bluuebunny/crossref_metadata_2025 huggingface dataset:
LGG-15. COMPREHENSIVE ANALYSIS OF MYB/MYB1-ALTERED GLIOMAS: A MULTI-INSTITUTIONAL EXPERIENCE OF 33 GLIOMAS
Authors: Moreira Daniel , Spiller Susan , Bouldin Thomas , Davidson Alan , Saba-Silva Nasjla , Sullivan Daniel , Tanaka Ryuma , Wagner Aaron , Wood Matthew , Gajjar Amar , Chiang Jason
Published: June 2021

Background

Pediatric diffuse gliomas harbor recurrent genetic alterations, including those in MYB and MYBL1. Regardless of histopathologic classification, low-grade diffuse gliomas with MYB/MYBL1 alterations represent a single disease entity. Additional insight is needed to define optimal therapeutic strategies for these tumors.

Methods

We retrospectively reviewed gliomas with MYB or MYB1L alterations treated or referred for pathologic review at St. Jude Children’s Research Hospital (St. Jude). Tumor specimens were centrally reviewed. Molecular characterization and clinical data were collated from St. Jude and referring institutions.

Results

Thirty-three patients were identified. Two tumors had MYBL1 alterations, while 31 had MYB alterations. MYB-QKI fusion was the most common alteration. Eighteen (55%) were male. The median age at diagnosis was 5 years (range, 0–40 years). Most tumors were in the cerebral cortex (22/33), and the most common presentation was seizures (16/33). Three patients (9%) presented with hydrocephalus and required cerebrospinal fluid diversion. Two patients (6%) presented with metastatic disease. Gross-total resection was achieved in 15 patients (45%). Of the 7 patients receiving cytotoxic chemotherapy, no substantial response was observed. Of the 6 patients who received RT, one had disease progression. The median follow-up was 5.9 years. The 5-year event-free survival was 88.1%, while the 5-year overall survival was 96.3%. Two patients died, one of unclear cause and one of treatment-related acute myelogenous leukemia. Using log-rank tests, no difference in outcomes was observed based on molecular characteristics, degree of resection, metastatic status, or treatment modality.

Conclusions

Although tumors with MYB and MYBL1 alterations present with varying molecular and clinical features, they represent a group of tumors with favorable outcomes. Further characterization is required to identify the subgroup of tumors with a higher propensity for progression.
TMOD-02. GEBTO: GENETICALLY ENGINEERED BRAIN TUMOR ORGANOIDS AS A NOVEL PRECLINICAL MODEL
Authors: Bunt Jens , Roosen Mieke , Egelmeers Evie , Maas Joris , Ode Zelda , Kool Marcel
Published: June 2021

Background

One of the bottlenecks in basic and translational research on pediatric brain tumors, is the lack of suitable and representative preclinical models to study tumor biology and drug sensitivity. Over the last decades, extensive molecular characterization has uncovered many entities and subgroups with their unique oncodriving events. However, this heterogeneity is currently not reflected in the models available, especially not for in vitro models.

Objectives

We aim to generate genetically engineered brain tumor organoids (GEBTO) to represent the molecular variety of embryonal brain tumors and ependymomas.

Method

Human brain organoids derived from embryonic stem cells are generated to represent the region of tumor origin. To mimic oncodriving events, DNA plasmids are introduced via electroporation in the organoid cells to knockout tumor suppressor genes or overexpress oncogenes.

Results

Cerebellar and cerebral forebrain organoids were generated as the tissue of origin for medulloblastoma and supratentorial ependymoma (ST-EPN), respectively. Based on the detection of GFP protein encoded by DNA plasmids, the organoid cells can be manipulated within a wide developmental window, which corresponds with the presence of the proposed cells of origin. Different oncodrivers and combinations thereof are now being tested to see whether they result in ectopic growth in cerebral or cerebellar organoids. When successful, the GEBTOs are histologically and molecularly characterized using (single cell) transcriptomic and epigenomic analyses to see how well they resemble human tumors.

Discussion

Although further development is required, GEBTOs provide a novel avenue to model especially rare pediatric brain tumors, for which tissue and therefore patient-derived models are limited. It also allows for in-depth analyses of the potential cells of origin and the contribution of different mutations to tumor biology.
TMOD-04. IMAGE-BASED DRUG RESPONSE PROFILING FROM PEDIATRIC TUMOR CELL SPHEROIDS USING PATIENT-BY-PATIENT DEEP TRANSFER LEARNING
Authors: Berker Yannick , ElHarouni Dina , Peterziel Heike , Oehme Ina , Schlesner Matthias , Witt Olaf , Oppermann Sina
Published: June 2021

Introduction

Image-based phenotypic drug profiling is receiving increasing attention in drug discovery and precision medicine. Compared to classical end-point measurements quantifying drug response, image-based profiling enables both the quantification of drug response and characterization of disease entities and drug mechanisms of actions. In pediatric precision oncology, we aim to study drug response in patient-derived 3D spheroid tumor cell cultures and tackle the challenges of a lack of image-segmentation methods and limited patient-derived material.

Methods

We investigate deep transfer learning with patient-by-patient fine-tuning for cell-viability quantification. We fine-tune a convolutional neural network (pre-trained on ImageNet) with many cell-line-specific and few patient-specific assay controls. The method is validated using 3D cell cultures in 384-well microplates derived from cell lines with known drug sensitivities and tested with primary patient-derived samples. Network outputs at different drug concentrations are used for drug-sensitivity scoring; dense-layer activations are used in t-distributed stochastic neighbor embedding and clustering of drugs.

Results

Cell-line experiments confirm expected hits, such as effective treatment with BRAF inhibitors in a BRAF V600E mutated brain tumor model and NTRK inhibitors in a cell line harboring an NTRK-fusion, indicating the predictive power of deep learning to identify drug-hit candidates for individual patients. In patient-derived samples, clustering of drugs further confirms phenotypic similarity according to their mechanisms of actions. Combining drug scoring with phenotypic clustering may provide opportunities for complementary combination treatments.

Conclusion

Deep transfer learning with patient-by-patient fine-tuning is a promising, segmentation-free image-analysis approach for precision medicine and drug discovery based on 3D spheroid cell cultures.
OMIC-01. THE LANDSCAPE OF EXTRACHROMOSOMAL CIRCULAR DNA IN MEDULLOBLASTOMA SUBGROUPS
Authors: Chapman Owen , Luebeck Jens , Wang Shanqing , Garancher Alexandra , Larson Jon , Lange Joshua , Wong Ivy Tsz Lo , Crawford John , Pomeroy Scott , Mischel Paul , Fraenkel Ernest , Wechsler-Reya Robert , Bafna Vineet , Mesirov Jill , Chavez Lukas
Published: June 2021

Extrachromosomal circular DNA (ecDNA) is an important driver of particularly aggressive human cancers. However, the prevalence of ecDNA, and its role in tumor development and progression in the different molecular subgroups of medulloblastoma (MB), remain unknown. To answer these questions, we have assembled a multi-institutional retrospective cohort of 472 MB patients with available whole genome sequencing (WGS) data, drawing from three cancer genomic data repositories and covering all MB subgroups (WNT, SHH, Group 3 and Group 4). Using recent computational methods to detect and reconstruct ecDNA, we find ecDNA in 66 patients (14%) and observe that the presence of ecDNA is associated with significantly poorer outcomes. By subgroup, ecDNA was found in 0/24 WNT (0%), 22/109 SHH (20%), 15/107 Group 3 (14%) and 20/181 Group 4 (11%) patients. Affected genomic loci harbor up to hundredfold amplification of oncogenes including MYC, MYCN, TERT, and other novel putative oncogenes. We further analyzed 24 patient-derived xenograft (PDX) and four cell line models of MB tumors. ecDNA was substantially more frequent in patient-derived models (17 of 29, 59%) than in our patient cohort. To elucidate the functional regulatory landscapes of ecDNAs in MB, we generated transcriptional (RNA-seq), accessible chromatin (ATAC-seq), and chromatin interaction (Hi-C) profiles of 6 MB tumor samples. In each case, we identify regulatory interactions that cross fusion breakpoints on the ecDNA, representing potential “enhancer rewiring” events which may contribute to transcriptional activation of co-amplified oncogenes. To test this hypothesis, we are currently conducting in-vitro CRISPRi screens targeting regulatory regions on the ecDNA of a MB cell line to determine whether these enhancers promote proliferation. In summary, our study analyzes the frequency, diversity and functional relevance of ecDNA across MB subgroups and provides strong justification for continued mechanistic studies of ecDNA in MB with the potential to uncover new therapeutic approaches.
OMIC-02. COGNITIVE DEFICITS AND ALTERED FUNCTIONAL BRAIN NETWORK ORGANIZATION IN PEDIATRIC BRAIN TUMOR PATIENTS
Authors: Seitzman Benjamin , Anandarajah Hari , McMichael Alana , Gu Hongjie , Barbour Dennis , Limbrick David , Shimony Joshua , Rubin Joshua , Perkins Stephanie
Published: June 2021

Pediatric brain tumor survivors experience significant cognitive sequelae from their diagnosis and treatment. The exact mechanisms of cognitive injury are poorly understood, and validated predictors of long-term cognitive outcome are lacking. Large-scale, distributed brain systems provide a window into brain organization and function that may yield insight into these mechanisms and outcomes. We evaluated functional network architecture, cognitive performance, and brain-behavior relationships in pediatric brain tumor patients. Patients ages 8–18 years old with diagnosis of a brain tumor underwent awake resting state functional Magnetic Resonance Imaging during regularly scheduled clinical visits and were tested with the National Institutes of Health Toolbox Cognition Battery. Age- and sex-matched typically developing children were used as controls. We observed that functional network organization was significantly altered in patients compared to controls (p < 0.001), with the integrity of the dorsal attention network particularly affected (p < 0.0001). Moreover, patients demonstrated significant impairments in multiple domains of cognitive performance, including attention (p < 0.0001). Finally, a significant amount of variance (R squared = 0.52, F = 3.2, p < 0.05) of age-adjusted total composite scores from the Toolbox was explained by changes in segregation between the dorsal attention and default mode networks. Our results suggest that changes in functional network organization may provide insight into long-term changes in cognitive function in pediatric brain tumor patients.
RARE-05. ANAPLASTIC ASTROCYTOMA AND OLIGODENDROGLIOMA PRESENTING AS SIMULTANEOUS PRIMARY BRAIN TUMORS IN A PEDIATRIC PATIENT: THE FIRST KNOWN REPORT OF A RARE CONDITION
Authors: Brown Amber , Chaleff Stanley
Published: June 2021

Multiple metastatic brain tumors and multiple histologically identical primary brain tumors have been reported in adults and children. The concurrent presence of multiple histologically distinct primary brain tumors is rare without prior chemotherapy, radiotherapy, or phacomatosis. Exceedingly rare are simultaneous histologically distinct primary brain tumors in children without therapeutic or genetic predisposition, with only five previously reported cases. Gliomas are the most common primary brain tumor in adults and children. Gliomas encompass a heterogenous group characterized by astrocytic, oliogodendroglial, and ependymomal histology, further subdivided into pathologic World Health Organization (WHO) grades I to IV. In children, grade I astrocytomas are the most common, with grade III astrocytomas (anaplastic astrocytomas) and oligodendrogliomas being rare. We report a case of simultaneous anaplastic astrocytoma and grade II oligodendroglioma in a pediatric patient. A previously healthy 6-year-old female presented with persistent headaches. Initial magnetic resonance imaging (MRI) demonstrated non-enhancing right frontal lobe and left peri-thalamic lesions without mass affect. Serial MRIs showed progression of both lesions, prompting frontal lobe biopsy, which revealed a grade II oligodendroglioma. The patient was started on standard low-grade glioma chemotherapy, which was stopped due to an allergic reaction. Following chemotherapy cessation, both lesions increased in size, and the peri-thalamic lesion demonstrated new heterogenous enhancement. The patient underwent gross-total resection of the peri-thalamic lesion and repeat biopsy of the frontal lobe lesion. Pathology confirmed the frontal lobe lesion to be a grade II oligodendroglioma and revealed the peri-thalamic lesion to be an anaplastic astrocytoma. The tumors were additionally proven molecularly distinct. The patient responded well to cranial radiotherapy and standard high-grade glioma chemotherapy. To the best of the authors’ knowledge, this is the first case of simultaneous anaplastic astrocytoma and oligodendroglioma in a child, increasingly unique given the histological and molecular rarity of the tumors in pediatric patients.
RARE-06. CLINICAL BURDEN AMONG PATIENTS WITH NEUROFIBROMATOSIS TYPE 1 (NF1) AND PLEXIFORM NEUROFIBROMA (PN) IN THE UNITED STATES (US)
Authors: Yang Xiaoqin , Yoo Hyun Kyoo , Amin Suvina , Cheng Wendy , Sipsma Heather , Sundaresan Sanjana , Zhang Lujia , Duh Mei Sheng
Published: June 2021

Background

Plexiform neurofibromas (PNs) occur in 30–50% of pediatric patients with neurofibromatosis type 1 (NF1), often resulting in debilitating pain and dysfunction. Real-world evidence describing the clinical disease burden among these patients is limited. This study aimed to characterize this burden among pediatric NF1 PN patients in the United States (US).

Methods

Caregivers of 82 patients ages 2–18 years with NF1 PN in the US who were treatment naïve or new users of selumetinib (defined as ≤1 month of use) were recruited through the Children’s Tumor Foundation to participate in an online cross-sectional survey from December 1, 2020 through January 14, 2021. Participants responded to items measuring patient demographic and clinical characteristics and the burden of debulking surgeries.

Results

On average, patients were 11.5 [standard deviation (SD)=4.0] years old and predominantly treatment naïve (97.6%). Most were white/Caucasian (85.4%), and 53.7% were female. Most patients had been diagnosed with NF1 and PN for >5 years (80.5% and 68.3%, respectively). A majority of patients (58.5%) had >20 café-au-lait spots. Most patients (59.8%) had >1 PN, with 11.0% reporting >5 PNs, frequently located on the back (40.2%) and head (32.9%). Common symptoms included pain (64.6%), disfigurement (32.9%), and motor dysfunction (28.0%). Common comorbidities included attention-deficit disorder (56.1%) and headaches (47.6%). Few patients had received complete resections of their tumors (12.2%), and 39.0% reported ≥1 debulking surgery. Among the 32 patients with debulking surgeries, 5 patients (15.6%) reported complications, including acute complications (60.0%) and post-operative symptoms (40.0%). Debulking surgery-related emergency room visits and hospitalizations were common (25.0% and 53.1%, respectively); mean length of stay per hospitalization was 5.9 (SD=6.2) days.

Conclusion

The clinical disease burden of NF1 PN among this pediatric patient population is substantial. While debulking surgeries are used for symptom management, they were related to considerable clinical sequelae.
RARE-12. PITUITARY ADENOMA SURGERIES IN COVID-19 ERA: EARLY LOCAL EXPERIENCE FROM EGYPT
Authors: Arnaout Mohamed
Published: June 2021

Background

The pandemic of COVID-19 has a great impact on all health-care services worldwide. Neurosurgical recommendations are to postpone the endoscopic endonasal pituitary surgeries during the pandemic. We would like to express our experience with urgent pituitary adenomas during the current COVID-19 pandemic.

Methods

In our country, COVID-19 has started to become a paramount problem by March 2020. Nine cases of pituitary adenomas have presented with urgent manifestations. The endoscopic endonasal approach was performed in eight patients, while a craniotomy was selected for a recurrent pituitary adenoma. Pre- and postoperative thorough clinical evaluations with chest CT scans were performed. Other strict infection control measures have been applied.

Results

In 8 weeks duration starting from the past days of February 2020, we have operated on four females and five males of pituitary adenomas. Visual deterioration was the main presenting symptom. The driving factor for surgery was saving vision in eight patients. Fortunately, the postoperative course was uneventful for all patients. No suspected COVID-19 infection has been reported in any patient or health-care team except one patient. In our city, PCR test was routinely not available.

Conclusion

In the era of COVID-19, strict infection control precautions should be employed to limit the possibility of transmission of any possible infection to patient or any of the surgical team. We believe that the risk of getting such infection is not increased by the endonasal approach. Long-term follow-up and large numbers of prospective studies are recommended to delineate the impact of COVID-19 infection on pituitary surgeries.
RARE-13. PRIMARY EMPTY SELLA SYNDROME AND PSEUDO-TUMOR CEREBERI: CORRELATION OF ASSOCIATION AND SURGICAL PLAN
Authors: Arnaout Mohamed
Published: June 2021

Introduction

Management of primary empty sella syndrome (ESS) is generally remaining a neurosurgical challenge due to lack of a well standardized approach. Pseudo-tumor cereberi (Benign or idiopathic intracranial hypertension) is commonly associated condition. In this study, we have demonstrated the relationship and surgical plan and outcome of such cases. Patients and Methods: We retrospectively studied 24 patients with primary empty sella syndrome (ESS) for two years who were diagnosed radiologically as ESS. Fundus and other ophthalmological examinations were done. Lumbar puncture and cerebrospinal fluid (CSF) manometer were evaluated in those with papilledema. All patients’ data were collected and analyzed.

Results

Basically, 24 patients (18 females and 6 males) were radiologically diagnosed as EES. 13 females and only one male were having symptoms of BIH. 17 patients (70.83%) had headache as the first presentation. Second most common presentation in our study was visual in 14 patients (58.3%). Two patients (8.3%) had pituitary hypersecretion namely; growth and prolactin hormones. In those (58.3%) confirmed to have BIH Theco-peritoneal shunts were inserted. Incidental cases (29.17%) without symptoms were followed up.

Conclusion

Although (ESS) is a well-known radiological hallmark for BIH, in our study not all patients had BIH. Interestingly, pituitary hyperfunction may be the first presentation in some rare cases. Generally, natural history of that entity was benign. Frequent follow-up by neurosurgeons and increased awareness of associations are advised. We believe a more prospective large number cohort is important to outline the natural history.
RARE-14. DISRUPTION OF GEMC1-MCIDAS MULTICILIOGENESIS PROGRAM PROMOTES CHOROID PLEXUS CARCINOMA
Authors: Singh Navleen , Sarowar Tamanna , Zahran Tasneerm , Zhao Haotian
Published: June 2021

Tumors of the choroid plexus (CP) are rare primary brain neoplasms mostly found in children. CP tumors exist in three forms: CP papilloma (CPP), atypical CPP, and CP carcinoma (CPC). Though CPP is more benign, CPC is a highly lethal and little understood cancer with poor survival rate and a tendency for recurrence and metastasis. CP tumors are thought to arise from CP epithelial cells that secrets cerebral spinal fluid and generate multiple cilia on their apical surface. Here we show that aberrant NOTCH and Sonic Hedgehog signaling in mice drive tumors that resemble CPC in humans. In contrast to CP epithelial cells with clusters of multiple cilia, NOTCH-driven CP tumors were monociliated, and disruption of the NOTCH complex restored multiciliation and decreased tumor growth. NOTCH suppressed multiciliation in tumor cells by inhibiting the expression of Geminin Coiled-Coil Domain Containing 1 (GEMC1), and multiciliate differentiation and DNA synthesis associated cell cycle protein (MCIDAS), early transcriptional regulators of multiciliated cell (MCC) differentiation. Consistently, Gemc1-Mcidas deficiency led to a lack of MCCs in the CP, and impaired the correction of the multiciliation defect in tumor cells by a NOTCH inhibitor. Disturbances to the GEMC1 program are commonly observed in human CPCs characterized by solitary cilia and frequent somatic TP53 mutations. Accordingly, CPC driven by deletion of tumor suppressors Trp53 and Rb1 in mice exhibits a cilia deficit consequent to loss of Gemc1-Mcidas expression. Taken together, these findings reveal that the GEMC1-MCIDAS multiciliogenesis program in the CP is critical for inhibiting tumorigenesis, whereas a defective multiciliation program promotes CPC and may represent a therapeutic avenue for this cancer.
RARE-17. HIGH-THROUGHPUT SCREEN IDENTIFIES POTENTIAL CHEMOTHERAPIES FOR CHOROID PLEXUS CARCINOMA TREATMENT USING INTRAARTERIAL STRATEGY
Authors: Martin Brice , Thomas Craig , Garman Tyler , Lin Daisy , Dahmane Nadia , Souweidane Mark
Published: June 2021

Choroid plexus carcinoma is a rare infantile brain tumor with an aggressive clinical course.1 There is no optimal treatment and survival is poor. Gross total surgical removal is the single most important predictor of survival.1 Gross total surgical removal rates are inconsistent and associated with significant morbidity owing to the hemorrhagic nature of these tumors compounded by a small circulating blood volume. Neoadjuvant systemic chemotherapy with “second look surgery” helps to achieve gross total surgical removal2 but has an inefficient pharmacokinetic profile and exposes children to dose- limiting toxic side effects. Hence, there is a strong need to identify and develop new agents and strategies to improve current choroid plexus carcinoma (CPC) treatment. Here, we report a high-throughput drug screening using a CPC cancer tissue-originated from a 7-year-old male patient and procured (Children’s Cancer Hospital Egypt) to identify new potent drugs. The selected candidates have been used as single agent and combination agent chemotherapy to propose a relevant study (e.g pharmacokinetics, toxicity, biodistribution, anticancer efficacy) for improving CPC treatment using a pre-existing intraarterial chemotherapy. A genetically engineered model has been developed by Shannon et al by breeding RosamTmG with Nestin-Cre to generate Nestin-cre/Rosa mTmG reporter mice overexpressing c-Myc, which provides a fully penetrant model of CPC in the lateral ventricle CP and 4th ventricle CP.3 This mice model will be used to explore in vivo the newly discovered drug combinations to treat the CPC tumor. 1. Hosmann, A. et al. Management of choroid plexus tumors—an institutional experience. Acta Neurochir. (Wien). 161, 745–754 (2019) 2. Schneider, C. et al. Neoadjuvant chemotherapy reduces blood loss during the resection of pediatric choroid plexus carcinomas *christian. J. Neurosurg. Pediatr. Pediatr. 16, 126–133 (2015) 3. Shannon, M. L. et al. Mice Expressing Myc in Neural Precursors Develop Choroid Plexus and Ciliary Body Tumors. Am. J. Pathol. 188, 1334–1344 (2018)
EPCT-02. COMPARISON OF TARGETED AGENTS RECOMMENDED BY THE CNS-TAP TOOL TO THOSE SELECTED BY A TUMOR BOARD IN A MOLECULARLY-DRIVEN DIPG CLINICAL TRIAL
Authors: Roberts Holly , Ravi Karthik , Marini Bernard , Kline Cassie , Mueller Sabine , Koschmann Carl , Franson Andrea
Published: June 2021

Recently, sequencing of diffuse intrinsic pontine glioma (DIPG) biopsy specimens has revealed genomic heterogeneity of these tumors, fueling an interest in individualized, targeted treatment options. The Pacific Pediatric Neuro-Oncology Consortium recently completed enrollment onto a feasibility study PNOC003: Molecular Profiling for Individualized Treatment Plan for DIPG (NCT02274987), in which a multidisciplinary tumor board recommended molecularly-targeted agents based on genomic and molecular profiling of each patient’s tumor. Separately, our group developed the Central Nervous System Targeted Agent Prediction (CNS-TAP) tool, which combines pre-clinical, clinical, and CNS penetration data with patient-specific genomic information to allow for numeric scoring of targeted anticancer agents to objectively evaluate these therapies for use in patients with CNS tumors. We hypothesized that highly-scored agents within CNS-TAP would overlap with the agents recommended by the tumor board in this study. For each PNOC003 participant, we utilized the genomic report to identify actionable alterations and input patient-specific data into CNS-TAP to identify the highest scoring agents. We compared high-scoring agents within CNS-TAP with recommendations from the PNOC003 tumor board for each of the enrolled 28 subjects. Overall, 93% (26/28) of patients had at least one agent recommended by both the tumor board and CNS-TAP. Additionally, 38% (37/95) of all agents recommended by the tumor board were also selected by CNS-TAP. Furthermore, we identified factors that likely contributed to the discordance between these two methods. Without clinician input, CNS-TAP is unable to account for drug-drug interactions, includes only designated anticancer agents, and cannot easily be updated in real time. However, CNS-TAP provides an objective evaluation of targeted therapies, whereas tumor boards are inherently subjective. Given the discordance identified between these methods and the strengths of each, a prospective study incorporating both CNS-TAP and a molecular tumor board for targeted therapy selection in DIPG patients is warranted.
EPCT-08. TRIAL WORKING GROUPS FOR PAEDIATRIC BRAIN TUMOURS
Authors: Rahman Ruman , Walker David , Campbell Emma , Aquilina Kristian
Published: June 2021

Introduction

Brain tumours are the biggest cancer killer in children and young adults. Several recent developments have the potential to change the treatment of brain tumours in children. These include ultrasound-mediated blood-brain barrier disruption, convection enhanced delivery, polymer delivery systems and electric field therapy, as well as intra-arterial, intra-CSF and intra-nasal chemotherapy. To date, there have been very few clinical trials to evaluate any of these. The science and technology underlying these developments is not traditionally embedded within the standard paediatric neuro-oncology network. In addition, custom-built hardware, novel surgical procedures and, in some cases, the testing and licensing of implantable devices, add difficulty at the regulatory level.

Methods

The authors participated in an international workshop funded by the charity Children with Cancer UK in 2016, where different experimental techniques aimed at optimising CNS drug delivery were discussed. Following this workshop and two subsequent workshops run by the CBTDDC (Children’s Brain Tumour Drug Delivery Consortium) in 2018 and 2020, the CBTDDC and the recently developed ITCC (Innovative Therapies for Children with Cancer) brain tumour group started working together to set up a new initiative. This aims to develop CNS-delivery-focused trial working groups for paediatric brain tumours.

Results

We have assembled a prestigious steering group, comprising international researchers and clinicians with expertise in diverse aspects of translational and clinical research in CNS drug delivery. At our first group meeting in March, participants will discuss the most effective ways of translating the emerging drug delivery modalities into clinical trials. Prioritised actions will be taken forward and the group will reconvene to discuss developments and next steps at a workshop in the Autumn.

Conclusion

We present this abstract to the SNO Paediatric conference to raise awareness of this initiative with the large number of relevant stakeholders who will be attending the event.
EPCT-10. DEBIO1347, AN ORAL FGFR INHIBITOR: RESULTS FROM A SINGLE CENTER STUDY IN RECURRENT/REFRACTORY FGFR ALTERED PEDIATRIC GLIOMAS
Authors: Farouk Sait Sameer , Gilheeney Stephen , Bale Tejus , Rosenblum Marc , Haque Sofia , Ibanez Katarzyna , Dinkin Marc , Vitolano Stephanie , Dunkel Ira , Karajannis Matthias
Published: June 2021

Background

Oncogenic driver alterations in FGFR are present in a subset of pediatric gliomas. Debio1347 is an orally available, highly selective FGFR 1–3 inhibitor that had a favorable safety profile and encouraging preliminary clinical activity in an adult phase 1 study.

Methods

Five children with progressive/refractory CNS tumors harboring an FGFR gene alteration following prior therapy were treated with Debio1347 at Memorial Sloan Kettering Cancer Center on single patient use protocols. Patients were treated using the 20 mg tablet formulation at the adult recommended phase 2 dose (80 mg/1.73 m2 * BSA once daily). Toxicities were graded using CTCAEv5.0 and imaging response assessments were performed every 8–12 weeks. RESULTS All AEs were grade 1–2. Most common treatment-related adverse events were hyperphosphatemia, ALT increased and hypoalbuminemia (4 patients). Two patients met criteria for partial response and two patients had stable disease. A 13 month-old patient with a spinal cord high-grade glioma harboring two FGFR1 mutations (V592M, K687E) had tumor reduction of 91.7% maintained for 12 months. A 26-month-old patient with a pilomyxoid astrocytoma harboring an FGFR1-TACC1 fusion had a tumor reduction of 74.5% maintained for 9 months. Molecular characterization of recurrent tumor from this patient demonstrated an NF1 deletion as a novel molecular mechanism of acquired resistance to FGFR inhibition. Prolonged disease stabilization was noted in an eight year-old patient with metastatic suprasellar pilomyxoid astrocytoma harboring an FGFR1 mutation (9 months) and in a 14 year-old patient with posterior fossa glioneuronal tumor harboring an FGFR3-TACC3 fusion (24 months and ongoing).

Conclusions

Debio1347 demonstrated tolerable toxicity and promising anti-tumor efficacy in pediatric patients with refractory FGFR altered gliomas. Specific attention to growth velocity and clinical symptoms with incorporation of imaging assessment of bone growth is warranted. Candidate biomarkers (FGFR1 V592M and K687E SNVs, FGFR-TACC fusions) may guide patient selection. Further studies in this population are warranted.
EPCT-13. SINGLE INSTITUTION RETROSPECTIVE ANALYSIS OF TUMOR MUTATIONAL BURDEN AND SURVIVAL IN PEDIATRIC BRAIN TUMORS
Authors: Parisi Rose , Patel Roshal , Weintraub Lauren
Published: June 2021

Tumor mutational burden (TMB) has been studied across numerous cancer types as a means of risk stratification. To examine the prognostic relevance of TMB to pediatric central nervous system (CNS) tumors, we conducted a retrospective analysis of patients at Albany Medical Center diagnosed from 2012 to present. Patients were <21 at diagnosis, had a primary CNS tumor and available genomic data. Forty-seven patients were included – 22 low-grade gliomas, 10 high-grade gliomas, 5 medulloblastomas, 3 ependymomas, 2 choroid plexus carcinomas, and 5 other CNS tumors, with a median follow up of 36 months, median age at diagnosis 10 (1–19), and 47% female. Median TMB was 1 mutation per megabase (mut/mb); range 0–6. Nine patients did not have available TMB data. Twenty-seven patients had driver mutations and other alterations implicated in cancer development including, including BRAF-KIAA1549 fusion (n=6), NF1 loss (n=5), FGFR1 amplification (n=4), TP53 inactivation (n=4), BRAF V600E mutation (n=3), and H3F3A K28M mutation (n=3). Patients with low TMB (<3 muts/mb; n=24) versus high TMB (≥3 muts/mb; n=14) had a survival of 87% versus 71%, respectively, at last follow-up. Of note, all but one patient in the low TMB cohort had localized disease at diagnosis versus three in the high TMB cohort. High TMB was more prevalent in high- (45%, 9/20) versus low-grade histologies (22%, 4/18). Patients with BRAF alterations had LGGs and low TMB (0–1 muts/mb) with all patients surviving at last follow up. Of the eight deaths observed (median 18 months from diagnosis) TMB was high in 4, low in 3, and unknown in 1; all had high-grade histology. Although limited, our data suggests higher TMB may be associated with worse outcome. This analysis will be expanded via a multi-institutional review of TMB and genomic alterations in pediatric CNS patients to better identify high-risk patients requiring alternative treatment strategies.
EPCT-14. GD2 CAR T-CELLS MEDIATE CLINICAL ACTIVITY AND MANAGEABLE TOXICITY IN CHILDREN AND YOUNG ADULTS WITH H3K27M-MUTATED DIPG AND SPINAL CORD DMG
Authors: Majzner Robbie , Ramakrishna Sneha , Mochizuki Aaron , Patel Shabnum , Chinnasamy Harshini , Yeom Kristen , Schultz Liora , Richards Rebecca , Campen Cynthia , Reschke Agnes , Mahdi Jasia , Toland Angus Martin Shaw , Baggott Christina , Mavroukakis Sharon , Egeler Emily , Moon Jennifer , Landrum Kayla , Erickson Courtney , Rasmussen Lindsay , Barsan Valentin , Tamaresis John , Marcy Anne , Kunicki Michael , Fujimoto Michelle , Ehlinger Zach , Kurra Sreevidya , Cornell Timothy , Partap Sonia , Fisher Paul , Grant Gerald , Vogel Hannes , Sahaf Bita , Davis Kara , Feldman Steven , Mackall Crystal , Monje Michelle
Published: June 2021

Background

We previously discovered high expression of the disialoganglioside GD2 on H3K27M+ gliomas and demonstrated preclinical efficacy of intravenous (IV) GD2-targeted chimeric antigen receptor (CAR) T-cells in preclinical models of H3K27M-mutated diffuse intrinsic pontine glioma (DIPG) and diffuse midline gliomas (DMGs). We are now conducting a Phase I clinical trial (NCT04196413) of autologous GD2-targeting CAR T-cells for H3K27M+ DIPG and spinal cord DMG. Here we present the results of subjects treated at dose level 1 (DL1; 1 million GD2-CAR T-cells/kg IV).

Methods

Four patients (3 DIPG, 1 spinal DMG; ages 4–25; 1M/3F) were enrolled at DL1. Three subjects with H3K27M+ DIPG received 1e6 GD2-CAR T-cells/kg IV on study. One patient with spinal DMG enrolled but became ineligible after manufacturing and was treated on an eIND at DL1. An Ommaya reservoir was placed in all subjects for therapeutic monitoring of intracranial pressure. Subjects underwent lymphodepletion with fludarabine/cyclophosphamide and remained inpatient for at least two weeks post-infusion.

Results

All subjects developed cytokine release syndrome (Grade 1–3) manifested by fever, tachycardia and hypotension. Other toxicities included ICANS (Grade 1–2) and neurological symptoms/signs mediated by intratumoral inflammation which we have termed Tumor Inflammation-Associated Neurotoxicity (TIAN). No evidence of on-target, off-tumor toxicity was observed in any patients. No dose-limiting toxicities occurred. CAR T cells trafficked to the CNS and were detected in CSF and blood. 3/4 patients exhibited marked improvement or resolution of neurological deficits and radiographic improvement. The patient treated on an eIND exhibited >90% reduction in spinal DMG volume but progressed by month 3. Re-treatment of this subject via intracerebroventricular administration resulted in a second reduction in spinal DMG volume by ~80%.

Conclusions

GD2-CAR T-cells at DL1 demonstrate a tolerable safety profile in patients with H3K27M+ DIPG/DMG with clear signs of T-cell expansion and activity including clinical responses.
EPCT-25. SMO PROTEIN DEPLETION IN SHH MEDULLOBLASTOMAS USING MICROBUBBLE-ENHANCED ULTRASOUND AND SIRNA LOADED CATIONIC NANOPARTICLES
Authors: Guo Yutong , Lee Hohyun , Fang Zhou , Velalopoulou Anastasia , Kim Jinhwan , Thomas Midhun Ben , Liu Jingbo , Abramowitz Ryan G , Kim YongTae , Coskun Ahmet F , Krummel Daniel Pomeranz , Sengupta Soma , MacDonald Tobey J , Arvanitis Costas
Published: June 2021

RNA-based therapies offer unique advantages for treating pediatric brain tumors. However, the systemic delivery remains a major problem due to degradation of unmodified RNA in biological fluids, poor brain accumulation, and poor cancer cell uptake or escape from the endosomal lipid bilayer barrier. While nanoparticle encapsulation can prolong circulation time and facilitate cellular uptake, their accumulation in brain tumor remains particularly poor due to their low permeability across the blood-brain barrier and limited intratumoral penetration. Focused ultrasound, when combined with circulating microbubbles (MB-FUS) provides a physical method to transiently modulate the brain tumor microenvironment (TME) and improve nanoparticle delivery. Here, we have examined the delivery of siRNA targeting the Smoothened (SMO) pathway, packaged in 50 nm cationic lipid-polymer hybrid nanoparticles (cLPH:siRNA-SMO), combined with MB-FUS in murine SmoA2 sonic hedgehog (SHH) medulloblastoma. At 30 hours after treatment, we observed the depletion of the SMO protein target, responsible for driving SHH medulloblastoma formation and growth, in mice that had received treatment with MB-FUS and cLPH:siRNA-SMO, but not with cLPH:siRNA-SMO alone. We also confirmed that SMO protein depletion was spatially achieved in the tumor regions with detected cLPH:siRNA-SMO using FISH assay, and that there was 15 fold induction of tumor cell apoptosis compared to tumors in mice that had received cLPH:siRNA-SMO alone. The limited induction of apoptosis was observed with either cLPH:siRNA (non-targeting) or MB-FUS and cLPH:siRNA (non-targeting), suggest that the observed apoptosis induction in the SmoA2 model was the direct result of SMO depletion rather than nonspecific effects of MB-FUS or cLPH:siRNA. Our findings provide a paradigm shift in drug delivery in brain tumors, where physical methods and nanotechnology are tuned together to develop rational strategies for the effective delivery of nucleic acids in brain tumors.
A Systematic Review and Meta-Analysis of Studies Evaluating the Effect of Medication Treatment for Opioid Use Disorder on Infectious Disease Outcomes
Authors: McNamara Katelyn F , Biondi Breanne E , Hernández-Ramírez Raúl U , Taweh Noor , Grimshaw Alyssa A , Springer Sandra A
Published: June 2021

The opioid epidemic has fueled infectious disease epidemics. We determined the impact of medications for opioid use disorder (MOUD) on treatment outcomes of opioid use disorder (OUD)-associated infectious diseases: antiretroviral therapy (ART) adherence, human immunodeficiency virus (HIV) viral suppression, hepatitis C virus (HCV) sustained virologic response, HCV reinfection, new hepatitis B virus infections, and infectious endocarditis-related outcomes. Manuscripts reporting on these infectious disease outcomes in adults with OUD receiving MOUD compared with those with OUD “not” receiving MOUD were included. Initial search yielded 8169 papers; 9 were included in the final review. The meta-analysis revealed that MOUD was associated with greater ART adherence (odds ratio [OR] = 1.55; 95% confidence interval [CI] = 1.12–2.15) and HIV viral suppression (OR = 2.19; 95% CI = 1.88–2.56). One study suggested a positive association between MOUD and HCV sustained virologic response. There is significant support for integrating MOUD with HIV treatment to improve viral suppression among persons with HIV (PWH) and OUD. Treatment of OUD among PWH should be a priority to combat the opioid and HIV epidemics.
Development of an Electronic Algorithm to Identify in Real Time Adults Hospitalized With Suspected Community-Acquired Pneumonia
Authors: Jones George , Amoah Joe , Klein Eili Y , Leeman Hannah , Smith Aria , Levin Scott , Milstone Aaron M , Dzintars Kathryn , Cosgrove Sara E , Fabre Valeria
Published: June 2021

Background

Community-acquired pneumonia (CAP) is a major driver of hospital antibiotic use. Efficient methods to identify patients treated for CAP in real time using the electronic health record (EHR) are needed. Automated identification of these patients could facilitate systematic tracking, intervention, and feedback on CAP-specific metrics such as appropriate antibiotic choice and duration.

Methods

Using retrospective data, we identified suspected CAP cases by searching for patients who received CAP antibiotics AND had an admitting International Classification of Diseases, Tenth Revision (ICD-10) code for pneumonia OR chest imaging within 24 hours OR bacterial urinary antigen testing within 48 hours of admission (denominator query). We subsequently explored different structured and natural language processing (NLP)–derived data from the EHR to identify CAP cases. We evaluated combinations of these electronic variables through receiver operating characteristic (ROC) curves to assess which best identified CAP cases compared to cases identified by manual chart review. Exclusion criteria were age <18 years, absolute neutrophil count <500 cells/mm3, and admission to an oncology unit.

Results

Compared to the gold standard of chart review, the area under the ROC curve to detect CAP was 0.63 (95% confidence interval [CI], .55–.72; P < .01) using structured data (ie, laboratory and vital signs) and 0.83 (95% CI, .77–.90; P < .01) when NLP-derived data from radiographic reports were included. The sensitivity and specificity of the latter model were 80% and 81%, respectively.

Conclusions

Creating an electronic tool that effectively identifies CAP cases in real time is possible, but its accuracy is dependent on NLP-derived radiographic data.
Brain and testis: more alike than previously thought?
Authors: Matos Bárbara , Publicover Stephen J. , Castro Luis Filipe C. , Esteves Pedro J. , Fardilha Margarida
Published: June 2021

Several strands of evidence indicate the presence of marked similarities between human brain and testis. Understanding these similarities and their implications has become a topic of interest among the scientific community. Indeed, an association of intelligence with some semen quality parameters has been reported and a relation between dysfunctions of the human brain and testis has also been evident. Numerous common molecular features are evident when these tissues are compared, which is reflected in the huge number of common proteins. At the functional level, human neurons and sperm share a number of characteristics, including the importance of the exocytotic process and the presence of similar receptors and signalling pathways. The common proteins are mainly involved in exocytosis, tissue development and neuron/brain-associated biological processes. With this analysis, we conclude that human brain and testis share several biochemical characteristics which, in addition to their involvement in the speciation process, could, at least in part, be responsible for the expression of a huge number of common proteins. Nonetheless, this is an underexplored topic, and the connection between these tissues needs to be clarified, which could help to understand the dysfunctions affecting brain and testis, as well as to develop improved therapeutic strategies.
Hedgehog signalling controls sinoatrial node development and atrioventricular cushion formation
Authors: Zhang Chaohui , Li Yuxin , Cao Jiaheng , Yu Beibei , Zhang Kaiyue , Li Ke , Xu Xinhui , Guo Zhikun , Liang Yinming , Yang Xiao , Yang Zhongzhou , Sun Yunfu , Kaartinen Vesa , Ding Keyue , Wang Jikui
Published: June 2021

Smoothened is a key receptor of the hedgehog pathway, but the roles of Smoothened in cardiac development remain incompletely understood. In this study, we found that the conditional knockout of
Smoothened
from the mesoderm impaired the development of the venous pole of the heart and resulted in hypoplasia of the atrium/inflow tract (IFT) and a low heart rate. The blockage of
Smoothened
led to reduced expression of genes critical for sinoatrial node (SAN) development in the IFT. In a cardiac cell culture model, we identified a Gli2–Tbx5–Hcn4 pathway that controls SAN development. In the mutant embryos, the endocardial-to-mesenchymal transition (EndMT) in the atrioventricular cushion failed, and Bmp signalling was downregulated. The addition of Bmp2 rescued the EndMT in mutant explant cultures. Furthermore, we analysed

Gli2
+

scRNAseq and

Tbx5
−/−

RNAseq data and explored the potential genes downstream of hedgehog signalling in posterior second heart field derivatives. In conclusion, our study reveals that Smoothened-mediated hedgehog signalling controls posterior cardiac progenitor commitment, which suggests that the mutation of
Smoothened
might be involved in the aetiology of congenital heart diseases related to the cardiac conduction system and heart valves.
Habitat filtering differentially modulates phylogenetic and functional diversity relationships between predatory arthropods
Authors: Ridel Aurélien , Lafage Denis , Devogel Pierre , Lacoue-Labarthe Thomas , Pétillon Julien
Published: June 2021

Mechanisms underlying biological diversities at different scales have received significant attention over the last decades. The hypothesis of whether local abiotic factors, driving functional and phylogenetic diversities, can differ among taxa of arthropods remains under-investigated. In this study, we compared correlations and drivers of functional diversity (FD) and phylogenetic diversity (PD) between spiders and carabids, two dominant taxa of ground-dwelling arthropods in salt marshes. Both taxa exhibited high correlation between FD and PD; the correlation was even higher in carabids, probably owing to their lower species richness. Analyses using structural equation modelling highlighted that FD and PD were positively linked to taxonomic diversity (TD) in both taxa; however, abiotic factors driving the FD and PD differed between spiders and carabids. Salinity particularly drove the TD of carabids, but not that of spiders, suggesting that spiders are phenotypically more plastic and less selected by this factor. Conversely, PD was influenced by salinity in spiders, but not in carabids. This result can be attributed to the different evolutionary history and colonization process of salt marshes between the two model taxa. Finally, our study highlights that, in taxa occupying the same niche in a constrained habitat, FD and PD can have different drivers, and thereby different filtering mechanisms.
Ethylene-regulated immature fruit abscission is associated with higher expression of
CoACO
genes in
Camellia oleifera
Authors: Hu Xiao , Yang Mi , Gong Shoufu , Li Hongbo , Zhang Jian , Sajjad Muhammad , Ma Xiaoling , Yuan Deyi
Published: June 2021

Immature fruit abscission is a key limiting factor in
Camellia oleifera
Abel. (
C. oleifera
) yield. Ethylene is considered to be an important phytohormone in regulating fruit abscission. However, the molecular mechanism of ethylene in regulating fruit abscission in
C. oleifera
has not yet been studied. Here, we found that the 1-aminocyclopropane-1-carboxylic acid (ACC) content was significantly increased in the abscission zones (AZs) of abnormal fruits (AF) which were about to abscise when compared with normal fruits (NF) in
C. oleifera
‘Huashuo’. Furthermore, exogenous ethephon treatment stimulated fruit abscission. The cumulative rates of fruit abscission in ethephon-treated fruits (ETH-F) on the 4th (35.0%), 8th (48.7%) and 16th (57.7%) days after treatment (DAT) were significantly higher than the control. The ACC content and 1-aminocyclopropane-1-carboxylate oxidase (ACO) activity in AZs of ETH-F were also significantly increased when compared with NF on the 4th and 8th DAT.
CoACO1
and
CoACO2
were isolated in
C. oleifera
for the first time. The expressions of
CoACO1
and
CoACO2
were considerably upregulated in AZs of AF and ETH-F. This study suggested that ethylene played an important role in immature fruit abscission of
C. oleifera
and the two
CoACOs
were the critical genes involved in ethylene's regulatory role.