bluuebunny/crossref_metadata_2025_split 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

Abstract

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

Abstract

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

Abstract

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

Abstract
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

Abstract
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 &lt; 0.001), with the integrity of the dorsal attention network particularly affected (p &lt; 0.0001). Moreover, patients demonstrated significant impairments in multiple domains of cognitive performance, including attention (p &lt; 0.0001). Finally, a significant amount of variance (R squared = 0.52, F = 3.2, p &lt; 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

Abstract
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

Abstract

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 &gt;5 years (80.5% and 68.3%, respectively). A majority of patients (58.5%) had &gt;20 café-au-lait spots. Most patients (59.8%) had &gt;1 PN, with 11.0% reporting &gt;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

Abstract

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

Abstract

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

Abstract
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

Abstract
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)