tbuckley/cabot-search huggingface dataset:
NFS-05. INCIDENCE OF BEVACIZUMAB ASSOCIATED TOXICITY IN CHILDREN WITH LOW GRADE GLIOMA WITH AND WITHOUT NF1
Authors: Alexander Yelak, Gilad Hamdani, Amit Dagan, Orli Michaeli, Helen Toledano
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Low grade gliomas (LGG), both sporadic &amp; Neurofibromatosis1 (NF1) associated, are the commonest pediatric brain tumors. When surgically unresectable, they may become progressive/ symptomatic and require chronic oncological treatment. Bevacizumab (BVZ; Avastin), a recombinant humanized monoclonal antibody to VEGF, has shown efficacy both as a single agent or combined with chemotherapy as second/ third line treatment of progressive LGG especially in the optic pathway. BVZ can be associated with adverse effects including hypertension (HTN) and proteinuria. Children with NF1 have known increased tendency to hypertension however there is no data comparing the frequency of side effects from BVZ in patients with or without NF1. METHODS Retrospective study of all LGG cases treated with BVZ diagnosed 2010-2023 in a tertiary oncology center. We graded hypertension, proteinuria, cardiac function, retinopathy &amp; bleeding according to the CTCAE v5.0 in NF1 and non-NF1 patients. RESULTS 16 children with LGG were treated with BVZ; 7 had NF1. 75% optic glioma, 25% other. All received BVZ as second or third line treatment in combination with chemotherapy. In the non NF1 group, 77% patients developed grade 2 HTN on BVZ treatment; none required medical intervention. 6 had grade 1 elevation of protein-creatinine ratio (median 0.38). In the NF1 group, 71% developed grade 2 or 3 HTN on BVZ treatment including a patient with aortic coarctation (CoA) who had worsening of previous HTN, 2 required antihypertensive therapy (p non-significant HTN non NF1 vs. NF1). Only 1 NF1 patient developed proteinuria. No patients in either group stopped BVZ prematurely for toxicity. Hypertension was reversible after cessation of BVZ in all except the patient with CoA. CONCLUSIONS Hypertension is more common than previously reported in both NF1 and non-NF1 patients treated with BVZ for LGG. Blood pressure should be monitored and treated appropriately. BVZ is safe in young patients with NF1.
HGG-42. COMBINED PRECLINICAL AND CLINICAL INVESTIGATION OF WHICH PEDIATRIC HIGH-GRADE GLIOMA SUBTYPES BENEFIT FROM CCNU/TEMOZOLOMIDE
Authors: Rebecca D Haase, Lindsay Kilburn, Mariella Filbin, Adam L Green
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The only chemotherapy regimen that has shown a clear survival benefit in pediatric high-grade glioma (pHGG) is combining temozolomide (TMZ) and lomustine (CCNU) with RT per COG ACNS0423. However, which pHGG subgroups benefit from this treatment is unknown. METHODS Through the Children’s Brain Tumor Network (CBTN) database, we found 20 pHGG patients treated with RT-TMZ-CCNU, along with 95 control patients who received other treatment. We compared overall (OS) and event-free survival (EFS) using the Log-rank test for the respective pHGG subtype. We used a patient-derived xenograft (PDX) model, representing newly diagnosed hemispheric pHGG (diffuse hemispheric glioma, G34R-mutant (DHG), to test the effects of combining TMZ-CCNU. RESULTS From our clinical (CBTN) data, we found that median OS for the RT-TMZ-CCNU group was significantly greater compared to the control cohort (990 days (d) vs. 427d, p=0.011), as was EFS (510 vs. 215d, p=0.0041). For patients with hemispheric tumors, median OS and EFS were significantly increased for the RT-TMZ-CCNU group (n=8) vs. controls (n=47) (OS 5,274 vs. 496d, p=0.018; EFS 903 vs. 271d, p=0.018). For patients with midline pHGG, median OS and EFS were not significantly different between the RT-TMZ-CCNU group (n=11) and controls (n=43). In our PDX model, we found that TMZ-CCNU led to long-term survival compared to vehicle control and single-agent treatment (p&amp;lt;0.001). DISCUSSION: Patients with hemispheric pHGG had a significant survival benefit from RT-TMZ-CCNU treatment, while those with midline pHGG did not. Hemispheric pHGG, which are enriched for H3G34 and IDH mutations, may be more likely to respond to RT-TMZ-CCNU. These findings are supported by preclinical data showing that mice with DHG, G34R-mutant were cured after TMZ-CCNU treatment. Given our results and those from ACNS0423, RT-TMZ-CCNU should be strongly considered for treatment of patients with hemispheric pHGG and as a backbone for future clinical trials in this population.
NFS-15. SPECIFIC FOR NF1, BASED ON SOCIAL COGNITION DEFICITS, MALADAPTIVE BEHAVIORS AS RISK FACTORS OF DIFFICULTIES IN THE SOCIO-EMOTIONAL FUNCTIONING
Authors: Justyna Korzeniewska
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The neurocognitive effects of NF1 include social cognition deficits, which are significant, because cause cognitive and social functioning. Social cognition is defined as cognitive processes related to the perception and understanding of cues in the environment that communicate social and interpersonal information and the ability to use those cues to interpret the thoughts and reactions of others and to modify one’s own behaviors to fit the social context. The purpose of the study was to describe cognitive deficits and behavioral phenotype of NF1, as well as looking for connections between deficits of social cognition and socio-emotional status in NF1. METHODS Psychological repeated testing and long-term observation was performed in 100 patients with NF1. Age at psychological diagnosis: 3 - 18 years. Full psychological outcome assessed cognitive, verbal and affective problems associated with manifestations of NF1. The patients were examined using battery of neuropsychological methods, psychological interview and analysis of medical history. For research of social functioning used subscales of Vineland Adaptive Behavior Scales (VABS-II) and Child Behavior Checklist (CBCL). We assessed also maladaptive behavior as a risk of social rejection. The main point of the assessment was to discover link between social cognition and challenging behaviors. RESULTS In the sample of patients with NF1 we observed specific social difficulties associated with emotional disturbances and social rejection. This specific behavioral phenotype and social cognition deficits disturbed learning process and their social life. Patients with NF1 were distinctly ineffective in interpersonal communications and establishing relations in the peer group as well as following the rules of social convention. CONCLUSIONS The results of our study suggest that social cognition deficits, are responsible for socio-emotional status of patients with NF1. Draft recommendations for diagnosis of specific emotional problems typical for NF1 and program of social development stimulation in NF1 will be presented and discussed.
HGG-40. UNRAVELING THE IMMUNOLOGIC VULNERABILITIES OF DIFFUSE HEMISPHERIC GLIOMA, H3 G34-MUTANT
Authors: Robert T Galvin, Negar Sadeghipour, Joanne Xiu, David M Ashley, Manmeet S Ahluwalia, Sonikpreet Aulakh, R Stephanie Huang, David A Largaespada
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Insights into the pathogenesis of diffuse hemispheric glioma, H3 G34-mutant (DHG-G34), an incurable high-grade glioma, have opened new therapeutic possibilities. The DHG-G34 oncohistone mutation impairs the epigenetic regulator SETD2, which normally orchestrates DNA-mismatch-repair and negatively regulates Polycomb Repressive Complex 2 (PRC2). In DHG-G34, a mismatch-repair-deficiency phenotype is predicted, but an anti-tumor immune response is notably absent, which we hypothesize is linked to the aberrant transcriptional repression by PRC2. Here, we investigate DHG-G34 immunosuppression mechanisms in a real-world multi-omics cohort and cell line model. METHODS Clinical, molecular, and immunologic characteristics of a DHG-G34 cohort, sequenced at Caris Life Sciences, are contrasted against diffuse midline glioma (DMG) and pediatric low-grade glioma (LGG). KNS-42 DHG-G34 cell line was exposed to valemetostat (a EZH1/2 inhibitor) or DMSO in-vitro. Flow cytometry and RNA-sequencing were utilized to determine differential immunologic characteristics. RESULTS 29 DHG-G34, 51 DMG, and 52 LGG were identified. DHG-G34 median OS was 15.4 mo., like DMG (HR=1.1, p=0.686). Common DHG-G34 alterations were TP53 (93.1%), ATRX (69.0%), PDGFRA (31.0%). Tumor mutational burden (TMB) was high, &amp;gt;=10mt/MB, in 10% of DHG-G34, with 0 DMG or LGG events (p&amp;lt;0.01, q&amp;gt;0.05), but innate and adaptive immune fractions and antigen-presenting genes were decreased (fold-change: 0.19–0.83, q&amp;lt;0.05). In KNS-42, PRC2 inhibition upregulated MHC class 1 (p&amp;lt;0.001). Of 402 missense variants, 43 were upregulated following EHZ2 inhibition, and 4 were downregulated (q&amp;lt;0.05). Among immunostimulatory genes, P2RX7, which engages T-cells, was downregulated in patient samples (q&amp;lt;0.001) and upregulated in EZH2 inhibited KNS-42 (q&amp;lt;0.001). CONCLUSIONS DHG-G34 has a propensity for high TMB but remains immunologically cold. Our pilot experiment suggests inhibiting PRC2’s unique role in DHG-G34 may sensitize DHG-G34 to an immune response by inducing MHC class 1 expression and transcriptional read-through of mutated transcripts. Understanding whether treatment induces TMB in DHG-G34 may affect timing of an immunotherapeutic intervention.
ETMR-21. PRIMARY DIFFUSE LEPTOMENINGEAL MELANOMATOSIS (PDLM) ASSOCIATED WITH INTRACRANIAL BLEEDING AND RAPID PROGRESSION IN A CHILD
Authors: Megan Sim, Glenda Hendson, Stephen Yip, Ash Singhal, Faizal Haji, Anvita Pauranik, Juliette Hukin, George Michaiel
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND PDLM is a rare and aggressive disease with limited cases reported worldwide and few cases in the pediatric population. Herein we report on clinical, histologic, and molecular/genetic findings of a young child with PDLM and rapid clinical progression. CASE STUDY A 12-year-old right-handed male presented with two months of intermittent fevers, progressive frontal headaches, lethargy, vomiting, and weight loss, and one month of focal seizures with altered awareness, speech arrest, eye deviation, and tonic posturing. Examination revealed bilateral papilledema and signs of increased intracranial pressure. A brain CT demonstrated increased density of the anterosuperior right frontal lobe and punctate focus of increased density along the left frontal lobe suggestive of hemorrhage. MRI revealed diffuse leptomeningeal thickening and enhancement throughout the brain and spinal cord. At biopsy, the frontal lesion was noted to be grossly abnormal and discolored, and on pathology demonstrated a melanocytic neoplasm infiltrating the subarachnoid space and extending into Virchow-Robin spaces. Tumor cells stained strongly for HMB45, vimentin, Melan-A, and PRAME and were BRAFV600E negative. RNA sequencing was negative for structural variants, Whole exome sequencing revealed a Tier I missense variant in NRAS (c.181C&amp;gt;A) among other copy number variations and loss of heterozygosity. Comprehensive ophthalmologic and dermatologic examinations as well as whole body PET/CT did not reveal any other sites of disease. He was due to commence immunotherapy with combination PD-1/CTLA-4 inhibitors but developed status epilepticus and raised intracranial pressure, warranting ventriculoperitoneal shunt insertion. Three days later, he had further deterioration with altered level of consciousness, hypertension, eye deviation, and vomiting. CT brain revealed large bifrontal hematomas with mass effect and care was redirected to palliation. CONCLUSION PDLM can be challenging to diagnose with a rapidly progressive course. Advanced molecular diagnostics may provide new targets for precision therapy, though overall outcomes remain dismal.
QOL-52. SOCIOECONOMIC METRICS AND THEIR UNIQUE ROLE IN PREDICTING COGNITIVE AND FUNCTIONAL MORBIDITY IN RACIALLY AND ETHNICALLY DIVERSE PATIENTS WITH PEDIATRIC BRAIN TUMOR (PBT)
Authors: Jenna A Chiang, Leanne Mendoza, Ashley M Whitaker
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Caregivers from more advantaged backgrounds have better understanding of their child’s needs, access to resources, and medical adherence, contributing to higher survival and neuropsychological (NP) outcomes in PBT, above and beyond diagnostic/treatment-related factors. Children with PBT from disadvantaged neighborhoods have increased medical morbidity, though cognitive morbidity is unknown. This study examines area deprivation index (ADI) quintiles (neighborhood disadvantage) in relation to established proxies for socioeconomic status (SES) and NP outcomes following PBT diagnosis. METHODS Parental education and median household income (SES proxies), as well as ADI quintiles (1-5, 5=most disadvantaged) were estimated for 120 PBT patients (ages 5-21; x̄=13.6 years, SD=3.8 years; 50% female). NP outcomes included estimated IQ (calculated from Wechsler Vocabulary/Matrix Reasoning) and/or the Adaptive Behavior Assessment System-Third Edition (ABAS-3). RESULTS Over 75% identified as minorities (53% Latinx, 10% Asian American, 5% Black, 8% multi/other). Findings revealed significant racial/ethnic disparities in household income [F(4,115)=11.208, p&amp;lt;.001] and ADI [F(4,108)=9.663, p&amp;lt;.001]. Parental education was correlated with household income [rs(80)=.490, p&amp;lt;.001] and ADI [rs(76)=-.477, p&amp;lt;.001]. Interestingly, household income [F(1,74)=7.498, p=.008] and parental education [F(1,49)=10.084, p=.003] significantly predicted IQ (SS=44-132; x̄=99.78, SD=14.66), while ADI did not. Neither SES proxy nor ADI predicted adaptive functioning (SS=51-120; x̄=90.12, SD=13.927), despite the relationship between IQ and adaptive functioning, r(47)=.273, p=.032. CONCLUSIONS The predictive value of household income (which varies by race/ethnicity) and parental education on cognition following PBT diagnosis continues to inform neuropsychological practice. While ADI is correlated with both established SES proxies, higher neighborhood disadvantage does not predict cognitive concerns in the same way, indicating potential unique housing factors (e.g., persons per room ratio) that may protect against cognitive morbidity (e.g., multigenerational living). Additional investigation is needed to understand why adaptive functioning is less susceptible to SES/ADI than cognition.
ETMR-20. CARDIOLIPIN ACYL CHAIN MODULATION AS A NOVEL MITOCHONDRIAL-FOCUSED THERAPEUTIC TARGET IN ETMR
Authors: Evangelos Liapis, Kelly C O’Neill, Annapurna Pamreddy, Allison Maas, Derek R Hanson, Claire L Carter
Journal: Neuro-Oncology (2024)

Abstract Embryonal tumor with multilayered rosettes (ETMR) is a highly aggressive CNS neoplasm that occurs almost exclusively in infants and is associated with an extremely poor prognosis. Dysregulated mitochondrial bioenergetics and dynamics have been associated with the initiation and progression of diverse cancers and studies have linked metabolic rewiring to chemotherapy resistance. Cardiolipins are mitochondrial-specific lipids that reside in the mitochondrial membrane and their fatty acid composition has been extensively shown to regulate mitochondrial function and dynamics. Despite the known functional significance of cardiolipin structure, their role in mitochondrial regulation of brain tumors remains ill-defined. Using mass spectrometry imaging, we identified a shift to shorter acyl chain cardiolipins within the rapidly proliferating embryonal tumor cells in patient samples and patient-derived cell lines grown as 3D tumorspheres. Western blot analysis of the enzymes involved in cardiolipin synthesis and remodeling identified a significant increase in the expression of the cardiolipin remodeling enzyme, LCLAT1/ALCAT1. Orthogonal imaging techniques including immunohistochemistry, transmission electron microscopy and super-resolution microscopy correlated shorter acyl chain remodeling of cardiolipin with fragmented mitochondria (increased fission) and aberrant cristae structure. Further studies identified increased expression of the fission protein Drp1, decreased expression of respiratory chain enzymes and altered respiration in the embryonal tumor cells. Ongoing studies will utilize multiple methods to modulate cardiolipin acyl chain structure and use MS and MSI to correlate cardiolipin fatty acid structure to mitochondrial function and growth inhibition in the embryonal tumor cells.
QOL-42. ANALYSIS OF LATE EVENTS AFTER RADIATION THERAPY FOR PRIMARY PEDIATRIC BRAIN TUMORS
Authors: Katerina Trkova, Ales Vicha, Lenka Krskova, Miroslav Koblizek, Barbora Ondrova, Marie Kopecka, Lucie Landova, Vladimir Benes III, Michal Zapotocky, David Sumerauer
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Late events after radiation therapy for primary brain tumors consist of secondary malignant neoplasms (SMN) and tumor recurrences. The incidence and biology of late events are not very well described. Therefore, we aimed to identify late events in our institutional cohort and describe their biology. METHODS A retrospective chart review of all irradiated pediatric brain tumor patients treated between 2000 and 2015 at our institution was performed to obtain demographics and clinical data of late events. Late events were defined as intracranial intraaxial SMN or tumor recurrence occurring later than 3 years after radiation therapy. A whole-genome methylation array was employed to identify the methylation class of the late event. RESULTS In the observed period, 267 patients received some form of cranial radiotherapy for primary brain tumor; high-grade glioma (HGG, n=66), medulloblastoma (n=74), ependymoma (n=50), germ-cell tumors (GCT, n=22), low-grade glioma (LGG, n=24), and other diagnoses (n=31). Out of the 174 patients who were alive and without an event after 3 years from the radiation therapy, 30 developed late events (16.8%), and 27 of them were histologically verified. Verified late events consisted of 8 SMNs (29.6%) and 19 primary tumor recurrences. SMNs were mainly radiation-induced gliomas (RIG, n=7) and one atypical teratoid/rhabdoid tumor (ATRT) after craniopharyngioma. All RIG tumors clustered with the “pediatricHGG_RTK1” methylation class. Tumor recurrences consisted of medulloblastomas (Group 4 and Wnt), ependymomas (PFA and ST_ZFTA), GCTs, gliomas (one NF1-associated HGG, one H3-altered thalamic glioma, one diffuse astrocytoma with BRAF-V600E mutation), and craniopharyngiomas. The overall survival rate 5 years after a late event was 39.7%, with a worse survival rate for SMN patients (14.3%) compared to those with recurrences (44.9%) (p=0.05). CONCLUSIONS Late events affected 16.8% of long-term survivors. Strikingly, SMNs represented almost 30% of late events and were associated with a very poor prognosis.
GCT-02. OPTIC PATHWAY PRIMARY GERMINOMA: DON´T MISS THE DIAGNOSIS
Authors: Regina M Navarro-Martin del Campo, Alma M Huerta-Hurtado, David Saldaña-Alcalá, Ana L Orozco-Alvarado
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Germ Cell tumors usually arise in the midline of brain; location in optic pathway (OP) is extremely rare. This case illustrates an OP primary Germinoma. METHODS A 9 years old female debuted with diminished visual acuity, it was diagnosed and treated as optic neuritis without improvement, a MRI evidenced a gadolinium enhancement with a very subtle thickening on the optic chiasm, along 3 non conclusive vascular like images in the left Virchow space. A differential diagnosis between endophytic Optic pathway glioma and germ cell tumor was made. RESULTS Assessment of AFP and Sub HCG in both blood and CFS was negative, endocrine evaluation confirmed Diabetes insipidus. A stereotaxic biopsy was performed and Pathology confirmed a Pure Germinoma. Non metastatic disease was confirmed as negative Spine MRI and acellular CFS. As a relevant familiar History the father had testicular Germinoma in his teenage. She was treated with 9 weeks of Carboplatin/V16 and radiotherapy as follows: whole ventricular 24 Gy and primary site 16.5 Gy for a total dose of 40.05 Gy. She is free of tumor at 3 follow up years with improvement in visual acuity and arginine vasopressin dependence. CONCLUSIONS This case illustrates a germ cell tumor primary arising in the optic pathway and aware us to consider it as a differential diagnosis with non-exophytic optic pathway Glioma being the biopsy mandatory to establish the correct diagnosis
QOL-43. COMPARISON OF SOCIAL DETERMINANTS OF HEALTH MEASURES ON IQ AND ACADEMIC OUTCOMES IN PEDIATRIC BRAIN TUMORS
Authors: Anthony R Gioia, Lisa A Jacobson, Sahaja Acharya, Rachel K Peterson
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Treatment for pediatric brain tumors impacts IQ and academic achievement; fewer studies have examined the role of social determinants of health (SDoH). To date, studies have primarily focused on family-based SDoH such as insurance type or parental education as predictors of cognition. Limited studies have examined community factors, though our work highlighted the role of education quality on IQ and academics in pediatric brain tumors. To our knowledge, no study has examined the predictive value of family and community-based SDoH. METHODS Participants included 151 pediatric brain tumor patients (M age at diagnosis=8.82) seen for a clinical neuropsychological evaluation (M age at evaluation=13.71). IQ was obtained from age-appropriate intelligence measures (WISC&amp;gt;6 years, DAS-II&amp;lt;6 years); untimed reading and math calculation were examined via WIAT/KTEA/WJ subtests. Family-based SDoH included insurance type (public, private) and maternal education (&amp;lt;high school degree, some college, &amp;gt;college degree). Community-based SDoH included the Area Deprivation Index (ADI) and Education, Health-Environment, and Social-Economic indices from the Childhood Opportunity Index (COI). Multiple regressions examined variance in IQ, reading, and math accounted for by each of the SDoH measures, after controlling for treatment exposures using the Neurological Predictor Scale (NPS). RESULTS Insurance [β=-.302, t(151)=-4.00; p&amp;lt;001] and Education [β=.235, t(151)=3.14; p=.002] accounted for 14.9% and 19.7% of the IQ variance, respectively. Education also accounted for 12.8% of the reading variance (β=.304, t(109)=3.40; p&amp;lt;.001). Both the Education [β=.570, t(107)=3.41; p&amp;lt;.001] and Social-Economic [β=-.381, t(107)=-2.28; p=.03] indices accounted for 7.7% and 11.3% of the math calculation variance, respectively. CONCLUSIONS Community, particularly those related to education and social &amp; economic resources, and family factors (e.g., insurance status) were associated with IQ and academic performance. Findings indicate the importance of investigating both family and community factors that may contribute to outcomes in pediatric brain tumors.