tbuckley/cabot-search huggingface dataset:
TRLS-14. PNOC022 REPORT: A COMBINATION THERAPY TRIAL USING AN ADAPTIVE PLATFORM DESIGN FOR PATIENTS WITH DIFFUSE MIDLINE GLIOMA AT INITIAL DIAGNOSIS, POST-RADIATION THERAPY, OR PROGRESSION
Authors: Cassie Kline, Andrea Franson, Anuradha Banerjee, Alyssa T Reddy, Shannon Raber, Carly Hoffman, Jane Minturn, Jasper van der Lugt, Evelien de Vos-Kerkhof, Dannis van Vuurden, Nicolas Gerber, Ana S Guerreiro Stucklin, Lindsay Kilburn, Jennifer Elster, Nicholas Whipple, Kenneth Cohen, Michal Yalon Oren, Sharon Gardner, Andrew Cluster, Susan Chi, Daniel Landi, Geoffrey McCowage, Josh Vo, Adam Resnick, Joanna Phillips, Aashim Bhatia, Elizabeth George, Arastoo Vossough, Ali Nabavizadeh, Steve Braunstein, Nalin Gupta, Michael Prados, Sebastian Waszak, Janel Long-Boyle, Annette Molinaro, Matthew Dun, Carl Koschmann, Javad Nazarian, Sabine Mueller
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Children with diffuse midline glioma (DMG) face dismal prognoses. PNOC DMG-ACT (DMG-Adaptive Combination Trial, PNOC022) is an open-label, international trial investigating the efficacy of combination therapies for patients with DMG. We present an early report on Cohorts 1-3, treated with ONC201, an orally available ClpP agonist, and paxalisib, a dual PI3K-mTOR inhibitor. METHODS Patients aged 2-39 years enrolled pre-radiation (Cohort 1), 4-14 weeks post-radiation (Cohort 2), or at progression (Cohort 3). Patients were randomized to receive ONC201 or paxalisib prior to surgery when biopsy was indicated and/or in combination with radiation when radiation was indicated. Those not planned for biopsy were required to submit archival tissue. All received maintenance therapy with weekly ONC201 (weight based adult equivalent of 625 mg) and daily paxalisib (27 mg/m2). Plasma and CSF samples for pharmacokinetics (PK) and biologic correlates were collected. RESULTS Between November 2021 and September 2023, 132 patients met critera for study therapy (Cohort 1=33; Cohort 2=69; Cohort 3=30; median age 9 years [range 2-37], n=73 female [55%]; n=86 pontine [65%]). Median overall survival (OS) from diagnosis is 13.2 months in Cohort 1 (lower 95% CI 11.1) and 15.8 months in Cohort 2 (lower 95% CI 13.9). Median OS from progression is 8.8 months in Cohort 3 (lower 95% CI 8.6). Most common non-hematologic grade 3 and above treatment-related adverse events (TRAE) were maculopapular rash (n=12); mucositis (n=8); colitis and hyperglycemia (n=7). Most common serious TRAEs were colitis (n=7) and hyperglycemia (n=6). We have collected 169 CSF samples and &amp;gt;600 plasma samples for ctDNA. Cohort 2 PK from CSF and plasma and CSF metabolomics and somatic mutation landscapes are being finalized. CONCLUSIONS We will present somatic mutation profiles, PK analysis, ctDNA, and metabolic signatures from the CSF in association with toxicity, survival, and tumor response via central imaging review.
HGG-16. PEDIATRIC-TYPE DIFFUSE HIGH-GRADE GLIOMA OF METHYLATION-BASED RTK2A AND RTK2B SUBCLASSES PRESENT DISTINCT RADIOLOGICAL AND HISTOMOLECULAR FEATURES
Authors: Arnault Tauziède-Espariat, Lea L Friker, Gunther Nussbaumer, Métais Alice, Manila Antonelli, Martin Benesch, Brigitte Bison, Volodia Dangouloff-Ros, Maria Luisa Garrè, Felice Giangaspero, Yura Grabovska, Jacques Grill, David T W Jones, Chris Jones, Michael Karremann, Christof M Kramm, Alan Mackay, Andrés Morales La Madrid, Thomas Perwein, Torsten Pietsch, David Sumerauer, Dannis van Vuurden, André O von Bueren, Monika Warmuth-Metz, Pieter Wesseling, Josef Zamecnik, David Castel, Gerrit H Gielen, Pascale Varlet
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse pediatric-type high-grade gliomas (pedHGG), H3-wildtype and IDH-wildtype, encompass three main methylome-based subclasses: pedHGG-MYCN, -RTK1A/B/C, and -RTK2A/B. Since their first description in 2017, tumors of pedHGG-RTK2A/B have not been further characterized and their clinical significance is unknown. METHODS A not yet published cases series on pedHGG with a gliomatosis cerebri (GC) growth pattern showed an increased incidence of pedHGG-RTK2A/B (n=18/40). We assembled a cohort of 14 additional methylation-based pedHGG-RTK2A/B tumors and pooled them with the GC tumors providing centrally reviewed radiological, histological, and molecular characterization. RESULTS Our cohort of 32 pedHGG-RTK2A/B tumors consisted of 25 RTK2A (78%) and seven RTK2B (22%) cases. The median age was 11.6 years (4-17) with an overall survival of 15.9 months (interquartile range 12.1-25.8). Of the additional unselected cases with available imaging (10 of 14), seven showed a GC phenotype at diagnosis or follow-up. In addition, pedHGG-RTK2B tumors exhibited bithalamic involvement (6/7, 86%). Histopathology confirmed a diffuse glial neoplasm in all cases with prominent angiocentric features in both subclasses. Most tumors (24/29, 83%) diffusely expressed EGFR, notably with a focal perivascular enhancement. Cells of pedHGG-RTK2A lacked Olig2 expression, whereas 43% (3/7) of pedHGG-RTK2B expressed Olig2. Loss of ATRX expression occurred in four pedHGG-RTK2B samples (57%). In sequencing analyses (RTK2A: n=18, RTK2B: n=5), EGFR alterations (n=15/23, 65%; predominantly point mutations) were commonly found in both subclasses. Mutations in BCOR (n=14/18, 78%), SETD2 (n=7/18, 39%), and TERT promoter (n=6/18, 33%) occurred exclusively in pedHGG-RTK2A tumors, while pedHGG-RTK2B tumors were enriched for TP53 mutations (4/5, 80%). CONCLUSIONS In conclusion, genotype-phenotype correlations in a multicenter series of pedHGG-RTK2A/B tumors revealed a highly diffuse-infiltrating tumor frequently exhibiting a GC phenotype. The two subclasses share particular histomolecular features (EGFR alterations, angiocentric pattern), whereas they differ in specific characteristics (pedHGG-RTK2A: Olig2 negativity, BCOR and SETD2 mutations; pedHGG-RTK2B: ATRX and TP53 alterations).
GCT-13. OUTCOMES OF INTRACRANIAL GERMINOMA TREATED AT A SINGLE UK PROTON CENTRE ACCORDING TO UK CHILDREN’S CANCER AND LEUKAEMIA GROUP (CCLG) GUIDELINES
Authors: Love Goyal, Anna France, Simona Gaito, Rovel J Colaco, Shermaine Pan, Daniel Saunders, Nicola Thorp, Gillian A Whitfield
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND After SIOP-CNS-GCT II closed in 2018, the CCLG recommended, with caveats, following the standard trial arms: 4 cycles of chemotherapy (Etoposide-Carboplatin alternating with Etoposide-Ifosfamide) followed by whole ventricular radiotherapy (WVRT) (24Gy/15fractions) and boost (16Gy/10fr) to the primary site(s) for localised germinoma and craniospinal irradiation (CSI) (24Gy/15fr) followed by boost (16Gy/10fr) to primary and metastatic sites for metastatic disease. Since 04/2021, the CCLG formally recommended omitting the boost for localised unifocal germinoma in complete radiological response after chemotherapy. From autumn 2022, we also omitted boosts to completely responded primary sites for localised bifocal germinoma. METHODS Retrospective reviewed of all patients referred to our proton centre 12/2018–06/2023. We collected patient, tumour and treatment factors, acute toxicities (CTCAE grade≥3), and event-free survival(EFS) from radiotherapy until 09/2023. RESULTS Forty-two patients (36M:6F) were included, 23 localised and 19 (including 3 incompletely staged) treated as metastatic. Primary sites: 21 pineal, 8 pituitary/suprasellar, 10 bifocal and 3 atypical (optic nerve, periventricular, thalamic). Diagnosis was by histopathology in 40 and bifocal disease with negative CSF and serum markers in 2. Median age was 15 years (IQR 13-16), median follow-up 13 months (IQR 6-15). Patients were treated according to CCLG guidance, apart from three patients with metastatic pure germinoma, of whom one received 2 cycles Cisplatin-Etoposide, and two received 5 and 3 cycles of Vinblastine before CSI, and one patient with metastatic germinoma plus teratoma who received 2 cycles of Cisplatin-Etoposide and non-germinoma radiotherapy doses (30Gy/20fr CSI, 24Gy/15fr cranial boosts). No patient had subsequent surgery. All remained progression free at last follow-up. Eight patients developed acute grade 3 toxicities: 3 vomiting (2 CSI, 1 WVRT), and 5 lymphopenia (all CSI). CONCLUSIONS Disease control was excellent, with no relapses to date. Proton therapy was well tolerated with low rates of acute high grade toxicities.
MDB-09. WNT AND GROUP 4 MEDULLOBLASTOMAS OF EARLY CHILDHOOD TREATED WITH HIGH DOSE CHEMOTHERAPY AND CRANIOSPINAL IRRADIATION SPARING APPROACH
Authors: Rose Daynielle Cansanay, Craig Erker, Erin Ratterman, Mary Pat Schlosser, Rebecca Ronsley, Chantel Cacciotti, Juliette Hukin, Sylvia Cheng, Natasha Pillay-Smiley, Vanan Magimairajan, Andrew Cluster, Mohamed S Abdelbaki, Ashley Margol, George Michael, Susan Chi, Ralph Salloum, Vijay Ramaswamy, Michal Zapotocky, Vicente Santa Maria Lopez, Helene Toledano, Kathleen Dorris, Martin Mynarek, Stefan Rutkowski, Alvaro Lassaletta, Eric Bouffet, Lucie Lafay-Cousin
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND WNT and group 4 medulloblastoma (MB) are rare in young children and their outcome when treated with radiation avoidance infant strategies is unknown. METHOD This retrospective international cohort included children less than 7 years of age, with molecularly characterized group 4 or WNT MB, treated with high-dose chemotherapy(HDC) and CSI sparing approach. RESULTS The current cohort includes 29 patients (19M/10F). For the 26 patients with group 4 MB (median age at diagnosis 45.9 months), 16 (61.5%) were M0 and 17 (65.3%) underwent initial gross total resection (GTR). The most common consolidation regimen used was three cycles of high dose carboplatin and thiotepa (65.5%) or a single cycle of high dose of carboplatin, etoposide and thiotepa (31%).Two received adjuvant focal radiotherapy. Sixteen patients (61.5%) relapsed at a median time of 21.4 months from diagnosis (median age of 5.2 years). Relapse was local for 50% of the patients. One patient underwent palliative management and 15 received radiation-based salvage therapy (2 focal, 13 CSI+/- boost).The median dose of CSI was 36Gy (18-36). Five of the 15 died of disease. Overall, at a median follow-up of 37.9 months from diagnosis, 17/26 (65.3%) patients were alive, six had died of disease and two of toxicity. All 3 WNT patients (median age at diagnosis 57.8 months) underwent GTR and two were M0. Two received sequential high dose carboplatin and thiotepa. One patient with initial partial response, progressed 2 months after treatment completion and received salvaged CSI (18Gy). All of them were alive at a median follow up of 88 months from diagnosis. CONCLUSIONS HDC and CSI sparing approaches led to a high rate of relapse for young patient with group 4 (61.5%). However, 2/3 were salvaged with radiation-based therapy given at a median age 5.2 yrs. Additional WNT patients are needed to better describe their management.
ETMR-31. A UNIQUE CASE OF CNS DIFFUSE, NON-SYSTEMIC ALK+ HISTIOCYTOSIS IN A PEDIATRIC PATIENT
Authors: Samantha J DeMarsh, Brent Orr, Nicholas Willard, Nathan Dahl
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Histiocytic disorders are a group of rare diseases with accumulation of of macrophages, monocytes, or dendritic cells in various parts of the body. ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 that is very rarely described in pediatrics. METHODS A 20 month old male presented to an adult hospital after a prolonged period of headaches, vomiting, and loss of developmental milestones. Imaging demonstrated severe hydrocephalus and extensive thickened leptomeningeal enhacement with mass effect. He underwent VP shunt placement and revision, a T7-T10 laminectomy, and tumor debulking. Extensive molecular testing, including DNA and RNA analysis by NGS was performed and a CLTC::ALK fusion was identified, along with Tier III DNA variants, yielding a diagnosis consistent with ALK-Positive Histiocytosis, with diffusivity in the CNS system. Full evaluation demonstrated no involvement of the peripheral nervous system or other systemic involvement. He initially demonstrated signs of neuro-irritation, altered tone, and lower extremity clonus. RESULTS After review of very little literature published on similar patients, although none with a clinical picture matching his, he was started on a treatment course of high dose dexamethasone, vinblastine, and lorlatinib targeting the ALK+, likely driver, mutation of his disease. On evaluation scans two months into treatment, he showed no change in his disease burden. He was transitioned to clofarabine cycles with daily lorlatinib for continued targetted therapy. After six total cycles, he demonstrated a high partial to complete remission (allowing for evidence of scarred tissue) and tremendous neurologic and developmental milestone gains. CONCLUSIONS This case demonstrates a unique presentation in which there is little described in the literature in way of clinical features or treatment standards, and further none exactly similar to this patient. After undergoing extensive evaluation and therapy modication, he responded remarkably well and continues to have optimal quality of life.
ATRT-01. MODELLING ATYPICAL TERATOID/ RHABDOID TUMOUR AND HEALTHY BRAIN CROSSTALK
Authors: Harry Dean Porter, Phoebe McCrorie, Mohammed Diksin, Cara Moloney, Richard Grundy, Ruman Rahman
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Atypical Teratoid/Rhabdoid Tumours (ATRT) are aggressive paediatric brain tumours which mostly occur in the first three years of life and which rapidly recur after surgical resection. There has been debate over the use of cytotoxic consolidation therapy due to the severity of off target effects associated with chemo/radiotherapy use in young patients. Astrocytes have previously been shown to support progression and therapy resistance of other brain tumours; however, their role in ATRT pathophysiology is yet to be elucidated. METHODS To better understand how adjacent “healthy” brain tissue may be complicit in ATRT recurrence, we have developed a 3D in vitro model in which ATRT cells are co-cultured with astrocytes within a bespoke decellularized human cerebellum extracellular matrix (ECM) hydrogel. RESULTS Immunofluorescence confirmed that human cerebellar ECM hydrogels retain human brain ECM components (hyaluronic acid, laminin, and fibronectin). ATRT-astrocyte co-culture spheroids were formed within the ECM hydrogel and observed to display a distinctive morphology relative to monoculture controls, with no difference in overall viability. Co-cultured tumour cells were successfully harvested from the model and isolated from astrocyte populations using fluorescence activated cell sorting. In both 2D and 3D culture, we have shown that astrocytes labelled with CM-DiI transfer this cell tracker dye to ATRT-MYC (BT12, BT16) and ATRT-TYR (BT37) cells, potentially indicating intercellular trafficking. Furthermore, in 2D culture ATRT-MYC (BT12 and BT16) cells form actin rich cell-cell processes with astrocytes when co-cultured in vitro. CONCLUSIONS This work represents a comprehensively characterised model of ATRT interaction with the healthy brain. Future work will analyse changes in ATRT cell transcriptomes when astrocytes are present in the model. By understanding how the presence of astrocytes in the tumour microenvironment may promote tumour survival and progression, we aim to use this data to identify candidate therapeutics to inhibit crosstalk and improve patient outcomes.
LGG-48. CLINICAL CHARACTERIZATION OF FGFR-ALTERED, PEDIATRIC LOW-GRADE GLIOMAS
Authors: Benjamin Posorske, Nishant Tiwari, Lisa Keller, Kathleen Dorris, Stewart Goldman, Lindsey M Hoffman, Ross Mangum
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric low-grade glioma (pLGG) is the most common central nervous system tumor of childhood. Most pLGGs are driven by BRAF alterations, but a subset harbor activating mutations or fusions of FGFR1/2/3. Significantly less is known about the biologic activity, clinical course, and response to targeted inhibition of these FGFR-altered gliomas (FGFR pLGG). We sought to define the epidemiologic characteristics, molecular signature, prognostic markers, and clinical course of patients with FGFR pLGG. METHODS We performed a multi-institution, retrospective chart review of pediatric neuro-oncology patients treated at two large, academic cancer centers from 2012 – 2023 with tumor molecular profiling demonstrating any FGFR alteration. RESULTS Sixteen eligible patients were identified; 9 (56%) were female and median age was 12 years of age (range 6 - 18 years). Reported histologies included pilocytic astrocytoma (4), rosette-forming glioneuronal tumor (3), low grade glial/glioneuronal tumor (3), low grade glioma NOS (2), intermediate grade astrocytoma (1), dysembryoblastic neuroepithelial tumor (2), and pilomyxoid astrocytoma (1). FGFR point mutations were seen in 10/16 (62.5%) patients followed by FGFR-TACC1 fusions in 4/16 (25%) patients and two patients with FGFR1 tandem duplication. Metastatic disease was noted at diagnosis in two patients and upfront gross total resection was achieved in four patients. The most common systemic therapy for the remaining patients was Vincristine and/or Carboplatin. All sixteen patients are alive at median follow up of 52 months (range 6 - 198 months). CONCLUSIONS FGFR pLGG represent a distinct subset of tumors with unique biologic properties and clinical activity. Additional studies are needed to investigate this unique patient population to appropriately adapt our therapeutic approach and improve patient outcomes.
IMMU-15. CARTART: A SURFACE TARGET IDENTIFICATION TOOL FOR TUMORS
Authors: Nikhil Joshi, Rakesh Murugesan, Ezra Beaubien, Olivia McManus, Cullen Wilson, Kyra Harvey, Deepak Mishra, Sreehita Hajeebu, Peter Madsen, Jessica Foster
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Cell surface proteins are valuable for generation of targeted and immune-based cancer therapies. While large molecular datasets are available for multiple central nervous system (CNS) tumors, identifying such targets on a tumor-level scale to generate novel therapeutics for patients is limited by a lack of analytical pipelines. Here, we present CARTarT (CAR-T Target identification Tool), a no-code, web application that utilizes user-inputted bulk transcriptomic data to identify putative surface targets for pediatric tumors. METHODS CARTarT was built on R 4.3.1 and performs differential gene expression between tumors and normal tissue (GTEX) utilizing an empirical bayes method. Data is then filtered based on predicted-surfaceome expression, non-immune cell expression, and limited normal tissue expression to mitigate possible off-target toxicities. Targets are finally scored using a weighted scoring metric based on RNA-level log fold change, t-value, average tumoral expression, and prevalence in oncogene databases to prioritize putative targets. Targets with a score less than 0.20 were removed from our final table. A total of 919 samples from OpenPedCan were utilized to validate the tool. RESULTS Amongst diffuse midline glioma specimens (n=196), we identified 100 putative surface targets. 60 (60%) of surface targets were previously identified oncogenic or cancer-associated genes. 17 surface targets (15%) are shown to have previously described immune or targeted therapeutics across cancer types, most notably identifying B7-H3, IL13RA2, EGFR, and GPC2. In addition, we identified 45 targets with potential across multiple pediatric neuro-oncologic malignancies (high grade glioma, medulloblastoma, ependymoma, atypical teratoid/rhabdoid tumor) including CHRNA5, GLP1R, B7-H3 and GPC2. CONCLUSION These findings highlight the potential utility of CARTarT as a no-code solution for surface target identification and describe established and novel surface targets across numerous pediatric CNS tumors. We present CARTarT to the scientific community as an open-access opportunity to advance immune-based and targeted therapies for tumors.
NFS-23. ASSOCIATION OF LOCALIZED MAGNETIC RESONANCE IMAGING FEATURES IN ANTERIOR VISUAL PATHWAY WITH VISUAL ACUITY LOSS AMONG CHILDREN WITH NF1-OPG
Authors: Zhifan Jiang, Abhijeet Parida, Xinyang Liu, Yucheng Tang, Holger R Roth, Michael J Fisher, Roger J Packer, Syed Muhammad Anwar, Robert A Avery, Marius George Linguraru
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Half of children with optic pathway gliomas associated with neurofibromatosis type 1 (NF1-OPG) are at risk for vision acuity (VA) loss. NF1-OPGs manifest along the anterior visual pathway (AVP), where the overall shape and volume from MRI have been recently associated with VA loss. To investigate the added value of localized features within the optic nerves (ONs) and chiasm, we propose an automatic deep-learning framework for VA loss prediction from volumetric and radiomic analysis of ONs, chiasm, and AVP. METHODS We collected MRIs of 60 children with NF1-OPG from Children’s National Hospital (CNH, GE platform) and 75 from Children’s Hospital of Philadelphia (CHOP, Siemens platform). MRI sequences included T1-, T2-weighted and T2-FLAIR. Experts annotated the AVP to establish ground truth. Neuro-ophthalmic evaluation identified VA loss (LogMAR &amp;gt;= 0.2) in 52/135 children. Automatic AVP segmentation was performed using the Swin transformer network. ONs and chiasm were split through template-based registration. Brain volume, tumor location, child age, and 1,172 radiomic features were used to predict VA loss using support vector machines. Sequential feature selection associated with risk VA loss was done using sensitivity and univariate statistical tests (ANOVA). We compared predictions based on new ON and chiasm analysis with results based on AVP alone. RESULTS Balanced accuracy, sensitivity, specificity, and AUROC of VA loss prediction were 0.865, 0.882, 0.857, 0.899, respectively. Significant risk factors were maximal image intensity and gray level run length entropy in T2-FLAIR for ONs, and image intensity range in T2-FLAIR for chiasm. AUROC based on analysis of AVP alone dropped to 0.728 (p-value=0.028). CONCLUSIONS Deep learning-based analysis indicates an association of new localized MRI features in ONs and chiasm with VA loss, which show enhanced capability in predicting VA loss. This automated framework has the potential to accelerate and guide the treatment decisions for children with NF1-OPGs.