bluuebunny/crossref_metadata_2025_split huggingface dataset:
MODL-24. Focused ultrasound-mediated blood-brain barrier opening and panobinostat in a thalamic syngeneic murine DMG model is feasible and safe.
Authors: Webster Carrion Andrea , Wei Hong-Jian , McQuillan Nicholas , Tazhibi Masih , Kokossis Danae , Berg Xander , Minns Hanna , Zhang Xu , Zhang Zhiguo , Wang Junqiang , Fernandez Ester Calvo , Jan Chia-Ing , Padilla Oscar , Gartrell Robyn D , Becher Oren , Jr James H Garvin , Pavisic Jovana , Szalontay Luca , Konofagou Elisa E , Zacharoulis Stergios , Wu Cheng-Chia 
Published: June 2022

Abstract
Diffuse Midline Glioma with H3K27M mutation (DMG) is an aggressive unresectable central nervous system tumor of the brainstem, midline thalamus, or spine. Prognosis is poor and systemic agents have been ineffective partially due to limited permeability of the blood brain barrier (BBB). Non-invasive low intensity focused ultrasound (FUS) can be used for BBB opening (BBBO). Our preclinical studies showed safety and feasibility of targeting and BBBO in the brainstem; however, to our knowledge, FUS-guided BBBO for thalamic DMG has yet to be reported. RNA-seq was performed on mouse syngeneic DMG cells 4423 (PDGFB+, H3.3K27M, p53−/−) and results recapitulated molecular programs seen in human tumors. 4423 cells were injected into the thalamus of male B6 (Cg)-Tyrc-2J/J mice at 1.6mm lateral and 1.8mm posterior to the bregma at a depth of 3.2mm. MRI at 14-21 days post injection confirmed thalamic tumor growth. Histological analysis with Hematoxylin and Eosin stain was consistent with thalamic DMG. Tumor implantation rate was 85% and median survival was 38 days post injection. To test safety and feasibility of BBBO for thalamic tumors, a 1.5 MHz FUS transducer was used with concurrent microbubble injection. BBBO assessed by contrast-enhanced MRI. FUS achieved BBBO targeting the thalamic tumor without increased morbidity or mortality and BBB closure was observed on day 3 post-sonication. Next we tested the tolerance of drug delivery with panobinostat post-FUS at a dose of 20mg/kg weekly. The results are preliminary at this time; however, animals tolerated the combination therapy without morbidity or mortality. Preclinical models are crucial to improve the development of new therapeutic strategies. Establishing this syngeneic thalamic DMG murine model provides the opportunity to test FUS as a non-invasive drug delivery technology for thalamic DMG compared to brainstem DMG, and to re-visit therapeutic agents previously considered ineffective due to limited penetration of the BBB.
MODL-25. Radiation and focused ultrasound–mediated blood–brain barrier opening for DMG: safety and feasibility of combinatorial therapy
Authors: McQuillan Nicholas , Tazhibi Masih , Wei Hong-Jian , Pouliopoulos Antonios , Bendau Ethan , Carrion Andrea Webster , Berg Alexander , Kokossis Danae , Zhang Xu , Zhang Zhiguo , Englander Zachary , Yoh Nina , Jan Chia-Ing , Gartrell Robyn D , Garvin James , Szalontay Luca , Konofagou Elisa , Zacharoulis Stergios , Wu Cheng-Chia 
Published: June 2022

Abstract
Diffuse midline glioma (DMG) is a pediatric tumor with dismal prognosis. Systemic therapeutic strategies have been unsuccessful to date and radiotherapy (RT) remains the standard of care. A central impediment to systemic therapy is the blood-brain barrier (BBB), which precludes drug delivery to the tumor site. Focused ultrasound (FUS) with intravenous microbubbles can transiently and non-invasively circumvent the BBB to enhance drug delivery. Nevertheless, it remains unclear whether FUS is safe at the brainstem in combination with clinical doses of RT. In this study, we hypothesized that FUS-mediated BBB-opening (BBBO) is safe and feasible with 39 Gy RT. To establish a safety timeline, we administered FUS to the brainstem of nontumor bearing mice concurrent with or adjuvant to radiation; then, we validated our findings in a syngeneic orthotopic xenograft DMG model which received repeated sonication concurrent with RT. Male B6 (Cg)-Tyrc-2J/J albino mice received intracranial injection of 4423 mouse DMG cells (PDGFB+, H3.3K27M, p53−/−) at a location posterior and lateral to the lambda. A clinical RT dose of 39 Gy in 13 fractions was delivered to the brainstem with the Small Animal Radiation Research Platform (SARRP) or the XRAD-320 irradiator. FUS was administered with a 0.5 MHz transducer, and both BBBO and tumor volume were monitored with MRI. FUS-mediated BBBO in nontumor bearing mice receiving RT did not affect cardiorespiratory rate, motor function, and tissue integrity. Moreover, tumor bearing mice tolerated repeated brainstem BBBO concurrent with RT. 39 Gy over 13 fractions offered local control, although disease progression occurred in all animals approximately 3-4 weeks post-RT. Ultimately, repeated FUS-mediated BBB opening concurrent with RT is safe and feasible. In our brainstem DMG model, relapse occurs, making it ideal for future tests of combinatorial RT and FUS-mediated drug delivery.
MODL-28. Patient-derived, three-dimensional organoid platform for pediatric brain tumor modeling
Authors: Baubet Valerie , Beale David , Mariarita Santi , Viaene Angela , Madsen Peter , Jacob Fadi , Ming Guo-li , Hongjun Song , Phillip Storm , Koptyra Mateusz , Adam Resnick 
Published: June 2022

Abstract
Brain tumors have become the leading cause of cancer-related death in children. An important hurdle to scientific and clinical progress in the field has been the limited availability of preclinical tumor models. Historically, few pediatric brain tumor cell lines have been established and these often poorly recapitulate the phenotypes of the original tumors. In recent years, the Children’s Brain Tumor Network (CBTN) has accelerated the development of patient-derived cell lines and xenografts, offering these resources to the community through open-source access. While these models are extremely valuable, their development process can be lengthy and result in clonally selected lines which presents a challenge for studying complex tumor biology. To address the need for three-dimensional tissue culture, our group in conjunction with CBTN, utilized organoid culture from fresh tissue specimens obtained directly from surgical resection of various pediatric brain tumor histologies. This resulted in the development and banking of over 30 organoid models, which included ependymoma, high-grade glioma, medulloblastoma, atypical teratoid-rhabdoid tumor, diffuse midline glioma, and low-grade glioma diagnoses. Tissue was processed within an hour post extraction and cultured with universal media composition for each diagnosis. Organoid growth was observed within 2-3 weeks of initiation and continued for up to three months before banking. Banked organoids established growth upon return to culture. Phenotypic analysis revealed organoid cell composition that represented clinical histology. Importantly, organoids returned to culture post-banking demonstrated similar cell composition to those in the original culture, indicating their utility for subsequent preclinical testing. Here we provide a simple and efficient workflow for the generation and characterization of three-dimensional tumor organoids generated from fresh surgical pediatric brain tumor tissue. The platform has the potential to accelerate investigations into tumor biology and empower a diverse array of translational studies for the pediatric brain tumor field.
RONC-02. Clinical outcome after craniospinal irradiation with pencil beam scanning proton therapy for children and young adults/adolescents with brain tumors
Authors: Bachmann Nicolas , Vazquez Miriam , Bolsi Alessandra , Pachigolla Suvidya , De Angelis Claudio , Ahlhelm Frank , Lomax Antony , Pica Alessia , Weber Damien Charles 
Published: June 2022

Abstract
BACKGROUND: Craniospinal irradiation (CSI) is an essential treatment component to achieve cure for some brain tumors in children and young adults/adolescents (C-AYAs). Multimodal treatment approaches are however associated with treatment-related late toxicities in these developing patients. Pencil beam scanning proton therapy (PBSPT) allows for a minimization of dose delivered to organs at risk and the brain integral dose and, thus, potentially also a reduction of radiation-induced adverse events. We report the clinical outcome and toxicity rates after CSI for C-AYAs treated with PBSPT. METHODS: We reviewed 71 C-AYAs with a median age of 7.4 years (1.7 – 21.3) who received CSI with PBSPT. Medullobastoma (n=42, 59%) and ependymoma (n=8, 11%) were the most common histologies. Thirty-four (48%) patients presented with metastatic disease at diagnosis. Sixteen (23%) patients were treated for tumor recurrence/progression and 9 (13%) patients underwent re-irradiation. Median prescribed total dose was 54 GyRBE (18 – 60.4) and median craniospinal dose 24 GyRBE (18 – 36.8). Toxicities were recorded according to CTCAE v5.0. RESULTS: With a median follow-up time of 24 months (2 – 195), 12 (17%) patients died due to progressive disease. Eight (11%) patients experienced local failure and 15 (21%) distant failure after PBSPT. Estimated 2-year OS, LC and DC was 86.9%, 86.0% and 80.4%, respectively. Grade 3 acute toxicity (thrombocytopenia, neutropenia, nausea) was observed in 5 (7%) patients. Late grade 3 toxicities (stroke, cataract and CNS necrosis) were observed in 3 (4%) patients, 8, 9 and 16 months after PBSPT, respectively. One (1%) patient developed grade 4 CNS necrosis 8 months after CSI. Late grade ≥3 toxicity free rate was 92.3% at 2 years. No radiation-induced secondary cancer was observed. CONCLUSION: Excellent tumor and brain/spinal distant control and a low late grade ≥3 toxicity rate after CSI were observed in our cohort of C-AYAs treated with PBSPT.
RONC-04. Relationship between proton therapy and the development of the limbic system in pediatric posterior fossa tumors
Authors: Leenders Anne E M , de Robalo Bruno M Brito , Janssens Geert O R , Hoving Eelco W , Lequin Maarten H , Partanen Marita H 
Published: June 2022

Abstract
BACKGROUND: Pediatric brain tumor survivors may develop neuropsychological impairments after treatment. The first months after treatment could be a crucial time-window where the development of the brain may be affected by different types of treatments. For example, deficits in memory and learning related to hippocampal damage have resulted in radiotherapy dose constraints to the hippocampus. However, other limbic system substructures, important for cognition or behavior, may suffer from collateral doses. Therefore, we investigated the early effect of treatment on limbic structure volume. We hypothesized that radiotherapy (vs. no radiotherapy) would contribute to a decrease in volume of the limbic structures. METHODS AND MATERIALS: Thirty-eight patients with a tumor in the posterior fossa region (medulloblastoma n=12; pilocytic astrocytoma n=24; other=2) who were diagnosed between June 2018 and September 2020 and were alive ≥1 year diagnosis were included. Patients receiving neurosurgery only (n=26) were compared to patients treated with neurosurgery, proton therapy and chemotherapy (n=12). Limbic structures were automatically segmented in 111 MRI scans. These structures were amygdala, hippocampus (CA1+CA2/3), subiculum, dentate gyrus, parahippocampal gyrus, fornix, mammillary bodies, nucleus accumbens and thalamo-anteroventral nucleus of thalamus. RESULTS: Analyses revealed a significant negative effect of time on the amygdala (p&lt;0.01), hippocampus (CA1) (p&lt;0.001), and dentate gyrus (p&lt;0.01). This indicates that these structures decreased in volume within the first year after diagnosis, independent of radiation treatment. Furthermore, an interaction effect was found between time and radiation in the subiculum (p=0.02) and fornix (p=0.052). CONCLUSION: These results indicate that the volumetric decline were stronger for the patients that received proton radiation. Future comparisons will test how results relate to the volumes in healthy children of the same age. Also, we will investigate whether this abnormal development is associated to the radiation dose and how it relates to the neuropsychological outcomes of the child over time.
RONC-07. Fractionated radiotherapy is required to accurately mimic neurostructural late effects in preclinical models
Authors: Whitehouse Jacqueline , Howlett Meegan , Buck Jessica , Somers Kale , Lawler Jessica , Hii Hilary , Carline Brooke , Kuchibhotla Mani , Sewoo Bhedita , Rosenow Tim , Feindel Kirk , Ebert Martin , Mehnert Andrew , Gottardo Nicholas , Endersby Raelene 
Published: June 2022

Abstract
Pediatric brain cancer patients treated with fractionated radiotherapy commonly develop long-term late side-effects including cognitive deficits. Many preclinical models of late effects have been developed that use a single, high dose of radiotherapy, which does not mimic the fractionated schedule children receive clinically. This study aimed to create a mouse model of late effects using clinically-relevant fractionated radiotherapy, and to measure the effects on the developing brain. Juvenile mice were treated at postnatal day 16 with a single dose of 8Gy whole brain radiation, or a mathematically-equivalent fractionated dose of 18Gy (9 x 2Gy daily fractions). Sham control mice received a CT scan, or 9 x sham CT scans. Mice were allowed to grow to young adulthood (63 days). Ex vivo anatomical MRI scans were performed along with diffusion tensor imaging (DTI) and histology. Mice receiving a single 8Gy radiation dose exhibited significantly decreased volumes in areas including the olfactory bulbs (-19%), hippocampus (-7%), corpus callosum (-9%) and motor cortex (-9%). In contrast, mice receiving fractionated radiotherapy showed fewer significantly decreased regions, although olfactory bulbs were reduced (-12%). Furthermore, doublecortin-positive cells were significantly reduced in the dentate gyrus indicating profound effects of radiotherapy on murine neural stem cells. Few radiotherapy-induced differences were observed by DTI, and immunohistochemistry revealed no changes in myelin basic protein, suggesting that white matter is minimally altered in mice. These results show that preclinical models exhibit treatment-induced late effects, and that commonly-used experimental approaches of single dose radiotherapy induce more neurological changes than an equivalent fractionated dose, thus may over-estimate radiotherapy-induced late effects. We have developed a clinically-relevant fractionated dosing protocol in mice, which replicates late effects experienced by children, and can be used to measure long-term effects of novel chemo/radiotherapy treatment combinations, ensuring children with brain cancer receive treatment both effective and safe treatment.
RONC-18 Radiosurgery for Primary and Metastatic CNS Malignancies in the Pediatric Population
Authors: Chen Katherine , Raleigh David , Sneed Penny , Fogh Shannon , Nakamura Jean , Boreta Lauren , Banerjee Anuradha , Mueller Sabine , Auguste Kurtis , Gupta Nalin , Braunstein Steve 
Published: June 2022

Abstract
PURPOSE: The purpose of this study is to describe outcomes after pediatric radiosurgery for malignant CNS lesions. METHODS: Retrospective chart review was performed for 31 pediatric patients treated at a single institution with Gamma Knife stereotactic radiosurgery (SRS) for primary or metastatic CNS malignancies between 2000-2020. RESULTS: 25 patients were treated with SRS for focal recurrences of primary CNS malignancies, 1 patient was treated in the adjuvant setting after initial resection, and 5 patients were treated for brain metastases. Primary CNS histologies included ependymoma (n=14), glioma (n=4), medulloblastoma (n=2), and meningioma (n=2). 65% were WHO grade 3 or 4. 71% of patients had received a prior course of involved-field external beam radiation to the brain to a median dose of 59.4 Gy in 33 fractions. Median age at SRS was 14 years (range 4-21). Radiosurgery was predominantly performed in a single fraction to a median dose of 17 Gy to a total of 42 targets among 29 patients. Two patients underwent fractionated radiosurgery to 30 Gy in 5 fractions for larger lesions. Median follow up after SRS was 44 months. 7 patients (23%) had no evidence of disease after SRS at a median follow up of 39 months. 6 patients (19%) developed local recurrence at the site of their treated lesion at a median of 13 months after SRS. 20 patients (65%) developed recurrent disease in the CNS outside of the radiosurgery field at a median of 11 months after SRS. 4 patients developed toxicity from SRS related to radiation treatment effect, all of which occurred within 1 year of SRS. CONCLUSIONS: SRS for malignant CNS lesions in the pediatric population provides effective local control and is well-tolerated. However, there remains a substantial risk of distant CNS failures given the nature of recurrent or metastatic disease in these patients.
SWK-01. Partnership between caregivers, patients and healthcare professionals: promoting collaboration in a complex care pathway in pediatric neuro-oncology
Authors: Granero Anita , Bertozzi Anne Isabelle , Baudou Eloise , Oliver Kathy 
Published: June 2022

Abstract
Children with a brain tumor and their families encounter, from the moment of diagnosis, a complex, multidisciplinary and multisite journey. Oscar's Angels (OA) is an association of trained patient advocate volunteers within a hospital structure who provide daily support to pediatric neuro-oncology patients and their families in complex care pathways. The association promotes collaboration in healthcare by facilitating a strong link between the daily reality of patients and their families and that of the hospital. OA volunteers are active and fully accepted members of the hospital multi-disciplinary team and collaborate on a very high level in the care of pediatric patients. Such a collaborative setting is possible because the work of OA is structured around three principles: Innovative, practical and theoretical initial and ongoing training and quality assessment of volunteers Patient and family support from Oscar’s Angels volunteers throughout the care pathway Government certification, institutional representation and active collaboration in educating healthcare professionals about the importance of patient advocacy and patients’ needs Operating in France since 2001 and in Italy since 2017 (with more than 600 and 200 families respectively supported last year), the OA volunteering program is specifically tailored to the needs and demands of hospitals and families. It can therefore be successfully reproduced in many settings. OA’s services come at no cost to hospitals. This is particularly important for implementing the program in developing countries where healthcare resources are extremely limited. But it is also relevant in developed countries as well where healthcare budgets are under strain. In 2020 an informal internal OA survey highlighted that the patient/family/volunteer/healthcare professional interface provides added value for all of these stakeholders. A formal survey will be conducted in 2022 to corroborate these results.
SWK-04. Investigation on Anxiety and Depression of Parents of Children with Central Nervous System Tumors
Authors: Yang Huajun , Zhang Yangqiong , Lai Mingyao , Li Juan , Cai Linbo 
Published: June 2022

Abstract
OBJECTIVE: Family members of children with Central Nervous System（CNS） tumors are often accompanied by anxiety, depression and other adverse emotions, which have a great impact on the quality of life of children. This study aims to investigate the incidence of anxiety and depression in parents of children with CNS tumors. METHODS: One of the parents of 165 children with CNS tumors who were hospitalized in Guangdong Sanjiu Brain Hospital from January 2021 to December 2021 were evaluated for anxiety and depression by SAS and SDS self-rating Depression Scale. The evaluation scores were compared with anxiety scores of normal Chinese population RESULTS: Our study cohort completed 165 questionnaires. Among them, 68 persons (41.21%, 68/165) had anxiety, and the anxiety score was (48.78±9.33), which was statistically significant compared with the normal Chinese population (29.78±10.01) (P &lt; 0.01). 100 persons (60.61%, 100/165) had depression, and the depression score of the cohort was (55.02±9.98), higher than that of the normal population (33.46, 8.55), with statistical significance (P &lt; 0.01). CONCLUSION: The parents of children with CNS tumor are the high risk group of anxiety and depression, which should arouse more clinical attention.
SWK-07. Family mental health screening early after a diagnosis of pediatric brain tumor
Authors: Rodemann Ashley , Hartmann Mary , Limbrick David , Abdelbaki Mohamed , Cluster Andrew 
Published: June 2022

Abstract
INTRODUCTION: A new diagnosis of a brain tumor in a child has significant emotional consequences for every member of the family. Nevertheless, early phases of oncologic care rarely provide formal mental health screening. METHODS: We implemented a mental health screening protocol for families and patients with a newly diagnosed brain tumor admitted to our pediatric intensive care unit (PICU) at the time of diagnosis. Screening instruments were selected based on their previous validation and relevance to both a brain tumor diagnosis and PICU admission. Parents were contacted by a member of our team within 2 weeks of their child’s diagnosis, and completed the screening independently within the next 2 weeks via an online interface. Parent proxy reports for the children were used when necessary. Scores were shared with the family and neuro-oncology team. When indicated, supportive counseling was offered. RESULTS: Eighteen patients have met criteria for mental health screening. Of these, 8 patient and parent dyads have completed the screening (mean patient age 8.6 years; 75% white; 50% female). Of the families that completed the evaluation, most parents (62.5%) reported that their child’s diagnosis negatively impacted their health-related quality of life (HRQL), while 87.5% of children themselves reported a lower HRQL. Most children (66.7%) self-reported having symptoms outside of normal range for anger, anxiety and depression and 100% had scores outside of normal range for pain interference with their daily lives. Only half of eligible families accepted referrals for new mental health support. CONCLUSION: Both children with a new diagnosis of brain tumor and their parents are at risk for impaired mental health and quality of life early after diagnosis. A systematic approach to these concerns at the time of diagnosis may be helpful.