bluuebunny/crossref_metadata_2025_split huggingface dataset:
OTHR-19. Disordered cell migration in the cerebral cortex caused by Lin28A overexpression and Wnt pathway activation in neural precursor cells
Authors: Navolic Jelena , Middelkamp Maximilian , Sumislawski Piotr , Ruck Lisa , Krisp Christoph , Dottermusch Matthias , Schlüter Hartmut , Neumann Julia E 
Published: June 2022

Abstract
LIN28A overexpression and mutations of the Wnt pathway gene CTNNB1 have been described in rare malignant brain tumors of early childhood. In order to investigate the interplay of the oncogenic proteins Lin28A and Ctnnb1 during embryonal brain development, we overexpressed these components in neural progenitor cells in vivo. The sole overexpression of either Lin28A, stabilized Ctnnb1 (Ctnnb1Δex3) or the combination of both in hGFAP-positive forebrain precursor cells did not lead to brain tumor formation but resulted in distinct phenotypes in the cerebral cortex during embryonal development. The hGFAP-cre::IsI-Lin28A (GL) mouse model showed transiently increased proliferation in the cerebral ventricular zone and proper isocortical layering. hGFAP-cre::Ctnnb1Δex3fl/+ (GB) and hGFAP-cre::Ctnnb1Δex3fl/+::IsI-Lin28A (GBL) mice developed a hydrocephalus and showed disturbed cortical layering. GB mice displayed cerebral hypoplasia with a thinned cortex, while the GBL cortices showed variable thickness. Immunostainings with the pial marker Laminin and dendritic marker Map2c revealed a porous pia mater and aggregations of neurons above the pial border in the GBL model at embryonal day 14 (E14.5). At later embryonal stage (E18.5), the GBL model showed also large blood vessels located in deeper cortical layers. Proteome analyses of GB and GBL cortices revealed decreased abundance of the Lissencephaly associated component Reelin-receptor Lrp8 compared to hGFAP-cre control mice. Additionally, we found 92 proteins, which were altered specifically in the GBL mouse model. These results indicate that the co-expression of Lin28A and Ctnnb1Δex3 in neural precursor cells does not lead to brain tumor formation but results in neuronal migration disturbances with ectopic neurons in the subarachnoid area. Whereas the GB phenotype is reminiscent of human lissencephaly type I, GBL brain morphology showed similarities to neuronal overmigration observed in the migration disorder of human Cobblestone (Type II) Lissencephaly.
OTHR-22. Malignant mesothelioma (MM) as second cancer in childhood brain tumor survivors: the first child with neurofibromatosis type 2 and concurrent MM
Authors: Crocco Marco , Verrico Antonio , De Marco Patrizia , Ognibene Marzia , Capra Valeria , Romano Ferruccio , Moreiro Cristina , Bennicelli Elisa , Salfi Nunzio , Barra Salvina , Rizzo Francesca , Rossi Andrea , Milanaccio Claudia , Garrè Maria Luisa , Piccolo Gianluca 
Published: June 2022

Abstract
We report two cases of malignant mesothelioma (MM) in childhood brain tumor survivors. A 40-year-old man, who was treated at the age of ten with chemotherapy and craniospinal radiotherapy (up to 54.5 Gy) for a pineal secreting non-germinomatous germ cell tumor, had persistent fever, fatigue, and weight loss. A total body CT scan revealed several pulmonary and abdominal wall nodularities. The histological examination on a biopsy diagnosed a biphasic MM. The karyotype and array-CGH of peripheral blood were normal; a FISH of tumor cells showed a breakage of locus EWSR1 (22q12.2). In this case, environmental exposure was identified (asbestos in public water tanks). His MM followed an aggressive course and resulted in death after three months. A twelve-year-old boy affected by severe neurofibromatosis type 2 (NF2) already treated with several neurosurgical exeresis and chemotherapy lines (hydroxycarbamide, bevacizumab, sirolimus), developed multiple abdominal lesions, associated with pleural effusion and weight loss. The CT scan showed the thickening of the left pleura and multiple peritoneal nodules. The cytological examination on thoracentesis diagnosed an epithelioid MM. The karyotype on paracentesis-obtained cells revealed monosomy of chromosomes 14 and 22, loss of Y, and trisomy of 6, 10, 11, 16, and 20. NGS is currently ongoing to exclude germline or somatic second hits. Importantly, no exposure to asbestos was found. Less than 2% of MMs occur below 45 years of age; it is a rare secondary tumor in cancer survivors and environmental or genetic contributing causes are often detectable on a careful investigation. Variants in NF2 are considered to be the second most common after those in BAP1. To our knowledge, this is the first child with NF2 and concurrent MM reported to date. Compared to the expected prognosis, his MM has followed a mild course, and one year after diagnosis he is still alive.
OTHR-26. A pilot study of clinical minimal residual disease detection in pediatric embryonal brain tumors
Authors: Cole Bonnie , Lockwood Christina , Paulson Vera , Lee Amy , Hauptman Jason , Goldstein Hannah , Vitanza Nicholas , Crotty Erin , Leary Sarah 
Published: June 2022

Abstract
Cell-free DNA (cfDNA) presents an opportunity for measurement of minimal residual disease (MRD) in pediatric central nervous system (CNS) tumors. In this pilot study, we sought to evaluate the clinical use of low-pass whole genome sequencing (LP-WGS) of cfDNA in cerebrospinal fluid (CSF) of patients with embryonal neoplasms. 31 CSF samples were collected from 16 patients with molecularly characterized medulloblastoma (12), embryonal tumor with multilayer rosettes (2), and CNS embryonal tumors, NEC (2). Samples were collected at various treatment time points. Processing included centrifugation and freezing prior to cfDNA extraction, repair, adapter ligation, amplification, purification, and sequencing on an internally-developed and clinically-validated LP-WGS assay utilizing custom-developed bioinformatics and molecular pathologist review. 29 of 31 samples (94%) had adequate cfDNA in CSF for LP-WGS analysis. Copy number variants (CNVs) compatible with tumor were detected in 23 of 29 (79%) samples, including isodicentric chromosome 17, monosomy 6, MYCN amplification, and regional amplification of chromosome 19. In all cases with detectable cfDNA alterations in CSF, CNV were compatible with the molecular findings in tumor tissue. Two CSF samples had additional chromosomal alterations detected at the time of tumor progression that were not identified in the original tumors. All 9 lumbar puncture samples (100%) collected at initial staging had CSF cfDNA alterations indicative of MRD while corresponding cytologic evaluations of the same samples were positive in only 1 of 9 (11%). No MRD was detected in the single sample evaluated at the end of therapy time point. These findings suggest that LP-WGS of cfDNA in CSF represents a sensitive and clinically useful test for detection of MRD in patients with embryonal tumors of the CNS independent from CSF cytology. Future prospective studies are warranted to determine whether LP-WGS analysis of cfDNA in CSF can predict tumor recurrence and early treatment resistance in our patients.
OTHR-32. The Pediatric Targeted Therapy 2.0 registry: robust molecular diagnostics for precision oncology
Authors: Ecker Jonas , Selt Florian , Sturm Dominik , Sill Martin , Korshunov Andrey , Capper David , Hirsch Steffen , Dikow Nicola , Sutter Christian , Müller Carina , Sigaud Romain , von Deimling Andreas , Pajtler Kristian W , van Tilburg Cornelis M , Jones David T W , Sahm Felix , Pfister Stefan M , Witt Olaf , Milde Till 
Published: June 2022

Abstract
BACKGROUND: The Pediatric Targeted Therapy (PTT) 2.0 program was established to enable precision oncology for relapsed pediatric oncology patients by performing a set of molecular analyses on tumor samples to improve diagnostic accuracy and to detect actionable alterations. METHODS: International pediatric oncology patients with relapse or progression after standard of care treatment independent of histological diagnosis were included. Required material was an FFPE sample from any disease episode available to perform a DNA methylation array, customized targeted gene panel sequencing (130 genes), RNA Sanger sequencing in selected cases, and a pathway-specific immunohistochemistry (IHC) panel. For sequencing a blood sample was used as paired constitutional DNA, allowing for detection of potential cancer predisposition syndromes. All molecular results were discussed in an interdisciplinary tumor board and reported back to the submitting centers. The clinical impact of reported findings was assessed by a serial questionnaire-based two year follow-up. RESULTS: n=266 patients were registered, the molecular workup was successfully performed for n=263 (99%) patients. The most frequent diagnostic category was central nervous system tumors (n=172/263, 65%). Integrated molecular diagnostics suggested a refined or changed diagnosis in n=95/172 (55%) brain tumors. Actionable targets were detected in n=106/172 (61%) cases. In n=11/155 (7.1%) of brain tumor patients pathogenic or likely pathogenic constitutional DNA variants with clinical relevance were identified, n=5 (45%) of which were previously unknown. Clinical follow-up of revealed that n=11/131 (12%) of brain tumor patients received mechanism-of-action based treatment matched to the molecular findings in PTT2.0. CONCLUSIONS: Molecular diagnostics adds robust and clinically relevant information on diagnosis, actionable alterations, and cancer predisposition syndromes in CNS and other pediatric tumors even when tissue from the current disease episode is limited.
OTHR-35. Health-Related Quality of Life and Social Determinants of Health within Children with Brain and Spinal Cord Tumors
Authors: Knight Kelsey , Balsara Karl , Coven Scott 
Published: June 2022

Abstract
Social determinants of health (SDOH) have a significant impact on health, well-being, and quality of life (QOL). Validated tools to assess these disparities have been developed but not utilized prospectively in children with central nervous system tumors (CNS). OBJECTIVE: To establish a baseline assessment of health-related quality of life and associated social determinants of health in children with CNS tumors in Indiana. METHOD: We implemented the Pediatric Quality of Life Inventory™ (PedsQL™) for patients (ages 0-21 years) diagnosed with a CNS tumor evaluated in the neuro-oncology clinic from July 2019-January 2022. A higher score is associated with better quality of life. Patient's address was utilized to obtain Area Deprivation Index (ADI) and Child Opportunity Index (COI). ADI allows for rankings of neighborhoods by socioeconomic disadvantage at state or national level (1-10: 1 is least disadvantaged). COI measures the quality of resources in a patients’ community, with five categories ranging from very low- to very high-opportunity. RESULTS: We assessed 107 patients and their parents. The ADI decile within Indiana ranged 1 to 10 (median 5, mean 5.3); national percentile ranged 7 to 100 (median 71, mean 67.3). Overall COI mean was 3, with sub-scores for education - 2.9, health/environment - 2.6, and social/economic - 3.1. The PedsQL™ was completed by 96 parents and 91 patients. Physical mean was 67.4 and 71.2, psychosocial mean 67.8, 68.9, and total mean 67.7, 69.8, respectively. Simple linear regressions demonstrated a correlation between increasing disparity and decreasing quality of life across all dimensions. CONCLUSION: This is one of the first studies to associate a decrease in pediatric quality of life with disparities of social determinants of health. These data demonstrate the need for expanded prospective evaluation to track social determinants of health that may impact on the quality of life in children diagnosed with CNS tumors.
OTHR-36. Management of Central Diabetes Insipidus (CDI) with Low-Dose Vasopressin Infusion in Patients with Non-Germinomatous Germ Cell Tumors (NGGCT) Requiring Hyperhydration during Chemotherapy
Authors: Fitzgerald Caroline , Matson Kathryn 
Published: June 2022

Abstract
Primary intracranial germ cell tumors (GCT) represent 3-5% of central nervous system tumors with non-germinomatous germ cell tumors (NGGCTs) comprising approximately one-third. Located in the pineal and suprasellar regions, the tumors can cause central diabetes insipidus (CDI). Induction chemotherapy for NGGCT includes ifosfamide. Due to the risk of hemorrhagic cystitis associated with ifosfamide, 3000 mL/m2/day of intravenous fluids is administered. Oral desmopressin (DDAVP), the mainstay of treatment for CDI, has a long duration of action, variable intensity and can lead to hyponatremia and water intoxication due to the retention of large quantities of free water. Therefore, DDAVP is held during hyperhydration resulting in significant diuresis leading to patient discomfort and increased risk for wide electrolyte fluctuations. The volume of dextrose-containing IV fluids also places patients at risk for hyperglycemia and other metabolic disturbances. Patients with NGGCTs and CDI at our institution are admitted to the ICU for ifosfamide cycles due to the need for close monitoring and prompt interventions. ICU admission can delay therapy and potentially places patients in a setting where staff are unfamiliar with chemotherapy administration, increasing the risk of safety-related events. From a cost, resource, and patient care perspective, these admissions are suboptimal. This prompted a search for evidence to maintain patients safely out of the ICU. A literature search provided case studies citing the use of low-dose IV vasopressin. In collaboration with our endocrine and pharmacy colleagues we created a protocol to treat patients with CDI receiving chemotherapy with hyperhydration with a low-dose, easily titratable intravenous vasopressin infusion, to keep urine mildly diluted to allow enough diuresis to decrease injury while preventing excessive fluid losses and wide variations in electrolytes.
OTHR-40. DICER 1- a rare , but important tumor driver in malignant progressive brain tumors
Authors: Fried Iris , Rosiman Laila , Fisher Yael 
Published: June 2022

Abstract
BACKGROUND: DICER mutation is a known tumor driver involved in pleuropulmonary blastoma ,renal tumors, masses in the thyroid and ovary and multiple other manifestations. Brain tumors are considered to be a rare manifestation of germline DICER mutation. Currently, brain imaging is not included in the standard follow up of patients with DICER germline mutation, and data re the prevalence of somatic DICER mutations in brain tumors is limited. AIMs: evaluation of prevalence of DICER mutations in a large cohort of rare/relapsed brain tumors. METHODS: over the last year all patients with tumors lacking curative standard therapy in Israel were sent for next generation sequencing,. Molecular evaluation was done using either panel based evaluation (ONCOMINE/Foundation) or whole exome and whole transcriptome (INFORM consortium). Epidemiological data as well as clinical outcome were provided by the treating physician. RESULTS: Between April 2021 and January 2022 one hundred twenty nine samples were sent for molecular analysis, 58 of them were brain tumors. Six patients had DICER associated malignant tumors , 33% of them were brain tumors . One patient with pinealoblastoma was diagnosed with a highly metastatic disease associated with a very grave prognosis. CONCLUSION: brain tumors are an important group among malignant DICER associated tumors. Surveillance may lead to early detection which may be associated with a better outcome.
OTHR-43. Composition of cell-free miRNA in cerebrospinal fluid and plasma as a monitoring tool for pediatric brain tumors
Authors: Anne Coyle , Hollawell Madison , Rathi Komal , Beck Christopher , Choudhari Namrata , Smith Tiffany , Peter Madsen , Storm Phillip , Resnick Adam , Foster Jessica , Koptyra Mateusz 
Published: June 2022

Abstract
Current clinical management of pediatric brain tumor patients involves non-invasive imaging studies to monitor therapeutic response and tumor progression. However, results are often inconclusive and unable to capture biological changes that presage progression on imaging. Non-invasive diagnostics, also termed liquid biopsy, have emerged for detection of cell-free cancer material but there are no such standard, clinically defined biomarkers or methods for pediatric brain tumors. Circulating miRNA presents an attractive biomarker platform given its stability in bio-fluids, selective expression in tumors and release from tumor cells into the extracellular environment. Technology development has permitted high throughput analysis of material obtained from biofluids including plasma and cerebrospinal fluid (CSF). We performed miRNA profiling across a cohort of 54 pediatric brain tumors from different histologies (low grade glioma, ependymoma, germinoma, medulloblastoma, atypical teratoid rhabdoid tumor and high-grade glioma) using CSF (33) and plasma (53) with HTG EdgeSeq platform. CSF and plasma specimens clustered independently of each other providing separate biomarker platforms. Consensus clustering performed on CSF specimens revealed clusters correlated with disease severity (tumor grade). We identified miRNA targets closely correlated with tumor grade (p&lt;0.001), tumor dissemination or metastases (p&lt;0.001) and survival (p=0.001). Similarly in plasma, through consensus clustering we identified cohorts with correlation to tumor grade. While distinct from those identified in CSF, specific plasma miRNA also correlated with clinical (tumor grade; p&lt;0.001, dissemination or metastasis; p=0.002) and demographic (gender; p=0.001) features. Independently, histology-specific miRNA signature was also identified for low grade glioma, medulloblastoma and germinoma in plasma and CSF. The results present differential expression of cell-free miRNAs in plasma and CSF as biomarkers associated with diverse clinical diagnostic and prognostic measures. Further utilization of this approach provides unique platforms (plasma and/or CSF) to inform liquid biopsy-based management in the clinical setting.
OTHR-44. Building narrative competence on the neuro-oncology team: a narrative medicine approach to fostering unity and resilience for work with pediatric brain tumor families
Authors: Riley Kathy 
Published: June 2022

Abstract
Narrative medicine relies on recognizing, taking in, reflecting on and responding to the stories of suffering in others. Drawing on the practice of the close reading of literature and reflection through writing, healthcare professionals gain fresh insights into their own stories and in turn connect in meaningful ways to stories of illness in their patients (Charon, 2001). The lived experience of pediatric neuro-oncology teams seesaws between hard-fought victories and stories of pain, loss, and even death. For patients who survive, many face life-long challenges that impact long-term quality of life. Learning to be an eyewitness of both beauty and pain in literature and art and writing about that witness helps teams reflect on the stories that shape them and their patients as they process the unthinkable in their work. This type of narrative competence requires what Sayantani DasGuspta refers to as narrative humility (Das Gupta, 2008). Narrative humility recognizes that stories of illness are ambiguous, contain contradictions, and belong wholly to the patient, and encourage providers to explore the role their own narrative brings to the clinician-patient relationship (Das Gupta, 2008). This narrative competence enables team members to find new ways to navigate their practice and foster team unity. Connecting to their own narrative allows them to connect to the narratives of others. They learn to be uncomfortable, to feel pain or joy, and to find power in being physically present with someone who is healed, feels marginalized, or is wounded. By listening closely to the stories of illness and loss in others and reflecting on their own stories through narrative medicine techniques, they learn to engage with the stories that define both their patients and their team dynamics. This theoretical and practical presentation explores the principles of narrative medicine and applies them to the particular experience of neuro-oncology teams.
PATH-04. Array-based global DNA Methylation profiling of mouse brain tumors allows comparison to human tumors
Authors: Schoof Melanie , Spohn Michael , Dorostkar Mario , Neyazi Sina , Bockmayr Michael , Swartling Fredrik , Kawauchi Daisuke , Gilbertson Richard , Taylor Jessica , Pei Yanxin , Glass Rainer , Cheng Jiying , Galarza Natalia Moreno , Hench Juergen , Herms Jochen , Jurmeister Philipp , Schweizer Leonille , Capper David , Harter Patrick , Thomas Christian , Hasselblatt Martin , Blattner-Johnson Mirjam , Jones David , Frank Stephan , Kerl Kornelius , Schüller Ulrich 
Published: June 2022

Abstract
The classification of human brain tumors by global DNA methylation profiling has become an essential part of modern integrated neuropathological diagnostics. It has proven to reliably identify known and novel brain tumor (sub-)types that are biologically and clinically distinct. Therefore, this technique has critically improved diagnostic accuracy and risk stratification of brain tumor patients. Although indispensable for the understanding of tumor biology and for preclinical drug trials, the comparison of genetically engineered mouse models to human brain tumors is still difficult. The assessment of tumor morphology only provides an approximate picture, and transcriptomic data from human brain tumors are sparse and suffer from platform-related technical incomparability. Here, we show array-based DNA methylation profiling of well-established murine brain tumors, such as Wnt and Shh medulloblastoma, YAP and RELA ependymoma, ETMR, and AT/RT. Similar to human brain tumors, unbiased clustering methods revealed distinct methylation profiles and mean methylation levels for mouse brain tumors types. Analyses were possible for fresh-frozen as well as for paraffin-embedded tissue, and copy number alterations could be inferred from methylation profiles. Most importantly, first results suggest that inter-species comparisons allow the classification of brain tumors from known or novel mouse models based on the constantly growing spectrum of human brain tumor types and subtypes with hundreds of thousands of available datasets. As an example, upon DNA methylation profiling, cerebellar tumors arising in Math1-cre::SmoM2Fl/+ mice display the highest similarity to human SHH medulloblastoma when compared to multiple human brain tumor entities including WNT and Non-WNT/Non-SHH medulloblastoma. These results suggest that global DNA methylation profiling may add another very important level of information to the characterization of genetically engineered mouse models.