tbuckley/cabot-search huggingface dataset:
PALC-03. MEDICAL AID IN DYING: EXPERIENCE IN THE CENTER FOR CANCER AND BLOOD DISORDERS AT CHILDREN’S HOSPITAL COLORADO
Authors: Shelby Winzent-Oonk, Chelsea Vallejos, Molly Hemenway, Holly B Lindsay, Adam L Green
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medical Aid in Dying (MAiD) is now legal in 10 US states and Washington, DC, allowing terminally ill patients to self-administer medications to peacefully end their life. There is little published on pediatric hospitals’ approach to young adult patients requesting MAiD. METHODS We review the two patients who have participated in MAiD at the Center for Cancer and Blood Disorders at Children’s Hospital Colorado (CHCO). We also explore publicly available Colorado MAiD statistics. RESULTS Between 2017 and 2022, there have been 1,090 prescriptions written for MAiD medication in Colorado, 5 of which were for patients aged 18-34 (0.5%). Two of these patients were treated at CHCO. Patient A was a 26 year old male with a CNS non-germinomatous germ cell tumor whose treatment was complicated by mucormycosis and severe engraftment syndrome. He relapsed 23 months after completing therapy. He had neurologic decline including ataxia and blindness, at which time he requested MAiD. Patient B was a 24 year old male with multiply recurrent IDH-mutant medullary high grade glioma. With metastatic progression, he had many tumor-related symptoms including dysphagia, dysarthria, and weakness impacting his activities of daily living, so he requested MAiD. Both patients had multidisciplinary care conferences with neuro-oncology, social work, ethics, psychology, and palliative care. After completing psychological evaluation and all steps required by law, they were prescribed DDAMP2 (digoxin 50 mg, diazepam 1 gram, morphine 15 grams, and propranolol 2 grams). Both patients took the medications and died peacefully. Barriers encountered included infrequency of MAiD requests leading to unclear policies and processes. CONCLUSIONS Young adults represent a small but important subset of those seeking MAiD prescriptions. Despite challenges, patients were able to receive MAiD without delay in a compassionate manner. Our experience may be applicable to other pediatric hospitals facing these requests.
LGG-43. LASER-ASSISTED ENDOSCOPIC RESECTION OF TECTAL GLIOMA IN A 3-YEAR-OLD CHILD
Authors: Francesco Tuniz, Sara Fabbro, Daniele Piccolo, Marco Vindigni, Ilaria Liguoro, Chiara Pilotto, Maristella Toniutti, Serena D’Agostini, Maria Cristina De Colle, Enrico Pegolo, Paola Cogo, Miran Skrap
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric tectal gliomas generally have a benign clinical course. However, some patients may present with non-communicating hydrocephalus needing endoscopic procedures. Historically, lasers have been used in neurosurgical procedures including neuroendoscopy, but their adoption was limited by a significant rate of complication due to their inappropriate wavelength and uncontrollable tissue interaction. Recently, a 2-micron near-infrared laser with adequate wavelength and minimal tissue penetration became available. CASE-REPORT We describe the case of a 3-year-old child who presented with gait ataxia, papilloedema and headache. Magnetic Resonance (MR) was performed and he was diagnosed with obstructive hydrocephalus due to tectal glioma. Endoscopic third ventriculostomy (ETV) and simultaneous endoscopic biopsy were performed during the same surgery using a single burr hole with a rigid endoscope, a 2-micron continuous-wave thulium laser and the aid of neuronavigation. After tumoral sample removal, the laser was used for hemostasis and to evaporate tissue near the tumour without mechanical stress to the brain tissue. The final histological analysis identified a non-otherwise specified (NOS) low-grade glioma. The hospitalization was uneventful and the boy was discharged home after 4 days. No new cognitive impairment was reported secondary to this procedure and the symptoms present in the preoperative period completely improved. At 1-year follow-up, neurological examination findings were unremarkable, and there was no radiographic evidence of tumour progression. CONCLUSIONS The use of the neuroendoscopic laser permits cutting and coagulating simultaneously, avoiding multiple instruments’ use (forceps and coagulation). It therefore makes neuroendoscopic procedures more straightforward with a minimum need to change tools, and particularly suitable also in a pediatric setting.
ATRT-10. ANTI-B7-H3 CHIMERIC ANTIGEN RECEPTOR NK CELLS SHOW ANTIGEN SPECIFIC CYTOTOXICITY AGAINST ATYPICAL TERATOID/ RHABDOID TUMORS<i>IN VITRO</i> AND<i>IN VIVO</i>
Authors: Jun Choe, Sachiv Chakravarti, Natalie Holl, Ruyan Rahnama, Megan Zinsky, Danielle G Jones, Stamatia Vorri, Arjun Modi, Eric H Raabe, Challice L Bonifant
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Atypical teratoid/rhabdoid tumors (AT/RTs) are the most common malignant CNS tumor in infants. AT/RT patients have a 5-year overall survival rate of ~35% and high rates of relapse, emphasizing a dire need for new safe and effective therapies. These therapy-resistant tumors frequently overexpress cell surface molecule B7-H3 (CD276). CAR-NK cells have several advantages over CAR-T cells. NK cells can be obtained from healthy donors and produced as an “off-the-shelf” product. NK cells also have a lower risk of inflammatory toxicity and graft-versus-host disease compared to T-cells when transferred across the HLA barrier. METHODS We have designed a library of variable affinity B7-H3-targeted CARs, produced γ-retroviral vector, and used this for generation of B7-H3 CAR-NK cells. We verified B7-H3 expression in a panel of AT/RT cell lines, and further engineered firefly luciferase expressing AT/RT (CHLA06.ffLuc, BT12.ffLuc, BT37.ffLuc) as well as a CHLA06-derived B7-H3 knockout. We developed an orthotopic CHLA06.ffLuc xenograft model. We tested CAR-NK cell functionality using in vitro co-culture and cytotoxicity assays. In vivo study was performed in our xenograft with intratumoral delivery of CAR-NK cells. RESULTS B7-H3 targeted CAR-NK cells demonstrate target-specific cytotoxicity when compared to untransduced NK cells (36.8±12.5% vs. 72.4±24.2% at effector:target ratio of 1:1, n=3). CRISPR/Cas9 mediated knockout of B7-H3 in target cells abolished the difference in CAR vs. no-CAR NK-mediated target killing. When delivered intracranially to CHLA-06 orthotopic xenograft bearing mice, B7-H3 CAR NK cells eliminate tumor cells and prolong survival, whereas unmodified NK cells did not (log-ranked median survival = 20 vs. 84 days, p&amp;lt;0.0001). CONCLUSIONS Targeting AT/RTs with an anti-B7-H3 CAR-NK cell therapy may provide a safe and effective treatment for patients who have extremely limited therapeutic options. Direct intracranial injections of cell therapies into pediatric patients is currently being explored in clinical trials.
DIPG-83. RBPJ-SIX1 AS A TUMOR SUPPRESSOR AXIS IN DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Anna Racanelli, Chen Shen, Samantha L Gadd, Mili Chizhik, Ruby Setara, Yi Ge, Alexander J Schüpper, Montserrat Puigdelloses, Dolores Hambardzumyan, Nadejda M Tsankova, Oren J Becher
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is a rare, incurable pediatric brain tumor that arises in the brainstem. Despite decades of clinical trials, no treatments have proven effective at prolonging survival for children with this disease. A deeper insight into the epigenetic and genetic changes driving DIPG are imperative for identifying therapeutic targets. A defining feature of DIPG is the histone H3 lysine to methionine mutation at residue 27 (H3K27M), which prevents H3K27 trimethylation. The H3.1K27M mutation, specifically, co-segregates with mutations in the Activin A receptor ACVR1. Tumor cells with both mutations have significantly higher levels of the transcripts and proteins that inhibit proneural gene expression in the NOTCH signaling pathway. METHODS We used the replication-competent avian sarcoma-leukosis virus long terminal repeat with splice acceptor/tumor virus A (RCAS/Tv-a) system to evaluate the role of various NOTCH signaling proteins in a genetically engineered mouse model of DIPG. We also performed RNA sequencing of specific NOTCH signaling protein knockout DIPG models. RESULTS Knocking out Hairy of Enhancer Split-1 (Hes-1) in combination with H3K27M and ACVR1 mutations did not significantly reduce survival compared to control. However, knocking out Recombination Signal Binding Protein for Immunoglobulin kappa J region (RBPjk)—a transcriptional regulator upstream of Hes-1—did significantly reduce survival compared to wild-type RBPjk expression. RNA sequencing of RBPjk knockout tumors revealed that Sine Oculis-related Homeobox 1 (Six1) was the most top most differentially expressed gene. To assess whether Six1 downregulation drives DIPG tumorigenesis in RBPjk knockout tumors, we overexpressed Six1 in a murine model of DIPG with H3.3K27M and p53 loss. Six1 overexpression did not significantly prolong survival or decrease tumor grade but trended toward significance. However, Six1 overexpression significantly increased tumor cell proliferation. CONCLUSIONS These results indicate that Six1 could function as a potential tumor suppressor in DIPG, necessitating further exploration.
DIPG-28. CHEMOGENOMIC PROFILING OF HDAC ISOFORMS REVEALS A PARADIGM OF ESSENTIALITY WITH THERAPEUTICALLY RELEVANT IMPLICATIONS IN H3K27-ALTERED DIFFUSE MIDLINE GLIOMA
Authors: Andrew Groves, Rebecca Poetschke, Tingjian Wang, Diana H Chin, Yaw Asante, Hyunmin Kim, Shanging Gu, Maria Trissal, Jenna Labelle, Gustavo Alencastro Veiga Cruzeiro, Kristen L Jones, Amy Cameron, Louise Clark, Quang- De Nguyen, Berkley E Gryder, Mariella G Filbin, Jun Qi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse midline glioma (DMG), H3K27-altered, is a lethal pediatric brain tumor driven by epigenetic dysregulation. Histone deacetylase (HDAC) inhibitors have been identified as a promising drug class; however, the precise mechanism of efficacy for these agents in DMG has not been fully explored. Furthermore, their translational potential has been limited by off-target effects and poor CNS penetration of clinically available drugs. METHODS We investigated the genetic and chemical dependencies of HDAC isoforms in DMG cell lines using CRISPR/Cas9 screening and an HDAC inhibitor toolbox. We identified an HDAC inhibitor termed “Compound 26” with class I isoform selectivity and excellent CNS penetration (brain/plasma AUC of &amp;gt;7). Effects of Compound 26 on DMG cells was evaluated in-vitro through assessment of cytotoxicity, proliferation and apoptosis. Mechanistic studies were undertaken using bulk RNAseq and HiChIP (H3K27ac, H3K27me3). Efficacy of Compound 26 in-vivo was determined using an aggressive orthotopic xenograft model. RESULTS We confirmed that HDAC class I isoforms are dependencies in DMG cell lines, with HDAC2 representing a selective dependency that is highly expressed in patient tumors. Compound 26 is cytotoxic in DMG cells, reducing proliferation through cell cycle arrest. Differential expression analysis confirmed profound effects on cycling programs with Compound 26 treatment. Furthermore, analysis of genome structure using HiChIP revealed global increases in H3K27ac contacts, with notable spreading along key cell cycle gene bodies such as p16 (CDKN2A). Interestingly, treatment with Compound 26 also significantly increased global H3K27me3 contacts, which is canonically decreased in H3K27-altered DMG. Most importantly, Compound 26 was well tolerated, effectively crossed the blood-brain barrier, and significantly extended survival in an aggressive DMG-orthotopic xenograft model. CONCLUSIONS This study comprehensively outlines the reliance of DMG cells on HDAC class I isoforms, elucidates novel mechanisms for this dependency, and highlights a compelling new agent to bypass prior translational pitfalls
MODL-14. TARGETING GL1/GL2-DNMT1-UHRF1 EPIGENETIC COMPLEX DISRUPTION VIA BET INHIBITION IMPAIRS SHH MB DEVELOPMENT
Authors: Nitish Jangde, Daniel Wynn, Isabelle Egan, David Robbins, Nagi Ayad
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Sonic Hedgehog Medulloblastoma (SHH MB) shares 30% among all molecular subtypes of medulloblastomas (MBs). Constitutive activation of SHH signaling in the cerebellum’s granular cell precursors (GCPs) is critical for this MB development. When SHH receptor PATCHED-1 (PTCH1) is mutated, stimulation of this receptor by SHH ligand binding leads to derepression of heterotrimeric GTP-binding protein–coupled receptor Smoothened (SMO) eventually altering the activity, location, and stability of the three downstream glioma associated oncogene (GLI) family members: GLI1, GLI2, and GLI3. GLI1 and GLI2 mostly function as transcriptional activators, while GLI3 mainly plays a repressor role. The bromodomain and extra-terminal domain (BET) family of proteins comprises four conserved members (Brd2, Brd3, Brd4, and Brdt), which are critical regulators of GLI1 and GLI2-mediated transcription. METHODS In the present study, we pharmacologically inhibited BETs with a previously described BET inhibitor, BMS986158, and a novel BET inhibitor, UM002, discovered by our lab. We treated human SHH MB cells (ONS76 cells) in vitro and ex vivo in mouse SHH MB cells (from Ptch1 conditional knockout mice) with minimum effective concentrations of these inhibitors. We screened for GLI1/GLI2-DNMT1-UHRF1 epigenetic complex components expressions by immunoblotting and assessed the effectiveness of inhibiting their interactions by performing PLA assays. RESULTS In this study, we show that pharmacological inhibition of BETs leads to attenuated GLI1 and GLI2 levels. This GLI1 and GLI2 inhibition eventually disrupts the previously reported GL1/GL2, DNMT1-UHRF1 epigenetic complex, which is crucial for SHH MB development. A previously described BET inhibitor, BMS986158, and a novel BET inhibitor, UM002, synthesized and characterized by our lab can inhibit BETs. This could be a potential therapeutic approach targeting GLI-associated epigenetic complexes to treat SHH medulloblastoma.
BIOM-04. ALTERED IMMUNE ACTIVATION AND REDUCED LYMPHOPOIESIS IN TREATMENT NAÏVE PEDIATRIC BRAIN TUMOUR PATIENTS
Authors: Giada Del Baldo, Marco Rosichini, Maria Vinci, Andrea Carai, Antonella Cacchione, Carmen Dolores De Luca, Francesca Benini, Shirley Genah, Marianna Concetti, Angela Mastronuzzi, Franco Locatelli, Enrico Velardi
Journal: Neuro-Oncology (2024)

Abstract Pediatric central nervous system (CNS) tumors are the most common solid tumor in children. Despite improvements in diagnostic and therapeutic approaches over time, treatment effectiveness remains unsatisfactory. Optimal immune function is critical to protect against development and dissemination of cancer and to offer the ideal conditions for the success of anticancer treatment. Here we analyzed the peripheral immunological features of patients affected by pediatric brain tumors, the process of de novo T- and B-cell development and its association with the lymphopenia often observed in these patients. Eighty-six steroids-naïve pediatric patients with CNS tumors at the onset of the disease were included in the study. Brain tumors were classified into low-grade gliomas (LGG: n=44, 51%), pediatric-type diffuse high-grade gliomas (pHGG: n=16, 19%), medulloblastoma (n =9, 10%), and other CNS tumors (n =17, 20%). Patient’s peripheral immunological status was analyzed by flow-cytometry and by evaluating T-cell receptor excision circles (TRECs) and kappa-deleting excision circles (KREC) to quantify T- and B-cell neogenesis. Although all patients showed tendencies towards low lymphocyte counts, this effect was particularly evident in pHGG patients. T-cells of pHGG patients displayed a shift from naïve to effector memory phenotype compared to age-matched controls. On the other hand, LGG patients were characterized by an expansion of the T-central memory pool and higher expression of T-cell activation markers. Both patient cohorts exhibited decreased frequency of B-cells with activated phenotype. Interestingly, pHGG patients exhibited reduced thymic function as revealed by reduced levels of the recent thymic emigrant population and TRECs. In addition, LGG and pHGG patients were characterized by lower KREC values, suggesting suboptimal B-cell formation. At diagnosis, pediatric patients with brain tumor show alterations in their immunological status and reduced thymic and medullary lymphopoiesis, particularly pronounced in pHGG, which may contribute to explain the systemic lymphopenia characterizing these patients.
RADT-05. MATURE OUTCOMES OF A PHASE II PROSPECTIVE STUDY OF PROTON RADIOTHERAPY FOR LOCALIZED BRAIN TUMORS
Authors: Soo Kang, Emily Anderson, Benjamin Bajaj, Keith Allison, Sara Gallotto, Miranda Lawell, Alisa Perry, Torunn Yock
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Proton radiotherapy (PRT) is a highly targeted form of radiation that spares more normal brain tissue compared to modern photon radiotherapy. Therefore, we expect the late effect profile in children treated with PRT with curable brain tumors should be improved. METHODS Between 2010-2022, 100 patients were enrolled, treated with PRT, and then followed for disease control, hearing, neurocognitive and endocrine outcomes. Late effects of the tumor and treatment delivered were graded using CTCAE v4.0. RESULTS Median age at PRT was 8.0 years (1.1-20.8) and median follow up was 8.7 years (0.3-12.7). Tumor types included 40 (40%) ependymomas, 19 (19%) low grade gliomas (LGG), 21 (21%) craniopharyngiomas, and 20 (20%) other histologies. 26% of patients were treated with chemotherapy in addition to PRT. The location of PRT was 38 (38%) infratentorial, 56 (56%) supratentorial, and 6 (6%) both. The median radiation dose was 52.2 GyRBE (48.6-59.4). 8-year event-free survival (EFS) and overall survival (OS) was 71.7% and 86.2% for all patients. 8-year EFS and OS was 59.9% and 82.4% for ependymomas, 78.2% and 94.7% for LGG, 80.0% and 87.7% for craniopharyngiomas and 79.1% and 84.7% for all other tumor types. 19% of patients had new grade 3+ toxicities that were at least possibly related to radiotherapy. Baseline full-scale intelligence quotient (FSIQ) was 98.0 and follow-up FSIQ was 101.8 (p=0.14). 43% of patients had new endocrine deficiencies after radiation. 8 patients suffered new high-grade hearing loss after PRT. Dosimetry on critical brain structures was collected and correlated with late effects. More details will be presented at the conference. CONCLUSION PRT remains an effective treatment for children with curable brain tumors. While late effects of the tumor and treatment are still present, the overall burden of late effects is lower than other reports.
QOL-01. FEASIBILITY AND EFFICACY OF DIETARY AND LIFESTYLE INTERVENTIONS FOR HYPOTHALAMIC OBESITY DURING CHILDHOOD: A SYSTEMATIC REVIEW
Authors: Ichelle van Roessel, M van den Brink, J Dekker, B G Ruitenburg- van Essen, W J E Tissing, H M van Santen
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Hypothalamic obesity may be encountered in children with genetic or syndromal disease or after (treatment of) a suprasellar tumor. There is currently no effective treatment for hypothalamic obesity, and dietary and lifestyle interventions are the cornerstone of obesity treatment. The obesity in patients with HD is the consequence of decreased satiety feelings (hyperphagia), in combination with a decreased resting energy expenditure and increased fat storage due to hyperinsulinemia. We searched the literature for evidence on feasibility and efficacy of dietary and lifestyle interventions for childhood hypothalamic obesity. METHODS A systematic search was conducted in Pubmed, EMBASE, Cochrane and CINAHL. Studies assessing the feasibility, safety or efficacy of any dietary or lifestyle intervention in children with hypothalamic overweight or obesity, were included. Risk of bias was assessed with an adapted Cochrane Risk of Bias Tool. RESULTS In total, twelve studies were included, with a total number of 118 patients (age 1 – 19 years) of whom one with craniopharyngioma, one with ROHHAD-NET syndrome, 50 with monogenic obesity and 66 with Prader-Willi syndrome. Four studies reported on feasibility: all diets were judged to be feasible. Seven studies reported on the effect of a dietary intervention; a well-balanced restrictive caloric diet (30% fat, 45% carbohydrates and 25% protein) and various hypocaloric diets (8-10 kcal/cm/day) were effective in terms of weight stabilization or decrease. No negative effect on linear growth was reported. Four studies reported on specific lifestyle interventions. Combined dietary and lifestyle intervention resulted in decreased BMI, however BMI returned to baseline values in the long-term. CONCLUSIONS Hypocaloric diet or restrictive macronutrient diet with lower percentage of carbohydrates seems feasible and effective for childhood hypothalamic obesity. Lifestyle interventions only resulted in BMI decrease in short-term, indicating that additional guidance is needed to successfully implement lifestyle interventions in this group of patients.
NFS-26.<i>RB1</i>-ALTERED SUBTYPE (GROUP A) PINEOBLASTOMA AS A PART OF «TRILATERAL RETINOBLASTOMA» PHENOMENON: NEURO-ONCOLOGICAL AND OPHTHALMIC-ONCOLOGICAL VIEW
Authors: Andrey Sergeevich Levashov, Yuriy Alexandrovich Serov, Tatyana Leonidovna Ushakova, Anna Mikhailovna Stroganova, Marina Vladimirovna Ryzhova, Sergey Kirillovich Gorelyshev, Shavkat Umidovich Kadirov, Alexandra Igorevna Terentyeva, Marina Vladimirovna Grigoryeva, Vladimir Georgievich Polyakov, Olga Valeryevna Gorovtsova, Vasiliy Andreevich Grigorenko
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND RB1-altered subtype (Group A) pineoblastoma as a part of «Trilateral retinoblastoma» is an extremely rare phenomenon. But over the past 10 years, the incidence of this disease has been increasing. Optimal therapeutic strategy is unknown. The aim of this study was to estimate the incidence of this phenomenon among patients with retinoblastoma, age at onset of retinoblastoma/RB1-altered pineoblastoma and genetic, gender, age predisposition. DESIGN/METHODS From 2019 to 2023 years 256 pediatric patients with de novo retinoblastoma were treated in the FSBI «N.N.Blokhin National Medical Research Center of Oncology». RB1-altered pineoblastoma was revealed in 9 cases (3,5% of all patients, 9,5% among patients with bilateral retinoblastoma, 6,6% for patient with the onset of retinoblastoma under the age of 12 months). Diagnosis was determined according to familial history, retinal camera and MRI data, histology, immunohistochemistry and Illumina Infinium methylation EPIC Bead Chip method (FFPE tumor samples), NGS and MLPA methods for detection of RB1 germline mutation status (blood samples). Therapeutic options for patients with RB1-altered subtype pineoblastoma were presented as like–COGARET0321, like–HIT–MED2017/2020, selective intra-arterial chemotherapy, intravitreal chemotherapy, transpupillary thermotherapy, brachytherapy. RESULTS Gender ratio was 1:2 (3 male and 6 female). In all cases, intraocular retinoblastoma was bilateral. Family history was revealed in two cases. Age at onset of retinoblastoma: less than 6 months in 8 cases, all cases less 2 years, median 3±1,9 months [1,5-20,5]. Median age at onset of RB1-altered subtype pineoblastoma was 20,5±7,3 months [1,5-57,5]. A synchronous variant of the disease was identified in 5 cases, metachronous in 4. Pineoblastoma of pineal region was detected in 7 cases, suprasellar region in 2. Six out of 9 patients are alive, median follow-up 16,5±5,1 months [1,5-43,0]. CONCLUSION It is necessary to expand both regional and international interdisciplinary cooperation to develop an optimal algorithm for the diagnosis and treatment of this disease.