bluuebunny/crossref_metadata_2025_split huggingface dataset:
SURG-02. MAGNETIC RESONANCE-GUIDED HIGH-INTENSITY FOCUSED ULTRASOUND (MRGHIFU) FOR TREATMENT OF LOW GRADE GLIOMA IN A PEDIATRIC PATIENT
Authors: Chesney Kelsi , Patel Nirali , Keating Gregory , Packer Roger , Keating Robert 
Published: June 2023

Abstract

INTRODUCTION
Transcranial magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU) has demonstrated efficacy in the treatment of adult essential tremor through targeted thermoablation visualized in real-time with MR thermography. The minimally invasive nature of MRgHIFU and lack of ionizing radiation makes it an appealing treatment modality for pediatric patients. There is limited data describing MRgHIFU for pediatric brain tumors. This case report describes the use of MRgHIFU to treat a low grade glioma in a pediatric patient.

METHODS
A prospective, non-randomized, single-arm study enrolled patients 8-22 years old with benign intracranial tumors requiring intervention to be treated with the ExAblate 4000 System. Clinical and radiographic examinations were performed at the following intervals after treatment: 1 day, 14 days, 3 months, 6 months, and 1 year.

RESULTS
One patient was treated with MRgHIFU in 2022. A 12 year-old female with headaches and Neurofibromatosis Type 1 (NF1) without prior medical or surgical treatment presented with a progressive enhancing lesion in the right parieto-occipital region. Stereotactic biopsy confirmed pathological diagnosis of a low-grade glioma. MRgHIFU was used to treat the lesion with 5 sonications ranging 600-800 watts resulting in immediate T2 and FLAIR changes. There were no complications or adverse events. MRI demonstrated slight volume reduction after one year. The patient scored herself a 7 on the Patient Global Impression of Change scale for considerable improvement. Her headaches improved and she participates actively in school and sports.

CONCLUSION
MRgHIFU is an attractive alternative to open craniotomy and/or radiation for pediatric patients with benign brain tumors. In our experience with one patient, the use of MRgHIFU for treatment of a low-grade glioma demonstrated safety in addition to radiographic disease control at 1 year with favorable patient impression scores. Additional patient enrollment and extended follow-up time will be necessary to determine generalizability and therapeutic longevity.
SURG-05. MRI-GUIDED FOCUSED ULTRASOUND BLOOD-BRAIN BARRIER DISRUPTION INCREASES DRUG DELIVERY AND EFFICACY IN AN ORTHOTOPIC DIPG MODEL
Authors: Martinez Payton , Nault Genna , Steiner Jenna , Wempe Michael , Pierce Angela , Brunt Breaunna , Slade Mathew , Mongin Andrew , Song Jane , Song Kang-Ho , Ellens Nicholas , Serkova Natalie , Green Adam , Borden Mark 
Published: June 2023

Abstract
Diffuse intrinsic pontine glioma is the most common and deadliest pediatric brainstem tumor and is difficult to treat with chemotherapy in part due to the blood-brain barrier (BBB). Focused ultrasound (FUS) and microbubbles (MBs) have been shown to cause BBB disruption (BBBD), allowing larger chemotherapeutics to enter the parenchyma. Panobinostat is an example of a promising in vitro agent in DIPG with poor BBB penetrance. In this study, we hypothesized that using FUS to disrupt the BBB allows higher concentrations of panobinostat to accumulate in the tumor, providing a therapeutic effect. Mice were orthotopically injected with a patient-biopsied DIPG cell line, BT-245. After two weeks of growth, MR images guided FUS targeting to the tumor location. Microbubbles (25µl/kg, IV) and FUS (Frequency: 1.515 MHz, PNP: 0.77MPa, PRF: 1Hz, PL: 10ms, treatment time: 3 minutes) were applied to half the mice. Passive cavitation data (PCD) was collected and analyzed. Panobinostat was given (10mg/kg IP) to all mice. After 1.5 hours, a subset of mice were sacrificed to determine the concentration of panobinostat in tumor and cortex areas. We showed a 3-fold drug concentration increase in the tumor region while only slightly increasing the concentration in the forebrain. The remaining mice received three weekly treatments. Half were treated with FUS/MB and panobinostat, while others received panobinostat only. MRI was taken weekly to evaluate BBBD extent and tumor growth. PCD during treatments showed ideal cavitation of microbubbles illustrating safety and consistency across all treatments. The combination of panobinostat and FUS exhibited a tumor size decrease of 71% on MRI compared to panobinostat alone. Furthermore, FUS/MB improved the mean survival from 21 to 31.5 days (p=0.0001). Our study demonstrates that FUS-mediated BBBD can increase the delivery of panobinostat to an orthotopic DMG tumor, providing a strong therapeutic effect and increased survival.
OTHR-02. CHIMERIC AURORA A KINASE (AURKA) DEGRADERS EFFICIENTLY TARGET N-MYC
Authors: Valinciute Gintvile , Eing Lorenz , Mihalic Jeffrey , Casey Colleen E , Tian Hua , Adhikari Bikash , Guiducci Cristiana , Rountree Ryan , Grohmann Christoph , Sridharan Sangita , Lu Ya-Wen , Vezina-Dawod Simon , Wegrzyniak Eric , Chaterjee Abhinav , Hansen Gwenn M , Maris John M , Mossé Yael P , Eilers Martin , Wolf Elmar , Roussel Martine F 
Published: June 2023

Abstract
MYC family proteins are primary drivers of oncogenic processes in a variety of cancer histologies. N-myc overexpression and amplification induce aggressive pediatric cancers, the most common of which are solid extracranial tumors in children (neuroblastoma, NB) and malignant pediatric CNS tumors (medulloblastoma, MB). Due to the oncogenic addiction observed in these tumor types, N-myc is considered an attractive therapeutic target. However, direct small molecule targeting of N-myc remains technically challenging. Alternative approaches to target this pathway include inhibiting proteins thought to stabilize N-myc, such as Aurora A kinase (AURKA). While inhibition of AURKA was found to be effective in preclinical tumor studies, no AURKA inhibitors have been approved for clinical use due to a lack of efficacy. Here, we aim to develop chimeric degrader molecules suitable for preclinical and clinical use that degrade AURKA and concomitantly reduce N-myc levels. We used automated solid-phase synthesis to generate a library of &gt;1000 chimeric degraders using derivatives of six known AURKA ligands (Series 1-6). Due to the limitations of using N-myc-driven MB cells in vitro, we employed NB cells as the proof-of-concept model. While the degraders based on five of the ligands showed efficient AURKA degradation, only degraders based on series 3 and 6 could also diminish N-myc. Selected series were further characterized in pharmacokinetic and pharmacodynamic experiments using NB tumor xenografts implanted in the flank in CD1-nude mice. In summary, chimeric degraders based on two individual AURKA ligands efficiently degraded AURKA and N-myc in vitro and in vivo, providing the foundation for further development of novel therapies for patients with N-myc-driven cancers. Further studies will focus on assessing antitumor properties of lead candidates in NB and patient-derived orthotopic MB xenograft models.
OTHR-07. CIRCULATING MIRNAS AS A NON-INVASIVE MONITORING TOOL FOR PEDIATRIC BRAIN TUMORS
Authors: Coyle Anne , Rathi Komal , Arif Shehbeel , Hollawell Madison , Beck Christopher , Choudhari Namrata , Smith Tiffany , Naqvi Ammar , Madsen Peter , Tucker Alexander , Storm Phillip , Resnick Adam , Foster Jessica , Koptyra Mateusz 
Published: June 2023

Abstract
Current management of pediatric brain tumor patients relies on imaging as the only non-invasive tool available for monitoring therapeutic response and tumor progression. Results are often inconclusive and unable to capture biological changes that presage progression on imaging. Circulating miRNA provides an attractive non-invasive platform because miRNA’s essential role in regulating gene expression, stability in bio-fluids, selective over-expression in tumors, and subsequent active release from tumors into the extracellular environment. We aimed to establish the prognostic and monitoring value of miRNA biomarkers for pediatric brain tumors. We performed miRNA profiling of CSF (n=33) and plasma (n=53) samples across a cohort of 54 pediatric brain tumors from 6 histologies (low grade glioma, ependymoma, germ cell tumor, medulloblastoma, atypical teratoid rhabdoid tumor and high-grade glioma). We utilized unsupervised consensus clustering, differential expression, and machine learning methods to explore miRNA biomarkers. Plasma miRNA signatures were correlated with WHO Grade while CSF signatures revealed a correlation with leptomeningeal disease and higher disease burden (p&lt;0.05). The expression of circulating miRNA revealed histology-specific signatures for low grade glioma, medulloblastoma and germinoma in plasma and CSF (p&lt;0.05). We identified miRNA signatures of significant translational value: (1) A medulloblastoma specific miRNA in CSF can serve as a potential biomarker for tumor monitoring (medulloblastoma specificity was confirmed in independent tissue-based dataset); (2) Pilocytic astrocytoma can be distinguished from high grade glioma in CSF; (3) Most intriguingly, in plasma, miRNA expression identified pilocytic astrocytoma that had relapsed in several months after initial intervention (p&lt;0.05). These results support circulating miRNA in plasma and CSF as biomarkers of diverse clinical diagnostic and prognostic measures. Further utilization of this approach provides unique platforms to inform liquid biopsy-based management in the clinical setting.
OTHR-08. MULTIDISCIPLINARY APPROACH TO PAEDIATRIC BRAIN CANCER BIO-BANKING IMPROVES ENROLLMENT, FACILITATES DISCOVERY RESEARCH, AND ENABLES BETTER ACCESS TO DIAGNOSTIC AND THERAPEUTIC STUDIES
Authors: Zhukova Nataliya , Habarakada Dilru , Drinkwater Caroline , Danks Andrew , Xenos Chris , Kumar Beena , Haddad Lauren , Daniel Paul , Sun Claire , Wood Paul , Super Leanne , Janson Lisa , Cain Jason , Firestein Ron , Downie Peter 
Published: June 2023

Abstract
Despite the significant progress made in the multi-modal treatment of childhood malignancies over the last four decades with a concomitantly increased cure rates, the benefit is still largely limited to patients with leukemias, lymphomas and localized non-CNS solid tumors, leaving patients with high-risk non-CNS solid tumours and most CNS malignancies with minimal advancements. More research is critical to understand what drives these cancers and to investigate the best ways to deliver curative therapies. Translational research relies on patient-derived tissue samples, animal models and cell-cultures to understand the biological, genetic, and molecular mechanisms of disease. To facilitate patient care and outcomes it is becoming increasingly important that paediatric clinical trials include tissue availability as part of eligibility criteria, making collection and storage of patient tissue a mandate of personalized medicine and a pillar of modern paediatric cancer medicine.
Monash Children’s Cancer Biobank was established in 2011. Since 2017, a total of 64 patients were diagnosed with CNS malignancies across all grades, with an overall 69% of patients’ tissues being bio-banked at the time of initial diagnosis. Through the combination of an educational forum, regular multi-disciplinary meetings, and the early involvement of medical oncology and biobank staff, with our neurosurgical and clinical pathology colleagues, as part of patient management planning, the tissue acquisition for bio-banking increased from 44% to 82% over the course of 5 years. This consequently led to a 100% enrollment to tissue-enabling studies allowing for banking of both fresh-frozen tissue and living cell-line models, facilitating discovery research efforts as part of the Victorian Paediatric Cancer Consortium’s molecular analysis pipeline (https://vicpcc.org.au/dashboard). This significantly improves opportunities for identification of targetable pathways, access to targeted therapies, enrollment onto treatment clinical trials and identification of patients with cancer predisposition syndromes.
OTHR-10. COLLABORATIVE EFFORTS FOR HOSPITAL-BASED BIOBANK DEVELOPMENT AND OPTIMIZATION TO ENSURE QUALITY PEDIATRIC SPECIMENS FOR TRANSLATIONAL RESEARCH
Authors: Lebert Brittany , Gonzalez-Vega Maxine , Elbabaa Samer , Hegert Julia , Wright Avery , Aguilar-Bonilla Ana , Smith Amy 
Published: June 2023

Abstract
In recent years, drastic improvements in sequencing technologies have led to a better understanding of the specific genetic drivers of cancer. However, one of the greatest barriers to these discoveries is access to primary patient tumor tissue, especially in cancers of the Central Nervous System (CNS). In many cases tissue from surgery is processed and stored in Formalin-Fixed Paraffin-Embedded (FFPE) blocks, which sets limitations on downstream applications. In 2015, our team launched an initiative to collect and efficiently store samples from pediatric CNS tumor patients during surgeries and autopsies. Through extensive collaboration between Neuro-Oncology, Neurosurgery, Pathology, and our Translational Laboratory, we have optimized the collection process to effectively preserve sample integrity and therefore maximize their potential usage. To date, we have collected over 4,509 samples from 293 patients (636 flash-frozen tissue, 1,026 plasma & buffy coat, 748 serum, 996 whole blood, 316 Cerebrospinal Fluid (CSF), and 787 parental blood samples). In addition, we have cultured 31 primary cell lines and collected over 242 dissociated tumor specimens for implantation into patient-derived xenograft (PDX) mouse models. Through our partnership with neurosurgery and pathology, we are permitted to attend surgeries and autopsies to immediately flash-freeze tumor tissue in liquid nitrogen, typically within minutes of the tissue being removed from the body. This immediate flash-freezing process aims to ensure specimen integrity and preserve molecular profiles. From there, the tissue is either stored in our -140oC freezer for future use or sent to partnered consortiums, including the Children’s Brain Tumor Network (CBTN) and Gift from a Child. Since the optimization of the collection process, the focus has now shifted to investigating the efficacy of our storage methods by quantifying DNA/RNA integrity over time. By ensuring the successful preservation of the samples, we can maximize their impact in the pediatric neuro-oncology research field.
OTHR-14. PROFILE & OUTCOME OF BRAIN TUMORS IN THE YOUNG CHILDREN &lt; 3YEARS OF AGE: EXPERIENCE FROM A TERTIARY CANCER CENTER IN INDIA
Authors: Thankamony Priyakumari , Nair Manjusha , Rajeswary Binitha , CS Guruprasad , VR Prasanth 
Published: June 2023

Abstract
During the 5 year period from 1st January 2009- 31st December 2013, 33 children&lt; 3 years age presented with brain tumor (7.56 % of all brain tumors among in children aged 0-14 years) . 54.5% were boys. Vomiting(69.7%) ataxia(36%) & head ache(24%) were the most common symptoms. Common histology included Medulloblastoma (36%) , Astrocytoma ( 21%) & Ependymoma ( 18%).Others included ATRT, glioma, ganglioglioma, PNET, Pineoblastoma & choroid plexus carcinoma. 63% were infratentorial & 37% were supratentorial. 58% had gross total resection & 36% had residual disease post surgery .64% of children received chemotherapy with baby brain protocol consisting of Inj VCR 0.06mg/kg IV - D1 &Inj Cyclophosphamide 50mg/kg IV infusion D1 (Cycle A) alternating with Inj CDDP 4m/kg as IV infusion D1&Inj Etoposide 6.5mg/kg IV infusion D1-3( Cycle B) as A – A – B Q3 weeks followed by definitive RT at completion of 3 years or earlier if they relapse on chemotherapy . At a median follow up of 34 months ( ( 2 mo- 106 mo ) 3 year RFS & OS were 20% & 56% respectively. OS was better for Ependymoma ( 100%) & Astrocytoma (80%) compared to (56% )for Medulloblastoma.
XRT-02. SINGLE-CELL RNA SEQUENCING IDENTIFIES FUNCTIONAL MACROPHAGE SUBSETS THAT ARE ENRICHED IN RESPONSE TO DIFFERENTIAL PHAGOCYTOSIS INDUCTION AGAINST GLIOMA
Authors: Lakshmanachetty Senthilnath , Riemondy Kent , Donson Andrew , Balakrishnan Illango , Venkataraman Sujatha , Vibhakar Rajeev , Foreman Nicholas , Mitra Siddhartha 
Published: June 2023

Abstract
Pediatric diffuse midline gliomas (DMGs), are fatal brain tumors of childhood arising in the ventral pons. Currently, radiation therapy (RT) is the mainstay treatment for DIPG. However, RT is not a curative treatment and provides only temporary relief for most patients. Recent advances in immunotherapy have yielded some fantastic opportunities to effectively treat patients with high-grade pediatric brain tumors. In this study, we demonstrate that fractionated RT (4Gy X 3) induces immunogenic cell death and activates multiple damage-associated molecular patterns (DAMPs) on DMG/DIPG cells. Furthermore, combining 4Gy X 3 with anti-CD47 therapy enhances the in vitro phagocytosis of DIPG/DMG cells by peripheral blood mononuclear cell-derived macrophages. Next, using single-cell RNA sequencing (scRNA-seq), we investigated the transcriptomic profile of macrophages that were co-cultured with irradiated or non-irradiated DMG cells in the presence of anti-CD47 monoclonal antibodies for 24 hours. Our findings identified eleven distinct macrophage clusters displaying different gene expression patterns in all the treatment conditions. However, PBS treatment led to a marked increase in macrophages expressing antigen-presentation genes (HLA-DR and HLA-DQB1). 4Gy X 3 treatment led to the enrichment of macrophages expressing genes related to the oxidative phosphorylation pathway, whereas anti-CD47 treatment led to the enrichment of macrophages expressing genes related to interferon-gamma response and ERK-signaling pathway. Lastly, mice intracranially transplanted with DMG/DIPG that received 4Gy X 3 and anti-CD47 therapy showed a significant decrease in tumor growth and an increase in survival rate than those receiving either monotherapy alone. We are currently performing scRNA-seq validation studies on tumors obtained from orthotopic and syngeneic models of DMG. In summary, our results highlight the functional heterogeneity of macrophages and suggest that combining fractionated RT with anti-CD47 therapy has distinct anti-tumor effects and can be used as a therapeutic approach for treating DIPG patients.
XRT-05. LITHIUM PREVENTS RADIATION-INDUCED HIPPOCAMPAL MICROGLIA SENESCENCE IN A MOUSE MODEL OF PEDIATRIC CRANIAL RADIOTHERAPY
Authors: Rodrigues Carlos , Preka Efthalia , Lastra-Romero Alejandro , Zisiadis Georgios Alkis , Zisiadis Christodoulos , Fragkopoulou Adamantia , Blomgren Klas 
Published: June 2023

Abstract
Radiotherapy is essential in the treatment of high-grade brain tumors. While often lifesaving, it typically results in long-term complications in 50-96 % of the treated individuals, where cognitive deficits are particularly debilitating, especially in pediatric patients. Although the survival rates have improved dramatically, there are currently no treatments or preventive strategies available to ameliorate the late cognitive complications. Lithium (Li), long used to treat patients with bipolar affective disorders, has been shown to reduce irradiation-induced cognitive deficits in rodent models by preventing apoptosis of the neuronal stem and progenitor cells in the hippocampus and stimulating their division. However, except for these anti-apoptotic and pro-neurogenic effects, there is limited understanding of how Li exerts its actions in the brain. This work aimed to further elucidate the mechanisms behind the protective action of Li in the irradiated young brain. To this end, post-natal day (PD) 21 C57BL6/J mice were intraperitoneally injected with lithium chloride (4 mmol/kg) and subsequently kept on a Li carbonate diet for 4 weeks. Control animals were injected with saline and administered an equivalent control diet. At PD25, the animals were subjected to a single dose of 8 Gy whole brain irradiation, and 6 weeks after irradiation, they were sacrificed, and their hippocampi were harvested for single-cell RNA sequencing and RT-qPCR. The attained results showed that irradiation induced hippocampal microglia senescence, as judged by the increased expression of the senescence-associated genes Cdkn1a, Cdkn2, Ccl12, C/Ebp and others in this cellular population. Conversely, Li prevented microglia senescence by activating the Bcl2 family of genes, as confirmed by the lower expression of the abovementioned senescence-associated genes in the Li-treated animals. These results provide the first step towards understanding the action of Li in the brain and confirm its potential to become the first pharmacological treatment for irradiation-induced late cognitive effects.
TRLS-04. PRECLINICAL VALIDATION OF A NOVEL THERAPEUTIC STRATEGY FOR CHOROID PLEXUS CARCINOMA
Authors: Martin Brice , Garman Tyler , Laramee Madeline , Wang Amy , Zhang Xiaohu , Beck Erin , Wilson Kelli , Klumpp-thomas Carleen , Mcknight Crystal , Xu Xin , Hagen Natalie , Holland David , Thomas Craig , Thomas Nadia , Souweidane Mark 
Published: June 2023

Abstract
Choroid plexus carcinoma is a very rare pediatric tumor located in the fourth and lateral ventricles of the brain. It is known to have a severe clinical history and significant side effects because of intensive and noxious chemotherapies. Due to the disease’s rarity and the scarcity of biologically relevant substrates, the advance of new therapeutical techniques for this condition has been exceedingly constrained. A human patient-derived CPC cell line (CCHE-45, Children Cancer Hospital Egypt) was subjected to a high-throughput screen (HTS); 427 top hits were identified, highlighting critical molecular targets in CPC. Additionally, a combination screen with numerous different targets identified synergistic combinations that lead the way for brand-new CPC therapies. Based on in vitro efficiency, CNS penetrance ability and feasible translational potential, two combinations using a DNA alkylating or topoisomerase inhibitors in combination with an ataxia telangiectasia mutated and rad3 (ATR) inhibitor (topotecan/elimusertib and melphalan/elimusertib respectively) were validated in vitro and in vivo. Pharmacokinetic studies revealed greater CNS penetrance via intra-arterial (IA) delivery compared to intravenous (IV) delivery, as well as increased CNS penetrance for melphalan/elimusertib combination. Transcriptome analysis was used to evaluate the mechanisms of melphalan/elimusertib synergistic effect; deregulation of several carcinogenic pathways (e.g. MYC, mTOR, p53) as well as the activation of vital biological processes were revealed (e.g. DNA repair, apoptosis, hypoxia, interferon gamma). In a CPC genetic mouse model, IA administration of melphalan and elimusertib significantly increased survival. To the best of our knowledge, this work is the first using human CPC cells to identify several prospective combinatorial treatments and it highlights the effectiveness of IA delivery for the treatment of CPC.