tbuckley/cabot-search huggingface dataset:
METB-06. PEDIATRIC BRAIN TUMOURS: A SINGLE INSTITUTIONAL EXPERIENCE OF NEXT GENERATION SEQUENCING-BASED TARGETED PANEL EVALUATION
Authors: Sridhar Epari, Prachi Bapat, Mamta Gurav, Omshree Shetty, Aekta Shah, Ayushi Sahay, Maya Prasad, Arpita Sahu, Vikash Singh, Prakash Shetty, Aliasgar Moiyadi, Archya Dasgupta, Abhishek Chatterjee, Girish Chinnaswamy, Tejpal Gupta
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric brain tumours (pBT) are molecularly diverse and with the advent of targeted-therapies it is important to decipher molecularly. METHODS Single institutional non-consecutive pBT (&amp;lt;18 years) cohort include – a. high-grade glial tumour (HGG; H3-wildtype, IDH1/2-wildtype, immunohistochemically MMR-protein-proficient, negative for NTRK/ALK-rearrangements by FISH in &amp;lt;3 years), b. high-grade CNS neuroepithelial tumour, NOS (cNET), c &amp; d. pilocytic astrocytoma (LGG-PCA), and low-grade glial/glioneuronal tumour LGG-LGGNT), histologically not typical of PCA nor any defined entity that were negative for BRAFV600mutations, KIAA1549- BRAF (16-9, 15-9, &amp; 16-10) fusions, e. low-grade glial tumour with diffuse architecture (LGG-DLGG) that were negative for IDH1R132/IDH2R172-mutations. These were evaluated for NGS-based-panel (42 genes, 137 RNA fusions, and 24 genes for amplification – STS-plus-panel Sophia Genetics). RESULTS 41 cases (HGG: 12, cNET:2, LGG-PCA: 10 &amp; 1, LGG-LGGNT: 13 &amp; LGG-DLGG: 3) formed the study-cohort. a. HGG: 5 were &amp;lt;3 years (supratentorial [ST]: 3; posterior-3rd-ventricular [p3v]: 1 &amp; posterior-fossa [PF]: 1), 2 showed mutations in TP53-exons 5 &amp; 6 respectively, one ST case showed SND1-AKT2 (9:7) fusion. Of 6-18 years (all ST location), 3 showed TP53-mutations, one showed PDGFA &amp; KIT-amplification with SF3B1-mutation and one showed BRAFV600E-mutation. b. cNET: BRAFV600E and TP53-mutation was observed in each of the case respectively. c. LGG-PCA: one case showed FAM131B-BRAF (2:9) fusion. One KIAA1549- BRAF (15-9) fusion case was evaluated as it progressed, showed additional TP53-mutation. d. LGG-LGGNT: one (4/F; PF location) showed EGFR-gains with TERT-promoter (C228T) mutation (like adult-type glioma), one showed NF1-exon 12 mutation with KIAA1549-RAD51 (18:4) fusion, one showed CDKN2A-exon 2 mutation and one (midbrain) case showed BRAFV600E-mutation. e. LGG-DLGG: one (11/M, occipital-SOL) showed KEAP1-exon 5 mutation with KIAA1549- BRAF (15:9) fusion. CONCLUSIONS TP53-mutations is common in HGG, infantile HGG can show non-ALK/NTRK fusions. LGG can show non-BRAF/KIAA1549-fusions, rarely can show KEAP1 mutations and adult-type-like alterations. Target-panel NGS-based assay can help to molecularly decipher to a certain extent, especially for instituting targeted-therapies.
HGG-33. HIGH GRADE TRANSFORMATION OF CNS TUMOR WITH BCOR:CREBBP FUSION: A CASE REPORT
Authors: Abbey Rocco, Mary Beck, Michele McHugh, Ashley Lampe, Ashley Meyer, Andrea Ogle, Margaret Shatara, Andrew Cluster, Mohamed S Abdelbaki, Nicole M Brossier
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The discovery of unique EP300:BCOR and CREBBP:BCORL1 fusions has extended the spectrum of BCOR altered CNS tumors previously associated with BCOR internal tandem duplication (ITD). Due to the rarity of CNS tumors with BCOR alterations, there is limited information on the clinical outcomes and the effective treatment strategies. METHODS Literature review and retrospective chart analysis RESULTS An 18-year-old male who presented with seizures was found to have a left temporal mass. Histologic diagnosis was low grade glioneural tumor harboring a pathogenic CREBBP:BCOR1 fusion, matching to CNS tumor with EP300:BCOR/BCORL1 fusion by methylation. A re-resection aimed at gross total resection was then performed. Histologic examination revealed residual glioma with focal high-grade transformation, Ki67 up to 35% and CDKN2A loss via FISH analysis. The patient was treated with focal radiation to 54Gy. He remains disease- and seizure-free 1 month post radiation therapy. This case displayed some similarities to previously reported cases, including oligodendroglial- or ependymoma-like features, positivity for Olig2 and/or GFAP, presence of calcifications, and branching capillary networks. However, this case had less frequent mitoses than previously reported cases. In a series of 21 patients with BCOR altered tumors, BCOR-fusion tumor patients had a more favorable PFS compared to BCOR-ITD tumors. In a reported case series of high grade BCOR altered CNS tumors, 5 out of 8 patients remained alive, all of whom received radiation therapy as a primary treatment or at relapse. There is one prior report of an EP300:BCOR tumor undergoing high-grade transformation; increased mitoses, cellularity, and necrosis were observed. This case was lacked necrosis. CONCLUSIONS The optimal treatment for BCOR altered tumors of the CNS is largely unknown given the limited reported cases. Radiation therapy in addition to gross total resection may be an effective treatment leading to more favorable PFS and OS.
LMIC-15. OUTCOMES OF PEDIATRIC MEDULLOBLASTOMA IN LOW- AND MIDDLE-INCOME COUNTRIES: A REPORT OF 330 PATIENTS FROM 8 COUNTRIES
Authors: Rosdali Diaz-Coronado, Eddy Hernandez-Broncano, Tatiana Negreiros-Chinchihuara, Sandro Casavilca-Zambrano, Danny A Campos, Ronny E Baticulon, Ana Patricia A Alcasabas, Kathleen Khu, Ahmer Hamid, Nida Zia, Yumna Syed, Bisma Yousuf, Nuha Omran, Hend A Sharafeldin, Khaled Seddik, Shady Fadel, Estuardo Pineda, Ana Polanco, Jen Chun Foo, Revathi Rajagopal, Dharmendra Ganesan, Regina Navarro-Martin del Campo, Luis Arredondo-Navarro, Gabriela Escamilla, Rafael Ruvalcaba, Beatriz García, Paloma Amarillo, Cesar A Villegas, Godwin Job, Lane Faughnan, Meenakshi Devidas, Ibrahim Qaddoumi, Daniel C Moreira
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND AND AIMS Reports from low-and middle-income countries (LMICs) indicate lower survival in medulloblastoma (MB), though these studies are mainly from single institutions. This multi-institutional, retrospective study aimed to analyze the outcomes for MB in 9 centers in 8 LMICs. METHODS Patients &amp;lt;18 years old with newly diagnosed MB, treated from January 2014 to December 2018 in Egypt, El Salvador, Malaysia, Mexico, Pakistan, Peru, Philippines, and Uruguay were included. Data on demographics, clinical presentation, treatment and biological characteristics were collected. Factors associated with patient outcomes were analyzed. RESULTS The study included 330 patients with a median age of 7.7 years. Of these, 49 patients (15%) were &amp;lt;3 years old and 212 (64%) were male. Eighty-eight patients (26%) had experienced symptoms for &amp;gt;3 months at diagnosis. Gross total resection was achieved in 153 (47%) patients. Sixty-three patients (19%) experienced post-operative infections. Eighty-four patients (24%) had metastatic disease at diagnosis. The histologic subtype was not specified in 98 cases (30%), and 25 patients (7%) had molecular subgroups identified. Radiotherapy was administered to 216 patients (64%). The median number of chemotherapy cycles was 8 (range 0-14). There were 64 patients (19%) who abandoned treatment, and 24 patients (7%) died due to treatment-related toxicity. The 5-year event-free survival (EFS) was 44±4%, while the 5-year overall survival was 58±4%. The 5-year EFS for patients &amp;lt;3 years was 42±9%, while 44±4% for older patients (p=0.49). The 5-year EFS for patients with metastasis was 38±7%, while it was 46±4% for patients without metastasis (p=0.13). CONCLUSIONS This large, multinational cohort of MB in LMICs describes poor outcomes, which may be attributed to delays in care, high abandonment rate, surgical complications, treatment-related mortality and a low fraction of patients receiving radiotherapy. Interventions to build care capacity can be prioritized based on these data.
EPEN-26. DRUG SCREENING IN PATIENT-DERIVED MODELS OF POSTERIOR FOSSA A EPENDYMOMA REVEALS NOVEL PHARMACOLOGICAL VULNERABILITIES
Authors: Jon D Larson, Darren Finlay, Rabi Murad, Yan Yuen Lo, Ming Zhao, Antony Michealraj Kulandai Manuvel, Sachin A Kumar, Ian Pass, Charles Handley, Robert J Wechsler-Reya, Michael D Taylor, Kristiina Vuori, Lukas Chavez, Michael Jackson
Journal: Neuro-Oncology (2024)

Abstract Ependymoma (EPN) is the third most common malignant intracranial pediatric brain tumor. The most common and aggressive EPN subgroup, posterior fossa ependymoma group A (PFA-EPN), occurs predominantly in younger children and has a 5-year progression free survival of only 33%. Despite progress in the molecular characterization and subtyping of EPN, the standard treatment remains surgery with adjuvant radiation therapy. There is currently no approved role for chemotherapy in PFA-EPN. As such, identifying novel therapies for PFA-EPN is an important unmet medical need. To define therapeutic sensitivities for PFA-EPN, we performed a drug screen on three patient-derived PFA-EPN cell lines. We found that PFA-EPN cell lines were sensitive to several clinically relevant drugs, most notably those targeting epigenetic regulators. This is of a particular interest as a common molecular feature of PFA-EPN is the global reduction of the repressive post-translational histone modification H3K27me3 due to transcriptional EZHIP overexpression or H3 K27M mutations. To further characterize our PFA-EPN cell lines, we performed optical genome mapping analysis, revealing previously undescribed structural variants affecting genes encoding proteins responsible for signaling and transcription. One PFA-EPN sample that showed profound sensitivity to EGFR inhibitors, also had a duplication of a genomic region containing the EGFR ligand encoding genes, AREG, BTC, EREG, and EPGN. We are currently working to validate these results in larger cohorts of PFA-EPN models. Collectively, these findings provide new clues on drugs, signaling and putative therapeutic targets in these rare yet aggressive tumors.
CP-02. DAYTIME SLEEPINESS AND HEALTH-RELATED QUALITY OF LIFEIN PATIENTS WITH CHILDHOOD-ONSET CRANIOPHARYNGIOMA
Authors: Laura V Mann-Markutzyk, Julia Beckhaus, Jale Oezyurt, Carsten Friedrich, Hermann L Müller
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Adamantinomatous craniopharyngioma (CP) is a rare embryonal malformation originating from remnants of the craniopharyngeal duct and located in the sellar and/or parasellar area. Overall survival rates are high (92%), but frequently quality of life (QoL) is severely impaired in patients with CP involving hypothalamic structures. Tumor- and/or treatment-related hypothalamic lesions result in disturbances of circadian rhythms including increased daytime sleepiness. METHODS After a median follow-up interval of 10 years (range: 1-39 years), 119 patients (63 female/ 56 male) with CP, recruited in KRANIOPHARYNGEOM 2000/2007 and KRANIOPHARYNGEOM Registry 2019 between 2000 and 2022, were analysed for daytime sleepiness by Epworth scale (ES) and for QoL by EORTC QLQ-C30 questionnaire. RESULTS CP patients (n= 85) with pathologically increased ES score (ES score &amp;gt; 12) had worse QoL (p = 0.003), when compared with CP patients with normal ES score (n= 34). Pathologically increased daytime sleepiness (ES score) was negatively correlated with QoL (r= -0.395; p&amp;lt; 0.001). Surgical hypothalamic lesions (71% of patients) were associated with higher ES scores, whereas such impact could not be observed for presurgical hypothalamic involvement of CP (73% of patients). CONCLUSIONS As increased daytime sleepiness plays an important role for QoL in survivors of CP, treatment of disturbances of circadian rhythms with medication such as central stimulating agents is recommended. For prevention of increased daytime sleepiness, hypothalamus-sparing surgical treatment strategies should be considered as state of the art in patients with CP.
LMIC-18. RESOURCES FOR THE PRACTICE OF PEDIATRIC NEURO-ONCOLOGYIN MEXICO: A CROSS-SECTIONAL EVALUATION
Authors: Daniela Arce-Cabrera, Gabriela Escamilla-Asiain, Melisa Nájera-Castillo, Regina Navarro-Martín del Campo, Mariana Ortiz-Azpilcueta, Francisco Pantoja-Guillén, Farina Arreguín González, Imelda Zapata-Sosa, Jocelyn Lugo-Juárez, Daniel Santillán-Cortés, Andrés Morales- La Madrid, Daniel Moreira, Alma Benito-Reséndiz
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The evaluation of existing resources and services is key to identify gaps and prioritize interventions to expand care capacity for children with central nervous system (CNS) tumors. We sought to evaluate the resources for pediatrc neuro-oncology (PNO) in Mexico. METHODS A cross-sectional online survey with 35 items was designed to assess PNO resources and services. The survey was distributed to the members of the Mexican Association of Pediatric Oncology and Hematology (AMOHP). RESULTS Overall, responses from 33 institutions were obtained. Responding institutions covered 9 healths systems in Mexico, including private and public institutions. Most of the participating centers have at least 2 pediatric oncologists, so in up to 42% of cases, the approach to children with brain tumors is initiated by a pediatric oncologist. Only half of the responding centers have complete chemotherapy treatments. Only 18% of the centers had access to targeted therapy. The majority (88%) of institutions had a blood bank, but 4 of the participating centers did not have a PICU. All centers have a pathologist but only perform basic immunohistochemistry techniques and have an average diagnostic timeframe of 2 weeks. Surgical treatment is usually available 8 to 14 days after the patient is admitted in 45% of centers. Some centers have radiotherapy available at the facility, others must be sent to other hospitals, but most (42%) can start radiotherapy within the first week after treatment is requested. Infectious processes are a common cause of death in children with brain tumors and only the centers have a half-integrated palliative care team. CONCLUSIONS This is the first situational overview of the resources available in Mexico, showing disparities in resource capacity and lack of a specific and efficient diagnosis that allow early initiation of treatmen. These data will allow for the prioritization of interventions.
IMG-08. SYNTHESIZING MISSING MRI SEQUENCES IN PEDIATRIC BRAIN TUMORS USING GENERATIVE ADVERSARIAL NETWORKS; TOWARDS IMPROVED VOLUMETRIC TUMOR ASSESSMENT
Authors: Dimosthenis Chrysochoou, Ariana Familiar, Deep Gandhi, Phillip B Storm, Arastoo Vossough, Adam C Resnick, Christos Davatzikos, Ali Nabavizadeh, Anahita Fathi Kazerooni
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Standard MRI sequences, such as pre- and post-contrast T1w, T2w, and FLAIR images, are essential for optimizing segmentation of tumor subregions and evaluating treatment responses in pediatric brain tumors (PBTs). However, MRI sets are often incomplete due to imaging artifacts or inconsistent acquisition protocols across various centers. Generative Adversarial Networks (GANs) have been effectively utilized to generate missing MRI sequences for adult brain tumors. This study applies image-to-image translation models using GANs to synthesize missing FLAIR images from T2w images in PBTs. METHODS This retrospective study developed two GAN models, pix2pix in both 2D and 3D, trained and validated on T2w and FLAIR image pairs from 79 and 19 patients, respectively, with pediatric-type diffuse high-grade gliomas (diffuse midline glioma (DMG) including diffuse intrinsic pontine glioma (DIPG)), collected from the Children’s Brain Tumor Network (CBTN). The 2D pix2pix model processes each T2w MRI volume slice-by-slice, generating corresponding FLAIR slices to reconstruct the complete image volume. The 3D pix2pix model allows translation of 3D FLAIR volumes directly from T2w volumes without the need for individual slice processing and reconstruction. The quality of the generated FLAIR volumes was evaluated using Structural Similarity Index (SSI; best closer to 1) and Mean Squared Error (MSE; best near 0) on the validation set. RESULTS The 2D and 3D models achieved robust performance with median SSI, MSE of 0.88, 0.004, and 0.92, 0.002, respectively. CONCLUSIONS The GAN models developed in this study effectively generate missing FLAIR MRI volumes from corresponding T2w images in PBTs. The 3D model, outperforming 2D, speeds the overall processing pipeline by eliminating volume slicing and reconstruction. Future work includes assessing the impact of these synthesized images on the accuracy of our pretrained autosegmentation models in differentiating tumor subregions and measuring tumor volumes in longitudinal MRIs.
ETMR-15. RECLASSIFICATION OF CHILDHOOD CENTRAL NERVOUS SYSTEM PRIMITIVE NEUROECTODERMAL TUMOR: CLINICAL FEATURES AND OUTCOME
Authors: Marie Simbozel, Arnault Tauziède-Espariat, Raphaël Saffroy, Delphine Guillemot, Gaëlle Pierron, Lauren Hasty, Emmanuè le Lechapt, Fabrice Chrétien, Jacques Grill, Léa Guerrini-Rousseau, Samuel Abbou, Stéphanie Bolle, Franck Bourdeaut, Sandra Raimbault, Antoine Gourmel, Yves Réguerre, Claire Pluchart, Jill Serre, Cécile Faure-Conter, Thomas Blauwblomme, Kevin Beccaria, Stéphanie Puget, Pascale Varlet, Christelle Dufour
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The “central nervous system primitive neuroectodermal tumor” (CNS-PNET) nosology was removed from the World Health Organization (WHO) classification after DNA methylation profiling and new tumor entities characterized by specific recurrent genetic alterations were described. The aim of this study was to re-evaluate the diagnosis of CNS-PNET and to describe their clinical characteristics. METHODS Patients aged &amp;lt; 18 years with CNS-PNET or unclassified tumor, who were treated at Gustave Roussy between 1999 and 2019 or enrolled in the PNET HR trial were retrospectively identified. The study included all patients with sufficient archival material for diagnosis re-evaluation. RESULTS Sixty-two patients were eligible for the current analysis. The central histopathological review proposed a diagnosis according to the WHO classification in 58 cases. Out of these cases, 34 embryonal tumors were identified: 22 Embryonal Tumors with Multilayered Rosettes (ETMR), 4 CNS neuroblastomas with FOXR2 activation (CNS NB-FOXR2), 4 CNS high-grade neuroepithelial tumors with BCOR alteration (CNS HGNET-BCOR), 4 medulloblastomas. Another 24 tumors were classified as non embryonal tumors: 11 high-grade gliomas, 5 ependymomas, 4 pineoblastomas, 2 teratomas, one desmoplastic small round cell tumor, and one pilocytic astrocytoma. Four tumors without suspected diagnosis after first analysis remain unclassified after DNA methylation profiling. The 5-year event-free survival and overall survival for patients with ETMR were 14% (95% CI, 4.7-39%) and 27% (95% CI, 14-54%) respectively. For patients with CNS HGNET-BCOR and CNS NB-FOXR2 the median time to relapse was respectively 11 months (range, 0.5 to 1.3 year) and 3.1 years (range 1.7 to 4.4 years). CONCLUSIONS This study confirmed that the former nosology of CNS PNET does not correspond to a homogenous class but encompasses a diversity of rare histomolecular entities with specific clinical characteristics and outcomes.
ATRT-08. ATYPICAL TERATOID RHABDOID TUMOR IN AN ADULT PATIENT WITH DOWN SYNDROME
Authors: Dallin Judd, Kaith K Almefty, Tamara Z Vern-Gross, Lindsey M Hoffman, Nishant Tiwari, Jennifer A Vaughn, Ross Mangum
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Atypical teratoid/rhabdoid tumor (ATRT) is a malignant, highly aggressive embryonal tumor of the central nervous system. Long-term survival remains dismal despite aggressive multimodal therapy, including a maximal safe surgical resection and intensive systemic chemotherapy +/- radiation therapy. While these tumors typically present in infancy or early childhood, there are scattered case reports of adult-onset ATRT. Making prognostic conclusions or therapeutic decisions for this older patient population remains challenging due to the paucity of these reports. CASE REPORT A 25-year-old female with Down syndrome presented with nausea, vomiting, dysphagia, and facial droop and was found to have an avidly enhancing, left cerebellopontine angle mass. There was initial clinical suspicion for leukemic chloroma given the patient’s Down syndrome status and known association with higher rates of hematologic malignancy concurrent with a dramatic scarcity of solid tumors in the Down syndrome population. However, histology demonstrated sheets of high-grade rhabdoid cells with loss of INI1 expression, pathognomonic for ATRT. Further sequencing defined a frameshift mutation in SMARCB1 (p.C298), and methylation profiling matched with high confidence to the MYC subclass of ATRT. The patient was treated with subtotal surgical resection and focal proton radiation, followed by chemotherapy on a modified regimen based on the Children’s Oncology Group protocol, ACNS0333. Systemic methotrexate and all consolidative high-dose chemotherapy with stem cell rescue were omitted due to concern for heightened risk of treatment-related toxicity. The patient remains alive and clinically asymptomatic 19 months from diagnosis. CONCLUSION This report represents the first known case of ATRT in an adult patient with Down syndrome, offering unique mechanistic insight into the tumorigenesis of ATRT. Adult ATRT is a rare entity without standardized treatment or established prognostic understanding. Further studies are needed to define an appropriate risk-adapted therapeutic approach for this patient population.
METB-02. GENETIC COUNSELLING IN SOTOS AND NS1-RELATED OVERGROWTH SYNDROMES PREDISPOSING TO BRAIN TUMORS
Authors: Nouha Bouayed Abdelmoula, Balkiss Abdelmoula
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Sotos and many other overgrowth syndromes are among the rare tumor predisposition syndromes that might be under-recognized in pediatric neuro-oncology practice. NSD1 gene (5q35), belonging to the histone lysine methyltransferases family, is involved in the majority of Sotos patients who exhibited haploinsufficiency and loss-of-function variants of the gene, but also in other overgrowth entities such as Beckwith-Wiedemann syndrome. Somatic mutations in this gene are likewise responsible of numerous cancers, particularly brain tumors. Here, we aim to assess the neurologic cancer risks and provide genetic counseling for appropriate clinical follow-up in Sotos syndrome. METHODS From our genetic counseling database at the medical University of Sfax (Tunisia), we selected among patients presented for genetic management of overgrowth syndromes, those with Sotos syndrome. RESULTS Only two Tunisian consanguineous pedigrees were enrolled in this study. Two boys were diagnosed with typical Sotos syndrome based on the three major clinical manifestations: specific facial dysmorphism, mental retardation and excessive growth including advanced bone age and macrocephaly. Chromosomes 5 in both pedigrees did not show structural abnormalities. During genetic counselling, parents were informed about the molecular testing options and the advantage of the exome sequencing. Furthermore, they were informed about the rate of cancer predisposition (3%) and the gains of neurologic and neuro-oncologic management, particularly regarding the intellectual disability and the increased risk of developing neural crest tumors, astrocytoma, glioma/glioblastoma and neuroblastoma cancer, during childhood. CONCLUSIONS Neurological pediatric malignancies are described in patients with Sotos syndrome, but the genotype-phenotype correlation is still unclear. It is suggested that NDS1 disruptions in Sotos patients trigger specific patterns of DNA methylation alterations leading to the development of cancer. Accurate molecular exploration is needed in the heterogeneous Sotos condition in order to improve the management according to the implicated gene and to benefit in the future from targeted therapies.