tbuckley/cabot-search huggingface dataset:
HGG-24. DIFFERENTIAL CELL SURFACE PROTEOMICS OF FLOTILLIN-1, HMGB1 AND AMINOPEPTIDASE N IN H3 MUTATED PAEDIATRIC HIGH-GRADE GLIOMAS
Authors: Hannah Fairley, Chloe Walugembe, Rob Layfield, Farhana Haque
Journal: Neuro-Oncology (2024)

Abstract High-grade gliomas (HGG) are the deadliest central nervous system tumour in children. Despite this, treatment options remain elusive, leaving children with a dismal prognosis. Histone H3.3 mutations, K27M and G34V/R have been identified as the two most common recurrent somatic mutations in paediatric HGG (pHGG). These mutations are present in 50% of pHGG compared to only 1% in adult gliomas. Our previous proteomic research on cell membrane protein through protein MS data analyses have identified different signatures of differentially expressed cell membrane proteins in H3-G34R/V mutated pHGG cells, in comparison to H3 wild type tumour cells in culture. Among these proteins we have identified flotillin-1, HMGB1 (High mobility group box 1) and aminopeptidase N. Flotillin-1 is associated with numerous malignancies and HMGB1 also functions as an oncogene and aminopeptidase N is a cell surface metalloprotease involved in tumour progression. We have now verified the expression and localisation of these cell surface proteins in H3 mutated and wild type tumour cells, in order to validate as targets for developing novel therapeutics. Expression and localisation of flotillin-1, HMGB1 and aminopeptidase N in H3.3 mutated pHGG cell lines in comparison to H3 wildtype glioma and control cells was analysed, using different protein expression assays including immunofluorescence microscopy and western blotting. Experimental analyses showed statistically significant differential protein expression and localisation of these proteins. Flotillin-1 had increased cell membrane localization in H3 mutated cells.HMGB1 expression was increased, while aminopeptidase N expression was decreased in the H3 mutated cells in comparison to wildtype pHGG. This new knowledge of the cell membrane proteomics of H3 mutated pHGG may help us utilise Flotillin-1, HMGB1 and aminopeptidase N, as potential therapeutic targets for these unique H3 mutated children’s brain tumours.
DIPG-56. BRAINSTEM TUMOR BIOPSY: A SINGLE INSTITUTE EXPERIENCE OF SAFETY AND FEASIBILITY IN A LOW-MIDDLE INCOME COUNTRY (LMIC)
Authors: Farrah Bashir, Muzamil Hamid Hussain, Gohar Javed, Ehsan Bari, Ather Enam, Bilal Mazhar Qureshi, Shayan Sirat, Diana Thomas, Richard Drissi, Sara Khan, Maryam Fouladi, Cynthia Hawkins, Khurram Minhas, Eric Bouffet, Naureen Mushtaq
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Brainstem tumors account for 10-15% of all pediatric central nervous system tumors and carry a dismal prognosis. These include a wide spectrum of histological diagnosis therefore, in most specialized centers stereotactic biopsies for brainstem tumors are considered safe and standard practice. However, this approach continues to pose a challenge in LMIC’s. METHODS We retrospectively reviewed data of patients presenting with brainstem tumors at Aga Khan University Hospital, Pakistan, between 2014 and 2023. In addition to histopathological analysis, whole-genome sequencing and RNA sequencing were also performed on 6 tumors. RESULTS We identified 39 patients with brainstem tumors; amongst these 56.4% were females. Median age at diagnosis was 9 years (IQR: 5.1-11). Most cases presented with walking difficulty (74%) and cranial nerve palsies (46%). Median duration of symptoms was 30 days (IQR: 20-60). On imaging large proportion were intrinsic pontine tumors (53.8%) followed by brainstem (30.8%) and cerebellopontine angle (15.4%). 21 patients underwent stereotactic biopsy with 86% performed after 2016. 43% were intrinsic pontine tumors. Histopathology analysis showed a wide spectrum with diffuse midline glioma in 28% of cases, pilocytic astrocytoma, anaplastic astrocytoma and ganglioglioma in 33%, 14% and 9% of cases respectively. Rare entities identified included embryonal tumor with multilayered rosettes, atypical teratoid rhabdoid tumor and schwannoma (5%). Biopsies were uneventful in 81% of cases. Complication of biopsy in 2 patients included cranial nerve palsy and subdural hemorrhage. No patient died due to complications of biopsy. Surgical and medical management was altered in 9 patients due to availability of histological diagnosis. CONCLUSIONS We present the first study demonstrating safety and feasibility of stereotactic biopsy for brainstem tumors in LMIC. These biopsies should be considered for atypical brainstem tumors and should be performed in well-equipped tertiary neurosurgical facilities by trained neurosurgeons in LMIC.
ETMR-23. CNS SARCOMAS WITH<i>CIC</i>- OR<i>ATXN1</i>-ALTERATIONS — A META-ANALYSIS OF CLINICAL AND MOLECULAR FEATURES IN A LARGE SERIES OF PATIENTS
Authors: Neal Geisemeyer, Aniello Federico, Martin Sill, Marc Rosenblum, Tejus Bale, Monika Mauermann, Daniel Schrimpf, Pascal Johann, Jessica Pickles, Kenneth Aldape, Arnault Tauziède-Espariat, Martin Hasselblatt, Dominik Sturm, Anna Tietze, Andreas von Deimling, Philipp Sievers, Felix Sahm, Johannes Gojo, Katja von Hoff, Stefan M Pfister, Marcel Kool
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND In 2021, the 5th WHO classification of central nervous system (CNS) tumors acknowledged CNS sarcomas with CIC alterations as a distinct tumor type, which may also expand to non-CIC alterations including ATXN1. To tackle the lack of treatment protocols for these highly aggressive tumors, we conducted a meta-analysis to provide an overview of clinical and molecular characteristics, define clinically relevant subtypes, and ultimately advise on treatment guidelines. METHODS We collected molecular and clinical data for &amp;gt;200 patients with CIC- or ATXN1-altered CNS sarcomas by screening our in-house DNA methylation database (581 potential patients initially identified), publication databases (50 patients), and contacting centers worldwide (60 patients). Tumor tissue (FFPE and fresh frozen) for further molecular characterization was obtained from a subset of patients. DNA methylation-based clustering analyses (t-SNE, UMAP, consensus partitioning) were performed, integrating gene fusion details (RNAseq, FISH), copy-number variations, and clinical patient data to identify associations between (epi-)genetic and clinical parameters. RESULTS Most prominent fusion partners for CIC (n=47) and ATXN1 (n=9) were NUTM1 (n=18), LEUTX (n=17) and DUX4 (n=15). Clustering analyses of DNA methylation patterns indicated several epigenetic subtypes associated with different fusion types. Potential clinical implications are still under evaluation. Age distribution of patients at diagnosis in this cohort ranged from two months to 71 years (median=7.5 years). We observed no gender bias. Survival analyses are currently being performed, first results on survival and follow-up studies will be shown at the symposium. CONCLUSION We show first-of-its-kind data describing a large cohort of CNS sarcomas with CIC or ATXN1 alterations, outlining molecular and clinical characteristics, which may facilitate the development of guidelines for optimal treatment of these tumors based on retrospective response data. New molecular insights may also open up an avenue for targeted therapeutic approaches.
HGG-28. THE IMPACT OF CMMRD IN HIGH-GRADE GLIOMA PATIENTS, A RETROSPECTIVE ANALYSIS OF 7 YEARS IN LMIC; AN IRRDC STUDY
Authors: Naureen Mushtaq, Khurram Minhas Khurram Minhas, Farrah Bashir, Soha Zahid, Anirban Das, Cynthia Hawkins, Uri Tabori, Eric Bouffet
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Constitutional mismatch repair (MMR) deficiency (CMMRD) is a genetic cancer predisposition syndrome presenting among children and young adults. This study is the first to evaluate CMMRD prevalence among high-grade glioma patients in Pakistan, a country with high consanguinity rates. METHODS We reviewed data of patients younger than 18 diagnosed with pediatric high-grade glioma, anaplastic astrocytoma, and diffuse midline glioma with CMMRD testing between 2016 and 2023. Tumor slides of all included cases were prepared and sent to Sick Kids Toronto to review the MMR protein stains via multi-gene panels. RESULTS Forty-five patients were identified (62.3% females); median age of 11. Headache (88.9%) was the most common symptom, followed by vomiting (60%) and seizures (37.8%); median duration of symptoms was two months. Histopathology revealed 73.3% pediatric high-grade glioma, 22.2% Anaplastic Astrocytoma, and 4.4% Diffuse Midline Glioma. Thirty-six patients (80%) had a cerebral tumor, 13.3%, and 6.7% had a posterior fossa and midline tumor, respectively. CMMRD was positive in 15 of 45 patients (33.3%). Eight patients (53.4%) had CMMRD with loss of PMS 2, two (13.3%) had loss of PMS 2 and MLH 1, two (13.3%) had loss of MSH 2, two (13.3%) had loss of MSH 6, and only one patient had loss of MSH 6 and MSH 2. Consanguinity correlated with CMMRD (P=0.045), but family history of malignancy was not significant (P=0.202). One-year overall survival of all patients, with a median follow-up of 4.8 months, was 44.4 %, whereas 1-year overall survival compared to CMMRD was 33.3%, with a median follow-up of 7.2 months (P=0.616) CONCLUSION We found high prevalence of CMMRD among pediatric high-grade glioma patients and patients with consanguinity. The findings of our study emphasize the importance of genetic testing and counseling. Timely accurate diagnosis is essential as decreased response to conventional treatment regimens may increase disease burden.
QOL-45. SOCIAL DETERMINANTS OF HEALTH PREDICT NEUROPSYCHOLOGICAL OUTCOMES IN PEDIATRIC BRAIN TUMOR SURVIVORS
Authors: Anthony R Gioia, Lisa A Jacobson, Sahaja Acharya, Rachel K Peterson
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric brain tumors and their treatment impact cognition including intellectual functioning (IQ), attention, working memory, and processing speed. Few studies have examined the role of social determinants of health (SDoH) on cognition in pediatric brain tumors. To date, studies have primarily focused on family-related SDoH factors such as insurance status or parental education as predictors of cognition. To our knowledge, no study has examined multiple indicators of SDoH to determine which family-based and community-based predict cognition. METHODS Participants included 151 pediatric brain tumor patients (M diagnosis age=8.82) seen for a clinical neuropsychological evaluation (M evaluation age=13.71). IQ, brief attention (WISC/DAS-II Digits Forward), working memory (WISC/DAS-II Digits Backwards), and processing speed (WISC Coding) were obtained from age-appropriate measures (WISC&amp;gt;6 years, DAS-II&amp;lt;6 years). Family-based SDoH indicators include insurance type (public, private) and maternal education (&amp;lt;high school degree, some college, ≥college degree). Community-based SDoH include the Area Deprivation Index (ADI) and Childhood Opportunity Index (COI). Multiple regressions examined variance in IQ, attention, working memory, and processing speed accounted for by the SDoH measures, after controlling for treatment exposures using the Neurological Predictor Scale. RESULTS Insurance accounted for 14.9% of the IQ variance [β=-.316, t(151)=-4.18; p&amp;lt;.001]; COI accounted for 18.3% of the IQ variance [β=.202, t(151)=2.70; p=.008]. Insurance accounted for 12% of the variance in attention [β=-.324, t(152)=-4.22; p&amp;lt;.001], and 17.5% of the variance in processing speed [F(2,134)=15.399, p&amp;lt;.001]. In the working memory model, insurance [β=-.179, t(148)=-2.19; p=.03] and ADI [β=-.171, t(148)=-2.11; p=.04], accounted for 5.3% and 7.5% of the variance, respectively. CONCLUSIONS Findings highlight the important contribution of both family and community factors on neuropsychological outcomes in pediatric brain tumors. Nuances of the data will be discussed as they relate to clinical care and research.
LMIC-05. THE ROLE OF CENTRALIZATION IN PEDIATRIC NEURO-ONCOLOGY: EVIDENCE FROM A DEVELOPING COUNTRY
Authors: Julieta Hoveyan, Eduard Asatryan, Saten Hovhannisyan, Ruzanna Papyan, Armine Lazaryan, Armen Mkhitharyan, Narek Matinyan, Niko Arzumanyan, Mariam Minasyan, Irina Melnichenko, Elya Minasyan, Zeena Salman, Ibrahim Qaddoumi, Samvel Iskanyan, Lusine Hakobyan, Lilit Sargsyan, Samvel Danielyan, Gevorg Tamamyan, Samvel Bardakhchyan, Simon Bailey, Nisreen Amayiri
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Several studies from developed countries showed that centralization of pediatric cancer care is associated with survival benefits. The role of centralization might be crucial in pediatric neuro-oncology where multidisciplinary approach is essential. The aim of this study is to evaluate the impact of centralization in neuro-oncology in a developing country. METHODS In 2019, the consolidation of three pre-existing pediatric oncology units in Armenia resulted in the centralization of pediatric cancer care. After 2019 all patients undergo chemotherapy and follow up at the Pediatric Cancer and Blood Disorders Center of Armenia. This analysis compares demographic data, tumor characteristics and management of 54 patients diagnosed before centralization (2009-2018) and 66 patients diagnosed after centralization (2019-2023). RESULTS After centralization the incidence of recorded newly diagnosed CNS tumors in Armenia has dramatically increased (2.4 times). Six cases of CNS tumors diagnosed before 2019 were first registered after centralization. Assessment for metastatic status in embryonal tumors after centralization improved (20% vs 93.75%, p=0.0001). In addition, increased molecular testing was achieved (5.56% vs 31.8%, p=0.001). The number of patients getting access to multidisciplinary care and discussions via teleconference increased dramatically (5.56% versus 86.4%, p=0.0001). A trend toward a shorter median time from first symptoms to diagnosis was found (1.75-month vs 1-month, p=0.85). In addition, significant changes in the underlying pathology were recorded. Before and after centralization embryonal tumors, low-grade gliomas and high-grade gliomas accounted 37% vs 24.25%, 22.2% vs 31.8% and 11.1% vs 15.15% of CNS tumors, respectively. The availability of follow-up information marginally increased after centralization (83.3% vs 87.8%, p=0.48). CONCLUSIONS CNS tumors especially low-grade gliomas were frequently not registered before centralization. The current study proves that centralization helps to improve CNS tumors registration, diagnosis, and evaluation as well as facilitating multidisciplinary care. Further research is needed for evaluating the survival benefits of centralization.
HGG-26. MLH1, MSH2, MSH6, AND PMS2 IMMUNOHISTOCHEMISTRY REPRESENTS A HIGHLY SENSITIVE SCREENING METHOD FOR MISMATCH REPAIR DEFICIENCY SYNDROMES IN PEDIATRIC HIGH-GRADE GLIOMA
Authors: Lea L Friker, Thomas Perwein, Andreas Waha, Evelyn Dörner, Rebecca Klein, Mirjam Blattner-Johnson, Julian P Layer, Dominik Sturm, Gunther Nussbaumer, Kornelius Kerl, Ulrike Hennewig, Marius Rohde, Axel Karow, Ingmar Bluemcke, Ann Kristin Schmitz, Harald Reinhard, Nina A Herz, Pablo Hernáiz Driever, Susanne Wendt, Annette Weiser, Ana S Guerreiro Stücklin, Nicolas U Gerber, André O von Bueren, Claudia Khurana, Norbert Jorch, Christian P Kratz, Matthias Eyrich, Michael Karremann, Michael Hölzel, David T W Jones, Torsten Pietsch, Gerrit H Gielen, Christof M Kramm
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric central nervous system (CNS) tumors can occur as first manifestations of cancer predisposition syndromes (CPS) resulting from pathogenic variants in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2. Early detection of MMR deficiencies (MMRD) may warrant the therapeutic use of checkpoint inhibitors and enable genetic consulting for the patient’s families. METHODS We prospectively screened 128 pediatric high-grade gliomas (pedHGG) for MMR protein expression by immunohistochemistry (IHC) as part of the HIT-HGG-2013 clinical trial. We compared IHC results to independently collected patient information on CPS including MMRD to test the method’s efficiency in screening for Lynch syndrome and Constitutional MMRD syndrome CMMRD. RESULTS From 128 successfully tested tumors, ten cases (10/128, 7.8%), showed loss of expression of at least one of the MMR proteins. In seven of the ten affected patients (7/128, 5.5%), genetic testing uncovered heterozygous (6/10) or homozygous (1/10) pathogenic germline variants in MMR genes (MLH1, MSH2 or MSH6) confirming the diagnosis of Lynch syndrome respectively CMMRD. In three cases (3/128 2.3%), MMR alterations were restricted to tumor tissue. The group of diffuse midline gliomas, H3 K27-altered, (67/128, 52.3%) did not show MMR alterations, while either somatic or germline MMR mutations were detected in two of eight patients with diffuse hemispheric glioma, H3 G34-mutant. In 88 patients (88/128, 68.8%) either clinical or molecular-genetic information on CPS could be provided. All ten patients with signs of MMRD were successfully detected by IHC from tumor tissue. CONCLUSIONS IHC for MMR proteins represents a highly sensitive screening method for MMRD in pedHGG. Considering the occurrence of at least 11.5% (7/61) of MMRD in pediatric patients with diffuse high-grade glioma excluding DMG, MMRD IHC should be part of routine diagnostics as cost-effective, broadly available and robust screening method.
QOL-47. FINANCIAL TOXICITY IN PEDIATRIC NEUROSURGICAL ONCOLOGY
Authors: Alexandra M Giantini Larsen, Samantha Brown, Anne Reiner, Caitlin Hoffman, Jeffrey Greenfield, Mark Souweidane, W Christopher Newman
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Financial toxicity encompasses the negative impact of medical costs on patients. To our knowledge, financial toxicity in pediatric neurosurgical oncology remains unstudied. METHODS All pediatric neurosurgical cases from 2016 to 2020 performed at Memorial Sloan Kettering Cancer Center were included. Financial toxicity (FT) was defined as patients experiencing: bankruptcy, bills sent to collections, settlement, or timed payment plan, expression of financial concern to social work, or utilization of copay, financial, or social work philanthropy assistance programs. FT was assessed in the 2 years pre- and post- surgical intervention for all patients. RESULTS Two hundred and ninety-five surgical procedures across 203 patients were analyzed. The rate of FT in the two years prior to the first neurosurgical procedure was 17% (34/203). The most common toxicities were financial assistance program (47%), social work philanthropy (29%), and bills sent to collections (24%). The rate of FT for the subset of patients surviving at least 2 years after surgery was 34% (30/87) with the most common toxicities being financial assistance program (33%), collections (33%) and social work philanthropy (27%). The majority of patients who experienced FT had at least one commercial insurance policy (56% for the pre-surgical cohort, 70% for the post-surgical cohort). For all 203 patients, the 2-year cumulative incidence of FT following first neurosurgical procedure was 19% (CI:14%,25%) with those experiencing pre-operative toxicity having a significantly higher two-year cumulative incidence of FT at 62% (95%CI: [43%,76%], p&amp;lt;0.001) following first neurosurgical procedure. Patients without FT prior to first procedure had a two-year cumulative incidence of FT of 11% (95%CI: [7%,16%], p&amp;lt;0.001). CONCLUSIONS FT rates are substantial in the pediatric neurosurgical oncology population. Pre-operative FT influenced post-surgical FT. The most common toxicity was financial assistance program utilization. The majority of patients and families who experienced FT had at least one commercial insurance plan.
QOL-41. FEASIBILITY OF PREOPERATIVE NEUROPSYCHOLOGICAL EVALUATION IN PEDIATRIC BRAIN TUMOR PATIENTS: IS IT POSSIBLE TO ASSESS BEFORE SURGERY?
Authors: Borja Esteso-Orduña, Felisa Vázquez-Gómez, José Luis Moreno-Carrasco, Marta Pérez-Somarriba, Serafín Castellano, Susana Cartas-Carrión, Verónica Cantarín, Silvia Cámara-Barrio, Sebastián Galas, Roser Mingarro Mezquita Mingarro-Mezquita, Isis Alonso-García, Concepción Fournier-Del Castillo, Álvaro Lassaletta
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND We aim to evaluate the feasibility of pre-surgical neuropsychological assessment in pediatric brain tumor patients and to examine the impact of various factors on cognitive changes during follow-up. METHODS Between 2021 and 2023, we analyzed the timing of pre-surgery neuropsychological evaluations, completion rates, referral sources, non-referral rates, as well as general cognitive ability, executive and socioemotional functioning in relation to clinical variables. RESULTS There were 11 preoperative evaluations (mean referral time=2.45 days) and 12 postoperative but pre-oncologic evaluations, reflecting the timing of referrals (M=13.92 days). Referrals came mainly from oncology (17 patients) and rehabilitation (6 patients) teams. Ten patients lacked preoperative or pretreatment neuropsychological referral, 7 discontinued follow-up, and 7 died. 10 patients showed full cooperation, 4 families didn’t complete questionnaires, 3 assessments were adapted due to clinical conditions, 1 patient did not cooperate and 7 were developmental assessments. Six patients’ IQ or Development Quotient (DQ) was below normal at preoperative assessment, despite a group mean of z=0.22. Only three patients had a developmental delay diagnosed at time of presurgery evaluation, 2 of whom had comorbid AED. The remaining patients had no previous diagnosis. At post-treatment evaluation, 15 patients experienced a significant decline in IQ/DQ (t=5.157; p=0.000) and worsened in executive functioning (t=-2.462; p=0.042), while 8 patients improved IQ/DQ scores (t=3.672; p=0.008) with no significant changes in executive (t=1.462; p=0.203) or socioemotional (t=-0.218; p=0.836) functioning. CONCLUSIONS Early neuropsychological assessment is paramount in pediatric patients with a brain tumor. However, it is not always feasible and presents significant challenges: requiring adaptation to the patient’s clinical status, coordination across departments, and managing the family’s emotional response to potential diagnoses. Incorporating preoperative neuropsychological assessment into care protocols is essential to analyze premorbid cognitive and behavioral functioning and to improve patient management and guide targeted interventions.