tbuckley/cabot-search huggingface dataset:
MDB-62. SUBGROUP AND SUBTYPE-SPECIFIC OUTCOMES IN METASTATIC INFANT MEDULLOBLASTOMA
Authors: Akanksha Senapati, Holly Lindsay, Stephen Gilheeney, Tejus Bale, Michael Taylor, Dong-Anh Khuong-Quang, Eric Bouffet, Sara Khan, Marie-Lise van Veelan, Johan M Kros, Alexandre Vasiljevic, Ian Pollack, Lola Chambless, Nalin Gupta, William A Weiss, Nada Jabado, Jaroslav Sterba, Michal Zapotocky, Jordan R Hansford, Vijay Ramaswamy
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Metastatic infant medulloblastoma (MB) is a major challenge given the devastating long-term effects of craniospinal irradiation to the developing brain. However large cohorts of metastatic infant medulloblastoma have not been analysed to date. METHODS A multicentre molecularly informed international cohort of children &amp;lt;6 years old with metastatic medulloblastoma was assembled and analysed. RESULTS Eighty-four patients with a median age of 2.95 (0.66-6.58) years were identified. 48.8% were Group3-MB, 23.8% Group4-MB and 27.4% SHH-MB. 78% of Group3-MB were subtype II (40.4%) and IV (38.1%), 50% of Group 4 were subtype VII, and within SHH, SHHß and SHHγ were 52.2% and 43.5% respectively. 28.5% of all Group3-MB harboured MYC amplification. A multivariable analysis incorporating subgroup, MYC amplification and upfront craniospinal irradiation revealed that survival was superior for SHH patients compared to Group 3 irrespective of MYC status (Group3-veMYCamp: HR 3.05 95%-CI 1.05-8.87 p=0.04, Group3+veMYCamp HR 7.87 95%-CI 2.49-24.87 p=0.00044). Group 4 had a trend to a poor outcome (HR 2.63 95%-CI 0.82-8.39 p=0.1). SHH subjects had a superior outcome with 5-year PFS of 0.657 (95%-CI 0.47-0.92), without a significant difference between SHHß and SHHγ. High-dose chemotherapy regimens portended to a superior outcome for both subtypes of SHH-MB. 5-year PFS for non-radiated SHH-MB was 61% (95%-CI 40.8-91.4), compared to non-radiated Group3-MB (18.5%; 95%-CI 5.4-62.8) and Group4-MB (20%; 95%-CI 3.4-100). SHH-MB patients had more local than metastatic relapses compared to non-SHH-MB (p=0.01). CONCLUSIONS In the largest study dedicated to metastatic infant medulloblastoma assembled to date, outcomes for infants with Group 3- and 4-MB with metastatic disease treated with radiation sparing approaches is dismal despite intensified regimens. MYC amplification portends to a near uniformly fatal prognosis with current treatment irrespective of upfront radiotherapy. Novel radiation sparing approaches are urgently needed for this group. Infants with both metastatic SHHß and SHHγ benefit from intensified therapy.
NURS-23. THE ROLE OF THE ADVANCED PRACTICE PROVIDER IN THE PAIRED NORMAL SPECIMEN PROCESS AT A TERTIARY CARE CENTER
Authors: Molly S Hemenway, Shelby Winzent-Oonk
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Paired tumor - normal specimen testing is standard of care to improve the timing and knowledge of genetic variations present in the brain tumor cell and germline. A new process was developed to ensure the paired normal specimen (PNS) testing was completed. METHODS The Neuro-Oncology Advanced Practice Provider (APP) is integral in the process of ordering and obtaining the PNS. RESULTS In the last 15 months, this tertiary care center has performed more than 90 pediatric brain tumor biopsies and/or resections. APPs identify patient surgery dates via the neurosurgery calendar. On the day of surgery a PNS is ordered for the Solid Tumor panel (predetermined by pathology and neuro-oncology) and “Include germline variant resolution information if applicable?” is answered as “No”. The laboratory runs the next generation sequencing (NGS) on PNS and tumor but the findings remain blinded until a second order is placed to “unblind” the specimen. By doing so, the treating physician collaborates with a genetics counselor prior to discussing with the family. Initial difficulty included patient identification, ordering, and collecting PNS. The APPs developed a shared list with patient identifiers, surgery date, order and collection date of PNS which has ensured less than 5% of PNS have been missed. Challenges include weekend surgeries, APPs out of office, and communication to nursing to collect PNS. Updated protocol includes ordering PNS, messaging shift nurse with order explanation and request to collect. Additionally, the pathology team now messages the APPs if a PNS is not submitted and the tumor is undergoing NGS. CONCLUSIONS Comprehensive processes ensure that paired normal – tumor testing is completed in a timely manner and during the same admission with surgery to ensure better insurance coverage and less cost to families, as well as earlier results of somatic and germline variants.
NURS-13. NEUROCOGNITIVE SIDE EFFECTS OF PEDIATRIC BRAIN TUMORS: A CONTINUING CHALLENGE
Authors: Kasey Rangan, Courtney Baker Briamonte, Micah Higgins, Carly Hoffman, Susan Holtzclaw, Michele McHugh, Ashley Meyer, Shannon Raber, Cindy Schmus, Kenny Seidl, Marylynne Strachan, Kaaren Waters, Lanipua Yeh-Nayre
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric brain tumors pose a considerable challenge in clinical oncology, necessitating multimodal treatment approaches. Many of these have the potential to impact cognition on vulnerable, young brains. While advancements in therapies have improved survival rates, neurocognitive outcomes continue to be one of the most challenging late effects that affect quality of life for pediatric brain tumor survivors. METHODS We conducted a literature review to identify 1) current treatment approaches for pediatric brain tumors, 2) the neurocognitive effects that survivors of pediatric brain tumors experience, and 3) appropriate interventions that can be implemented to mitigate those neurocognitive effects. RESULTS Novel chemotherapeutic agents, such as molecularly targeted therapies, are increasingly implemented in a personalized approach to treatment. New approaches to radiation therapy, particularly proton therapy, have shown promise in minimizing cognitive decline compared to traditional photon therapy. Advances in neuroimaging techniques have enabled a more detailed understanding of structural and functional brain changes associated with treatment. While these newer treatment modalities are promising, their long-term side effects are mostly unknown and bear close monitoring over time. Because neurocognitive side effects continue to underscore the impact of pediatric brain tumor treatments, recent studies often specifically evaluate the cognitive side effects as well as attempt to personalize treatments to reduce cognitive damage. CONCLUSIONS Recent research findings reinforce the enduring concern of neurocognitive side effects in pediatric brain tumor survivors. The integration of advanced therapeutic modalities and targeted supportive care interventions may hold the key to optimizing treatment outcomes while minimizing cognitive morbidity. Continued research efforts are essential for refining treatment protocols and developing personalized strategies to safeguard neurocognitive function in this vulnerable population. Additionally, studies exploring the role of supportive care interventions, such as cognitive rehabilitation and neuroprotective strategies, demonstrate potential avenues for mitigating cognitive sequelae but require ongoing research.
EPID-07. INCIDENCE OF PAEDIATRIC BRAIN TUMORS IN AN ITALIAN REGIONAL COHORT: AN EPIDEMIOLOGICAL STUDY FROM 2012 TO 2023
Authors: Maristella Toniutti, Chiara Pilotto, Sara Pedicini, Enrico Pegolo, Maurizio Mascarin, Elisa Coassin, Valentina Kiren, Marco Rabusin, Francesco Tuniz, Marco Vindigni, Serena D’Agostini, Maria Cristina De Colle, Paola Elisa Cogo, Ilaria Liguoro
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Central nervous system (CNS) tumors are the most common solid cancer in children, second only to leukaemia. METHODS We conducted a retrospective epidemiological study of primary CNS tumors diagnosed in children up to 16 years of age between 2012 and 2023, in order to estimate the incidence in a regional cohort of 1,2 million inhabitants (Northeastern Italy). Only primitive lesions were enrolled, relapses were excluded. RESULTS Over a period of twelve years, 100 new diagnoses were made (44% Female, 56% Male) with a mean age of 8,92 years (range 0-16 years) at time of onset. In terms of location, we recorded an equal number of supratentorial and subtentorial diagnoses (50% vs 50%). A time-series analysis was performed to verify possible variations in the incidence rate of brain tumors over years, and no significant change was described (R2 0.301, p=0.06). However, after 2017 a significant increase was noted (R2 0.725, p=0.015), as the incidence of new diagnosis quite doubled, from 3.16 in 2018 (95%CI 3.15-3.17) to 5.59 in 2023 (95%CI 5.57-5,61). Data were therefore divided in two groups: 2012-2017 (group 1), and 2018-2023 (group 2). There were no differences in terms of gender or age. The number of low-grade (LG) and high-grade (HG) diagnosis were compared: HG tumors, including high grade glioma, ependymoma and medulloblastoma, were significantly higher in the group 2 than group 1 (27/50, 54% vs 6/43, 14%, p&amp;lt;0.001). CONCLUSIONS In childhood, CNS tumors incidence has been fairly stable in the last twelve years in our regional cohort, but a recent concern of an increased rate of high-grade diseases emerged according to our data. In case of a confirmation of this trend, further analysis will be required in order to understand the reason.
LGG-20. SELUMETINIB IN PEDIATRIC PATIENTS WITH RELAPSED/REFRACTORY OPTIC PATHWAY/HYPOTALAMIC LOW GRADE GLIOMA: A MONOINSTITUTIONAL EXPERIENCE
Authors: Elisabetta Schiavello, Veronica Biassoni, Olga Nigro, Giovanna Gattuso, Nadia Puma, Luca Bergamaschi, Valeria Colombo, Marco Paolo Schiariti, Giorgio Giovanni Carrabba, Maura Rita Massimino
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric low-grade gliomas (pLGG) are the most common central nervous system tumors in children. The optic pathway and hypothalamic (OPH) frequent localizations are correlated with multiply relapses due to inoperability, thus emphasizing the need for alternative treatments. The results of activation of the BRAF oncogene through a tandem duplication resulting in a KIAA1549–BRAF fusion is the most common genetic aberration. Selumetinib is an oral mitogen-activated protein kinase (MEK) 1/2 inhibitor with promising efficacy and good tolerability on relapsed/refractory pLGG. METHODS From January 2021 to January 2024 three patients with refractory OPH-pLGG with KIIA1549-BRAF fusion were treated with Selumetinib 25 mg/sqm/day (compassionate use) all after two lines of chemotherapy. They were males, mean age at diagnosis 8 months, at starting Selumetinib 74 months. All had partial surgery at diagnosis and two of them other debulking surgeries during the treatment. All patients had numerous events of hydrocefalous with need of shunt revision. RESULTS Two patients experienced grade-3 stomatitis, one grade 3 nausea-vomiting, one grade 3 gastritis, one grade 1 increased level of CPK (CTCAE-V5.0). For grade 3 toxicity Selumetinib had to be stopped for a maximum of 7 days with clinical benefit. Two of them have completed treatment with Selumetinib, one is ongoing after 20 months, all with radiological stable disease at MRI. Median time of treatment is 26 months (range 20-30 months). All three experienced a trend in reduction of emergency room admission for ventricular-shunt problems. Median PFS at starting Selumetinib was 62 months, median OS is 97 months. CONCLUSIONS Selumetinib has a good profile of toxicity, allowing a good quality of life procrastinating radiotherapy and reducing surgery events in a context of heavily pretreated relapsed/refractory patients. Further data are needed on both visual and auxological parameters and late side effects.
EPID-03. CURE FRACTION AND LONG TERM SURVIVAL ESTIMATES FOR PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS IN EUROPE – RESULTS OF THE POPULATION-BASED EUROCARE PROJECT
Authors: Raoull Hoogendijk, Riccardo Capocaccia, Jasper van der Lugt, Mariëtte Kranendonk, Eelco Hoving, Pieter Wesseling, Otto Visser, Dannis van Vuurden, Gemma Gatta, Henrike Karim-Kos
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Time trends in cure fractions and up-to-date long-term survival have not been reported for clinically relevant groups of pediatric central nervous system (CNS) tumors although it provides important information for planning long-term clinical follow-up. METHODS We analyzed data on 15,242 children (&amp;lt;15 years) diagnosed with a CNS tumor between 1998-2013 from 31 European countries with follow-up until 31/12/2014. Cure fraction, the proportion of patients not anymore at risk of dying from progression or relapse was estimated using a mixture cure model with a parametric cancer survival curve function and assuming constant long-term mortality from other causes, including other cancers. Additionally, model-based up-to-date 15-year observed survival (OS) was estimated for the period 2010-2013. RESULTS The cure fraction for ependymomas increased from 65% in 1998-2001 to 79% in 2010-2013. However, as a result of the high long-term mortality rate of 16 per 1000 surviving patients per year, ependymomas had an estimated 15-year OS of 62%. For diffuse astrocytomas the cure fraction increased 6 percent-points to 84%, and 15-year OS was 74%. Cure fraction for glioblastomas increased from 15% to 20%. Long-term mortality for surviving glioblastoma patients was null resulting in a comparable projected 15-year OS of 20%. For medulloblastomas the cure fraction increased with 4 percent-points to 56% in 2010-2013, and a comparable 15-year OS of 56%. AT/RTs including PNETs together with high-grade gliomas (HGGs) were the only groups for which the cure fraction did not change over time: 34% and 24%, respectively. Estimated 15-year OS was 28% for AT/RTs including PNETs and 19% for HGGs. CONCLUSIONS As a result of high long-term mortality, the difference between cure fraction and 15-year OS was the highest for ependymomas and diffuse astrocytomas. Further investigation into underlying reasons (e.g., late effects of treatment) are needed to reduce the extra risk of deaths.
GCT-01. CENTRAL NERVOUS SYSTEM GERM CELL TUMORS – GENERATING A CONSENSUS IN THEIR DIAGNOSIS AND MANAGEMENT
Authors: Mohamed S Abdelbaki
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Despite the excellent outcomes of central nervous system (CNS) germ cell tumors (GCTs), there still exists significant differences in how GCTs are diagnosed and managed in different parts of the world. Additionally, the long-term toxicities and morbidities of the current therapies, and their substantial negative impact on the social wellbeing of our patients should clearly indicate that the current achievements are not enough. Further, important molecular data have emerged over the past decade that we have not witnessed their translation into any of the ongoing clinical trials. METHODS A comprehensive review of all major CNS GCT clinical trials will be discussed, in addition to a detailed review of the several issues of debate. Moreover, the latest developments in molecular landscape of GCTs will be provided in order to identify the hurdles that affect their incorporation in GCT clinical trials. RESULTS Tumor marker cut-offs that differentiate between germinoma and non-germinomatous germ cell tumors are clearly different between the various groups around the world. Additionally, differences exist in the chemotherapy backbones, radiation therapy field and dose, and the appropriate regimens to treat some of the rarer GCTs. Furthermore, there is no clear guideline on how to treat patients who do not achieve complete response after chemotherapy. CONCLUSIONS Discussing the clear differences that exist in the diagnosis and management of CNS GCTs is a critical first step in generating a clear consensus between the North American, European, Asian, and Latin American groups, which will certainly guide future clinical trials, improve the outcomes as well as the long-term treatment effects for this group of patients.
LGG-24. PEDIATRIC GANGLIOGLIOMA WITH GERMLINE BRCA2 MUTATION
Authors: Anya Gupta, Mirna Lechpammer, Margaret Shatara, Abbey Rocco, Mary Beck, Michele McHugh, Ashley Lampe, Ashley Meyer, Andrea Ogle, Andrew Cluster, Mohamed S Abdelbaki, Nicole M Brossier
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND BRCA1 and BRCA2 are genes associated with breast and ovarian cancer development in adults. Their influence on brain tumor formation is less understood. METHODS Retrospective review RESULTS An 11 year-old girl was diagnosed with ganglioglioma after presenting with seizures. Tumor sequencing revealed three mutations: a PDAP1-BRAF fusion, a BRAF-HIP1 non-canonical fusion, and a pathogenic BRCA2 variant D252*fs. Upon further review, a family history of breast cancer in the grandmother and several great-aunts was identified, and genetic testing confirmed this mutation to be germline. We then conducted an institutional review and identified a second pediatric low-grade glioma (pilocytic astrocytoma) patient with a pathogenic mutation in BRCA2 (T3085Fs*26) in addition to a BRAF-KIAA1549 fusion; the family declined germline BRCA2 testing. BRCA1/2 knockout models have demonstrated that both genes play a role in brain development. Concurrent BRCA2 and TP53 loss triggers formation of early onset murine medulloblastoma, a finding not observed with TP53 loss alone. In human patients, heterozygous and biallelic mutations in BRCA2 were identified as risk factors for medulloblastoma development in a recent integrative genomic analysis. Retrospective review CONCLUSION We report two cases of BRCA2 mutation in pediatric low-grade gliomas, one of which was confirmed to be germline. While somatic variants of BRCA2 have been reported in both high- and low-grade glioma, their role in these tumors has not been established to date. The BRCA2 tumor predisposition syndrome increases the risk of some types of brain tumors such as medulloblastoma, although the risk remains low compared to the risk of developing breast or ovarian cancer later in life. More evidence is required to determine whether BRCA2 germline mutations can similarly increase the risk of glioma formation.
HGG-47. SPATIAL SINGLE-CELL PROTEOMIC ANALYSIS MAPS THE DISTINCT PEDIATRIC-TYPE DIFFUSE HIGH-GRADE GLIOMA TUMOR ENTITIES AND DEFINES THEIR TUMOR AND IMMUNE MICROENVIRONMENTS
Authors: Lucia Lisa Petrilli, Giulio Spinozzi, Lucia Di Crocco, Antonio Salanitro, Sabrina Rossi, Dario Bressan, Alfredo Cerimele, Francesca Diomedi-Camassei, Evelina Miele, Antonella Cacchione, Giada Del Baldo, Giovanna Stefania Colafati, Andrea Carai, Franco Locatelli, Angela Mastronuzzi, Maria Vinci
Journal: Neuro-Oncology (2024)

Abstract Paediatric-type diffuse high-grade gliomas (pDHGG) are a group of molecularly and clinically defined tumor entities of the central nervous system. The investigation of the spatial organization of pDHGG tissues may provide new insights to decipher their heterogeneous nature and identify vulnerabilities in their aggressive behaviour. Here we exploit Imaging Mass Cytometry (IMC), a spatial biology approach enabling multiplex tissue phenotyping at single-cell resolution. We used 16 total formalin-fixed paraffin-embedded (FFPE) tissues from 4 patients including 1 Diffuse hemispheric glioma H3G34-mutant (DHG-H3G34), 1 Diffuse pediatric-type high-grade glioma H3-wildtype and IDH-wildtype (DHGG-WT) and 2 Diffuse midline glioma H3K27-altered (DMG-H3K27, 1 H3.3K27M and 1 H3.1K27M). Classical pathology assessment and DNA methylation profile were also performed. For IMC staining, 2 metal-tag custom-designed antibody panels (tumour and immune) of 31 antibodies were used. The panels include antibodies for differentiated and stem-cell markers, extracellular matrices, immune markers and H3K27M and H3.3G34R variants. An IMC analysis pipeline was developed: images are extracted in tiff format from the proprietary MCD files produced by Hyperion instrument, filtered to remove hot pixels via top-hat and OpenCV in Python, segmented using steinbock and analysed using the IMC Data Analysis toolbox in R, using docker. A total of 209 mm2 of tissue were analysed. IMC analysis showed that DHG-H3G34 displays a higher heterogeneity in terms of cell phenotypes compared to the other tumor entities. Moreover, immune infiltrate of T, B cells, NK and monocytes was observed in the DHG-H3G34 and DHGG-WT tissues, while the DMG-H3K27 had low/no immune infiltrate with the H3.3K27M showing higher PDL-1 expression. Analysis of longitudinal and multi-region samples highlighted trajectories of tumor evolution and identification of extracellular matrix niches in tumor core versus the infiltrative front. Our study provides novel insights into pDHGG complex biology by investigating their tissue architecture, spatial organization and cell-cell interactions.
NFS-18. LOWER BODY SURFACE AREA IS ASSOCIATED WITH INCREASED LIKELIHOOD OF PLEXIFORM NEUROFIBROMA RESPONSE TO MEK INHIBITION
Authors: Chelsea Kotch, Eva Dombi, Andrea Gross, Brian Weiss, Sabine Mueller, Alyssa T Reddy, Sébastien Perreault, Mélanie Alves, Symone Brown, Yimei Li, Brigitte C Widemann, Michael J Fisher
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND MEK inhibitors (MEKi) are altering the management approach for plexiform neurofibroma (PN), with high rates of treatment response to multiple MEKi. Despite these successes, a subset of PN fail to respond and little is known about the clinical features associated with treatment response. METHODS We performed a retrospective cohort study integrating clinical trial data (NCT01362803, NCT02407405, NCT02096471, NCT03231306, NCT03363217) to identify baseline clinical features associated with response of PN to MEKi. Partial response (PR) was defined as ≥20 percent reduction in tumor volume from baseline. RESULTS Of 232 eligible participants, adequate clinical trial and imaging data was available for 223 participants. In the primary analysis of 184 participants with central response evaluation, the median age was 15.2 years with a median tumor volume of 488 milliliters at clinical trial enrollment. One hundred and eighteen (64%) participants achieved a PR with median time to PR of 8 cycles. Thirty-five participants (19%) required a dose reduction prior to 6 cycles of therapy due to toxicity. Younger age and lower body surface area (BSA) were significantly associated with PR in univariate analysis while female sex and typical PN appearance (versus nodular) on imaging approached significance. In multivariable analysis, only lower BSA was significantly associated with response while typical PN appearance approached significance. In the multivariable analysis of pediatric participants treated per BSA-based dosing, lower BSA was the only feature significantly associated with PR. In the expanded analysis of all 223 participants, lower BSA and typical PN appearance were significantly associated with PR. CONCLUSION Lower BSA and typical appearance of PN were associated with PR to MEK inhibitors. Future studies of MEK inhibitor for PN should integrate tumor pharmacokinetic-pharmacodynamic analyses to prospectively explore the impact of BSA on treatment response.