tbuckley/cabot-search huggingface dataset:
DIPG-27. MATCHED PRIMARY-RELAPSE PEDHGG PATIENT-DERIVED XENOGRAFT MODELS TO IDENTIFY THERAPY RESISTANCE PROFILES
Authors: Srijita Barnerjee, Miao Zhao, Gabriela Rosen, Thale Olsen, Wojciech Michno, Fredrik J Swartling, Karl O Holmberg, Géraldine Giraud
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND We established patient-derived xenografts (PDXs) from matched primary-relapse pairs of pediatric high-grade gliomas (pedHGGs) in collaboration with the Swedish Childhood Tumor Biobank. Further, we used human iPSC derived cortical organoids to evaluate interactions between glial and tumor cells under treatment pressure potentially lost in xenograft models. Using this setup, we hope to follow tumor relapse evolution and to identify novel mechanisms behind treatment evasion and relapse formation. METHODS Tumoral singel cell suspensions from matched primary-relapse pairs are injected orthotopically in immunodeficient NOG mice. We establish in vitro 2D models in stem cell conditions from the first generation of animals transplanted. Lentivirus-based labelling with GFP/Luciferase was done on PDX-derived cell lines to allow cell tracking and to quantify efficacy of drug screening efforts. Co-culture of these cells with normal cells in 3D assembloids were performed using 150-250 days old cortical organoids. Single-cell RNA sequencing and bulk RNA sequencing (RNA-seq) on patient biopsies, their corresponding PDXs from first generation of mice, and PDX-derived cell lines, was performed to track potential changes in vivo and in vitro and to further validate primary-relapse specific evolution. RESULTS 2D and 3D cell cultures offered efficient labeling and we quantified differences in sensitivity to standard therapy between primary and relapse samples. PDX models and assembloids highlighted pedHGG growth patterns, modes of invasion and cell interactions, especially astrocyte-tumor cell interactions. These 3D models also allow for further validation of targeted drug testing based on multiomics data (WGS, methylation and RNA-seq) from the patient biopsies. CONCLUSION PedHGG primary-relapse in vitro 2D cell line/ in vivo 3D assembloid models together with PDXs is a robust approach to study different aspects of relapse-specific tumor biology. Our results offer insights aiding the development of novel therapeutics inhibiting relapse mechanisms already in the first line of treatment.
QOL-03. BONE HEALTH IN CHILDREN WITH SUPRASELLAR AND THALAMIC LOW GRADE GLIOMA; AN UNDERSTUDIED PROBLEM
Authors: IMAA van Roessel, J E Gorter, B Bakker, M M van den Heuvel-Eibrink, M H Lequin, J van der Lugt, L Meijer, A Y N Schouten- van Meeteren, H M van Santen
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Children with a supratentorial midline Low Grade Glioma (LGG) may be at risk for impaired bone health due to hypothalamic-pituitary dysfunction, obesity, exposure to multiple treatment modalities, and/or decreased mobility. The presence of impaired bone health and/or its severity in this population has been understudied. We aimed to identify the prevalence and risk factors for bone problems in children with supratentorial midline LGG. METHODS A retrospective study was performed in children with supratentorial midline (suprasellar or thalamic) LGG between 1-1-2003 and 1-1-2022, visiting the Princess Máxima Center for Pediatric Oncology. Impaired bone health was defined as presence of vertebral fractures or collapse, any fractures not related to (the intensity of) trauma, treatment with bisphosphonates, and/or very low bone mineral density (BMD). RESULTS In total, 161 children were included, with a median age at tumor diagnosis of 4.7 years (range 0.1 – 17.9) and a median follow-up of 6.1 years (range 0.1 – 19.9). ‘Any’ bone problem occurred in 22.4% (36/161) and nontraumatic fractures in 3.7%. Impaired visual capacity was associated with bone problems in multivariate analysis (OR 3.56 95% CI 1.30 – 9.76, p = 0.014). CONCLUSIONS In this retrospective evaluation, bone problems and decreased BMD were prevalent in 36.1% of children with supratentorial midline LGG. Risk to develop bone problems appears to be multifactorial, but visual capacity seems highly relevant. Surveillance of bone health must be an aspect for awareness in the care and follow-up of children with a supratentorial midline LGG.
LGG-45. LOW DOSE CARBOPLATIN – ETOPOSIDE REGIMEN IN PEDIATRIC PATIENTS WITH LOW GRADE GLIOMA
Authors: Marco Tellini, Marco Di Nicola, Carla Fonte, Barbara Castelli, Milena Guidi, Flavio Giordano, Ludovico D’Incerti, Federico Balducci, Maria Luigia Censullo, Mirko Scagnet, Lorenzo Genitori, Anna Maria Buccoliero, Benedetta Bianchi, Iacopo Sardi
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Chemotherapy remains the cornerstone in case of incompletely resected pedatric Low Grade Glioma (pLGGs) and for recurrent tumors in unfavorable locations. Based on previous cisplatin etoposide regimen (INT Milan strategy), we tried to reduce toxicity and achieve a similar tumor control using a modified regimen composed of CBCDA-etoposide. METHODS From August 2012 to December 2023 we treated 79 pLGGS (45 F (57%), 34 M (43%)) with carboplatin (400 mg/m2 day 1) and etoposide (100 mg/2 day 1-3) at 4-6 weeks interval with 10 cycles in one year or until disease progression. Median age at diagnosis is 7 years. Seventeen patients were affected by neurofibromatosis type 1 (21.5%). 28 pLGGS affected visual pathway (35.4%). Treatment was delivered for clinical symptoms and/or radiological evidence of progression. RESULTS According to RAPNO criteria, on brain magentic resonance imaging (MRI) at the end of treatment 40 patients had stable disease (50.6%), 10 had partial response (12.7%), 7 had major response (8.9%), 5 had minor response (6.3%), 2 presented complete remission (2.5%), 13 patient had disease progression (16.5%). 2 patients are undergoing treatment (2.5%). Acute toxicity was unremarkable. During follow up (median time 59,5 months) 9 children (11,4%) developed audiological alterations but 2 of them also received radiotherapy. 14 patients presented hematological toxicity CTCAE grade 3 or 4 (17,7%). During follow up 30 patients developed a progressive disease (38%) and require further treatments and only one patients died because of progressive disease. Overall survival was 98,7% (78/79). CONCLUSIONS The combination of low doses CBCDA-etoposide seems equally effective with a lower hematological and audiological toxicity compared to other regimens.
HGG-19. H3- AND IDH-WILDTYPE DIFFUSE PAEDIATRIC-TYPE HIGH-GRADE GLIOMA WITH<i>MYCN</i>-AMPLIFICATION: AN INDICATION CRITERION FOR LI-FRAUMENI SYNDROME TESTING
Authors: Jen Chun Foo, Kein Seong Mun, Sok Kun Tae, Kenneth Tou En Chang
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND: In the current World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) (5th edition), the introduction of a molecular layer to the integrated diagnosis not only helps to characterize and prognosticate paediatric CNS tumors but the molecular alteration may predict a potential therapeutic option with a targeted agent. Furthermore, certain gene alterations may be a presage of germline alterations or cancer predisposition syndromes, portending significant implications to the index patients and their families. We report a 5-year-old boy diagnosed with non-metastatic left hemispheric H3-wildtype and IDH-wildtype diffuse paediatric-type high-grade glioma with MYCN-amplification, who was subsequently found to have Li-Fraumeni syndrome. He presented with a 3-day history of facial asymmetry, unsteady gait and right sided weakness. There was no family history of malignancy. Initial MRI revealed a restricting and enhancing solid cystic lesion (5.9 x 4.3 x 5.8cm) in the left frontal-temporal-parietal region. Tumor debulking was performed. Histopathological examination by the local pathologist revealed features of high-grade glioma. Second pathology review with next generation sequencing confirmed H3-wildtype and IDH-wildtype diffuse paediatric-type high-grade glioma with MYCN-amplification and TP53 p.Y103* mutation. He was started on focal radiotherapy and oral temozolomide but succumbed to local and metastatic progressive disease. After genetic counselling, his DNA extracted from blood was sent for targeted exome sequencing and germline mutation of TP53 was demonstrated. Cascade screening of the family members were negative of TP53 mutation. Guerrini-Rousseau et al reported that 57% (n=7) of H3-wildtype and IDH-wildtype diffuse paediatric-type high-grade glioma with MYCN-amplification harboured germline TP53 pathogenic variants. This case further highlights the importance of screening of Li-Fraumeni syndrome in patient with H3-wildtype and IDH-wildtype diffuse paediatric-type high-grade glioma with MYCN-amplification even in the absence of a family history.
ETMR-27. ANTI-ANGIOGENIC METRONOMIC THERAPY OF RARE TUMOURS OF THE CENTRAL NERVOUS SYSTEM
Authors: Hannah Schned, Christine Haberler, Andreas Peyrl, Amedeo Azizi, Lisa Mayr, Barbara Aistleitner, Katja von Hoff, Marcel Kool, Mimi Kjaersgaard, Katerina Trkova, Nicolas Andre, Maria Aliotti Lippolis, Cora Hedrich, Clara Köller, Natalia Stepien, Irene Slavc, Johannes Gojo
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Improvement of molecular diagnostics has led to significant changes in the categorization of paediatric brain tumours, unveiling novel tumour entities in the latest 2021 WHO classification of central nervous system (CNS) tumours (5th edition), particularly within the group of rare tumours of the CNS (encompassing rare embryonal and sarcomatous tumours (REST) and gliomas). However, treatment recommendations are currently based on small patient cohorts lacking standardized protocols, with even more limited options for progressive or relapsed disease. METHODS Patients from specialized European oncologic centres diagnosed or reclassified as REST receiving anti-angiogenic therapy after relapse (Medulloblastoma European Multitarget Metronomic Anti-Angiogenic Trial - MEMMAT) will be analysed. RESULTS So far, 14 patients from Austria, Czech Republic, Denmark and France were identified, with molecularly reclassified 4 CNS tumours with BCOR/BCORL1 alteration (CNS BCOR/BCORL1), 4 CNS astroblastomas, MN1-altered (ABM_MN1), 3 embryonal tumours with multi-layered rosettes (ETMR) and 1 DICER1-mutated intracranial sarcoma (CNS DICER1) as well as 2 primitive neuroectodermal tumours (PNETs, reclassification ongoing). Initial histological classifications ranged from ependymoma group 3, ETMR, malignant peripheral nerve sheath tumour (MPNST) to EGFR-positive glioblastoma. In 2 cases categorization was unclear with either anaplastic ependymoma, plexus carcinoma or ETMR. 10 patients received standard MEMMAT protocol (biweekly intravenous Bevacizumab with oral drugs: Celebrex, Thalidomide, Fenofibrate, Cyclophosphamide/Etoposide alternating and intrathecal Etoposide and Cytarabine). In 4 cases therapy was modified with an individualized metronomic treatment regimen. CONCLUSION Therapy at initial diagnosis, duration of relapse-treatment, clinical as well as radiological response, overall survival, progression-free survival and molecular hallmarks will be presented.
LGG-44. CLINICAL AND MOLECULAR TUMOR CHARACTERISTICS OF ‘HIGHER RISK’ PEDIATRIC LOW-GRADE GLIOMAS
Authors: Tiago Rijsdijk, Julie A S Lammers, Eelco W Hoving, Pieter Wesseling, Bastiaan B J Tops, Lennart Kester, Lisethe Meijer, Netteke A Y Schouten- van Meeteren, Karina J Kersbergen, Jasper van der Lugt, Raoll Hoogendijk, Mariette E G Kranendonk
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND CNS WHO grade 1 pediatric low-grade gliomas (pLGGs) have an overall excellent survival. A small but relevant proportion of these patients, however, suffer from severe disease burden reflected in recurrent progression, metastasis or even death. To unravel clinicomolecular tumor characteristics that identify these ‘pLGG-higher risk’ patients we retrospectively analyzed clinical and molecular data of 223 patients from our center. METHODS All tumors were classified using histology, DNA methylation profiling and whole transcriptome analysis (RNA sequencing), with whole exome or panel DNA sequencing in a subset of cases, revealing a driver alteration in 100% of cases. Progression of disease was defined as continuous tumor growth upon treatment or need for multiple treatments. The effect of clinical and molecular variables on progression free survival was analyzed with the univariate and multivariate cox proportional hazard model. RESULTS The median follow-up of the entire cohort was 3,4 years. In univariate analyses the risk of progression significantly decreased with age (in years) at diagnosis (HR 0.92,p&amp;lt;0.001). For tumor location using hemispheric tumors as reference, chiasm/suprasellar LGGs showed a significantly higher risk of progression (HR 2.96,p&amp;lt;0.001). Type of molecular driver and sex was not associated with progression. In a multivariable model including age, location and driver, there was no longer a significant effect on progression for age but the effect of chiasm/suprasellar location remained intact. Furthermore, NF1 (HR 0.37,p0.02), and posterior fossa LGG (HR 0.24,p0.03) were both significantly associated with a lower risk of progression. CONCLUSIONS Our multivariate results show that the ‘pLGG-higher risk’ patients were characterized by a tumor in the chiasm/suprasellar location, while molecular driver (at least so far) did not affect risk of progression. Future work will focus on extending the cohort and integrating other multiomic data enabling to compose a prediction model for higher risk pLGG.
IMMU-09. PHASE 2 TRIAL USING INDOXIMOD-BASED CHEMO-IMMUNOTHERAPY FOR PATIENTS WITH CHILDHOOD BRAIN CANCER: INTERIM ANALYSIS OF THE GCC1949 STUDY (NCT04049669)
Authors: Theodore S Johnson, Rafal Pacholczyk, Eric K Ring, Dolly Aguilera, Robert C Castellino, Jason R Fangusaro, Bree R Eaton, Susan Chi, Kee Kiat Yeo, Trent R Hummel, Zuzana Berrong, Julianne Creager, Lisa Ingerski, Matthew Schniederjan, Chenbin Huang, Sarthak Satpathy, Beena E Thomas, Ramses F Sadek, Eugene P Kennedy, Manoj K Bhasin, Tobey J MacDonald, David H Munn
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Brain tumors are the leading cause of pediatric cancer-related death. METHODS We report interim outcome data from an ongoing multi-site phase 2 study (NCT04049669) of indoximod-based chemo-immunotherapy for patients 3-21 years of age with either recurrent brain cancer (ependymoma, medulloblastoma, high-grade glioma) or newly diagnosed diffuse intrinsic pontine glioma (DIPG). Treatment is oral IDO pathway-inhibitor indoximod (38.4 mg/kg/day, divided BID) plus temozolomide (200 mg/m2/day for 5 days) in 28-day cycles. Patients who may benefit from additional irradiation receive indoximod during the radiation regimen and are analyzed separately. RESULTS Planned accrual is 140; 80 patients have been treated to date. Estimated median follow-up time was 23.5 months (range 0.2 - 42.7 months), and indoximod-based therapy has been well tolerated. Estimated median overall survival (OS) was 23.8 months for recurrent ependymoma (n=31); 11.5 months for recurrent medulloblastoma (n=22); 5.7 months for recurrent HGG (n=18, includes diffuse midline glioma except primary DIPG); and 15.0 months for newly diagnosed DIPG (n=9). Single-cell TCR and RNA sequencing of serially collected blood samples was used to identify expanded CD8+ T cell clones with late-effector phenotypes, and their emergence was associated with significantly improved survival. In patients treated with immunotherapy, radiographic measurement of objective response is challenging, owing to the high incidence of mixed responses and pseudoprogression events. In our recently published phase 1 trial of indoximod (NCT02502708, Neuro-Oncology 26:348-361, 2024) we showed that 41% of relapsed patients had MRI evidence of objective response in at least one tumor using RAPNO criteria, and that these “responder” patients had 3-fold better median OS (25.2 months, p=0.007) than non-responders (7.3 months). To date, the phase 2 data is similar. CONCLUSIONS The GCC1949 phase 2 study is replicating the published phase 1 results, and we will present updated results from the first 80 patients in the GCC1949 trial.
HGG-17. DECIPHERING GENETICS AND EPIGENETICS OF HIGH-GRADE GLIOMAS WITH BRAF ACTIVATING ALTERATION IS SUPPORTING THE DISCOVERY OF A NEW INTRACRANIAL SARCOMA-LIKE BRAF POSITIVE ENTITY
Authors: Benoit Lhermitte, Thibaut Wolf, Damien Reita, Chinar Salmanli, Agathe Chammas, Marlène Deschuyter, Guillaume Gauchotte, Natacha Entz-Werlé
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The current WHO classification of Central Nervous System tumors recognizes several glioma types driven by the BRAFV600E mutation. These tumors mostly encompass pediatric low-grade gliomas. Nevertheless, a subset of them behaves as anaplastic gliomas and, currently, the unique predictive criterion linked to anaplasia is an elevated mitotic index (more than 2.5 mitoses/mm2). Histologically, the high-grade gliomas harboring BRAFV600E alteration mostly correspond to WHO grade 3 pleomorphic xanthoastrocytoma, IDH wild-type glioblastoma, entering the WHO grade 4 subset like the epithelioid subtype, and the rarer high-grade gliomas with piloïd features. These tumor types share their histomolecular features making differential diagnoses difficult. In this setting, DNA methylation profiling may be very useful to precise the integrative diagnosis. However, some of those high-grade forms failed in our experience to be classified in any methylation class with v11b4 version of the Heidelberg classifier. METHODS To understand the reasons explaining this standard classification failure, we investigated with multi-omics approaches (epigenetics, next-generation sequencing, RNAseq, proteomics and metabolomics) a well clinical characterized cohort of 17 high-grade pediatric intracranial tumors harboring this mutation. RESULTS Interestingly, almost all tumors show similar morphological features and associated passenger molecular alterations mostly CDKN2A homozygous deletion. When using the new v12.5 brain tumor classifier, the methylation profiling of the 2/17 unclassified tumors was clustering with a new MPNST (Malignant Peripheral Nerve Sheath Tumor) methylation entity. The RNAseq and proteomics analyses were showing a different molecular pattern from standard BRAF-mutated high-grade gliomas, even the clinical, radiological and histomolecular characteristics were comparable. CONCLUSION So, methylation profiling should be part of the mandatory molecular assessments to perform when a BRAF-mutated tumor is seen by neuropathologists. Furthermore, the multiomics analyses helped us to define a specific molecular pattern of this new BRAF-driven entity, where frequency and prognosis need to be determined on another larger series.
TRLS-15. “TAZNI”: A PHASE I/II COMBINATION TRIAL OF TAZEMETOSTAT WITH NIVOLUMAB AND IPILIMUMAB FOR CHILDREN WITH INI1-NEGATIVE OR SMARCA4-DEFICIENT TUMORS (NCT05407441)
Authors: Joanna S Yi, Jeffrey Czaplinski, Ketki Bhushan, Suzanne J Forrest, Neerav Shukla, Stephen Mack, Andrew Hong, Marylynne Strachan, Steven G Dubois, Wendy B London, Susan N Chi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Recent pediatric trials with EZH2 inhibitor tazemetostat monotherapy have demonstrated efficacy and disease stabilization in children with relapsed INI1/SMARCA4-deficient tumors: overall response rate (ORR) 14% in all patients (dose expansion cohort), and 24%, 33% and 22% response rates in ATRT, chordoma and epithelioid sarcoma, respectively (NCT02601937); and prolonged disease stabilization &amp;gt;6 months (NCT03213665). Leveraging the role of EZH2 in tumor immunity and increased immune signaling by tazemetostat, we hypothesized that combining this EZH2 inhibitor with checkpoint inhibitors may benefit pediatric patients with these rare cancers. METHODS “TAZNI” is a phase 1/2, multi-center trial of tazemetostat, nivolumab and ipilimumab for children with INI1/ SMARCA4-deficient tumors, administered either after standard upfront therapy or in the relapsed setting. All patients will receive standard nivolumab and ipilimumab doses/dosing schedule, with continuous tazemetostat dosing determined by disease strata: Stratum A- subjects with ATRT; Stratum B- all other (non-ATRT) tumors. Each stratum is subdivided by disease status: A1/B1- refractory disease; A2/B2- relapsed disease; and A3/B3- no evidence of disease. Part 1 of the study consists of two concurrent “rolling six” phase 1 studies to identify the recommended phase 2 dose (RP2D) by disease stratum. Two dose levels are planned, with one dose de-escalation. Part 2 will consist of two phase 2 studies to estimate the ORRs in substrata A1 and A2, in a Simon’s 2-stage design at the RP2D. All other substrata will have descriptive analyses. Patients may receive up to 26 cycles of therapy. Key inclusion/exclusion criteria include INI1 or SMARCA4 loss (by immunohistochemistry or molecular confirmation); age 6 mo - 21 yo; no prior immunotherapy; limited corticosteroid usage; and no concern for hematologic malignancy. This trial is currently ongoing and open to accrual. To date, four patients have enrolled and additional sites across the US are anticipated to open for enrollment (NCT05407441).
TRLS-08. ROVER: A PHASE 1/2 TRIAL IN PROGRESS OF AVAPRITINIB IN PEDIATRIC PATIENTS WITH SOLID TUMORS DEPENDENT ON KIT OR PDGFRA SIGNALING
Authors: Samuel Abbou, Carl Koschmann, Christof M Kramm, Lindsey M Hoffman, Ashley S Plant-Fox, Mohamed S Abdelbaki, Ashley Bui, Michela Casanova, Cornelis M van Tilburg, Dong-Anh Khuong-Quang, Susan N Chi, Hongliang Shi, Ilda Bidollari, Janet Hong, Preethi Swamy, Maria Roche, Daniel A Morgenstern
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Advanced pediatric solid tumors, including central nervous system (CNS) tumors with PDGFRA and/or KIT mutations/amplifications are aggressive diseases with limited treatment options. KIT alterations occur in germ cell tumors and high-grade glioma (HGG); platelet-derived growth factor receptor alpha (PDGFRA) alterations are common in sarcoma and HGG. No KIT-/PDGFRA-targeted therapies are currently approved for pediatric patients. The selective KIT and PDGFRA inhibitor avapritinib has demonstrated potent activity against KIT activation-loop (exon 17) and juxtamembrane (exon 11) mutants (IC50&amp;lt;2 nM), and PDGFRA activation-loop (D842V) mutants (half-maximal inhibitory concentration [IC50]=0.24 nM). Cellular IC50 of wild-type PDGFRA was 95 nM. CNS penetration in preclinical models (steady-state brain-to-plasma ratios, 0.74–1.00) indicates potential for CNS antitumor activity. Avapritinib is approved in the USA and Europe to treat adults with indolent systemic mastocytosis, in the USA for adults with advanced systemic mastocytosis (AdvSM), and in Europe for adults with AdvSM after ≥1 prior systemic therapy. Avapritinib is also approved to treat adults with unresectable/metastatic gastrointestinal stromal tumors harboring PDGFRA exon 18 mutations (including D842V) in the USA and PDGFRA D842V mutations in Europe. METHODS ROVER, a 2-part phase 1/2, multicenter, open-label study (NCT04773782), is investigating avapritinib (once daily, administered in continuous 28-day cycles) in pediatric patients aged 2 to &amp;lt;18 years with relapsed/refractory solid tumors that harbor PDGFRA and/or KIT mutations/amplifications or patients with diffuse midline glioma H3K27-altered (DMG-H3K27a). Objectives include safety, efficacy, and pharmacokinetics. Part 1 will enroll ≥12 patients; primary endpoint is to determine the recommended Part 2 dose (RP2D). Part 2 will enroll ≥25 patients at the RP2D; primary endpoint is objective response rate per RECIST v1.1 for solid tumors and Response Assessment in Neuro-Oncology for CNS tumors. Study enrollment is planned at 26 sites in 9 countries, including North America, Europe, and Asia/Pacific.