (p &lt; 0.05). Combination of miRNA targets for plasma or CSF with imaging-based features significantly improved histology specific multimodal diagnosis predictions.

CONCLUSIONS
These results demonstrate the potential utility of miRNAs as a pediatric brain tumor biomarker which when combined with imaging features can improve minimally and non-invasive diagnostics and the subsequent management of pediatric brain tumor patients.
CNSC-03. LINKING CELL FATE DETERMINATION IN THE EMBRYONIC FOREBRAIN TO PEDIATRIC HIGH-GRADE GLIOMA
Authors: Furst Liam M , Roussel Enola M , Leung Ryan F , George Ankita M , Firestein Ron , Faux Maree C , Eisenstat David D 
Published: June 2024

Abstract

BACKGROUND
Pediatric high-grade gliomas are treatment resistant, usually fatal cancers encompassing diffuse midline glioma, K27-altered (DMG), and diffuse hemispheric glioma, G34R/V (DHG). Most patients harbour canonical and non-canonical mutations in histone variants H3.1 and H3.3, leading to global epigenetic dysregulation and stalled differentiation states as oligodendroglial progenitor cells (OPC) in DMG and GABAergic interneuron precursors in DHG. DLX2 is a homeobox transcription factor that directly represses OPC cell fate and promotes GABAergic interneuron cell fate and migration during early neurogenesis. Methods & Results Our lab has shown DLX2 promoter occupancy of Gad1/Gad2, and early (Olig2, Nkx2.2) and late (Myt1, Plp1) genes required for OPC differentiation in vivo. Co-expression of DLX2 with these target sequences reduces reporter gene expression in vitro, and the Dlx1/Dlx2 double knockout (DKO) mouse showed increases in Olig2, Nkx2.2, and Plp-1 expression in vivo. Transient over-expression of a Dlx2-GFP construct into murine DMG cells resulted in significant increased expression of Gad1/2 isoforms and decreased Olig2 and Nkx2.2, global restoration of H3K27me3 and loss of H3K27 acetylation, as well as a reduction in migration, invasion, and colony formation in vitro. To validate in human pHGG, we first probed an RNA-seq database containing 62 patient-derived pHGG cell lines which demonstrated an inverse correlation between DLX2 expression and OLIG1/2. Cell fate changes in DHG cell lines were evaluated by knockout of DLX2 using CRISPR/Cas9. Concurrently, OLIG1/2-expressing DMG cell lines underwent stable transfection of a DLX2-mCherry overexpression construct in conjunction with a SOX2-BFP overexpression construct, confirmed by qPCR and immunoblot. Analysis of histone H3 marks, K27M, and OPC signature genes will be compared to OPC genes from Dlx1/Dlx2 DKO mouse ganglionic eminences.

CONCLUSIONS
Manipulation of DLX2 in pHGG provides a model system for assessing the contribution of a homeobox factor to cell fate decisions regulating differentiation and tumorigenicity.
CP-02. DAYTIME SLEEPINESS AND HEALTH-RELATED QUALITY OF LIFEIN PATIENTS WITH CHILDHOOD-ONSET CRANIOPHARYNGIOMA
Authors: Mann-Markutzyk Laura V , Beckhaus Julia , Oezyurt Jale , Friedrich Carsten , Müller Hermann L 
Published: June 2024

Abstract

BACKGROUND
Adamantinomatous craniopharyngioma (CP) is a rare embryonal malformation originating from remnants of the craniopharyngeal duct and located in the sellar and/or parasellar area. Overall survival rates are high (92%), but frequently quality of life (QoL) is severely impaired in patients with CP involving hypothalamic structures. Tumor- and/or treatment-related hypothalamic lesions result in disturbances of circadian rhythms including increased daytime sleepiness.

METHODS
After a median follow-up interval of 10 years (range: 1-39 years), 119 patients (63 female/ 56 male) with CP, recruited in KRANIOPHARYNGEOM 2000/2007 and KRANIOPHARYNGEOM Registry 2019 between 2000 and 2022, were analysed for daytime sleepiness by Epworth scale (ES) and for QoL by EORTC QLQ-C30 questionnaire.

RESULTS
CP patients (n= 85) with pathologically increased ES score (ES score &gt; 12) had worse QoL (p = 0.003), when compared with CP patients with normal ES score (n= 34). Pathologically increased daytime sleepiness (ES score) was negatively correlated with QoL (r= -0.395; p&lt; 0.001). Surgical hypothalamic lesions (71% of patients) were associated with higher ES scores, whereas such impact could not be observed for presurgical hypothalamic involvement of CP (73% of patients).

CONCLUSIONS
As increased daytime sleepiness plays an important role for QoL in survivors of CP, treatment of disturbances of circadian rhythms with medication such as central stimulating agents is recommended. For prevention of increased daytime sleepiness, hypothalamus-sparing surgical treatment strategies should be considered as state of the art in patients with CP.
CP-15. LONG-TERM OUTCOMES OF PAEDIATRIC CRANIOPHARYNGIOMAS: MULTI-CENTRE COMPARATIVE STUDY
Authors: Yamaki Vitor Nagai , Sidpra Jai , Peres Bruno Santanna , Massey Flavia , Quianga Catuto Domingos Alexandre , da Borsatto Guilherme Jose Costa , Telles Joao Paulo Mota , Silva Inês Nobrega , Martinez-Barbera Juan Pedro , Biswas Asthik , Mankad Kshitij , Gan Hoong-Wei , Marcus Hani J , Jeelani Noor ul Owase , Hargrave Darren R , Matushita Hamilton , Marie Suely Kazue Nagahashi , Aquilina Kristian 
Published: June 2024

Abstract

BACKGROUND
Craniopharyngioma (CP) account for 80% of childhood hypothalamopituitary tumours and, though benign, their proximity to the visual pathways, hypothalamus, and pituitary incurs significant long-term neurologic and endocrine morbidity. Informed surgical decision-making has the potential to reduce morbidity and improve outcomes.

METHODS
This multicentre retrospective observational study aimed to compare long-term outcomes of CP at two paediatric neurosurgery units (GOSH, UK, and USP, Brazil), delineating management paradigms associated with better prognosis. CP treated over a 20-year period were identified and standardized clinical outcomes recorded for comparative analysis.

RESULTS
123 patients were identified (USP=52; GOSH=71). No demographic differences were identified between series (mean age: USP=9.2±4.6; GOSH=8.2±4.1 years). Headaches (USP=75%; GOSH=62%) and visual deficits (USP=46%; GOSH=38%) were the most common presenting symptoms. Growth hormone deficiency at presentation was more common in the USP cohort (USP=62.5%; GOSH=35%; p=0.009). There was significantly more hypothalamic invasion in the GOSH cohort (Paris grade 2: GOSH=67.0%; USP=37.5%; p=0.026), but significantly larger cystic volumes in the USP cohort (USP=27.5±37cm3; GOSH=10.5±8.9cm3;p=0.004). These differences led to different surgical approaches, with more subtotal resections at USP (78%) and more cyst aspirations at GOSH (62%). 80% of patients at GOSH received RT compared to 32% at USP. Mean follow-up at GOSH was 7.5±4.8 years compared to 10.1±5.6 years at USP. Cognitive outcome did not vary. GOSH cohort presented higher rates of levothyroxine replacement (USP=67%; GOSH=86%;p=0.017). GOSH exhibited better hypothalamic outcomes (p=0.08) and better visual outcomes (field deficits: GOSH=44%; USP=66%;p=0.01). In multivariate analysis (n=123), subtotal/gross-total resection (OR0.17; 95%CI:0.05-0.55;p&lt;0.01) and older age at diagnosis (OR0.91, 95%CI:0.82-0.99;p=0.04) were associated with longer progression-free survival.

CONCLUSIONS
Comparative analysis of two large craniopharyngioma series identified different paradigms of surgical management driven by clinical-radiological presentation with similar long-term outcomes. Subtotal/gross-total resection was not related to worse clinical outcome or better progression-free survival.
DIPG-04. THE BENEFIT OF CRANIOSPINAL IRRADIATION (CSI) RESCUE IN PHASE 2 RANDOMIZED STUDY OF RADIOTHERAPY (RT), CONCOMITANT NIMOTUZUMAB AND VINORELBINE AND RE-IRRADIATION AT RELAPSE, VERSUS MULTIPLE ELECTIVE RADIOTHERAPY COURSES WITH CONCOMITANT VINORELBINE AND NIMOTUZUMAB FOR NEWLY DIAGNOSED CHILDHOOD AND ADOLESCENCE DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Massimino Maura , Biassoni Veronica , Mastronuzzi Angela , Schiavello Elisabetta , Barretta Francesco , Quaglietta Lucia , Milanaccio Claudia , Pecori Emilia , Cacchione Antonella , Ruscio Valentina Di , Chiesa Silvia , Scimone Giuseppe , Barra Salvina , De Martino Lucia , Nigro Olga , Ramaglia Antonia , Picariello Stefania , Verrico Antonio , Vallero Stefano , Mussano Anna , Vennarini Sabina , Calareso Giuseppina , Podda Marta , Gattuso Giovanna , Cinalli Giuseppe , Antonelli Manila , Dossena Chiara , Buttarelli Francesca Romana , Gianno Francesca , Minasi Simone , Modena Piergiorgio , De Cecco Loris 
Published: June 2024

Abstract

BACKGROUND
This trial evaluated feasibility,response,PFS/OS of a randomization comparing two different RT schedules for DIPG while administering the same systemic treatment. We moreover evaluated the benefit of craniospinal irradiation(CSI) in case of disseminated(D) relapse.

METHODS
Patients: 2-21 years-old with at least radiologically verified DIPG (MRI blindly reviewed at diagnosis,every 12 weeks thereafter) and symptoms duration below 6 months. Biopsy required if atypical imaging, also allowed after adequate consensus.Vinorelbine 20 mg/m2+nimotuzumab 150 mg/m2 were administered weekly for 12; thereafter every other week until tumor progression or for up to 2 years. Standard(ST) arm was full brainstem/focal tumor site RT at total dose of 54Gy(1.8Gy/day); for local progression re-irradiation was proposed at 19.8Gy, in case of dissemination CSI at 36Gy was offered.Experimental(SP) arm included three elective courses of RT at defined time-points(36Gy, 19.8Gy and 19.8Gy) with reirradiation for relapse at 9 Gy/36 Gy as above described. Incidences of local(L) and D progression were assessed in a competing risk setting.

RESULTS
55 patients were included from 4 Italian centers,27 in ST,30 males, median age 7.1 years. Median follow-up 39.1 months. Fifteen patients needed a shunt,13 during treatment;23 were biopsied,in 21 according to local protocols.22/23 tumors had H3.3K27 mutation. 53 relapsed, 34 L,13 D,6 L+D.Fifteen/19 with a D component receiving CSI had a median survival of 7.6 months after relapse, significantly higher than that of the 4 without CSI(median 2.9 months,P=0.020). Patients submitted to biopsies had more D(P=0.017) and less L progression(P=0.058). SP irradiation and any reirradiation at relapse were feasible and never produced significant radionecrosis.Median EFS/OS for the whole series were 8.4/14 months, respectively; not significantly different between patients with local vs. disseminated relapses.

CONCLUSIONS
Reirradiation, even if CSI, confirmed feasible and benefitted patients OS.Randomization results will be later reported.
DIPG-15. NOVEL CNS SENSING SYNNOTCH-CAR T CELLS FOR TARGETING DIFFUSE MIDLINE GLIOMA
Authors: Lakshmanachetty Senthilnath , Simic Milos , Haegelin Jeffrey , Watchmaker Payal , Long Haoyu , Deucker Jason , Zhu Robert , Sheperd Chanelle , Yu Wei , Ng Ben , Wang Yuan , Troyanskaya Olga , Cardarelli Lia , Sidhu Sachdev , Lim Wendell , Okada Hideho 
Published: June 2024

Abstract

BACKGROUND
Diffuse midline glioma (DMG), including Diffuse intrinsic pontine glioma (DIPG), is an aggressive brain tumor in children with limited treatment options. Recent developments of phase 1 clinical trials have shown early promise for chimeric antigen receptor (CAR) T cells in patients with DMG/DIPG. However, several barriers such as the absence of tumor-specific antigens, restricted trafficking to the tumor site, and poor persistence hinder the full therapeutic potential of CAR T cell therapy in DMG/DIPG.

METHODS
To safely target the glioma-associated antigens (GAAs) without attacking nomal tissues expressing the same antigens, we adopted a novel synthetic Notch (synNotch) receptor system and engineered T cell circuits employing a “prime-and-kill” strategy. In this system, a synNotch receptor recognizing the priming antigen, Brevican (BCAN), exclusively expressed on cells in the central nervous system (CNS) but not on non-CNS cells, locally induces the expression of a tandem CAR against GAAs, ephrin type A receptor (EphA2) and interleukin-13 receptor a2 (IL13Ra2), there by homogenously eliminating DMG/DIPG cells.

RESULTS
The α-BCAN synNotch⋄α-EphA2/IL-13Rα2 CAR (B-SYNC) T cells efficiently killed DMG/DIPG (BT-245, SF8628, SU-DIPGXIII, and SU-DIPGXVII) cells in vitro in the presence of priming cells (K562 cells expressing BCAN). Moreover, a single intravenous infusion of B-SYNC T cells significantly (P&lt; 0.001) prolonged the survival of immunodeficient mice bearing aggressive, orthotopic SF8628 DIPG xenografts and completely eradicated the tumor in more than 50% (4/7) of mice. Strikingly, we observed excellent homing, priming, activation, and persistence of B-SYNC T cells in the brain stem of mice bearing SF8628 xenografts. In contrast, constitutively active α-EphA2/IL-13Rα2 CAR T cells or untransduced T cells demonstrated a failure to migrate to the brain stem and improve the survival of mice.

CONCLUSIONS
Collectively, our findings strongly support the development of clinical trials evaluating the efficacy of B-SYNC T cells in DMG/DIPG patients.
DIPG-30. ELUCIDATING DOWNSTREAM MEDIATORS OF ONCOGENESIS INFOXR2-EXPRESSING DIFFUSE MIDLINE GLIOMAS
Authors: Tsai Jessica W , Coppola Marissa , Arounleut Phonepasong , Collins Jared B , Hart Patrick , Keshishian Hasmik , Jones David T W , Bandopadhayay Pratiti , Phoenix Timothy N 
Published: June 2024

Abstract

BACKGROUND
Diffuse midline gliomas (DMGs) are universally fatal pediatric tumors with a median survival of less than one year. Forkhead Box R2 (FOXR2) is a forkhead family TF that we have found to be aberrantly expressed in DMGs. FOXR2 expression is sufficient to enhance glioma formation, and we have shown that regulation of FOXR2 occurs through a previously unrecognized epigenetic mechanism. FOXR2 is necessary for proliferation in FOXR2-expressing DMGs. It is also a potent oncogene, sufficient to enhance cell proliferation and in vivo tumor formation. However, the downstream mediators of FOXR2-mediated gliomagenesis are poorly understood.

METHODS
We applied an integrative approach using proteomics, transcriptomics, in vitro cancer models, and in vivo in utero electroporation mouse models to systematically evaluate how FOXR2 mediates gliomagenesis.

RESULTS
We have found that FOXR2 is aberrantly activated in DMGs. FOXR2 enhances MYC protein stability, even in the presence of cycloheximide. However, FOXR2 also exerts its oncogenic effects through MYC independent functions. FOXR2 is highly enriched at E26-transformation (ETS) motifs and specifically activates ETS transcriptional gene sets. To identify FOXR2 protein-protein interactions, we performed immunoprecipitation and mass spectrometry to identify FOXR2 protein interactors. Moreover, we have performed both proteomic and phospho-proteomic analyses of FOXR2-expressing human neural stem cells. These proteomic studies have allowed us to identify proteins, phospho-sites, and signaling pathways that are highly enriched in FOXR2-expressing cells. These pathways could be potential therapeutic targets in FOXR2-expressing DMGs.

CONCLUSIONS
Taken together, this study elucidates how FOXR2 protein interactors mediate oncogenesis in FOXR2-expressing diffuse midline gliomas.
DIPG-48. PRECISION GUIDED THERAPY PROVIDES CLINICAL BENEFIT IN H3K27-ALTERED DIFFUSE MIDLINE GLIOMA
Authors: McKay Campbell , Power Phoebe , Staunton Jordan , Sriharan Shampavi , Jessop Sophie , Zhukova Nataliya , Trinder Sarah , Govender Dinisha , Barahona Paulette , Gifford Andrew J , Mignone Cristina , Xie Angela , Tax Gabor , Tsoli Maria , Dolman Emmy , Mayoh Chelsea , Wong Marie , Cowley Mark , Marshall Glenn , Trahair Toby , Lock Richard B , Ekert Paul , Haber Michelle , Tyrell Vanessa , Lau Loretta , Manoharan* Neevika , Ziegler* David S , Khuong-Quang* Dong-Anh 
Published: June 2024

Abstract

BACKGROUND
The utility of precision-guided therapeutic approaches to H3K27-altered diffused midline glioma (DMG) remains uncertain. The Australian Zero Childhood Cancer (ZERO) program combines molecular profiling (whole-genome sequencing (WGS), whole-transcriptome sequencing (RNAseq), and DNA methylation profiling), with in vitro high-throughput drug screening (HTS) and patient-derived xenograft (PDX) drug-efficacy testing in patients with high-risk cancer.

METHODS
We report on the cohort of patients enrolled with a DMG in the ZERO clinical trial between 2017 and 2023.

RESULTS
68 patients were enrolled, predominantly at diagnosis (87%), with pontine lesions (66%) at a mean age of 8.7 years. 59 (87%) patients had WGS + RNAseq successfully performed. Most tumors harbored an H3F3A mutation (n=50), followed by HIST1H3B (n=11), HIST1H3C (n=2), HIST2H3C (n=1) and EZHIP overexpression (n=4). 37 samples were suitable for cell culture, with HTS successfully performed in 25 cases, and PDXs established in 7. Precision-guided therapy (PGT) was recommended by the ZERO multidisciplinary tumor board for 53 patients (78%), including 5 recommendations guided by HTS. PI3K/mTOR inhibitors and MEK inhibitors were the most recommended PGTs. 21 patients (31%), receiving 24 PGTs, were eligible for survival analysis. The clinical benefit rate (per RAPNO) was 52% for patients receiving PGT, with 5 patients exhibiting PR and 6 patients SD &gt;6 months. Notably, the 5 PR included: a PR in a patient with BRAFV600E mutation to dabrafenib/trametinib, a near-CR in a patient with germline BRCA2 mutation to olaparib/durvalumab, a sustained PR in a patient with FGFR1 mutation to trametinib/bevacizumab and 2 patients with PIK3CA mutations who received PGT in the context of recent radiotherapy. Median overall survival of the PGT group was 21.2 months versus 11.8 months for the rest of the cohort (hazard ratio 0.67 [95%CI 0.39-1.1]).

CONCLUSIONS
These results, for the first time, highlight the potential clinical benefit of PGT in H3K27-altered DMG.
DIPG-53. AN EXCEPTIONALLY RARE CASE OF A DIFFUSE MIDLINE GLIOMA WITH CONCOMITANT H3.1 K27M AND G34R MUTATIONS IN THEHIST1H3C (H3C3) GENE
Authors: Reisz Zita , Pereira Rita , Nevis Smitha , Mackay Alan , Bhaw Leena , Grabovska Yura , Laxton Ross , Molinari Valeria , Burford Anna , Clark Barnaby , Bleil Cristina , Zebian Bassel , Weiser Annette , Carceller Fernando , Marshall Lynley , King Andrew , Bodi Istvan , Al-Sarraj Safa , Jones Chris , Clarke Matthew 
Published: June 2024

Abstract

BACKGROUND
Histone mutations (H3 K27M, H3 G34R/V) define subtypes of paediatric-type diffuse high-grade gliomas (HGG) (diffuse midline glioma (DMG), H3 K27-altered, diffuse hemispheric glioma (DHG), H3 G34-mutant). The WHO classification recognises exceptional cases where these mutations co-occur. We report one such case of a 2-year-old female presenting with neurological symptoms and lethargy.

METHODS
MRI imaging identified a brainstem lesion; a stereotactic needle biopsy was undertaken, followed by standard diagnostic neuropathology workflows including histology review, panel immunohistochemistry, DNA methylation profiling (Illumina EPIC BeadArrays, brain tumour classifier (MNP v12.5 R package)) and WES/WGS. Patient-derived in vitro cell cultures were established allowing further characterisation using RNAseq and chromatin immunoprecipitation assays with sequencing (ChIP-seq).

RESULTS
Histology showed diffusely infiltrating pleomorphic astrocytes, multinucleated cells, and conspicuous mitotic activity; the diagnosis was DMG, H3 K27-altered (immunohistochemistry: H3K27me3 loss, H3K27M positivity). DNA methylation profiling classified the tumour as ‘DMG, H3 K27-altered’ (calibrated score=0.99). WES/WGS revealed concurrent H3.1 K27M and G34R mutations (clonal, in the same reads) of HIST1H3C (H3C3), somatic variants in FGF11 and PIK3CA, and a pathogenic germline NBN variant. The RNAseq profile of the primary tumour and cell cultures clustered with H3 K27M-mutant tumours. Unbiased in vitro drug screening showed no selective sensitivities. ChIP-seq (H3K27ac, H3K27me3, H3K36me3, RNApol2 marks) showed features in keeping with DMG H3 K27M-mutant tumours (H3K27ac loci including OLIG2, IRX1/2, PKDCC). The patient was treated with adjuvant radiotherapy and everolimus, but progressed and passed away 13 months post-diagnosis.

CONCLUSION
This case is an exceptionally rare, complex variant of histone-mutant paediatric HGG, and the first reported occurrence in HIST1H3C (H3C3). It illustrates that in cis, the H3.1 K27M mutation demonstrates a dominance over molecular and clinical profiles compared to G34R, and highlights the importance of broad molecular profiling to identify such examples for further study.