bluuebunny/crossref_metadata_2025_split huggingface dataset:
RARE-15. THE MOLECULAR PROFILE OF SECONDARY MENINGIOMAS IN SURVIVORS OF CHILDHOOD NON-CENTRAL NERVOUS SYSTEM CANCERS
Authors: Corriveau-Bourque Catherine , Wong Derek , van Landeghem Frank , Snuderl Matija , Spavor Maria , Yip Stephen , Eisenstat David 
Published: June 2021

Abstract

Introduction
Cranial irradiation remains part of childhood cancer therapy and secondary meningiomas are a late effect. Secondary meningiomas are reported in patients who received low and high dose cranial irradiation and arise ~ 20 years post exposure. The molecular and genetic profile of primary meningiomas has been well studied; however, only a few studies describe these in radiation-induced meningiomas (RIM).

Methods
We identified patients followed at the Childhood Cancer Survivor Clinic, Stollery Children’s Hospital who had a history of non-central nervous system malignancies and received cranial irradiation who developed meningiomas between clinic inception in 1971 and June 2013. Whole exome sequencing (WES) as well as DNA methylation profiling were performed for patients where tumor and germline DNA were available.

Results
Of 96 patients who received cranial irradiation, 16 (16.7%) developed symptomatic meningiomas. This patient cohort is unique; all 16 patients received 2000–2400 cGy, suggesting a threshold dose. 9/16 (56%) had WHO Grade 2 meningiomas or greater and 7/16 (44%) were infiltrative. Post-surgical recurrences occurred in 43%. Patients experienced considerable morbidities directly attributable to the meningiomas or their treatment. 14 patients had samples suitable for further analysis. Preliminary results revealed that NF2 mutations were the most common (5). Other meningioma related genes with mutations identified in our patient cohort include TRAF7, AKT3, MSH4 (2), KMT2C (2), TET1 (2), KDM6A, and MLH3. Copy number alternations were noted with increased frequency on chromosomes 1p, 22q, 19q. 850k methylation analysis did not conclusively show any clustering. Ongoing studies include assessment of tumor mutation burden, RNAseq, and the mutational profile.

Conclusions
This study examined RIM in patients who received similar doses of radiation for their childhood cancer. To date, our findings are consistent with previously described primary and RIM mutations. Enhanced knowledge in secondary meningiomas is crucial for accurate patient counseling, prognostication, and treatment.
RARE-16. A PATIENT WITH MOSAIC POST-ZYGOTIC KRAS-G12D PATHOGENIC VARIANT PRESENTING WITH A SYMPTOMATIC SPINAL NEUROFIBROMA AND LARGE SEGMENTAL TRUNCAL CAFÉ AU LAIT SPOT
Authors: Demaliaj Dardan , Ji Jianglin , Deardorff Matthew , Chiarelli Peter , Tamrazi Benita , Hawes Debra , Biegel Jaclyn , Rosser Tena , Davidson Tom , Erdreich-Epstein Anat 
Published: June 2021

Abstract
An 11 year old boy presented with a three month history of progressive bilateral lower extremity weakness associated with recent intermittent incontinence. Spine MRI showed a right-sided T11-T12 paraspinal mass extending through the neural foramina into the epidural space and causing severe spinal cord compression. Skin showed a large macular lightly-hyperpigmented café au lait spot with irregular borders along the T10-T12 dermatome extending from the spine to approximately the anterior-axillary line. He was suspected to have segmental neurofibromatosis type 1 (NF1) as no additional clinical findings, radiographic features or family history of NF1 were identified. Patient underwent T10-12 laminectomy for resection of the epidural tumor component. Post-operative MRI showed resolution of the mass effect on the thecal sac and cord, with expected tumor residual lateral to the neural foramen. His residual spinal tumor and mild scoliosis remained stable over the two years of follow up to date. Pathological and molecular analysis of the resected tumor revealed a neurofibroma harboring an activating KRAS c.35G&gt;A, p.Gly12Asp (KRAS-G12D) pathogenic variant at 27% variant allele frequency. Melanocytes cultured from two hyperpigmented skin biopsies showed the same KRAS-G12D pathogenic variant. This KRAS-G12D pathogenic variant was not found in leukocytes, indicating a post-zygotic origin. No NF1 pathogenic variant was identified in tumor tissue, melanocytes or leukocytes. The clinical findings were consistent with a mosaic KRASopathy due to a post zygotic KRAS-G12D pathogenic variant. The presence of the KRAS variant in the spinal neurofibroma and overlaying café au lait spot without an NF1 etiology in associated tissues demonstrates overlapping variability of presentations of RAS-MAPK pathway disorders. This case highlights the need for full clinical and genetic evaluation of patients presenting with segmental neurocutaneous disorders.
RARE-20. A RARE CASE OF A PRIMARY CENTRAL NERVOUS SYSTEM NEUROENDOCRINE CARCINOMA AND SUCCESSFULL THERAPY IN A FIVE-YEAR-OLD CHILD
Authors: Stepien Natalia , Haberler Christine , Schmook Maria-Theresa , Gojo Johannes , Azizi Amedeo A , Czech Thomas , Slavc Irene , Peyrl Andreas 
Published: June 2021

Abstract
Neuroendocrine tumors (NETs) are rare neoplasms predominantly arising in the GI-tract or the lungs of adults. To date, only ten cases of primary CNS NETs have been reported with just three of them describing a neuroendocrine carcinoma (NEC) in patients aged 34–77 years and none occurring in a child. We report on a previously healthy 5-year-old boy, who presented with headaches, nausea and vomiting and was diagnosed with a left cerebellar solid mass with a cystic component, radiologically suggestive of a pilocytic astrocytoma. After gross-total resection, histological analysis revealed an epithelial tumor growing in a nest-like pattern with a very high mitotic frequency, staining positive for CK8, CK18 and CK19. Chromogranin A and synaptophysin expression indicated a neuroendocrine differentiation. Molecular analysis of the tumor tissue revealed a KRAS- splice-site mutation (c451-3C&gt;T). After extensive search for an extracranial primary, including Ga-68 DOTANOC-PET-CT, the diagnosis of a primary CNS NEC was made, and proton irradiation was performed. However, the patient developed an in-field recurrence just five weeks after the end of radiotherapy. The tumor was re-resected en-bloc, showing vital tumor tissue, demonstrating its aggressiveness. Chemotherapy consisting of etoposide, cisplatin and ifosfamide was initiated. After two cycles chemotherapy was continued with etoposide and carboplatin for another four cycles. The patient remains disease free one year after the end of relapse-treatment, supporting the beneficial effect of platinum- and etoposide-based chemotherapy for this tumor entity. Physical exam revealed a sagittal synostosis with a mild dolichocephaly. Interestingly, the KRAS-mutation was discovered to be a maternal germline mutation, previously described as likely benign. However, alterations of the RAS/MAPK pathway have been described in NECs and in craniosynostosis cases. It remains to be elucidated whether the KRAS-mutation is merely a variant of uncertain significance or might have been implicated in the development of this exceptional tumor.
RARE-24. IDENTIFYING INDIVIDUALS WITH PRIMARY CENTRAL NERVOUS SYSTEM TUMORS AT RISK FOR HEREDITARY CANCER SYNDROMES USING THE UTAH POPULATION DATABASE
Authors: Whipple Nicholas , Kohlmann Wendy , Cheshier Samuel , Yu Zhe , Curtin Karen , Schiffman Joshua 
Published: June 2021

Abstract

Background
CNS tumors are the most common solid tumors and the deadliest cancers in children. Approximately 10% of children with a CNS tumor harbor a hereditary cancer syndrome (HCS), but many will not be tested for a HCS. The Utah Population Database (UPDB) contains comprehensive cancer registry data for Utah families and can determine multigenerational cancer pedigrees across an archive of 5.8 million individuals. We hypothesize that the UPDB can identify children and families with HCSs not previously identified.

Methods
We queried the UPDB for individuals ages 0–39 diagnosed with a primary CNS tumor (malignant and benign) between 1966–2017 and generated cancer pedigrees of 3 generations or more for probands, extending to at least third-degree relatives. Specialized software calculated a familial standardized incidence ratio (FSIR) to determine families with excess clustering of CNS tumors. Clinical cancer genetics experts reviewed pedigrees to confirm patterns of HCS.

Results
We identified 4,634 CNS tumors in 4,550 individuals, of whom 2,233 (49%) reside in high-quality pedigrees containing ≥2 grandparents, at least 1 from both maternal and paternal sides. To identify families with excess clustering of CNS tumors, we selected pedigrees with an FSIR P&lt;0.05 and ≥2 affected patients, resulting in 161 high-risk families with a mean of 170 (median 96) relatives per pedigree of 3–6 generations. Among these 161 families, there were 2,017 unique relatives (first-third degree) of CNS probands with 2,355 tumors (any site), for a per pedigree average of 14.7 tumors in 12.5 relatives. Review of the 10 highest risk pedigrees indicated that 4 meet HCS criteria, including Li-Fraumeni (n=2), von Hippel-Lindau (n=1), and rhabdoid tumor predisposition (n=1).

Conclusion
The UPDB can produce multigenerational cancer pedigrees that identify individuals and families at risk of harboring a HCS who warrant germline testing. These findings should encourage clinicians to perform thorough family history screening.
EPCT-03. SERIAL PLASMA AND CSF CELL-FREE TUMOR DNA (CF-TDNA) TRACKING IN DIFFUSE MIDLINE GLIOMA PATIENTS UNDERGOING TREATMENT WITH ONC201
Authors: Cantor Evan , Wierzbicki Kyle , Tarapore Rohinton S , Thomas Chase , Cartaxo Rodrigo , Yadav Viveka Nand , Ravindran Ramya , Bruzek Amy K , Wadden Jack , Babilla Clarissa May , Kawakibi Abed Rhaman , Ji Sunjong , Ramos Johanna , Paul Alyssa , Wolfe Ian , Leonard Marcia , Robertson Partricia , Franson Andrea , Mody Rajen , Garton Hugh , Odia Yazmin , Kline Cassie , Vitanza Nicholas A , Khatua Soumen , Mueller Sabine , Allen Joshua E , Gardner Sharon , Koschmann Carl 
Published: June 2021

Abstract
Diffuse midline glioma (DMG) with the H3K27M mutation is a lethal childhood brain cancer, with patients rarely surviving 2 years from diagnosis. We conducted a multi-site Phase 1 trial of the imipridone ONC201 for children with H3K27M-mutant glioma (NCT03416530). Patients enrolled on Arm D of the trial (n=24) underwent serial lumbar puncture (baseline, 2, 6 months) for cell-free tumor DNA (cf-tDNA) analysis at time of MRI. Additionally, patients on all arms of the trial at the University of Michigan underwent serial plasma collection. CSF collection was feasible in this cohort, with no procedural complications. We collected 96 plasma samples and 53 CSF samples from 29 patients, including those with H3F3A (H3.3) (n=13), HIST13HB (H3.1) (n= 4), and unknown H3 status/not biopsied (n=12) [range of 0–8 CSF samples and 0–10 plasma samples]. We performed digital droplet polymerase chain reaction (ddPCR) analysis and/or amplicon-based electronic sequencing (Oxford Nanopore) of cf-tDNA samples and compared variant allele fraction (VAF) to radiographic change (maximal 2D tumor area on MRI). Preliminary analysis of samples demonstrates a correlation between changes in tumor size and H3K27M cf-tDNA VAF, when removing samples with concurrent bevacizumab. In multiple cases, early reduction in CSF cf-tDNA predicts long-term clinical response (&gt;1 year) to ONC201, and does not increase in cases of later-defined pseudo-progression (radiation necrosis). For example, a now 9-year old patient with thalamic H3K27M-mutant DMG underwent treatment with ONC201 after initial radiation and developed increase in tumor size at 4 months post-radiation (124% baseline) of unclear etiology at the time. Meanwhile, her ddPCR declined from baseline 6.76% VAF to &lt;1%, which has persisted, with now near complete response (15% tumor reduction) at 30 months on treatment from diagnosis. In summary, we present the feasibility and utility of serial CSF/plasma monitoring of a promising experimental therapy for DMG.
EPCT-04. RESULTS OF A PHASE 1 STUDY OF THE ONCOLYTIC ADENOVIRUS DNX-2401 WITH RADIOTHERAPY FOR NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Garcia-Moure Marc , Pérez-Larraya Jaime Gállego , Patiño Ana , Gonzalez-Huarriz Marisol , Jones Chris , MacKay Alan , Van der Lugt Jasper , Hulleman Esther , de Andrea Carlos , Astigarraga Itziar , García-Ariza Miguel , Lopez-Ibor Blanca , Villalba Maria , Lang Frederick F , Fueyo Juan , Gomez-Manzano Candelaria , Dobbs Jessica , Diez-Valle Ricardo , Alonso Marta M , Tejada Sonia 
Published: June 2021

Abstract

Background
A Phase 1, single center study is ongoing to evaluate the conditionally replicative oncolytic adenovirus, DNX-2401 (tasadenoturev), followed by radiotherapy (RT) in pediatric patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG).

Methods
Patients 1–18 years with newly diagnosed DIPG with no prior treatment, Lansky/Karnofsky performance score ≥ 70, and adequate organ function were enrolled. A tumor biopsy was performed followed by a single intratumoral injection of 1e10-5e10 virus particles (vp) DNX-2401. Conventional radiotherapy was initiated within 1 month of DNX-2401 administration.

Results
Enrolled subjects (n=12) had a median age of 9 (range 3–18) and performance scores of 90–100 (n=4; 33%) or 70–80 (n=8; 67%). As part of a dose escalation design, subjects were treated with 1e10 vp (n=4) or 5e10 vp DNX-2401 (n=8), which was then followed by standard RT in 11 of 12 subjects (92%). No dose-limiting toxicities were observed and the treatment regimen was well-tolerated. Adverse events (AEs) have been primarily mild to moderate and consistent with underlying disease. The most commonly reported AEs (≥ 5 subjects), regardless of study drug relationship, include headache, asthenia, vomiting, anemia, leukocytosis, and fever. Two SAEs have been reported including grade 3 lymphopenia and grade 3 abdominal pain. Tumor reductions have been observed and efficacy evaluations are ongoing. As of 09Dec2020, 12-month survival (OS-12) was 71% and 4 of 12 patients had survived &gt; 20 months. Four subjects continue to be followed for survival. Correlative analysis of tumor biopsy and peripheral samples is ongoing.

Conclusions
DNX-2401 followed by RT can be safely administered to pediatric subjects with newly diagnosed DIPG; clinical activity and preliminary survival are encouraging.
EPCT-07. ID1 IS A KEY TRANSCRIPTIONAL REGULATOR OF DIPG INVASION AND IS TARGETABLE WITH CANNABIDIOL
Authors: Nand Yadav Viveka , Harris Micah K , Thomas Chase , Stallard Stefanie , Woo Rinette , Siddaway Robert , Qin Tingting , Cummings Jessica R , Mullan Brendan , Siada Ruby , Ravindran Ramya , Niculcea Michael , Cao Xuhong , Castro Maria G , Lowenstein Pedro R , Mody Rajen , Chinnaiyan Arul , Hawkins Cynthia , Desprez Pierre , McAllister Sean , Venneti Sriram , Koschmann Carl 
Published: June 2021

Abstract
Diffuse intrinsic pontine gliomas (DIPGs) are lethal pediatric brain tumors with no effective therapies beyond radiation. The highly invasive nature of DIPG is key to its aggressive phenotype, but the factors and mechanisms contributing to this aggressive invasion are unknown. Inhibitor of DNA binding (ID) proteins, key regulators of lineage commitment during embryogenesis, are implicated in tumorigenesis in multiple human solid tumors. Prior work showed that recurrent H3F3A and ACVR1 mutations increase ID1 expression in cultured astrocytes. However, the impact and targetability of ID1 have not been explored in human DIPG. Exome and transcriptome sequencing analyses of multi-focal DIPG tumors and normal brain tissue from autopsy (n=52) revealed that ID1 expression is significantly elevated in DIPG samples. Higher ID1 expression correlates with reduced survival in DIPG patients and increased regional invasion in multi-focal autopsy samples. Analyses of developing mouse brain RNA/ChIP-Seq data revealed high ID1 expression and H3K27ac promoter binding in prenatal hindbrain compared to all other prenatal and postnatal brain regions. ChIP-qPCR for H3K27ac and H3K27me3 revealed that ID1 gene regulatory regions are epigenetically poised for upregulation in DIPG tissues compared to normal brain, regardless of H3/ACVR1 mutational status. These data support that the developing pons is regionally poised for ID1 activation. Genetic (shRNA) ID1 knockdown of primary human H3.3K27M-DIPG cells (DIPG007) resulted in significantly reduced invasion/migration and significantly improved survival of K27M-DIPG mice. Knockdown of ID1 in DIPG cells also resulted in down-regulation of the WNK1-NKCC1 pathway, which regulates tumor cell electrolyte homeostasis and migration. Finally, treatment of DIPG007 cells with cannabidiol (CBD) reduced ID1 levels, viability of DIPG cells and significantly improved survival of K27M-DIPG mice. In summary, our findings indicate that multifactorial (genetic and regional) epigenetic upregulation of ID1 drives DIPG invasiveness; and that targeting ID1 with CBD could potentially be an effective therapy for DIPG.
EPCT-11. RURALITY INDEX SCORE AND PEDIATRIC NEURO-ONCOLOGICAL OUTCOME IN ONTARIO
Authors: Kameda-Smith Michelle , Pond Gregory , Farrokhyar Forough , Seow Hsien 
Published: June 2021

Abstract

Introduction
Rapid access to neurosurgical decisions and definitive management are vital for the outcome of neurocritical patients. There are increased challenges of providing services and to maintain critical infrastructure for rural citizens. The relationship between rurality, marginalization and health outcomes has been identified as associated with higher mortality rates and higher rates of many diseases[G1].

Methods
Employing linked administrative databases, we retrospectively analyzed a population based cohort of patients diagnosed with a pediatric brain tumour between 1996 to 2017 in Ontario, Canada. The Ontario Marginalization Index was employed as a surrogate for rurality providing an overall Rurality Index for Ontario (RIO) in addition to the 2016 Ontario Marginalization Index (ON-MARG).

Results
Of 1457 patients included, 54.0% were male, 277 of whom were diagnosed in infancy (i.e., &lt; 3 years of age). Income quintile was evenly distributed with 11.5% classified as living in a rural area of Ontario. The median[G2] distance to the nearest pediatric neurosurgical hospital was 59.6km. The rurality index score (RIO) was 0 in 38.8% of children with the majority of patients with a RIO score of &lt;39. The ON-MARG identified 51.9% of patients living in communities with low concentration of individuals without income from employment. A higher RIO score was not a significant factor (Continuous p=0.092/Ordinal p=0.20) associated with length[G3] of follow up, indicating rurality was not a significant factor for determining compliance to[G4] clinical follow-up. However, a trend towards reduced follow-up compliance in the higher RIO score cohort was identified.

Conclusion
Rurality and social determinants of health of the region pediatric neuro-oncological patients reside were not associated with patient outcome but a trend towards lower follow-up compliance was identified when children were from regions with RIO&gt;39. Implementation of telehealth follow-up for these patients may overcome barrier to clinical follow-up.[G5]
EPCT-19. DRUG RESISTANCE IN MEDULLOBLASTOMA ADDRESSED WITH OLIG2 INHIBITOR, CT-179
Authors: Dismuke Taylor , Lim Chaemin , Gershon Timothy 
Published: June 2021

Abstract
Patients with medulloblastoma, the most common malignant pediatric brain tumor. need improved treatment options. Conventional medulloblastoma treatment, with resection, chemotherapy, and radiation, leaves survivors at risk of neurocognitive injury, growth defects, and psychosocial impairment. Moreover, there is no effective therapy for recurrent medulloblastoma. We seek to identify novel treatments that will address systemic toxicity and tumor recurrence. We tested a nanoparticle formulation of the CDK4/6 inhibitor, palbociclib (POx-palbo) in mice genetically-engineered to develop medulloblastoma (G-Smo mice) and found a significant anti-tumor effect that was consistently limited by the recurrence of OLIG2+ medulloblastoma stem cells. We then tested the hypothesis that directly targeting OLIG2 function would improve the efficacy of palbociclib and forestall resistance. We therefore examined the potential efficacy of CT-179, a first-in-class OLIG2 inhibitor, in G-Smo mice engineered to express luciferase as an SHH reporter. These studies showed that CT-179 decreased SHH signaling and prolonged event-free survival. Pharmacodynamic studies of G-Smo mice during treatment showed that CT-179 alters cell-cycle progression and promotes a shift towards cell-cycle arrest. Mechanistically, CT-179 decreased the Olig2 phosphorylation. The combination of CT-179 and POx-palbo increased event-free survival of G-Smo mice compared to either agent administered alone. Our studies show both the potential of the palbociclib CT-179 combination, and the potential for CT-179 to improve the efficacy of therapies limited by OLIG2+ stem cell recurrence. As OLIG2+ stem cells have been shown to drive recurrence to conventional therapy and OLIG2 phosphorylation disables p53-driven apoptosis, CT-179 may be a versatile agent to enhance both targeted and cytotoxic treatments.
EPCT-20. TECHNICAL FEASIBILITY SODIUM (23NA) MRI OF PEDIATRIC GLIOMAS
Authors: Bhatia Aashim 
Published: June 2021

Abstract
Pediatric glioma response to novel targeted therapy can be heterogeneous on conventional proton (1H) MRI. Sodium concentration, as measured with 23Na MRI in adult brain tumors can provide complementary assessment of tumor proliferation to conventional MRI. However, 23Na MRI pediatric brain tumor studies are lacking. Determine the technical feasibility of performing sodium23Na MRI on pediatric glioma patients. Prospective study of an immunotherapy trial for newly diagnosed and recurrent gliomas (high-grade gliomas, low-grade gliomas, brainstem gliomas) in which participants were imaged with 23Na MRI at 3.0 Tesla. The participants (n=26, 14 males) with median age of 11 years (range = 4–23 years of age) were prospectively evaluated with sodium. 23Na MRI is technically feasible in the pediatric population and can distinguish different types of pediatric gliomas at baseline.