bluuebunny/crossref_metadata_2025_split huggingface dataset:
MBRS-06. Gli3 INDUCES NEURONAL DIFFERENTIATION IN WNT- AND SHH- ACTIVATED MEDULLOBLASTOMA
Authors: Natsumeda Manabu , Miyahara Hiroaki , Yoshimura Junichi , Tsukamoto Yoshihiro , Oishi Makoto , Wataya Takafumi , Eberhart Charles , Kakita Akiyoshi , Fujii Yukihiko 
Published: December 2020

Abstract

BACKGROUND
We have previously investigated the expression of Gli3, a downstream target of the Sonic Hedgehog pathway, which main function is to suppress Gli1/2 in medulloblastomas. We found that Gli3 is associated with neuronal and glial differentiation in desmoplastic / nodular (D/N) type medulloblastomas (Miyahara et al., Neuropathology, 2013). In the present study, we investigated the expression of Gli3 in molecular subgroups.

METHOD
Thirty-one medulloblastomas treated at Niigata University between 1982 and 2013 were studied. Molecular classification into 4 subgroups (WNT-activated, SHH-activated, Group 3 and Group 4) using Nanostring and immunohistochemistry was performed. Furthermore, Gli3 and Gli1 expression in molecular subgroups was assessed using public data bases.

RESULTS
Nanostring was considered reliable (confidence &gt; 0.9) in 28 cases. Four cases were classified as WNT-, 5 cases as SHH-activated, 4 cases as Group 3 and 16 cases as Group 4. Gli3 was positive in 7 out of 9 (78%) WNT-/SHH- cases, but positive in only 8 out of 19 (42.1%) non-WNT-/SHH- subgroup cases (p = 0.1145, Fisher’s exact test). R2 database analysis confirmed that Gli3 was significantly elevated in WNT- and SHH-activated medulloblastoma. Gli1 was elevated in SHH-activated cases but suppressed in WNT-activated cases. IHC analysis revealed that Gli3 was elevated inside nodules showing neuronal differentiation in D/N type medulloblastoma. Results of single cell RNA analyses were consistent with those of IHC, Nanostring and R2.

CONCLUSION
These results suggest that Gli3 is elevated inside the nodules of SHH-activated medulloblastoma, whereas in WNT-activated cases, Gli3 diffusely suppresses HH signaling.
MBRS-16. MYC REGULATED LONG NONCODING RNA LNC-HLX-2–7 IS A PUTATIVE MOLECULAR MARKER AND A THERAPEUTIC TARGET FOR GROUP 3 MEDULLOBLASTOMAS IN CHILDREN
Authors: Katsushima Keisuke , Joshi Piyush , Stapleton Stacie , Garancher Alexandra , Vibhakar Rajeev , Raabe Eric , Eberhart Charles , Wechsler-Reya Robert , Jallo George , Perera Ranjan 
Published: December 2020

Abstract
Medulloblastoma (MB), a central nervous system tumor that predominantly affects children, requires aggressive therapy. Recent advances in the noncoding RNA genome could contribute to the sub-classification of medulloblastoma. The focus of this study is to identify novel long noncoding RNAs (lncRNAs) as molecular markers and potential therapeutic targets within each subgroup of MBs, in particular within Group 3. We analyzed publicly available 175 RNA-seq datasets to identify a group of putative lncRNA signatures that may be able to differentiate medulloblastoma subgroups accurately. Among those, lncRNA lnc-HLX-2–7 was highly upregulated in Group 3 MB cell lines, patient-derived xenografts, FFPE samples compared to other groups. CRISPR/Cas9 deletion of the lnc-HLX-2–7 followed by the fluorescence-activated sorting and generating monoclonal Group 3 MB cells significantly reduced the cell growth and 3-D colony formation together with the induction of apoptosis. Intracranial injection to mouse cerebellum using lnc-HLX-2–7 deleted cells resulted in reduced tumor growth compared to parental cells, and tumors were further characterized by single-cell sequencing. We identified that oncogene MYC regulates lnc-HLX-2–7 and its expression can be controlled by the small molecule JQ1, a BET-bromodomain (BRD4) inhibitor that disrupts interactions with MYC. RNA-FISH analysis using FFPE, PDX, and tissue microarrays revealed that lnc-HLX-2–7 expression is specific to Group 3 MB compared to other groups. We present supporting evidence that lnc-HLX-2–7 is a novel molecular marker and a potential therapeutic target for Group 3 MBs in children.
MODL-21. INTEGRATIVE APPROACHES IN FUNCTIONAL GENOMICS TO IDENTIFY GENETIC DEPENDENCIES IN PEDIATRIC BRAIN CANCER
Authors: Sun Claire , Drinkwater Caroline , Sooraj Dhanya , Bradshaw Gabrielle , Shi Claire , Fernando Dasun , Parackal Sarah , Gough Daniel , Cain Jason , Firestein Ron 
Published: December 2020

Abstract
The precise decoding of human genomes facilitated by the advancements in next-generation sequencing has led to a better understanding of genetic underpinnings of pediatric brain cancers. Indeed, it is now evident that tumours of the same type harbour distinct driving mutations and molecular aberrations that can result in different prognosis and treatment outcomes. The profounder insight into the the identity, amount and types of molecular aberrations has paved the way for the advent of targeted therapies in precision medicine. Nevertheless, less than 10% of pediatric cancer patients harbour actionable mutations. Strictly limited therapeutic options that are firstly available for brain cancers and secondly acceptable for children’s development further impede the breakthrough in the survival rate in pediatric brain cancers. This underscores a desperate need to delve beyond genomic sequencing to identify biomarker coupled therapies that not only featured with treatment efficacy in the central nervous system but also acceptable side effects for children. The Hudson-Monash Paediatric Precision Medicine (HMPPM) Program focuses on utilising genetic profiles of patients’ tumour models to identify new therapeutic targets and repurpose existing ones using high-throughput functional genomics screens (2220 drugs and CRISPR screen of 300 oncogenic genes). Using a large compendium of over sixty patient derived paediatric brain cancer models, we provide proof-of-concept data that shows an integrative pipeline for functional genomics with multi-omics datasets to perform genotype-phenotype correlations and, therefore, identify genetic dependencies. Herein, using several examples in ATRT, DIPG and HGG, we show how functional interrogations can better define molecular subclassification of tumours and identify unique vulnerabilities.
NFB-07. USE OF PEGYLATED INTERFERON α- 2b IN PEDIATRIC PATIENTS AFFECTED BY UNRESECTABLE PLEXIFORM NEUROFIBROMAS: MONOCENTRIC EXPERIENCE
Authors: Cacchione Antonella , Lodi Maria Chiara , Baldo Giada Del , Carai Andrea , Colafati Giovanna Stefania , Camassei Francesca Diomedi , Locatelli Franco , Mastronuzzi Angela 
Published: December 2020

Abstract

BACKGROUND
Neurofibromatosis type 1 (NF1) is autosomal dominant neurogenetic disorder characterized by progressive cutaneous, neurologic, skeletal, and neoplastic manifestations. Plexiform neurofibromas (PN) are one of the different types of neurofibromas that occur in these patients. Complete surgical resection is difficult due to the tumor infiltrative behavior. We evaluated pegylated interferon- α-2b (PI) in patients with unresectable progressive or symptomatic PN.

METHODS
Pediatric patients (1–21 years old) affected by unresectable PN, followed at Bambino Gesù Hospital, were treated with PI. We administered PI as a weekly subcutaneous injection at a beginning dose of 1.0 mcg/kg/wk, increased to 3.0 mcg/kg/wk if well tolerated. Paracetamol (15mg/kg) was given 30 minutes prior the dose of PI and then every 4–6 hours as needed. Patients were evaluated with Magnetic Resonance Imaging (MRI) every 12 months after treatment start in case of stable disease.

RESULTS
10 patients (3 females, 7 males) were enrolled. Median age was 12 years old. The median duration of treatment was 12,6 months. Grade 3 neutropenia (30%) and increased liver transaminases level (20%) were the most common toxicity. 6/10 patients experienced an improvement about pain. 7/10 patients showed clinical response. 1/10 patient had a radiological response at MRI, 1/10 experienced progression disease and 8/10 showed a stable disease at MRI evaluation.

CONCLUSIONS
Our study demonstrated that PI could be a suitable treatment for unresectable PN in terms of stabilization of the tumour size due to its antitumor activity although clinical response does not correlate with radiographic changes.
NURS-01. INTRACEREBROVENTRICULAR DRUG ADMINISTRATION FOR TREATMENT OF PEDIATRIC BRAIN TUMORS
Authors: Fitzgerald Caroline , Matson Kathryn 
Published: December 2020

Abstract
Intrathecal (IT) chemotherapy, given via lumbar puncture (LP) or an intracerebroventricular (ICV) device has become a safe and effective way to deliver chemotherapy into the cerebrospinal fluid (CSF) space. The blood brain barrier makes treating tumors with CSF dissemination difficult with systemic chemotherapy alone. IT chemotherapy is often necessary for tumors which disseminate into the CSF space including embryonal tumors and choroid plexus carcinomas. It is also used for relapsed or recurrent tumors. Giving IT chemotherapy via an ICV device instead of via an LP can be preferable as it requires no deep sedation and allows for more uniform drug distribution. Drugs given IT include methotrexate, cytarabine, hydrocortisone, etoposide, and topotecan. ICV devices can be placed in patients with adequate CSF flow and a flow study can be done if needed to confirm. Accessing the ICV device for administration of chemotherapy is typically done by a physician or nurse practitioner using sterile technique. Our institution has had success using music therapy and child life specialists for assistance with coping during the procedure as patients are awake. The procedure has few complications the most common being infection usually with skin flora. It can also cause nausea and headache. There are few long term risks.
PATH-09. SJMB12 CLINICAL TRIAL: DISCREPANCY BETWEEN LOCAL AND CENTRAL PATHOLOGY IN ASSESSING ANAPLASTIC MEDULLOBLASTOMA – REPORT FROM A SINGLE SITE EXPERIENCE
Authors: Khuong-Quang Dong-Anh , Williamson Karli , MacGregor Duncan , Orr Brent A , Gajjar Amar , Robinson Giles W , Sullivan Michael J , Hansford Jordan R 
Published: December 2020

Abstract

INTRODUCTION
SJMB12 is a phase 2 clinical trial led by the St. Jude Children’s Research Hospital (St. Jude) that enrolls patients with medulloblastoma based on their biological subgroup. The large cell/anaplastic (LCA) histologic variant has been identified as an important independent risk factor associated with poor outcome. However, the histologic criteria for LCA is subjective, making the distinction between anaplastic and non-anaplastic medulloblastoma difficult in some cases.

METHODS
Pathological central review was performed at St. Jude. For all patients enrolled in the study to date, concordance was assessed between the initial and central review diagnosis and histologic variant calls made at the Royal Children’s Hospital Melbourne (RCH) and at St. Jude, respectively.

RESULTS
Since the SJMB12 clinical trial opened locally in 2014, 34 patients were enrolled, and 31 were eligible for this retrospective study. A total of 12 (39%) cases with discordance were identified. The most frequent disagreement was between the designation of LCA (10 cases, 32%). In five cases the tumour was not designated as LCA variant locally. In five cases the initial designation of LCA was refuted centrally. Overall, this led to a change of treatment stratum for four patients (13%).

CONCLUSION
A high discordance rate exists between neuropathologists in the designation of LCA variant. Differences in interpretation of the subjective histologic criteria and inconsistencies in the material submitted for central review contributed to the discordance. Incorporation of more objective histologic criteria and implementation of unbiased diagnostic tools may improve the generalisability of future risk stratification.
PATH-23. ADULT SPINAL CORD ASTROBLASTOMA WITH EWSR1-BEND2 FUSION
Authors: Tsutsui Takeyoshi , Arakawa Yoshiki , Makino Yasuhide , Kataoka Hiroharu , Minamiguti Sachiko , Hirose Takanori , Nobusawa Sumihito , Nakano Yoshiko , Ichimura Koichi , Miyamoto Susumu 
Published: December 2020

Abstract
The most recurrent fusion of CNS high-grade neuroepithelial tumor with MN1alteration(HGNET-MN1) is MN1- BEN Domain Containing 2(BEND2) fusion. Recently, there was a report of a 3-month-old boy with spinal astroblastoma, classified as CNS HGNET-MN1 by DKFZ methylation classification but positive for EWSR1-BEND2 fusion(Yamasaki, 2019). Here, we report a 36-year old man with a spinal cord astroblastoma with EWSR1 alternation. The patient presented with back pain, gait disorder and dysesthesia in lower extremities and trunk was referred to our hospital. MRI showed intramedullary tumor in Th3-5 level, displaying low-intensity on T1 weighted image, high-intensity on T2 weighted image, and homogeneous gadolinium enhancement. Partial removal was performed with the laminectomy. The tumor extended to extramedullary and its boundary was unclear. Histological examinations showed the epithelium-like tumor cells with eosinophilic cytoplasm with high cellularity palisade, intracellar fibrosis, and mitosis. Immunohistochemical staining showed positive for Olig2, GFAP, EMA, SSTR2, S-100, but negative for p53, PgRAE1/AE3. The tumor was diagnosed as astroblastoma, and was classified as HGNET-MN1 by the DKFZ methylation classifier. However, the MN1 alternation was not detected by fluorescence in situ hybridization, instead EWSR1 and BEND2 alternations which suggested EWSR1-BEND2 fusion were detected. After radiation therapy of 54Gy/30fr with bevacizumab and temozolomide, the residual tumor reduced the size and his symptoms improved. This case provides evidence that EWSR1-BEND2 fusion is recurrent in HGNET-MN1 and, as previously reported, suggests the importance of BEND2 in this entity. These two cases suggested that it may be the BEND2 alteration that biologically defines the HGNET-MN1 subclass rather than MN1.
PATH-26. RNA SEQUENCING OF FORMALIN-FIXED PARAFFIN-EMBEDDED SPECIMENS IN DIAGNOSTIC ROUTINE IDENTIFIES CLINICALLY RELEVANT GENE FUSIONS
Authors: Stichel Damian , Schrimpf Daniel , Meyer Jochen , Wefers Annika , Sievers Philipp , Pfister Stefan M , Wick Wolfgang , Jones David T W , von Deimling Andreas , Sahm Felix 
Published: December 2020

Abstract
Pediatric brain tumor entities harbor a variety of gene fusions. Whilst other molecular parameters like somatic mutations and copy number alterations have become pivotal for brain tumor diagnostics, gene fusions are only less well covered by routinely applied methylation arrays or targeted next-generation sequencing of DNA. In a routine diagnostic setting we established and optimized a workflow for investigation of gene fusions in formalin-fixed paraffin-embedded (FFPE) tumor tissues by using RNA sequencing. Assessing different tools for calling fusions from raw data, we found relevant fusions in 66 out of 101 (65%) analyzed cases in a prospective cohort collected over 26 months. In 43 (43%) cases the fusions were of decisive diagnostic relevance and in 40 (40%) cases the fusion genes rendered a druggable target. Besides the relevance of pathognomonic fusions for diagnostics, especially the detection of druggable gene fusions yields direct benefit to the patients. This approach allows for an unbiased search for fusion events in the tested samples. Besides rare variants of established fusions which were not detected by prior targeted analyses, we identified previously unreported fusion events. Exemplified on KIAA1549:BRAF fusion, we in addition provide an overview of the detection accuracy of different methods, including breakpoint detection in DNA methylation array data and fusion gene detection in DNA panel sequencing data. Our data show that RNA sequencing has great diagnostic as well as therapeutic value by clinically detecting relevant alterations.
QOL-02. PERCEPTIONS OF LATE EFFECTS CARE NEEDS AMONG SURVIVORS OF PEDIATRIC BRAIN TUMOURS
Authors: Cacciotti Chantel , Fleming Adam , Tseitlin Hanna , Duckworth JoAnn , Marjerrison Stacey 
Published: December 2020

Abstract

OBJECTIVES
Pediatric brain tumour survivors are at risk of long-term consequences of therapy. Comprehensive late effects care may mitigate these risks, but the best care model is unclear. We sought to describe the care experience and quality of life (QOL) of pediatric brain tumour survivors at the McMaster Children’s Hospital joint adult/pediatric Neuro-Oncology clinic.

METHODS
Cross-sectional survey data were collected. Care needs were assessed with the Cancer Care Experience Questionnaire (CCEQ), Cancer Worry Scale (CWS), and Self-Management Skills Scale (SMSS). Quality of life was measured utilizing the PedsQL Brain Tumor Module. Data were analyzed descriptively.

RESULTS
Thirty-two childhood brain tumor survivors and/or their parents participated. Their malignancies included embryonal tumors (medulloblastoma/ATRT) (62%), ependymoma (22%), and germ cell tumours (16%). Among 77%, therapy included chemotherapy, surgery and radiation. Most respondents reported high quality cancer care, although some could not recall discussions of late effects risks and health promotion. Mean cancer worry scores were low (71.8 (± 28.4)). Survivors reported limited self-management skills (58.5 (±18.2)), with support required in clinic visits, arranging medical appointments, filling prescriptions and tasks of daily living. Overall median QOL scores were in the ‘good’ range (parental report 72.3 (±17.7), survivor 68.2 (±16.6)).

CONCLUSION
In comparison to other childhood cancer survivor cohorts, this group of long-term brain tumour survivors appear to have similar QOL, fewer cancer worries, and increased need for aid with self-management. Given this, along with the positive care experience reported, this clinic model of care appears to meet the needs of this population.
QOL-17. BIOLOGICAL CORRELATES OF QUALITY OF SURVIVAL AND NEUROCOGNITIVE OUTCOMES IN MEDULLOBLASTOMA; A META-ANALYSIS OF THE SIOP-UKCCSG-PNET3 AND HIT-SIOP-PNET4 TRIALS
Authors: Chevignard Mathilde , Bull Kim , Holt James , Heng Marie-Amelie , Kennedy Colin , Doz Francois , Lannering Birgitta , Rutkowski Stefan , Massimino Maura , Clifford Steven , Hicks Debbie 
Published: December 2020

Abstract
Relationships between biological factors (genetic, tumour molecular subgroup) and neurocognitive/Quality of Survival (QoS) outcomes in medulloblastoma survivors are emerging, based on studies of limited retrospective cohorts. Integrated investigations of the medulloblastoma late-effects pathway (considering biological, clinical and treatment factors), using larger clinically-controlled cohorts, are now essential to determine their independent significance and potential for clinical application. In a combined cohort of SIOP-UKCCSG-PNET3 and HIT-SIOP-PNET4 patients (n=150), molecular subgroup (MBWNT, MBSHH, MBGrp3, MBGrp4) was assessed against QoS measures [health status: HUI3; emotional and behavioural difficulties: SDQ; Health-related Quality of Life (HrQoL): PedsQL]. Additionally, in DNA remaining from HIT-SIOP-PNET4 (n=74), 39 candidate SNPs (involved in metabolism, DNA maintenance/repair, neural growth/repair and oxidative stress/inflammation) were genotyped by multiplexed MALDI-TOF MassArray and assessed against Wechsler Intelligence Scale (WISC) scores. Molecular subgroup was significantly associated with HrQoL and health status in univariate analyses; MBGrp4 predicted significantly worse outcomes than MBSHH and MBGrp3 (p&lt;0.05), but not in multivariate analyses taking into consideration other significant and reported QoS predictors (e.g. treatment, gender, age). In contrast, 6 SNPs were significantly associated with ≥1 WISC domain; 4/6 showed associations across domains. 3 SNPs were independently prognostic in multivariate analyses, and further significant associations were apparent at the gene (BDNF, APOE) and pathway (folate) level. This cross-discipline, international study encompassing two medulloblastoma trials has identified relationships between molecular subgroup, genotype and survivorship outcomes. These findings now require assessment in larger series, to inform our understanding of medulloblastoma survivorship outcomes and impact future disease management strategies.
QOL-53. GENOME ASSOCIATIONS WITH NEUROCOGNITIVE OUTCOMES, CEREBRAL MICROBLEEDS (CMBS), AND BRAIN VOLUME AND WHITE MATTER (WM) CHANGES IN PEDIATRIC BRAIN TUMOR SURVIVORS
Authors: Kline Cassie , Stoller Schuyler , Byer Lennox , Edwards Caleb , Prasad Rachna , Torkildson Joseph , Gauvain Karen , Samuel David , Lupo Janine , Morrison Melanie , Tong Elizabeth , Savchuk Solomiia , Valencia Christian Rodrigo Ugaz , Rauschecker Andreas , Rudie Jeffrey , Hoffman Thomas , Dubal Dena , Fullerton Heather , Mueller Sabine 
Published: December 2020

Abstract

OBJECTIVE
To identify genetic predictors of neurocognition, CMBs, brain volume, and WM changes in pediatric brain tumor survivors.

METHODS
Patients were selected from an existing cohort (RadART) if they had: 1) at least one neurocognitive evaluation using computer-based CogState; 2) available DNA; 3) standard imaging. Candidate gene or genome-wide genotyping was performed on all patients. CMBs were identified using a semi-automated algorithm developed in MATLAB. Volume of T2/FLAIR WM signal abnormality was measured using a semi-automated method based on a convolutional neural network. Brain volume and cortical thickness were measured using FreeSurfer volumetric analysis. Logistic and linear regression were done to compare phenotypes with candidate genotypes. Genome-wide efficient mixed-model analysis was done to compare neurocognition and CMBs. Gene set analysis was done using https://fuma.ctglab.nl/.

RESULTS
APOE4 was a candidate variant associated with non-lobar, larger volume CMBs (p&lt;0.05). At the GWAS-level (n=225), specific genes trended with visual memory, psychomotor function, and CMB count (p&lt;5x10-8). Using gene set analyses, there were gene set trends seen with CMB count and psychomotor function. Small sample size and low mutant allele frequency limited reliability of these findings. Preliminary volumetric analysis show reduced volume within the right parietal, medial occipital and inferior temporal lobes with increased cortical thickness in the left occipital and medial parietal lobe in patients carrying the ApoE4 allele. WM signal assessments are ongoing.

CONCLUSION
Genetic markers may be associated with neurocognition, CMBs, brain volume and WM changes in pediatric brain tumor survivors; however, larger cohorts are needed to confirm specific gene relevance.