tbuckley/cabot-search huggingface dataset:
QOL-04.<i>IN VIVO</i> MODELLING RECAPITULATES RADIOTHERAPY DELIVERY AND LATE-EFFECT PROFILE FOR CHILDHOOD MEDULLOBLASTOMA
Authors: Jemma Castle, Gary Shaw, Dominic Weller, Edward Fielder, Teklu Egnuni, Mankaran Singh, Roderick Skinner, Thomas von Zglinicki, Steven C Clifford, Susan Short, Satomi Miwa, Debbie Hicks
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma (MB) is the most common malignant paediatric brain tumour, with 5-year survival rates &amp;gt;70%. Survivors frequently suffer a wide-range of late-effects due to their tumour and its treatment. Cranial radiotherapy (CRT) to the whole-brain, with posterior fossa boost (PFB), underpins treatment for non-infants, however, radiotherapeutic insult to normal brain tissue has deleterious consequences to neurocognitive and physical functioning, and causes accelerated ageing/frailty. Unfortunately, approaches to ameliorate radiotherapy-induced late-effects are lacking and a paucity of appropriate model systems hinders their development. METHODS We have developed a clinically-relevant in vivo model system that recapitulates the radiotherapy dose, delivery and late-effect profile of childhood medulloblastoma, at an equivalent developmental stage. Consistent with human regimens, age-equivalent (postnatal days 28-37) C57Bl/6J mice received targeted, CT image-guided, CRT (human-equivalent 38 Gy, n=12) or CRT with PFB (human-equivalent 49 Gy, n=12), via the small animal radiation research platform (SARRP) and were longitudinally assessed for over a year. Late-effects were compared to a sham-irradiated group (n=12). RESULTS CRT was well tolerated, independent of PFB receipt, and no mice suffered severe acute toxicity. Mice were significantly more frail following irradiation (frailty index; p=0.0002) and had reduced physical functioning; time to fall from a rotating rod and grip strength were significantly lower (rotarod; p=0.026 and grip strength; p=0.006, respectively). Neurocognitive deficits were consistent with those observed in childhood MB survivors; irradiated mice displayed significantly worse working memory (Y-maze; p=0.009) and exhibited spatial memory deficits (Barnes maze; p=0.029). Receipt of PFB did not induce a more severe late-effect profile. CONCLUSION We conclude that our in vivo model of childhood MB radiotherapy recapitulates the late-effect profile of MB survivors. Our clinically-relevant model will facilitate both the elucidation of novel/target mechanisms underpinning MB late-effects and the development of novel interventions for their amelioration.
QOL-02. PREDICTING NEUROCOGNITIVE OUTCOMES AMONG CHILDREN EXPERIENCING VARYING DEGREES OF POSTOPERATIVE POSTERIOR FOSSA SYNDROME
Authors: Heather M Conklin, Darcy Raches, Raja B Khan, Jason M Ashford, Tong Lin, Arzu Onar-Thomas, Brian S Potter, Paul Klimo, Jr, Amar Gajjar, Giles W Robinson
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Postoperative posterior fossa syndrome (PFS) has historically been diagnosed as present vs. absent despite a continuum of severity in presentations. We recently demonstrated categorizing children into PFS1 (complete mutism) and PFS2 (diminished speech) has prognostic utility for neurological recovery. Given children who experience PFS are also at increased risk for neurocognitive impairments, we investigated whether these PFS variants predict neurocognitive outcomes while considering well-established risk factors (i.e., age and treatment intensity). METHODS Children treated for medulloblastoma at St. Jude on a prospective, risk-stratified protocol (SJMB12; NCT 01878617) were study eligible if they had at least two neurocognitive evaluations. SJMB12 participants received neurological and neurocognitive evaluations prior to irradiation and annually for 5 years. Neurocognitive outcomes included intellectual functioning (Wechsler Intelligence Scale for Children [WISC-IV] estimated IQ [EIQ]), processing speed (WISC-IV Processing Speed Index [PSI]), working memory (WISC-IV Working Memory Index [WMI]), and adaptive functioning (Behavior Assessment System for Children [BASC2] Activities of Daily Living [ADL]). RESULTS 149 patients (age at diagnosis= 10.7±5.6; 64% male; 9% 15Gy, 40% 23.4Gy, 51% ≥36Gy) were included. No significant differences between PFS1 (n=34) or PFS2 (n=16) compared to NonPFS (n=99) were identified in age, sex, or irradiation dose (ps&amp;gt;.05). Multivariable linear mixed models indicate NonPFS have better EIQ than PFS1 and PFS2 (p&amp;lt;.03), with EIQ improving over time (p=.01). NonPFS have better PSI than PFS1 and PFS2 (p&amp;lt;.001). PSI declines over time irrespective of age (p&amp;gt;.05); however, PSI declines for those receiving 36Gy while improving for those receiving 15Gy (p&amp;lt;.001). NonPFS have better WMI than PFS1 and PFS2 (p&amp;lt;.05); older age at diagnosis is associated with improvement in WMI over time (p&amp;lt;.0005). ADL declines only in PFS1 patients (p&amp;lt;.05). CONCLUSIONS PFS variants add value beyond established risk factors in predicting neurocognition. Severity of PFS, in addition to treatment intensity, predicts worse outcomes.
LGG-49. EVALUATING THE EFFECTS OF MIRDAMETINIB IN NF1-MUTANT LOW-GRADE GLIOMAS USING BOTH CULTURED CELLS AND A NOVEL ZEBRAFISH XENOGRAFT MODEL
Authors: Kaixuan Wang, Ming Yuan, Gianna Graziano, Anneliese Ceisel, Nimisha Krishnan, Jeff S Mumm, Charles Eberhart, Eric Raabe
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric low-grade gliomas (LGGs) with NF1 mutations represent a significant portion of childhood brain tumors. NF1 mutations lead to the dysregulation of the MAPK kinase and mTOR pathways, contributing to tumor growth. However, obtaining cell lines and xenograft animal models for NF1-mutated LGGs remains challenging due to their slow growth and less aggressive nature. Methods and RESULTS We examined the therapeutic efficacy of a novel MEK inhibitor mirdametinib in targeting the MAPK pathway within JHH-NF1-PA1 cells, a cell line derived from a low-grade optic pathway glioma originating from a patient with type 1 neurofibromatosis. Mirdametinib decreased p-ERK protein expression levels on western blot within four hours. We confirmed that mirdametinib significantly suppressed tumor cell proliferation by approximately 60% (BrdU staining (P&amp;lt;0.05), CellTiter Blue assay). β-galactosidase staining revealed approximately a 50% induction of cellular senescence in JHH-NF1-PA1 cells following mirdametinib treatment (P&amp;lt;0.05). We confirmed our findings using murine Nf1-null low grade glioma cell lines 1861 and 1491. To establish an in vivo model for drug testing, we utilized zebrafish due to their transparency, rapid reproduction, and short development time. Injecting RFP-labeled JHH-NF1-PA1 cells into the zebrafish at the 1000-cell stage, we monitored tumor growth using TECAN fluorescence detection from the third to eighth days post-injection. The fluorescence signals obtained from TECAN were validated by fluorescence microscopy. Western blot analysis confirmed a decrease in p-ERK levels within the zebrafish following mirdametinib treatment. We are evaluating the effect of mirdametinib on NF1 low grade glioma cell survival, migration and senescence in the zebrafish brain. CONCLUSION Our findings show that mirdametinib inhibits cell proliferation and induces senescence in NF1-mutated LGGs. Moreover, our zebrafish model provides a valuable tool for evaluating the efficacy of MEK inhibitors in vivo, particularly in cases where traditional xenograft models are difficult to establish.
NFS-22. INVESTIGATING MALIGNANT TRANSFORMATION IN NF1 PEDIATRIC GLIOMAS USING AN IPSCS-DERIVED CEREBRAL ORGANOID MODEL
Authors: Federica Tomasso, Wai Chin Chong, Shivaprasad Bhuvanendran, Sridevi Yadavilli, Roger Packer, Javad Nazarian
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Neurofibromatosis Type 1 (NF1) is an autosomal dominant tumor predisposition syndrome affecting 1 in 3000 children around the world. Although NF1 inactivation is recognized as the cause of low-grade glioma (LGG) development, little is known about subsequent genetic alterations that lead to malignant transformation. One of the limitations in understanding the molecular events underlying the malignant transformation of NF1 gliomas is the lack of appropriate NF1 preclinical models for its comprehensive profiling. OBJECTIVE Brain organoids have emerged as powerful in vitro models for studying the interaction between tumor cells and the tumor microenvironment. In this study, we present a novel cerebral organoid model, developed to investigate the molecular events leading to malignant transformation in NF1 pediatric gliomas. METHODS Induced pluripotent stem cells (iPSCs)-derived cerebral organoids were generated using NF1wt and NF1mut iPSCs, the latter reprogrammed from patients with plexiform neurofibromas (Carlos III Health Institute, Spain). Immunofluorescence analysis was performed at four different developmental stages to confirm their correct cytoarchitectural development and differentiation into heterogeneous cell populations. Furthermore, four mCherry-labelled isogenic glioma cells lines, RES 186 wild type, NF1-/-, CDKN2a-/-,NF1-/-/CDKN2a-/- were co-cultured with the developed cerebral organoids and their migration potential and invasiveness were compared using two-photon microscopy. RESULTS/DISCUSSION NF1mut cerebral organoids display ventricular-like zone at early stages of development (d15-d30), characterized by luminal Sox2+ neural stem cells surrounded by Tuj1+ immature neuron. These organized structures disappear at later stages, while progenitor cells start to differentiate into fully mature neurons and glial cells (d45-d60). Additionally, after 10 days of co-culture, all four RES186 isogenic cell lines infiltrated the organoid structure with different invasion patterns. The established organoid model will provide a platform for evaluating the impact of sequential mutational events on LGG transformation, taking into consideration the role exerted by the tumor microenvironment in supporting tumor cell invasion and migration.
BIOM-03. IMMUNO-ONCOLOGIC PROFILING OF PEDIATRIC BRAIN TUMORS REVEALS MAJOR CLINICAL SIGNIFICANCE OF THE TUMOR IMMUNE MICROENVIRONMENT
Authors: Adrian Levine, Liana Nobre, Anirban Das, Scott Milos, Vanessa Bianchi, Monique Johnson, Nicholas Fernandez, Lucie Stengs, Michelle Ku, Mansuba Rana, Ivana Fedoráková, Julie Bennett, Vijay Ramaswamy, Robert Siddaway, Uri Tabori, Cynthia Hawkins
Journal: Neuro-Oncology (2024)

Abstract With the success of immunotherapy in cancer, understanding the tumor immune microenvironment (TIME) has become increasingly important; however in pediatric brain tumors this remains poorly characterized. Accordingly, we developed a clinical immune-oncology gene expression assay, including the 18-gene tumor inflammation signature (TIS) as a marker of overall immune activation, and validated this with immunohistochemistry for key cell-type markers. We used this assay, in conjunction with public data from the Pediatric Brain Tumor Atlas (PBTA), to profile a diverse range of 1382 samples in total with detailed clinical and molecular annotation. Overall among the main types of pediatric brain tumors, low-grade gliomas (LGG) had the highest inflammation levels (regardless of genetic driver alteration) and medulloblastomas the lowest. In LGG we identified three distinct patterns of immune activation with prognostic significance in BRAF V600E-mutant tumors, specifically that higher inflammation predicted worse outcomes. In high-grade gliomas (HGG), we observed immune activation and T-cell infiltrates in tumors that have historically been considered exclusively immune cold. There were genomic correlates of inflammation levels, with BRAF-V600E-mutant HGG having the highest inflammation levels and suggesting these may be candidates for combination MEK inhibition and immunotherapy. In mismatch repair deficient HGG, we found that high TIS was a significant predictor of response to immune checkpoint inhibition, and demonstrated the potential for multimodal biomarkers (TIS plus tumor mutation burden) to improve treatment stratification. Importantly, while overall patterns of immune activation were observed for histologically and genetically defined tumor types, there was significant variability within each entity, indicating that the TIME must be evaluated as an independent feature from diagnosis. In sum, in addition to the histology and molecular profile, this work underscores the importance of reporting on the TIME as an essential axis of cancer diagnosis in the era of personalized medicine.
DIPG-55. DISSECTING THE ECOSYSTEM OF PEDIATRIC DIFFUSE MIDLINE GLIOMA
Authors: Julie Morscio, Sandra Jacobs, Frederik De Smet
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric gliomas are heterogeneous tumors encompassing high grade (pHGG) and low grade (pLGG) subtypes. For tumors not amenable to surgery, in particular high grade H3K27 mutant diffuse midline glioma (DMG), no curative options exist. DMG is characterized by 1) extensive heterogeneity of tumor cells that can exist in different interchangeable cellular states mimicking normal development and 2) extensive heterogeneity of the tumor microenvironment (TME). A better understanding of the DMG ecosystem is needed for therapeutic target identification. METHODS Publicly available single cell RNA seq data of DMG (n=17, Jessa et al. Nat. Genet. 2022), high grade pediatric glioblastoma (GBM, n=16, scPCA) and low grade tumors (ganglioglioma, n=5; pilocytic astrocytoma, n=14, scPCA) were analyzed to define key molecular characteristics and differences between these pediatric brain tumors. Doublet cells were removed from each dataset and tumor and TME cells were discriminated based on marker gene expression and inferred CNVs. RESULTS In DMG, glioma cellular states and TME heterogeneity differed depending on the tumor location. DMG arising in the pons harbored a bigger fraction of astrocyte-like glioma cells whereas oligodendrocyte-like cells were more abundant in thalamic tumors. In line with this observation, Liana cellular communication analysis inferred more intratumoral (autocrine) signaling involving oligodendrocyte-like glioma cells in thalamic tumors (e.g. NCAM1-PTPRZ1, NLGN4X-NRXN1, NTN1-DSCAM) than in pons tumors. Notably, the TME of thalamic tumors contained a bigger fraction of immunotolerant macrophages expressing CD163 or VSIG4. In contrast, pons tumors harbored a unique cluster of VEGFA expressing astrocytes, not found in GBM or pLGG. Liana analysis inferred COPA/APP-CD74 interaction between VEGFA+ astrocytes and CD163/VSIG4+ macrophages and microglia, potentially contributing to an immunotolerant TME in pons DMG. CONCLUSIONS In DMG, patterns of tumor and TME composition associated with tumor location were uncovered. Furthermore, unique TME celltypes could contribute to the particularly aggressive nature of these tumors.
RADT-04. ASSESSMENT OF CLINICAL AND NEUROLOGICAL ALTERATIONS BEFORE RADIATION THERAPY IN CHILDREN WITH MALIGNANT BRAIN TUMORS
Authors: Mara Lecchi, Alessandra Erbetta, Claudia Cavatorta, Olga Nigro, Chiara Maria Oprandi, Emilia Pecori, Veronica Biassoni, Elisabetta Schiavello, Paolo Grampa, Silvia Meroni, Anna Nigri, Denis Peruzzo, Ombretta Alessandro, Rita Laureanti, Luca Mainardi, Sabina Vennarini, Geraldina Poggi, Emanuele Pignoli, Paolo Verderio, Maura Massimino
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Young patients with malignant brain tumors show neurocognitive alterations as both consequences of the tumor and of treatments received. A prospective study of longitudinal radiation damages after focal RT was activated in 2017. We present the first analysis correlating tumor localization, symptoms, neurological/endocrinological impairments, surgery/ies if adopted, and cognitive assessments at the time of enrollment. METHODS Sixty-six children eligible for focal RT were enrolled and underwent a neurocognitive assessment based on standardized tests (“impaired”/“non-impaired”). The database included demographical, clinical and pathological variables. The latter, together with MRI morphological scans, were used to define different kind of damage scores. The pattern of associations between clinical variables and damage scores was investigated. RESULTS Patients median age was 8 years; the most frequent tumor was Ependymoma (41%) and Posterior Fossa (29%) was the prevalent tumor site. All but 5 children (with Germ Cell Tumors), had undergone surgery and 32 had undergone chemotherapy before irradiation and evaluations. Ad-hoc scores of neurological deficits and endocrine alterations were created to characterize each patient. Moreover, structural abnormalities were quantified in a score for each cortical/subcortical region. Patients with posterior fossa Ependymomas and infratentorial tumors showed higher neurological damage scores. Endocrine alterations were more serious in supratentorial tumors, specifically in patients with Craniopharyngioma and Germ Cell tumors of the sellar region and ventricular system. Deficit scores were not associated to the presence of hydrocephalus and surgery, unlike endocrine alteration scores. The median number of child’s structural damaged areas was equal to 2 (IQR: 2-3). Tumor sites of patients with an impaired or non-impaired full-scale IQ or visual-perception index, was found to be different. CONCLUSIONS The analysis of baseline evaluations highlights damages preexisting to irradiations and generated by multiple factors. In light of these findings, damages over time could be better investigated by distinguishing multiple generating factors.
DIPG-04. THE BENEFIT OF CRANIOSPINAL IRRADIATION (CSI) RESCUE IN PHASE 2 RANDOMIZED STUDY OF RADIOTHERAPY (RT), CONCOMITANT NIMOTUZUMAB AND VINORELBINE AND RE-IRRADIATION AT RELAPSE, VERSUS MULTIPLE ELECTIVE RADIOTHERAPY COURSES WITH CONCOMITANT VINORELBINE AND NIMOTUZUMAB FOR NEWLY DIAGNOSED CHILDHOOD AND ADOLESCENCE DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Maura Massimino, Veronica Biassoni, Angela Mastronuzzi, Elisabetta Schiavello, Francesco Barretta, Lucia Quaglietta, Claudia Milanaccio, Emilia Pecori, Antonella Cacchione, Valentina Di Ruscio, Silvia Chiesa, Giuseppe Scimone, Salvina Barra, Lucia De Martino, Olga Nigro, Antonia Ramaglia, Stefania Picariello, Antonio Verrico, Stefano Vallero, Anna Mussano, Sabina Vennarini, Giuseppina Calareso, Marta Podda, Giovanna Gattuso, Giuseppe Cinalli, Manila Antonelli, Chiara Dossena, Francesca Romana Buttarelli, Francesca Gianno, Simone Minasi, Piergiorgio Modena, Loris De Cecco
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND This trial evaluated feasibility,response,PFS/OS of a randomization comparing two different RT schedules for DIPG while administering the same systemic treatment. We moreover evaluated the benefit of craniospinal irradiation(CSI) in case of disseminated(D) relapse. METHODS Patients: 2-21 years-old with at least radiologically verified DIPG (MRI blindly reviewed at diagnosis,every 12 weeks thereafter) and symptoms duration below 6 months. Biopsy required if atypical imaging, also allowed after adequate consensus.Vinorelbine 20 mg/m2+nimotuzumab 150 mg/m2 were administered weekly for 12; thereafter every other week until tumor progression or for up to 2 years. Standard(ST) arm was full brainstem/focal tumor site RT at total dose of 54Gy(1.8Gy/day); for local progression re-irradiation was proposed at 19.8Gy, in case of dissemination CSI at 36Gy was offered.Experimental(SP) arm included three elective courses of RT at defined time-points(36Gy, 19.8Gy and 19.8Gy) with reirradiation for relapse at 9 Gy/36 Gy as above described. Incidences of local(L) and D progression were assessed in a competing risk setting. RESULTS 55 patients were included from 4 Italian centers,27 in ST,30 males, median age 7.1 years. Median follow-up 39.1 months. Fifteen patients needed a shunt,13 during treatment;23 were biopsied,in 21 according to local protocols.22/23 tumors had H3.3K27 mutation. 53 relapsed, 34 L,13 D,6 L+D.Fifteen/19 with a D component receiving CSI had a median survival of 7.6 months after relapse, significantly higher than that of the 4 without CSI(median 2.9 months,P=0.020). Patients submitted to biopsies had more D(P=0.017) and less L progression(P=0.058). SP irradiation and any reirradiation at relapse were feasible and never produced significant radionecrosis.Median EFS/OS for the whole series were 8.4/14 months, respectively; not significantly different between patients with local vs. disseminated relapses. CONCLUSIONS Reirradiation, even if CSI, confirmed feasible and benefitted patients OS.Randomization results will be later reported.
PALC-01. CARING FOR DYING CHILDREN: EXPERIENCES OF FAMILY CAREGIVERS OF CHILDREN RECEIVING PEDIATRIC PALLIATIVE TREATMENT
Authors: Müberra Tanrıverdi, Güleser Güney Yılmaz
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Caring for children living with life-threatening and life-limiting illnesses can be challenging for families. Parents’ roles as primary caregivers can be complex, with extensive responsibilities. METHOD A mixed-design study was conducted with the caregivers of 26 children receiving treatment in palliative care. In the qualitative part of the research, a semi-structured interview was conducted and the question “What does caring for a child with advanced stage cancer mean to you? What are your concerns and concerns?” were asked. In the quantitative part, the caregiving burden scale, Beck Anxiety Questionnaire and WHOQOL-BREF quality of life scale were used. The relationship between quality and other factors was examined with Pearson correlation analysis. Phenomenological content analysis was performed for qualitative data. RESULTS As a result of the analysis of the data, two main themes were identified. The main themes from family caregivers’ experiences included (1) fear and anxiety about losing their child, and (2) disconnection from other children and families. A statistically significant negative relationship was detected between caregivers’ caregiving burden, anxiety levels, quality of life and sub-parameters (General Health, Physical Health, Mental Health, Social Health, Environmental Health) (p&amp;lt;0.001). CONCLUSION Caring for a dying child with cancer can pose psychological challenges as well as medical and physical ones. Families’ resilience, family dynamics and quality of life can be significantly affected. Treatment processes in palliative and oncological care are multifactorial and should include families.