bluuebunny/crossref_metadata_2025_split huggingface dataset:
EPCT-05. Phase Ib study of unesbulin (PTC596) in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) and high-grade glioma (HGG): A report from the COllaborative Network for NEuro-Oncology Clinical Trials (CONNECT)
Authors: Lazow Margot A , Baxter Patricia , Stanek Joseph , Lane Adam , Rodriguez Diana P , Kumar Shiva Senthil , Leach James L , Mikael Leonie , Fuller Christine , Boué Daniel R , Pierson Christopher R , Thomas Diana , Breneman John , Palmer Joshua , Li Xiao-Nan , Salloum Ralph , Ashley David , de Blank Peter , Hwang Eugene , Leary Sarah E S , Plant Ashley , Crabtree Dorothy , Wahba Mona , Weetall Marla , Baird John , Leonard Jeffrey , Stewart Clinton F , Mardis Elaine , Fouladi Maryam , Drissi Rachid 
Published: June 2022

Abstract
BACKGROUND: The B-cell-specific Moloney murine leukemia virus integration site-1 (BMI-1) protein, implicated in self-renewal and DNA-damage signaling, is highly expressed in DIPG and HGG. Preclinically, BMI-1 modulation by unesbulin (PTC596 [which mediates hyperphosphorylation and subsequent degradation of BMI-1]) leads to DIPG/HGG cell proliferation blockade, mitotic abnormalities, and tumor cell sensitization to radiation-induced DNA damage. METHODS: This phase Ib study sought to determine the maximally tolerated dose/ recommended phase 2 dose (RP2D) of unesbulin administered concurrently with radiotherapy and adjuvantly in children with newly diagnosed DIPG or HGG. Patients were enrolled according to a Rolling-6 design and received oral unesbulin twice weekly during radiotherapy and as maintenance therapy. RESULTS: Twenty-seven patients enrolled (median age: 8.5 years [range: 2-18]), including 18 patients with DIPG and nine patients with HGG. Unesbulin was administered in capsule formulation in the first nine patients, then tablet formulation for subsequent patients. Within the capsule formulation group, three dose-limiting toxicities (DLTs) were observed in two patients on dose level 2 (grade 4 neutropenia). Within the tablet formulation group, four DLTs were experienced by three patients on dose level 2 (grade 3 ALT elevation, grade 3 dehydration/vomiting, grade 3 decreased ejection fraction, grade 4 neutropenia). Dose level 1 was declared the RP2D, and six additional patients enrolled in the expansion cohort at this dose without DLTs. Most common drug-related grade 3/4 toxicities were neutropenia (48%), leucopenia (35%), and elevated ALT (26%). Similar pharmacokinetic profiles were observed for capsule and tablet formulations, consistent with adult data. Survival outcomes and genomics results will be shared at time of presentation. CONCLUSIONS: The RP2D of unesbulin in children newly diagnosed with DIPG or HGG is 200mg/m2 twice weekly, concurrent with and following radiotherapy. The recently opened surgical cohort will assess intratumoral pharmacokinetics and inhibition of tumor BMI-1 signaling, with results forthcoming.
EPEN-01. Response assessment in pediatric intracranial ependymoma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group
Authors: Lindsay Holly , Massimino Maura , Avula Shivaram , Stivaros Stavros , Grundy Richard , Metrock Katie , Bhatia Aashim , Fernández-Teijeiro Ana , Chiapparini Luisa , Bennett Jeffrey , Wright Karen , Hoffman Lindsey , Smith Amy , Pajtler Kristian , Poussaint Tina Young , Warren Katherine , Foreman Nicholas , Mirsky David 
Published: June 2022

Abstract
INTRODUCTION: Ependymomas remain a major cause of cancer-related death in childhood and adolescence, with recurrence occurring in up to 50% of patients. Despite exciting molecular advances in understanding ependymoma tumorigenesis and recurrence, MRI remains the mainstay for assessing objective response to therapy and duration of disease stability. Standardized response assessment criteria for clinical trials studying pediatric intracranial ependymoma are critically needed in order to accurately compare results between studies. METHODS: To generate these standardized response criteria in pediatric intracranial ependymoma, a multidisciplinary team of pediatric neuro-oncologists, neuroradiologists, neurosurgeons, radiation oncologists, and molecular biologists formed the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group. The expert members reviewed relevant published literature, assessed current clinical practices, and engaged in iterative discussions to provide consensus recommendations for objective response assessment in pediatric intracranial ependymoma for use in prospective clinical trials. RECOMMENDATIONS AND CONCLUSIONS: The primary sequences for detecting and measuring disease and assessing radiologic response to therapy should be the contrast-enhanced T1-weighted sequence or T2-weighted sequence (T2 or T2-FLAIR) depending on which sequence the tumor is best visualized. When metastatic disease is present, only the three largest lesions will be followed in addition to any residual disease at the primary tumor focus. Importantly, the RAPNO working group notes that radiologic response to therapy is of limited value in clinical trials of patients with ependymoma, since most patients enroll on clinical trials with either no evidence of disease or only minimal disease. In recurrent or progressive disease that cannot be resected, true radiologic disease response to therapy is less clinically meaningful as a study endpoint than event-free and/or overall survival (representing prolonged stable disease) but may provide a signal of efficacy worthy of future exploration in patients with complete to near complete resections.
EPEN-03. USP7 is an interaction partner of EZHIP and potential druggable target in PFA ependymomas
Authors: Jenseit Anne , Camgöz Aylin , Mauermann Monika , Pfister Stefan , Kool Marcel 
Published: June 2022

Abstract
Ependymomas (EPN) arise in the supratentorial brain (ST-EPN), posterior fossa (PF-EPN), or the spinal cord (SP-EPN), in children and adults. Molecular profiling has identified distinct subgroups in each location. Among the three molecular subgroups of PF-EPN, PFAs are characterized by young median age at diagnosis, an overall balanced genome and bad clinical outcome (56 % 10-year OS). Therapy involves tumor resection and radiotherapy, but the role of chemo- or targeted therapies remains to be defined. Recently, we and others identified enhancer of zeste inhibiting protein (EZHIP) as potential driver of PFAs. By inhibiting EZH2, catalytic subunit of the polycomb repressive complex 2 (PRC2), EZHIP prevents the distribution of the epigenetic repressor mark H3K27me3. However, since EZHIP does not possess any known enzymatic functions, it does not seem to be the druggable target urgently searched for in PFA. We therefore focused on essential and potentially druggable interactions. Here, we present ubiquitin-specific protease 7 (USP7), a known cancer regulator with multiple inhibitors available, which has been shown to interact with EZHIP in non-PFA cells. We confirmed this interaction in PFA cells by co-immunoprecipitation and mass spectrometry, and showed that the EZHIP-USP7 interaction is independent of EZH2, a separate interactor of both. Functionally, we show that USP7 de-ubiquitinates EZHIP, preventing its degradation and thus stabilizing it. As EZHIP is essential for PFA cell survival, we aim to target EZHIP indirectly by affecting its stability regulation via USP7. Knockdown experiments showed a susceptibility of PFA cells to a USP7 loss, focusing on proliferation, apoptosis, and expressional changes induced by altered USP7 levels. Moreover, USP7 inhibitors highly affected the survival of different PFA cell lines at a low micromolar IC50 in vitro and in vivo treatments of PFA patient-derived xenografts with USP7 inhibitors are ongoing, hopefully helping to improve targeted therapies for PFA ependymoma patients.
EPEN-06. Comprehensive profiling of myxopapillary ependymomas identifies a distinct molecular subtype with relapsing disease
Authors: Bockmayr Michael , Harnisch Kim , Pohl Lara , Schweizer Leonille , Mohme Theresa , Körner Meik , Alawi Malik , Suwala Abigail , Dorostkar Mario , Monoranu Camelia , Hasselblatt Martin , Wefers Annika , Capper David , Hench Jürgen , Frank Stephan , Richardson Timothy , Tran Ivy , Liu Elisa , Snuderl Matija , Engertsberger Lara , Benesch Martin , von Deimling Andreas , Obrecht Denise , Mynarek Martin , Rutkowski Stefan , Glatzel Markus , Neumann Julia , Schüller Ulrich 
Published: June 2022

Abstract
Myxopapillary ependymoma (MPE) is a heterogeneous disease regarding histopathology and outcome. The underlying molecular biology is poorly understood, and markers that reliably predict the patients’ clinical course are unknown. We assembled a cohort of 185 tumors classified as MPE based on DNA methylation from pediatric, adolescent, and adult patients. Methylation patterns, copy number profiles, and MGMT promoter methylation were analyzed for all tumors, 106 tumors were evaluated histomorphologically, and RNA sequencing was performed for 37 cases. Based on methylation profiling, we defined two subtypes MPE-A and MPEB, and explored associations with epidemiological, clinical, pathological, and molecular characteristics of these tumors. Tumors in the methylation class MPE were histologically diagnosed as WHO grade I (59%), WHO grade II (37%), or WHO grade III tumors (4%). 75/77 analyzed tumors expressed HOXB13, which is a diagnostic feature not detected in other spinal ependymal tumors. Based on DNA methylation, our series split into two subtypes. MPE-A occurred in younger patients (median age 27 vs. 45 years, p=7.3e-05). They were enriched with WHO grade I tumors and associated with papillary morphology and MGMT promoter hypermethylation (all p&lt;0.001). MPE-B included most tumors initially diagnosed as WHO grade II and cases with tanycytic morphology. Copy number alterations were more common in MPE-A. RNA sequencing revealed an enrichment for extracellular matrix and immune system-related signatures in MPE-A. 15/30 MPE-A could not be totally resected compared to 1/58 MPE-B (p=6.3e-08), and progression-free survival was significantly better for MPE-B (p=3.4e-06, 10-year relapse rate 33% vs. 85%). We unraveled the morphological and clinical heterogeneity of MPE by identifying two molecularly distinct subtypes. These subtypes significantly differed in progression-free survival and will likely need different protocols for surveillance and treatment.
EPEN-29. Spatial transcriptomic analysis of ependymoma implicates unresolved wound healing as a driver of tumor progression
Authors: Donson Andrew , Fu Rui , Norris gregory , Willard Nicholas , Griesinger Andrea , Riemondy Kent , Amani Vladimir , Grimaldo Enrique , Harris Faith , Hankinson Todd , Mitra Siddhartha , Ritzmann timothy , Grundy Richard , Foreman Nicholas 
Published: June 2022

Abstract
Ependymoma is a childhood brain tumor that remains incurable in approximately 50 percent of cases, most commonly in posterior fossa subgroup A (PFA). Uncovering how heterogeneous cell types within the tumor microenvironment (TME) interact is crucial to a complete understanding of PFA disease progression. The underlying cellular components of the PFA TME have been revealed by single-cell RNAseq (scRNAseq), identifying divergent epithelial differentiation and epithelial-mesenchymal transition (EMT) lineages. Here, we utilize spatial transcriptomics (Visium) of 14 PFA samples, integrated with scRNAseq, to chart neoplastic and immune cell architecture, with a higher resolution of cellular heterogeneity than scRNAseq alone. At a gross level, all PFA were primarily comprised of neoplastic epithelial and mesenchymal transcriptomic spatial zones, each containing a diversity of hierarchical cellular stages. In all samples we revealed spatially and transcriptomically-distinct mesenchymal zone-associated subclusters, including a quiescent undifferentiated progenitor-like subpopulation and clusters with characteristics of early and late stage EMT. Two early stage EMT clusters were distinguished by signatures of either myeloid cell interaction or hypoxia, and both were demonstrated to be EMT-initiating processes in in-vitro PFA experimental models. Myeloid cell interaction is the predominant initiating stage of EMT in PFA, occurring in zones that are spatially distinct from hypoxia induced EMT. Other mesenchymal clusters represent later EMT stages characterized by wound repair and tissue remodeling. Increased proliferation was a general characteristic of epithelial zone clusters, which included a second undifferentiated progenitor-like population that showed a particularly high mitotic rate and was associated with histologically hypercellular areas. Given the biological parallels with normal wound healing, we propose that mesenchymal and epithelial zones interact to create a cycle of persistent tissue damage response and mitogenic re-epithelialization signals. Unresolved wound repair is therefore a potential driver of PFA progression, a new concept that could provide novel targets for effective therapeutic intervention.
EPID-05. A novel, clinically-relevant classification of pediatric CNS tumors for cancer registries using a clustering analysis
Authors: Moreira Daniel , Chen Yichen , Qaddoumi Ibrahim , Cioffi Gino , Waite Kristin , Ostrom Quinn , Kruchko Carol , Barnholtz-Sloan Jill , Devidas Meenakshi , Bhakta Nickhill 
Published: June 2022

Abstract
To accurately evaluate the burden of pediatric central nervous system (CNS) tumors, estimate resources for cancer control, and monitor outcomes, a classification system that segregates tumors into clinically relevant groups is essential. The current classification of CNS tumors included in the third revision of the International Childhood Cancer Classification does not identify key clinical groups, such as low- and high-grade gliomas. To address this need, a novel classification was embarked upon using ICD-O-3 codes, CBTRUS grouping, incidence, survival, and treatment modalities as inputs. For each ICD-O-3 code with &gt;50 new cases/year in CBTRUS from 2000 to 2016, 2 clinicians reached consensus defining the efficacy of three treatment modalities: surgical resection, radiotherapy, and chemotherapy. Then, patient level 5-year overall survival (OS) times were simulated based on total incidence and 5-year OS for each code. Subsequently, 5 factors were included as potential classifiers: tumor behavior, CBTRUS sub-group, and efficacy of the three treatment modalities. A “survival tree” was developed by using partitioning. Starting with the patient cohort (root), univariate cox proportional hazards model was used to identify statistically significant (P &lt; 0.05) factors. The factors with the largest hazard ratio were selected manually to create child nodes. Within each child node, the partitioning process was repeated on remaining factors until no statistically significant factor remained. This clustering yielded 4 main groups (low-, intermediate-, high-, and very high-risk tumors) and 11 subgroups, including “embryonal tumors” and “low-risk glial and glioneuronal tumors”. Further validation of the classification will be sought through a structured consensus process using multidisciplinary experts. This systematic method to develop a classification for pediatric CNS tumors will allow for more relevant estimations of outcomes and better estimation of resource utilization. Furthermore, this strategy could be replicated for other disease groups.
ETMR-02. Overexpression of Lin28A in neural progenitor cells in vivo does not lead to brain tumor formation but results in reduced spine density
Authors: Middelkamp Maximilian , Ruck Lisa , Krisp Christoph , Sumislawski Piotr , Mohammadi Behnam , Dottermusch Matthias , Meister Valerie , Küster Lukas , Schlüter Hartmut , Windhorst Sabine , Neumann Julia E 
Published: June 2022

Abstract
The RNA binding protein LIN28A is a stem- and progenitor marker and one of the factors necessary to induce pluripotent stem cells. An overexpression of LIN28A has been identified in malignant brain tumors called embryonal tumors with multilayered rosettes (ETMR) but its specific role during brain development remains largely unknown. Radial glia cells of the ventricular zone (VZ) are proposed as a cell of origin for ETMR. We asked whether an overexpression of LIN28A in such cells might affect brain development or result in the formation of brain tumors. Constitutive overexpression of LIN28A in hGFAP-cre::lsl-Lin28A (GL) mice led to a transient increase of proliferation in the cortical VZ at embryonic stages but no postnatal brain tumor formation. Postnatally, GL mice displayed a pyramidal cell layer dispersion of the hippocampus and altered spine and dendrite morphology, including reduced dendritic spine densities in the hippocampus and cortex. GL mice displayed hyperkinetic activity and differential quantitative MS-based proteomics revealed altered time dependent molecular functions regarding mRNA processing and spine morphogenesis. Phosphoproteomic analyses indicated a downregulation of mTOR pathway modulated proteins such as Map1b being involved in microtubule dynamics within a crosstalk of Gsk3b/Rho-Rac/Map1b signaling. In conclusion, we show that Lin28A overexpression transiently increases proliferation of neural precursor cells but it is not sufficient to drive brain tumors in vivo. In contrast, Lin28A impacts on protein abundancy patterns related to spine morphogenesis and phosphorylation levels of proteins involved in microtubule dynamics, resulting in decreased spine densities of neurons in the hippocampus and cortex as well as in altered behavior. Our work provides new insights into the role of LIN28A for neuronal morphogenesis and development and may reveal future targets for treatment of ETMR patients.
GCT-03. MonoGerm: A proposed phase II trial of carboplatin or vinblastine monotherapy induction prior to radiotherapy for intracranial germinoma
Authors: Murray Matthew , Apps John , Lawson Anna , Kirton Laura , Peet Andrew , Arvanitis Theodoros , Fern Lorna , Mitra Dipayan , Coleman Nicholas , Ajithkumar Thankamma , Bison Brigitte , Veal Gareth , Stark Daniel , Morana Giovanni , Nicholson James , Billingham Lucinda 
Published: June 2022

Abstract
BACKGROUND: Intracranial germinoma is chemosensitive but radiotherapy (RT) is needed for cure. In localised disease, three-drug standard-of-care (SOC) inpatient chemotherapy is used to reduce RT fields/dose. Concomitant diabetes insipidus is common, making chemotherapy delivery challenging. Small studies have demonstrated benefits from single-agent carboplatin or vinblastine in germinoma as an alternative to SOC. However, this needs prospective evaluation in a clinical trial. METHODS: We developed a trial, with a patient-public-involvement workstream, primarily evaluating whether single-agent chemotherapy (carboplatin or vinblastine) is non-inferior to SOC for inducing radiological complete response (CR) in localised disease, and is associated with reduced toxicity and improved quality-of-life (QoL), evaluated through patient-reported-outcome-measures (PROMs). RESULTS: The resultant proposed multi-centre, phase II proof-of-principle trial will investigate, in parallel, two single agents as monotherapy induction, in children/teenagers/adults with intracranial germinoma. Trial features include: a) Bayesian statistical design determining whether CR rate for either agent is sufficiently non-inferior to SOC; b) ‘Flip-flop’ design with alternating, continuous enrolment to the two single-agents, interim assessments after each recruited cohort, and early stopping rules for inferiority; c) Safety MRI, after 6-weeks of chemotherapy with real-time central-radiological-review; d) Proof-of-principle vinblastine monotherapy arm for metastatic patients awaiting definitive craniospinal-irradiation; e) State-of-the-art integrated imaging acquisition, QoL/PROM, pharmacokinetics and circulating microRNA studies to maximise information/learning; f) European and North American neuroradiological response criteria comparison and prospective evaluation of new consensus criteria. CONCLUSIONS: Trial results will: a) establish whether monotherapy is a treatment option in this setting, which may be practice-altering; b) use QoL/PROM data to inform on optimal treatment if results similar; c) use embedded radiological assessments to develop intracranial germinoma trials and facilitate European/US study comparisons; d) describe vinblastine pharmacokinetic data to inform future dosing schedules in this and other malignancies; and e) quantify circulating microRNAs, facilitating future non-invasive diagnosis/risk-stratification.
HGG-42. Evolutionary selection of key oncogenic alterations in patient-derived models of paediatric diffuse high grade glioma (PDHGG) subtypesin vitro andin vivo
Authors: Mackay Alan , Temelso Sara , Carvalho Diana , Kessler Ketty , Boult Jessica , Izquierdo Elisa , Pereira Rita , Potente Elisabet Fernandez , Burford Anna , Molinari Valeria , Bjerke Lynn , Grabovska Yura , Rogers Rebecca , Crampsie Shauna , Das Molina , Robinson Simon , Clarke Matthew , Jones Chris 
Published: June 2022

Abstract
PDHGG are a diverse group of childhood brain tumours comprising multiple subgroups carrying distinct molecular drivers. Patient-derived models accurately recapitulating this underlying biology are critical for mechanistic/preclinical studies aimed at improving patient outcome, however their behaviour over time in the environments in which they are propagated, and how this relates to the human disease, is largely unknown. To explore this, we collected 94 models of PDHGG established as 2D/3D stem cell cultures in vitro, and generated patient-derived xenografts (PDX) in 33/62 specimens implanted orthotopically in vivo. We carried out exome/targeted sequencing, methylation profiling and RNAseq to profile cells through their first 25 passages in culture, and sequential implantation from p0-p2 in mice. In 15/83 cultures, we observed enrichment of gene expression signatures of non-malignant cells over the first 5 passages, with concurrent depletion of somatic mutations/CNAs, excluding them from further study. Validated models retained tumour-matched genotypes, CNAs and driver alterations including H3.3G34R, H3.3/H3.1K27M, BRAF and ACVR1 over time, however subclonal alterations underwent selection in culture which profoundly altered their response to targeted drug treatment. In 6/7 PDGFRA-mutant models, activating mutations were selected against between p5-20 in 2D and/or 3D, whilst MAPK pathway mutations in NF1/PIK3R1 similarly diverged over 15 passages under different growth conditions, resulting in isogenic models with differential signalling, in vivo tumorigenicity, and in vitro sensitivity to multiple MEK inhibitors. In PDXs, serial xenografting reduced the time to tumour formation by up to half, with a concomitant shift in clonal architecture. Multi-region sequencing of diffusely-infiltrating tumours showed selection for alterations such as PIK3CA/NF1 at distant sites, with evidence for convergent evolution of subclonal mutations, as in human tumours. Understanding the evolutionary dynamics of targetable/predictive alterations in PDHGG model systems is key to developing new and effective therapeutic interventions in this highly heterogenous disease.