tbuckley/cabot-search huggingface dataset:
DIPG-25. RELATIONSHIP BETWEEN MOLECULAR CLASSIFICATION, ORIGIN AND PROGNOSIS IN DIFFUSE MALIGNANT GLIOMA IN CHILDREN
Authors: Naoki Kagawa, Tomoyoshi Nakagawa, Hideki Kuroda, Tetsuro Tachi, Ryuichi Hirayama, Noriyuki Kijima, Yoshiko Okita, Haruhiko Kishima
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Diffuse malignant gliomas that occurs in childhood is recognized as a biologically different disease from that in adults. Furthermore, with the recent development of molecular diagnostics, diffuse midline glioma (DMG), which occurs mainly in the thalamus and brainstem, frequently occurs in childhood and have poor prognosis. We report the relationship between imaging findings, origin, and prognosis of diffuse malignant glioma in children or young adult based on our case series. PATIENTS AND METHODS 43 cases of malignant glioma that occurred from childhood to young adult (below 30 years old) and were treated at our hospital since 2004 were registered in the analysis. Of the 42 cases, 24 cases were in brain stem, 11 cases in cerebral hemisphere, 6 cases in thalamus, and 1 case in cerebellar hemisphere. Histological diagnosis was possible in 31 cases, but without histological verification in 11 brain stem lesions. Histological diagnosis included 13 high-grade glioma (GBM, including NOS and G34R mutations), 11 DMG, and 7 anaplastic astrocytoma. RESULTS Of 13 cases of hemispheric high-grade gliomas, 2 cases had long-term survival (both cases received WT1 peptide vaccination), and 1 case survived for more than 5 years (total resection, MGMT methylation). Among the DMGs, 7 cases were found in brain stem (5 pons, 2 pontomedullary junction, 1 cerebellar peduncle, and 1 midbrain), 3 cases in the thalamus. Two cases of onset at the pontomedullary junction were found incidentally, and the symptoms gradually increased during follow-up, and multidisciplinary treatment was performed. Bilateral thalamus DMG with HIST1H3B mutation showed slowly growing and invasion. SUMMARY There were cases of pediatric hemisphere glioblastoma with long-term survival. In addition, the origin and imaging findings of DMG were various, and tumors that originate at the pontomedullary junction may be relatively favorable.
LMIC-10. GLOBAL MAPPING OF CLINICAL TRIALS FOR CHILDREN WITH CNS TUMORS
Authors: Margit Mikkelsen, Catrian Sotelo, Mackenzie Kelley, Michael Edwards, Daniel Moreira
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND While there has been an international call to increase access to pediatric oncology clinical trials, the current landscape of global clinical trials for pediatric central nervous system (CNS) tumors has not been described. We sought to analyze the availability of clinical trials available for children with CNS tumors worldwide. METHODS Clinical trials were included if they were interventional studies registered in International Clinical Trials Registry Platform (ICTRP) that included pediatric patients (≤17 years old) with a CNS tumor. PubMed and Google Scholar were used to identify peer-reviewed manuscripts describing the results of identified trials. RESULTS From 114,414 oncology trials, 322 studies met inclusion criteria. Geographically, 307 (95%) studies were sponsored by and conducted in high-income countries (HICs), while 15 studies (4.7%) were sponsored by and conducted in middle-income countries (MICs). No studies were registered in or accrued from low-income countries. Studies were mostly sponsored in the United States (244, 76%), United Kingdom (20, 6.2%), or France (13, 4.0%). Trials were mostly sponsored by individual institutions (168, 52%), followed by governmental organizations (100, 31%), collaborative groups (36, 11%) and pharmaceutical companies (18, 5.5%). Study characteristics differed with income status, with HICs registering mostly clinical trials for cancer-directed treatment (261, 85%) and MICs registering later phase supportive care-based or diagnostic trials (9, 60%). Of the studies included, 132 (43%) were published. There were similar rates of publishing results in HIC and MICs. Discussion: Low- and middle-income countries are under-represented in the global clinical research landscape of pediatric CNS tumors. Furthermore, these data describe the urgent needs to invest in clinical research infrastructure in LMICs and to foster collaborations that include LMICs as a critical step in achieving equity in global pediatric cancer care.
CP-10. DOES PRE-IRRADIATION GROSS TUMOR VOLUME PREDICT THE RISK OF PROGRESSION AFTER RADIATION THERAPY IN PEDIATRIC PATIENTS WITH ADAMANTINOMATOUS CRANIOPHARYNGIOMA?
Authors: Tamar Brooks, Dexiang Gao, Katie Dorris, David M Mirsky, Susan Staulcup, Eric Prince, Marina Moskalenko, Elizabeth Ignowski, Narine Wandrey, Kareem Fakhoury, Todd C Hankinson, Sarah A Milgrom
Journal: Neuro-Oncology (2024)

Abstract OBJECTIVE In a cohort of patients who were treated with resection and adjuvant radiotherapy (RT) for adamantinomatous craniopharyngioma (ACP), we explored whether gross tumor volume (GTV) at the initiation of RT was associated with the risk of progressive disease (PD) following treatment. METHODS Pediatric and adolescent patients who received surgery and RT for ACP at a single institution from 1998-2021 were identified. Univariable Cox regression analyses (UVA) were performed to assess the association between pre-RT GTV and PD after RT. Multivariable analyses (MVA) were used to control for potential confounders. Two different endpoints were used to define PD. The first definition was based on radiographic tumor growth and the second definition was the requirement for an additional tumor-directed intervention following the completion of RT. RESULTS 48 patients were eligible for inclusion. The median age at diagnosis was 7.9 years (range: 2.1-17.4). All patients were treated with surgery and RT with median dose of 52.2 Gy (range: 45-55.8 Gy) and median GTV of 9.86 cm3 (range 0.7-117.7 cm3). Upon follow-up, 8 patients experienced PD based on both definitions. Five-year EFS was 85.4% (95% CI: 74.1 -98.3%). On both UVA and MVA, GTV was significantly associated with a small increased likelihood of PD (HR 1.02, 95% CI 1.00 - 1.04, p=0.022). However, after exclusion of a single outlier with GTV of 117.7 cm3 prior to RT, a second analysis identified no significant association between GTV and PD (UVA: HR 1.03, p=0.4; MVA: HR 1.06, p=0.2). CONCLUSIONS For most patients with ACP, the GTV at the initiation of RT is not associated with the risk of PD. This finding suggests that aggressive tumor debulking for the purpose of improving the efficacy of RT may not be necessary. For giant ACPs, however, novel strategies may be necessary for tumor control.
ETMR-18. ADVANCING ETMR RESEARCH: NOVEL<i>IN VITRO</i> AND<i>IN VIVO</i> PRECLINICAL MODELS FOR DEVELOPING MORE EFFECTIVE TREATMENTS
Authors: Mieke Roosen, Sonja Krausert, Phylicia Stathi, Norman Mack, Benjamin Schwalm, Ina Oehme, Heike Peterziel, Chris Meulenbroeks, Mariëtte E G Kranendonk, Sabine L A Plasschaert, Eelco Hoving, Stefan M Pfister, Jens Bunt, Cornelis M van Tilburg, Olaf Witt, Marcel Kool
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Embryonal Tumor with Multilayered Rosettes (ETMR) is a rare and aggressive tumor that occurs mainly in infants under three years of age. Genetically, ETMRs are characterized by amplification and fusion of a microRNA cluster on chromosome 19 (C19MC) with TTYH1, present in ~90% of the tumors. ETMR patients still have a poor prognosis without any recent advances in treatment. A major limitation to develop more effective treatment strategies is the lack of sufficient preclinical models. METHODS Establishment of ETMR patient-derived xenograft (PDX) models and tumoroid lines, molecular characterization, high throughput in vitro drug screens, targeted drug treatments in vitro and in vivo. RESULTS We have established four new tumoroid and five new PDX ETMR models. These models faithfully recapitulate ETMR patients’ tumors based on their histological, transcriptomic, and methylome signatures. The in vitro models were derived from two patients and two PDX models and included three C19MC-amplified cell lines, of which two were a primary-relapse pair, and one a primary C19MC non-amplified model. In vivo we established the same models as PDX models subcutaneously plus an additional C19MC-amplified relapse model. High-throughput drug screening assays, using drug libraries with 225 clinically approved drugs and other small molecules, were conducted across the panel of in vitro models. Potential therapeutic candidates with promising activity in ETMR tumoroid lines identified from these screens include FGFR, XPO1, MTOR, MDM2 and topoisomerase inhibitors. CONCLUSIONS The establishment of novel preclinical models represents a significant advancement in ETMR research, offering a platform that captures the molecular complexity of the disease. The identification of several inhibitors shows the potential of these models for drug discovery and preclinical testing. Ongoing in vitro and in vivo experiments with these drugs and combinations aim to further validate their activity, moving towards the development of more effective therapies for ETMR patients.
LMIC-12. INFANT-TYPE HEMISPHERIC GLIOMA: CAN IT BE EFFECTIVELY MANAGED IN AN UPPER-MIDDLE-INCOME COUNTRY?
Authors: Natália Dassi, Julia D Balsanelli, Silvia R C Toledo, Francine T Gamba, Maria T S Alves, Sergio Cavalheiro, Patricia A Dastoli, Marcos D Costa, Frederico A Silva, Nasjla S Silva, Andrea M Cappellano
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Infant-type hemispheric glioma (IHGs) is a rare congenital tumor and a newly defined entity in the 2021 WHO classification for central nervous system tumors. It harbors, in mostly cases, a tyrosine kinase receptor rearrangement in NTRK family, ALK, ROS1 and MET. The aim of this study is to describe the demographic characteristics, treatment, and outcomes of a cohort of pediatric patients with IHGs in one single institution. METHODS A retrospective study was performed between 2012-2023. Overall survival (OS) was measured from diagnosis to date of death or last follow-up. The Kaplan–Meier method was used for survival analysis. RESULTS Fourteen patients were included. Median age was 4.4 months (range 0.1- 37months). All patients underwent neurosurgical resections, with a median of 2 (range 1-6). Eight patients performed molecular analyses showing three ALK, two NTRK, two ROS and one MET rearrangement. Twelve patients received chemotherapy-lines, four of them more than one schema, with a median of 3 (range 2-5). Three patients were submitted to focal radiotherapy after 3 years of age and three received target therapies (crizotinib/ alectinib, lolartinib and repotrectinib). In a median follow-up of 46.9 months (2-125months), the OS in 5/10 years was 73.9% and 55.4%, respectively. Four patients died, one due to neurosurgical complications at diagnosis, one from refractory seizure 47 months after diagnosis with no evidence of disease, and two due disease progression with eight and 74 months after initial diagnosis, the last one despite 2-lines of target therapy. CONCLUSION Our series reveals acceptable and encouraging survival rates, demonstrating that not only new molecular discoveries but also optimal multidisciplinary treatment makes a difference in survival of patients with IHG even in countries with limited resources. However, access to targeted therapy remains an obstacle to be overcome for the optimal management of these patients.
DIPG-10. SUBCLONAL POPULATIONS OF DIFFUSE MIDLINE GLIOMA CELLS PROMOTE TUMORIGENESIS THROUGH AP-1 TRANSCRIPTION FACTOR DYSREGULATION
Authors: Ketty Kessler, Yura Grabovska, Diana Carvalho, Anna Burford, Sara Temelso, Haider Tari, Valeria Molinari, Shauna Crampsie, Lu Yu, Jyoti Choudhary, Paula Proszek, Mike Hubank, Alan Mackay, Chris Jones
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Paediatric-type diffuse high-grade glioma (PDHGG) are brain tumours occurring largely in children, classified into distinct subgroups based upon their location and defining molecular alterations, with very poor clinical outcomes. The presence of a wide diversity of genotypically- and phenotypically-distinct subclones within individual tumours provides a substantial barrier to developing effective treatments. METHODS To understand their role, and how this may be exploited therapeutically, we established 218 subclones in vitro from 8 patient-derived PDHGG different cell lines, and characterised them using single-cell and bulk multi-omic approaches linked to high-content phenotypic screening. RESULTS Highly migratory subpopulations of diffuse midline glioma (DMG) cells were isolated, whereby RNAseq and proteomics identified a specific metaprogram associated with migration, enriched in AP-1 target genes, and common across a series of DMG patient-derived cells. Data integration of scRNAseq/scATACseq showed an opening of the chromatin at loci such as the early development transcription factors FOS and JUN (AP-1 targets) associated with their overexpression in highly migratory cells. Co-culturing these subclones with less motile patient-matched counterparts conferred an enhanced migratory capacity in these cells, so we sought to abrogate this via high-throughput screening of over 900 compounds aimed at selectively targeting DMG subclones grown in co-culture. Inter-clonal interactions were disrupted by a diverse set of compound classes including previously identified secreted protein inhibitors (MMP2/9i). Moreover, hits were seen with numerous neuroactive drugs inhibiting a series of neural receptors, ion channels, and transporters shown to be highly expressed in subpopulations of DMG cells, and linked to a common mechanism of action via AP-1. CONCLUSIONS Clinically available neuroactive drugs may therefore represent a novel therapeutic approach in targeting highly migratory cells within DMG, which undergo chromatin remodelling to confer a pro-tumorigenic programme via upregulation of AP-1 targets.
LGG-60. DISTRIBUTION AND CLINICAL SIGNIFICANCE OF FGFR ALTERATIONS IN PEDIATRIC AND AYA GLIOMAS
Authors: Liana Nobre, Sameer Farouk, Alexandra Larsen, Julie Bennett, I-Chen Ho, Robert Siddaway, Ingo Mellinghoff, Sebastien Perreault, Vanan Magimairajan, Valerie Larouche, Samuele Renzi, Nirav Thacker, Shayna Zelcer, David Ellison, Mariarita Santi, Nasrallah MacLean, Sara Stone, Tejus Bale, Matthias Karajannis, Uri Tabori, Cynthia Hawkins
Journal: Neuro-Oncology (2024)

Abstract Fibroblast growth factor receptor (FGFR) alterations are prevalent in human cancers. In a large Canadian population-based cohort, encompassing over 1,300 pediatric and Adolescent and young adult (AYA) gliomas, FGFR mutations occurred in 10% of pediatric low-grade gliomas (LGG) and 20% of IDH-WT AYA LGGs. Here we assembled a large multi-institutional cohort including more than 300 mutated gliomas, aged 6 months to 87 years, 53% of which were LGG. High-grade gliomas were more common with increasing age; over 90% of pediatric cases were LGGs, compared to 30% in the AYA group. Fusions, predominantly seen in the pediatric group (70% of LGGs), contrast with FGFR3-TACC3 fusions frequent found in adult high-grade gliomas. Interestingly, FGFR mutations sometimes existed as sole drivers or co-occurred with other alterations (~30%), it is unclear how this alters tumor behavior, although gain of additional alterations could be implied in malignant transformation and poor prognosis. Despite higher incidence of high-grade gliomas in AYAs, their progression-free survival was significantly better than that of pediatric LGGs (p=0.007), largely due to the prevalence of hemispheric tumors amenable to gross total resection. Approximately 30% of our LGG cohort underwent adjuvant therapy; with available data for 28 patients, objective responses were noted in 2/12 to chemotherapy, 2/9 to MEK inhibitors, and 3/7 to FGFR inhibitors, respectively. With the increasing promise of precision targeted therapy, molecular profiling and assessment for FGFR alterations is essential. Although encouraging, further studies are needed to assess the benefit of FGFR inhibition in these patients.
DIPG-08. PROBING THE BLOOD-BRAIN-TUMOR-BARRIER WITH A MICROVASCULAR MODEL OF DIFFUSE MIDLINE GLIOMA
Authors: Kimberly R Bennett, Tessy Teboh, Cynthia Hajal, Roger D Kamm, Paula T Hammond, Joelle P Straehla
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric diffuse midline glioma (DMG) is a uniformly fatal brain tumor in children, with most patients surviving less than 12 months. Current treatment for DMG is limited, and outcomes for this tumor have not improved. The blood-brain-barrier (BBB) remains a key challenge for DMG therapeutics, preventing most drugs from entering brain tissue. Functional characterization of the blood-brain-tumor-barrier (BBTB) – the interaction between tumors and BBB vasculature – remains largely unexplored for DMG. There is a need for a preclinical model of DMG that can probe the functional, physiological, and biological properties of the BBTB in vitro as a platform to evaluate therapeutic efficacy that is representative of human physiology. METHODS To generate an in vitro model of DMG with human microvasculature (DMG-BBTB model), we co-cultured DMG neurospheres, human brain microvascular endothelial cells, human brain vascular pericytes, and human astrocytes. Cells are simultaneously seeded into microfluidic devices at varied concentrations within a fibrin matrix. Self-assembled microvascular networks are formed within 7-8 days and used for downstream functional and phenotypic assays. RESULTS Vascular morphology and solute permeability in microvascular networks are influenced by cell identity, growth pattern, and relative concentration. We show that DMG neurospheres exhibit different patterns of growth when co-cultured as uniform spheroids versus single cells in suspension. Devices representing each growth pattern are further characterized for paracellular diffusion and permeability compared to devices without DMG cells through perfusion of high molecular weight dextran. Permeability values are correlated to biologic features such as the abundance and localization of junctional proteins and transporters. CONCLUSIONS We developed a platform to evaluate the microvasculature of the DMG BBTB as a tool to develop new therapies informed by vascular biology. We probed the functional, physiological, and biological properties of the human DMG BBTB in vitro, and in ongoing work are assessing approved and experimental therapeutics.
MDB-04. LONG-TERM OUTCOME OF THE MILANO STRATEGY FOR HIGH-RISK MEDULLOBLASTOMA, INCLUDING THE IMPACT OF MOLECULAR SUBTYPE
Authors: Maura Massimino, Chiara Dossena, Francesco Minasi, Francesco Barretta, Francesca Romana Buttarelli, Veronica Biassoni, Matilde Oriani, Elisabetta Schiavello, Marica Ficorilli, Olga Nigro, Bianca Pollo, Manila Antonelli, Vittoria Donofrio, Marco Maggioni, Marcel Kool, Emilia Pecori, Sabina Vennarini, Francesca Gianno, olga nigro, Alessandra Erbetta, Luisa Chiapparini, Roberto Luksch, Elena Barzanò, Cristina Meazza, Marta Podda, Filippo Spreafico, Monica Terenziani, Luca Bergamaschi, Andrea Ferrari, Michela Casanova, Stefano Chiaravalli, Giovanna Gattuso, Simon Bailey, Piergiorgio Modena, Loris De Cecco
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Since 2008 we have been using the same strategy as for M+ medulloblastoma for all other high-risk subgroups(LC/A histology,TP53 mutations,and/or MYC/MYCN amplification). METHODS After surgery,patients &amp;gt;3-year-old received staging/histo-biological revision and sequential HD-methotrexate,HD-VP16,HD-Cyclo,HD-Carbo.HART-CSI,in two daily 1.3 Gy-fractions/5-days-a-week, reached doses tailored to age and pre-radiation response to chemotherapy:31.2 Gy under 10 years-old if CR+PR or no metastases,39 Gy in other/older patients.Boosts to posterior fossa/residual M+ deposits were given reaching total doses of 59.7–60 Gy and 9 Gy,respectively and avoided if metastatic nodules very big or patients very young.Two courses of high-dose thiotepa were delivered in case of not-optimal response after pre-RT phase and in all M0 patients either in pre/post-RT phase.Subgrouping was obtained through IHC and methylation EPICv2.0 in rescued samples. RESULTS Patients were 89,median age 8.8 years,64 males,median fup 136 months. OS/PFS/EFS at 5/15-years were 75.9/66.5%,71.1/69.8%,68.2/65.3%,respectively; 6/28 fatal events were not correlated to medulloblastoma relapse(four 2nd tumors).Sex,age below 10/over 15 years, post-sugical residues,histological subtype(#24 LC/A,#57 classic,#7 nodular-desmoplastic),MYC amplification(#17),CSI dose reduction(#31),absence of boosts(#16),use of myeloablative courses(#45),presence/absence of metastases(#77 M+) did not impact prognosis.Patients progressing after pre-HART chemotherapy(#14) and SD+PD after HART(# 10) did significantly worse(P&amp;lt;0.001)with 1/0 survivors, respectively.Subgrouping done in 44/89 patients so far,showed significant worse PFS/EFS for patients with SHH-tumors(#11, 2 with constitutional Tp53-mutations) vs. groups3 and 4(11 and 22 patients, respectively).Patients younger than 10 had worse response to CT and less boosts (P=0.03 in both) but could receive lower CSI-doses if stratified according to CT-response. CONCLUSIONS This strategy, partly adopted in the ongoing SIOPE protocol, confirmed satisfying results in all high-risk categories; SHH tumors appeared the most aggressive in this context.
ETMR-16. PEDIATRIC SPINAL EMBRYONAL TUMORS; PATHOLOGICAL INSIGHTS INTO THIS RARE ENTITY
Authors: Archita Juneja, Manali Ranade, Omshree Shetty, Ayushi Sahay, Aekta Shah, Maya Prasad, Girish Chinnaswamy, Arpita Sahu, Vikas Singh, Prakash Shetty, Aliasgar Moiyadi, Arychya Dasgupta, Abhishek Chatterjee, Tejpal Gupta, Sridhar Epari
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Spinal cord is an extremely uncommon primary location for the CNS embryonal group of tumours. This study aims to collate the immunohistological spectrum of these rare spinal CNS embryonal tumours, diagnosed in the institute during the last 20 years. METHODS Of the total 446 spinal tumours, 15 were embryonal tumours. Of these, 5 were metastases, four from medulloblastoma and one from AT/RT (diagnosed subsequently) which were excluded and thus the study cohort comprised 10 cases. Eight were atypical teratoid/rhabdoid tumour (AT/RT; 80%), and 2 were embryonal tumour with multilayered rosettes (ETMR; 20%). RESULTS Six AT/RT cases were of ≤2 years age; while other two were 6 and 11 years of age with a M:F ratio of 1.3:1 (thoracic: 4; cervical: 2; lumbar: 2). Histologically, rhabdoid-like morphology (87.5%), necrosis (100%), and calcification (25%) were noted. All of them were of INI1 protein (SMARCB1)-deficient., all of them were negative for brachyury and all were variably positive for AE1/AE3. Two ETMR cases were of &amp;lt;2 years of age, females and at lumbar and cervical levels respectively. C19MC amplification by FISH was done for one case which was not amplified. Histologically, one of them showed a medulloepithelioma-like pattern; while the other showed multilayered rosettes and neuropil-like matrix. LIN28A strong positivity, retained nuclear staining for INI1 protein and negativity for AE1/AE3 was noted in both. Significant BCOR positivity was seen in one but was negative for SATB2. CONCLUSIONS Spinal embryonal tumours are extremely rare and metastases needs to be ruled out before considering as primary. AT/RT is the most common embryonal tumour in the spine, commonly SMARCB1(INI1)-deficient. ETMR can also encountered in the spinal location.