tbuckley/cabot-search huggingface dataset:
MDB-58. REDUCED CRANIOSPINAL DOSE FOR NEWLY DIAGNOSED HIGH-RISK MEDULLOBLASTOMA IN CHILDREN YOUNGER THAN 5 YEARS OLD: RETROSPECTIVE EXPERIENCE FROM SFCE
Authors: Jihann Oozeerally, Christelle Dufour, Cécile Faure, Aude Cardine, Emilie De Carli, Marie-Sophie Merlin, Leslie Andry, Nicolas André, Céline Icher, Sébastien Klein, Anne Pagnier, Chloé Puiseux, Claire Briandet, Gwenaelle Duhil De Benaze, Stéphanie Bolle, Laetitia Padovani, Clara Flumian, Anne-Isabelle Bertozzi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND High Risk medulloblastoma (MB) treatment strategy is based on an intensive multimodal treatment including surgery, chemotherapy and radiotherapy. French adapted PNET HR +5 is based on high-dose chemotherapy and age-stratified (18 Gy &amp;lt; 3 yo, 23 for 3-5 yo, 36 Gy for &amp;gt; 5 yo) craniospinal dose irradiation to reduce long-term side-effects of radiotherapy. METHODS To estimate progression-free (PFS) in a national multi-institutional retrospective study, we enrolled children younger than 5 yo with newly diagnosed high-risk MB treated according to adapted PNET HR +5 trial. RESULTS Thirty-seven children from 15 French hospitals (median age, 3.4 yo; range, 0.7-4.8) with confirmed high-risk MB were included. 15 patients (39%) were less than 3 years old. 29 patients (81%) had metastatic disease. Group 3 was the most represented molecular subgroup. 5-year PFS and OS was 59 % and 77 %, respectively. According to dose of craniospinal irradiation, PFS for 18 Gy, 23.4 Gy and 36 Gy patient groups were 100 %, 75 % and 45%, respectively. Treatment was well tolerated. One toxic death was declared. Analysis of longitudinal neurocognitive performance is ongoing. CONCLUSIONS the French strategy comprising high-dose chemotherapy and age-adapted craniospinal irradiation is promising with a high rate of survival in young children and must be confirmed by a prospective trial.
MDB-59. INTEGRATIVE PROTEO-GENOMICS TO DECIPHER MOLECULAR MECHANISMS UNDERLYING SUBGROUP-SPECIFIC HETEROGENEITY IN MEDULLOBLASTOMA
Authors: Yiran Li, Brian L Gudenas, Kyle S Smith, Hong Lin, Kelsey C North, Taha Soliman, Jennifer Hadley, Melissa Batts, Sandeep K Dhanda, Natasha Atkinson, Kimberly S Mercer, Anthony High, Zuo-Fei Yuan, Xusheng Wang, Junmin Peng, Martine F Roussel, Giles W Robinson, Brent A Orr, Paul A Northcott
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma (MB), an aggressive pediatric brain cancer, poses significant treatment challenges due to its complex disease biology, comprising a collection of discrete molecular subtypes that require different treatment. Although the genomics, transcriptomics, and epigenetic landscapes of biologically distinct MB subgroups are well-annotated and have contributed to enhanced diagnostics and risk stratification, the intersection of these molecular layers with the MB proteome remains poorly defined METHODS To overcome this knowledge gap, we sought to create a deep proteomics and phospho-proteomics cohort from a large MB clinical trial cohort (SJMB12), comprising 166 primary patient tumors, complemented with matched DNA methylation, whole-exome sequencing (WES), and RNA sequencing (RNA-seq) datasets. Proteomics data were interrogated using unsupervised computational techniques and evaluated for pathway enrichment and kinase activity. To complement these bulk tumor datasets, we investigated the tumor microenvironment focusing on immune and glial cell populations, using single-nuclei RNA and ATAC sequencing (snRNA-seq and snATAC-seq) for validation RESULTS Distinct proteomics subgroups were identified, correlating with established MB clinical subgroups and unveiling previously unrecognized proteomics subgroups. The integration of proteomics with mutational data revealed downstream effects of genetic alterations not evident in the transcriptome, implicating novel molecular mechanisms contributing to disease pathogenesis. Protein-protein interaction networks discovered novel signaling hubs and pathways, highlighting the power of proteomics to detect subgroup-specific drivers of disease that may represent attractive therapeutic vulnerabilities CONCLUSIONS Our multi-omics approach applied to a large series of primary MB patient tumors revealed novel mechanisms underlying MB subgroup biology that were previously hidden at the genetic, epigenetic, and transcriptional level. These findings offer a comprehensive, systems biology view of MB pathogenesis, fostering provocative insights that serve as a foundation for future discovery and the development of more effective personalized treatment strategies.
LGG-19. SLIPPED CAPITAL FEMORAL EPIPHYSIS (SCFE): A RARE ADVERSE EVENT ASSOCIATED WITH FGFR TYROSINE KINASE INHIBITOR THERAPY IN A CHILD
Authors: Meziane Brizini, Tina Drimes, Catherine Bourne, Jessica Streilein, Annie Drapeau, Jens Wrogemann, Lori Anne Archer, Marc Del Bigio, Magimairajan Issai Vanan
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND FGFR tyrosine kinase inhibitors (FGFR-TKIs) are being increasingly used off-label in children with hard-to-treat tumors harboring specific FGFR alterations. We report a case of Slipped Capital Femoral Epiphysis (SCFE), an on target skeletal toxicity of a pan-FGFR TKI inhibitor, erdafitinib. METHODS Data was extracted from chart review of the patient and literature search for the use of FGFR-TKIs in children and their side effects. RESULTS A 13-year-old boy was diagnosed to have a optic pathway/ hypothalamic glioma with signs of increased intracranial pressure and obstructive hydrocephalus requiring placement of ventriculo-peritoneal (VP) shunt. Sequencing of the tumor showed FGFR1-Tyrosine kinase domain internal tandem duplication (FGFR1-KD-ITD) and was negative for BRAF mutation/ fusion. Two weeks later, he was treated for a VP shunt infection (surgical revision and 6 weeks antibiotics). He developed hypothalamic obesity with rapid weight gain and BMI &amp;gt;30. After a four-month delay from the initial diagnosis, he was started on erdafitinib a pan-FGFR1-4 inhibitor, through a special access program. At 12 weeks of treatment, he developed persistent knee pain. X-ray of the hips showed slipped capital femoral epiphysis (SCFE) of the right hip. Erdafitinib was discontinued and he underwent surgery with in-situ pinning of the right hip and prophylactic pinning of the left hip. MRI at the time of stopping the medication showed a 30% decrease in the size of the tumor, which has remained stable at 6 months follow up. CONCLUSIONS Based on our experience and literature review of pediatric patients who are treated with pan-FGFR TKIs, we recommend: a) monitoring both rate of weight gain/ BMI for obesity and growth velocity while on therapy and b) update the drug toxicity profile of FGFR TKIs to include skeletal toxicities and inform parents/ patients of these toxicities at the time of consent for therapy.
OTHR-01. ALK-DRIVEN INFANT-TYPE HEMISPHERIC HIGH-GRADE GLIOMA AND CNS HISTIOCYTOSIS SUCCESSFULLY TREATED WITH A SECOND GENERATION ALK-INHIBITOR: MOLECULAR CHARACTERIZATION SAVES THE DAY
Authors: Omar Chamdine, Rasees Alotaibi, Qasim Alharbi, Hiba Altarrah, Lulwah Abduljabbar, Asrar Alzaher, Mahmoud Taha, Sultan Alsaiari, Wissam Alisawi, Jalilah AlSadeq, Marwah Abdulkader, Fatima Alhaddad
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Molecular characterization of brain tumors (BT) is increasingly becoming essential for diagnosing and managing central nervous system (CNS) tumors. Infant BT is a particular category of pediatric CNS tumors that poses a challenge to the neuro-oncologist. METHODS Here, we present two distinctive cases where molecular characterization significantly influenced diagnosis, management, and outcome. RESULTS The first case is a 2-year-old boy presented with generalized seizures. MRI of the brain showed multiple dural-based tumors. Biopsy was consistent with ALK-positive histiocytosis (KIF5B-ALK fusion). Additional lesions were detected in the right kidney and left femoral head. Despite three months of LCH-based therapy, the tumor progressed. Chemotherapy was halted, and treatment with alectinib was initiated. Follow-up MRIs after 3 and 6 months showed marked regression and a complete resolution of the lesions, respectively. The second case is a 12-month-old boy who exhibited developmental regression and increased head circumference over the past three months. MRI revealed a large complex right ventricle mass measuring 8.6x7.2x8 cm. Subtotal resection was complicated by severe intracranial bleeding, requiring prolonged intensive care stay. The initial pathological diagnosis was anaplastic ependymoma. He received two cycles of neoadjuvant chemotherapy followed by a second look surgery, which failed to achieve a gross total resection. Molecular testing by this time identified an ALK-CCDC85A fusion, altering the diagnosis to infant-type hemispheric glioma. He was started on alectinib. MRI after 3 and 6 months showed a favorable response with an overall improvement in his cognitive function. Both patients tolerated alectinib well, remaining on therapy for 6 and 12 months, respectively. No toxicities were reported. CONCLUSION These cases illustrate the transformative role of molecular characterization in managing infants with CNS tumors, highlighting its potential as a game-changer in pediatric neuro-oncology.
MDB-56. CLINICAL OUTCOME AND SURVIVAL OF INFANT MEDULLOBLASTOMA PATIENTS: THE BAMBINO GESÙ CHILDREN’S HOSPITAL EXPERIENCE
Authors: Giada Del Baldo, Valentina Di Ruscio, Annalisa Lo Sasso, Giacomina Megaro, Antonella Cacchione, Iside Alessi, Andrea De Salvo, Giulia Albino, Selene Cipri, Emanuele Agolini, Evelina Miele, Sabrina Rossi, Isabella Giovannoni, Giovanna Stefania Colafati, Sabina Vennarini, Maria Vinci, Andrea Carai, Angela Mastronuzzi
Journal: Neuro-Oncology (2024)

Abstract Young children diagnosed with medulloblastoma (MB) pose a significant challenge due to the high susceptibility of the developing brain to neurotoxic agents such as craniospinal irradiation (CSI). Different innovative strategies were developed with the aim to enhance outcomes while either delaying or avoiding CSI. We describe a case series of patients affected by infant MB treated according to the Italian Infants High Risk recommendation. Retrospective data from 42 children with MB younger than 5 years of age at diagnosis treated between 2007 and 2023 at Bambino Gesù Children Hospital were recorded. Demographic, clinical, surgical, radiological, molecular, and histopathological data were collected. Overall survival (OS) and event-free survival (EFS) were calculated using the Kaplan-Meier method. Seventeen patients were excluded for first-line radiotherapy. Conclusively, 25 patients (13 male, 12 female) with a median age of 25.3 months at diagnosis were eligible for the analysis. Eleven patients had metastatic disease at diagnosis. Histotype: 13/25 classic, 6/25 desmoplastic nodular (DNMB), 4/25 extensive nodularity (MBEN) and 2/25 large cell/anaplastic. DNA methylation profile: SHH-subgroup: 12/25, group 3: 8/25 and group 4: 5/25. MYC amplification was detected in 3 cases. In five cases a cancer predisposition syndrome was found. The median duration of follow-up was 48 months. EFS at 12, 24 and 60 months was 80% (95%CI: 58.4-91.1), 72% (95%CI: 50.1-85.5), and 68% (95%CI: 46.1-82.5), respectively. OS at 12, 24 and 60 months was 80% (95%CI: 67.3-96), 80% (95%CI: 58.4-91.1) and 68% (95%CI: 46.1-82.5) respectively. Significant better survival was found for MBEN/DNMB histotype, with no significant difference between molecular subgroups. We reported high EFS and OS in a population of infant MB treated according Italian Infants High Risk recommendation. Our patients presented an average intelligence quotient in the normal range at a median follow-up of 4 years from diagnosis and no long-term toxicity after treatment.
EPID-06. PEDIATRIC BRAIN TUMOUR DIAGNOSTIC DELAY DURING COVID-19 PANDEMIC IN A REGIONAL NEURONCOLOGY CENTRE
Authors: Martina Pozzi Mucelli, Maristella Toniutti, Sara Pedicini, Ilaria Liguoro, Serena D’Agostini, Maria Cristina De Colle, Francesco Tuniz, Marco Vindigni, Enrico Pegolo, Elisa Coassin, Maurizio Mascarin, Paola Elisa Cogo, Chiara Pilotto
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The Pediatric Central Nervous System (CNS) tumors incidence has increased in the last decades. A diagnostic delay could be related to adverse effects involving neurosurgical approach. Moreover, many studies report that Coronavirus-19 pandemic has even increased the diagnostic delay of solid tumors, in particular CNS types. METHODS We conducted a retrospective study including all pediatric patients who received a diagnosis of CNS tumor at Udine Hospital between January 2020 and December 2021. Our first aim was to assess if there has been a variation in the incidence rate and a possible diagnostic delay of CNS pediatric tumors during 2020-2021. As a secondary objective we evaluated if the Coronavirus-19 pandemic has affected our ability to identify tumor relapses caused by delays in planning follow-up exams and imaging. Data of every patient were recorded and compared with data from a historical cohort recruited between 2000 and 2011. RESULTS 25 patients were enrolled in the study: 19 (11 males) were diagnosed with a primitive CNS tumor, 7 (3 males) with a secondary lesion. Incidence rate during 2020-2021 was 5.17 per 100.000 inhabitants (age 0-18 years) and median diagnostic interval was 6.7 weeks, both higher than in the historical cohort (but not statistically significant). Median age was 10 +/- 4,7 age (IQR 25°-75°5,9-13,7). No substantial variation of clinical presentation was detected, although some symptoms were found to be more frequent than in the past. A significant rise in the number of high histological grade tumors was recorded (63% vs 12%, p value &amp;lt; 0.001), but there was no difference in tumor relapses diagnostic delay (median 6,7 weeks compared with 5 weeks in historical cohort). CONCLUSIONS Coronavirus-19 pandemic had no impact in diagnostic delay, planning and execution of follow-up exams in children with CNS tumors.
EPID-04. CAUSES AND LONG-TERM COURSE OF OTOTOXICITY IN PEDIATRIC MEDULLOBLASTOMA AND EPENDYMOMA PATIENTS – CUMULATIVE PLATINUM AND COCHLEAR IRRADIATION DOSE MATTER
Authors: Elif Öz, Annika Hardt, Rolf-Dieter Kortmann, Rudolf Schwarz, Beate Timmermann, Brigitte Bison, Monika Warmuth-Metz, Katja von Hoff, André O von Bueren, Nicolas U Gerber, Gudrun Fleischhack, Torsten Pietsch, Stefan M Pfister, Dominik Sturm, Martin Mynarek, Stefan Rutkowski, Denise Obrecht-Sturm
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Ototoxicity is a well-known side effect of treatment with platinum-containing chemotherapy and radiotherapy (RT). Nevertheless, precise dose-effect relationships are still lacking. METHODS Patients from the HIT2000 trial receiving first-line treatment for medulloblastoma (MB) or ependymoma (EPN) who were alive at last follow-up and had at least one audiogram prior to and after administration of chemotherapy with cisplatinum and radiotherapy were included into this study. Treatment details (incl. cochlear irradiation dose [CID]) and audiological outcome were analyzed. The ototoxicity was graded using the HIT scoring. RESULTS Courses of 101 patients were analyzed. Median audiology follow-up was 6 years [range: 1.0–18.1 years]. Ototoxicity grade ≥1 was documented for n=66 patients (65.4%). For n=27 this resulted in treatment modification. Univariable analyses revealed different proportions of ototoxicity (grade ≥1) regarding histology (CMB: 50/65, LCAMB: 3/3, DMB/MBEN: 8/12, EPN: 5/21; p&amp;lt;0.001), tumor location (supratentorial: 3/9, infratentorial: 63/92; p&amp;lt;0.001), metastatic status at diagnosis (M0: 46/77, M+: 20/24; p=0.003), radiation field (CSI: 59/75, local RT: 6/21, no RT: 1/5; p&amp;lt;0.001), CID (continuous variable, p=0.001) and cumulative cisplatinum dose (continuous variable, p&amp;lt;0.001). Certainly, disease specific parameters (histology/staging) were related to treatment intensity (cisplatinum/irradiation dose). Multivariable analyses confirmed the impact of cumulative cisplatinum dose (p=0.01) and CID (p=0.04). ROC-analyses allowed the definition of cut-offs for high risk of ototoxicity grade ≥1 (cisplatinum: 70mg/m2 BSA, CID: 37.5 Gy) and ototoxicity risk estimation, when applying doses above the respective cut-offs (cisplatinum dose increase by 1mg/m2 BSA results in 4% higher risk for ototoxicity grade ≥1; CID dose increase by 1 Gy results in 4.6% higher risk for ototoxicity grade ≥1). CONCLUSIONS Ototoxicity affects a majority of children receiving adjuvant treatment for MB and EPN. To avoid disabilities and negative effect on quality of live, dosage of cisplatinum and radiotherapy should be scrutinized and reduced whenever possible.
NURS-20. A PATIENT AND FAMILY EDUCATION PROJECT: COMPREHENSIVE RESOURCE FOR MEK INHIBITOR-INDUCED PARONYCHIA
Authors: Jacqueline O’Connell Apelquist, Kasey L Burnside, Sarah Day, Vless Trinidad, Kasey Rangan, Kaaren Waters, Lara G Smith
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Targeted therapies for pediatric tumors of the central nervous system have recently brought promising results as well as new challenges in the clinical management of these patients. FDA approval of MEK inhibitors has prompted a significant increase in use of these agents in pediatric neuro-oncology patients. MEK inhibitors are commonly used for treatment of pediatric low and high-grade gliomas, as well being a proven treatment for plexiform neurofibromas. Cutaneous reactions to targeted therapy occur frequently, with paronychia arising in more than half the patients. METHODS Despite providing a robust MEK inhibitor skin care in-service at the start of treatment, the multidisciplinary neuro-oncology team identified a need for specific paronychia education for patients undergoing therapy with MEK inhibitors. The education content was developed following a thorough literature review of MEK inhibitors and associated side effects. Evidence-based information was selected to create a clear, concise, one-page educational resource. RESULTS The educational flyer addressed five key educational objectives including defining and reviewing paronychia as an expected side effect of MEK inhibitor therapy, discussing strategies for prevention and management of paronychia, and identifying when to contact a healthcare provider for paronychia support. Content included written and pictorial definitions to aid in recognition of paronychia, bulleted list and visual guide for preventive nail maintenance, recommendations and instructions for over-the-counter management strategies, review of therapies that may be prescribed, and specific guidelines on when to seek prompt medical attention. This flyer served as a valuable educational tool, equipping individuals undergoing MEK inhibitor therapy with knowledge about paronychia, prevention, and effective management. CONCLUSION MEK inhibitor-induced paronychia is an undesirable side effect that can impact adherence to treatment. By empowering patients and families with this educational resource, healthcare providers may enhance patient engagement, promote adherence to treatment, and optimize quality of life.
MDB-51. PHASE II INTERVENTIONAL STUDY TO EVALUATE THE SAFETY AND EFFICACY OF STANDARD AND HIGH-DOSE CHEMOTHERAPY COMBINED WITH CRANIOSPINAL IRRADIATION WITH PROTON THERAPY IN PATIENTS WITH METASTATIC MEDULLOBLASTOMA AND OTHER EMBRYONIC CANCERS: PRELIMINARY RESULTS
Authors: Milena Guidi, Carla Fonte, Marco Tellini, Marialuigia Censullo, Barbara Castelli, Carlotta Gemma Gori, Laura Giunti, Marco Di Nicola, Anna Maria Buccoliero, Chiara Caporalini, Flavio Giordano, Barbara Rombi, Isacco Desideri, Alessandra Pugi, Katia Tortora, Daniela Greto, Lorenzo Genitori, Maria Carmela Leo, Iacopo Sardi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The high risk medulloblastoma remains a leading cause of cancer-related death in children. METHODS A total of 18 patients have been enrolled from February 2018 to May 2022.The median age was 7,5 years (range; 12 males and 6 female). The protocol predicted the first phase of induction with 4 cycles of chemotherapy. After induction patients with favorable histology without evidence of disease were enrolled to proton therapy (with concomitant vinorelbine biweekly). The maintenance phase with Lomustine repeated every 9 weeks and vinorelbine every 3 weeks for overall 12-18 months (PR). Conversely LC/A MB, were subjected to consolidation phase with high dose of chemotherapy with tiothepa followed by autologous HSC transplant and successive maintenance phase of 6 months. RESULTS At October 2023, the median follow up was 24 months. After the induction phase 14 patients showed CR, 2 PR, 1PD, 1SD. At subsequent re-evaluations two with PR, showed disease control, one CR and the other SD and the patient with PD showed CR. Patient with SD showed an unchanged state of the disease. During the reporting period two patient died for progression of the underlying disease. At 24 months from the start of treatment the PFS was 75,4 % (95% CI: 34.1% - 87.6%) and at 15 months the OS was 86,1% (95% CI: 68.1% - 99.2%). The principal expected side effects of chemotherapy were hematology toxicity and 58% rate of GH deficiency. Among the unexpected side effect was CMV retinopathy with complete blindness and leukoencephalopathy after high dose of thiotepa and proton irradiation. We reported only one case of ototoxicity. CONCLUSIONS The use of proton therapy combined with intensive chemotherapy and myeloablative chemotherapy only in selected cases and always before irradiation has proven feasible and effective in the treatment of high-risk patients medulloblastomas and other embryonic tumors.
MDB-50. CAR-T CELL-DERIVED EXOSOMES LOADED WITH THERAPEUTIC SIRNA IS A PROMISING TECHNIQUE IN THE TREATMENT OF SUBGROUP 3 MEDULLOBLASTOMA
Authors: Murad Alahdal, Ranjan J Perera
Journal: Neuro-Oncology (2024)

Abstract Medulloblastoma (MB) is a childhood life-threatening tumor that occurs in the cerebellum. This tumor showed resistance against several types of immunotherapies like anti-PD1, cancer vaccines, monoclonal antibodies (mAbs), and even CAR-T cells. Subgroup 3 MB is the worst threatening subtype that poorly responds to treatment. Interestingly, our data showed that the HLX gene a transcription factor that regulates cell growth is highly expressed in G3-MB and associated with poor prognosis. The siRNA-HLX inhibited tumor growth in vitro and in vivo and promisingly showed long survival in the immunocompetent mouse model. We developed CAR-T-Exosomes that can pass brain-blood barriers (BBB) and deliver therapeutic siRNA to the brain tumor. Further analysis revealed that CAR-T-Exosomes contain T cell cytotoxicity materials that can destroy tumor cells and induce anti-tumor immune response. Promisingly, the expression of HLX was significantly inhibited in the tumor cells and the anti-tumor immune response was enhanced. CAR-T-Exosomes have high safety and can induce anti-tumor response without stimulation of immunotoxicity side effects like cytokine release syndrome (CRS). In this study, we are highlighting anti-EPHA2-CAR-Exosomes as a highly specific type of tumor CAR-T-Exos immunotherapy due to a very low expression of EPHA2 in normal cells and overexpression in medulloblastoma, particularly G3-MB. Therefore, we speculate significant inhibition of tumor growth and activation of CTL effector cells in the tumor microenvironment. This study provides a new biological technique for delivering tumor suppressor RNAs and developing specific anti-tumor immune responses. Indeed, the promising safety of anti-EPHA2-CAR-T cell exosomes compared to cell-based immunotherapy.