bluuebunny/crossref_metadata_2025_split huggingface dataset:
MBCL-50. DISMAL OUTCOME OF HIGH RISK MEDULLOBLASTOMA TREATED WITH CHEMOTHERAPY FIRST APPROACH IN MALAYSIA
Authors: Quah Shiao Wei , Rahman E J Abdul , Ibrahim H Mohd , Muda Z , Othman I S , Unni M N Mohamed , Gunasagaran K , Ang M P , Goh C B , Teh K H 
Published: December 2020

Abstract

INTRODUCTION
Patients with high risk medulloblastoma are treated either with high dose chemotherapy or hyperfractionated radiotherapy. Both approaches are not feasible in resource-limited countries. POG9031 trial has reported favourable outcome for high risk medulloblastoma using standard chemotherapy and radiotherapy only. Hence, we have adopted the protocol using chemotherapy first approach due to logistical reasons.

OBJECTIVE
To review the outcome of children diagnosed with high risk medulloblastoma in Hospital Kuala Lumpur.

METHODS
Patients diagnosed with high risk medulloblastoma between January 2015 and June 2018 treated using the chemotherapy first approach as per POG9031 protocol were identified. Data was then extracted and analysed.

RESULTS
Nine patients were identified, 3 boys and 9 girls. Median age was 9.3 years (range 2.6 – 15.9 years). Median follow up for survivors are 3.6 years. Five patients (55.6%) had macroscopic metastatic disease at diagnosis. All patients had significant residual disease post-op. Only 3 patients are disease free till last follow up, giving a 3 years event free survival of 16%. Of the 6 patients who had relapsed, 4 have died, giving a 3 years overall survival of 46%. Patients with no metastasis at diagnosis (M0) fared better with 3 years event free survival of 38%, but 3 years event free survival for patients with macroscopic metastatic disease (M+) was 0%.

CONCLUSION
Outcome of children with high risk medulloblastoma treated with chemotherapy first approach was dismal.
MBRS-10. QUIESCENT SOX9-POSITIVE CELLS BEHIND MYC DRIVEN MEDULLOBLASTOMA RECURRENCE
Authors: Bolin Sara , Savov Vasil , Borgenvik Anna , Rosén Gabriela , Olausson Karl Holmberg , Zhao Miao , Garancher Alexandra , Rahmanto Aldwin Suryo , Hutter Sonja , Mainwaring Oliver , Rusert Jessica , Sundstrom Anders , Richardson Stacey , Fotaki Grammatiki , Hill Rebecca M , Dubuc Adrian M , Kalushkova Antonia , Remke Marc , Čančer Matko , Jernberg-Wiklund Helena , Ramaswamy Vijay , Chen Xingqi , Taylor Michael D , Sangfelt Olle , Schüller Ulrich , Clifford Steve C , Wechsler-Reya Robert J , Weishaupt Holger , Swartling Fredrik J 
Published: December 2020

Abstract
Tumor recurrence is the leading cause of death in medulloblastoma, the most frequent malignant pediatric brain tumor. Recurrence occurs when subpopulations of cancer cells evade standard therapy by acquiring features of immune escape, metastatic spread, and treatment resistance. The transcription factor SOX9 correlated with treatment resistance and dissemination in aggressive Group 3 medulloblastoma. By studying paired primary-recurrent medulloblastoma samples and patient-derived xenograft models, we identified rare SOX9-positive slow-cycling, therapy-resistant tumor cells that accumulate in relapses and in metastases. In an inducible transgenic Group 3 tumor model, doxycycline treatment kills all tumor cells by turning MYC off. However, when MYC expression was redirected to the SOX9 promoter, recurrences from rare, dormant SOX9-positive cells developed with 100% penetrance. Expression profiling revealed that recurrences were more inflammatory, metastatic, and showed elevated MGMT methyltransferase levels which depleted recurrent cells when selectively inhibited. Our model explains how recurrences develop from SOX9-induced quiescence in MYC-driven brain cancer.
MBRS-39. MAP4K4 CONTROLS PRO-INVASIVE SIGNALING IN MEDULLOBLASTOMA CELLS
Authors: Migliavacca Jessica , Capdeville Charles , Grotzer Buket Seçkin, Michael , Baumgartner Martin 
Published: December 2020

Abstract
The molecular mechanisms contributing to distant dissemination and local recurrence of medulloblastoma, the most common malignant brain tumor in childhood, are poorly understood and no targeted anti-invasion therapies exist till date. We explored regulators and effectors of MAP4K4, a pro-invasive kinase overexpressed in MB and associated with metastatic progression in different solid malignancies. MAP4K4 is upregulated both at mRNA and protein levels in primary pediatric brain tumors compared to normal cerebellum. MAP4K4 is required for growth factor- and irradiation-induced migration and invasion of medulloblastoma cells. It furthermore promotes turnover and activation of the receptor tyrosine kinase c-Met and of the ß1 integrin adhesion receptor 1. To characterize these clinically relevant consequences and to identify druggable targets of MAP4K4 function, we profiled the interactome of MAP4K4 in starved and growth factor stimulated medulloblastoma cells. To systematically address MAP4K4 impact on receptor expression and turnover, we determined the MAP4K4-dependent surface proteome in medulloblastoma cells. We found that MAP4K4 is part of the striatin-interacting phosphatase and kinase (STRIPAK) complex and that STRIPAK component striatin 4 is controlling cell motility and invasiveness in medulloblastoma cells. Invasiveness of medulloblastoma cells is abrogated by a truncation mutant of MAP4K4 lacking the striatin 4 interaction domain. We furthermore found that MAP4K4 mediates growth factor-induced surface expression of solute carriers and immunomodulatory proteins involved in chemoresistance and immune evasion. Thus, our study identified MAP4K4 as a missing link between pro-tumorigenic growth factor signaling and tumor cell functions relevant for disease progression. It may help identifying druggable vulnerabilities in medulloblastoma cells to restrict tumor growth and dissemination. 1. Tripolitsioti, D. et al., Oncotarget9, 23220–23236 (2018).
MBRS-43. ELUCIDATING HOW NOVEL EXTRACELLULAR MATRIX SUBTYPES DIFFERENTIALLY IMPACT THE SURVIVAL OF MEDULLOBLASTOMA SUBGROUPS
Authors: Johnson James , Linke Franziska , Merry Catherine L R , Coyle Beth 
Published: December 2020

Abstract
Medulloblastoma (MB) is the most common malignant paediatric brain tumour and frequently exhibits metastasis and chemoresistance. MBs are categorised into four molecular subgroups (WNT, Sonic hedgehog, Group 3 and Group 4), each associated with different demographics and clinical features. We have shown that the expression of specific extracellular matrix proteins in the brain tumour microenvironment differ between subgroups. A prime example is laminin (an ECM glycoprotein) the expression of which correlates with good overall survival in the SHH subgroup and poor overall survival in Group 4. Our aim is to determine the cause of this difference in survival. Candidate laminin-responsive-genes (LRGs) were identified using the Cavalli data set and RNA-Seq analysis of MB cells grown on 3D hydrogels with and without laminin. The role of laminin in the regulation of MMPs and the other LRG candidates was investigated by qRT-PCR, western blotting and zymography in 2D and long-term 3D-hydrogel assays. Thus far we have shown that in CHLA-01-R (metastatic Group 4 cell line) three of our LRGs are upregulated in response to laminin in 2D, as well as in preliminary 3D studies. Additionally, we have observed a unique MMP9 secretion profile of SHH cells grown in 3D compared to 2D, suggesting that our 3D assay allows us to observe relevant phenotypes absent in 2D culture. We are now in the process of identifying which of these LRG candidates are involved in metastasis and chemoresistance. This will enable the elucidation of novel therapeutic targets and crucially increase our understanding of MB-microenvironment interactions.
MBRS-47. RAPID MOLECULAR SUBGROUPING OF MEDULLOBLASTOMA BASED ON DNA METHYLATION BY NANOPORE SEQUENCING
Authors: Masliah-Planchon Julien , Girard Elodie , Euskirchen Philipp , Bourneix Christine , Lequin Delphine , Blanluet Maud , Aillaud Jean-Baptiste , Doz Francois , Bourdeaut Franck , Delattre Olivier 
Published: December 2020

Abstract
Medulloblastoma (MB) can be classified into four molecular subgroups (WNT group, SHH group, group 3, and group 4). The gold standard of assignment of molecular subgroup through DNA methylation profiling uses Illumina EPIC array. However, this tool has some limitation in terms of cost and timing, in order to get the results soon enough for clinical use. We present an alternative DNA methylation assay based on nanopore sequencing efficient for rapid, cheaper, and reliable subgrouping of clinical MB samples. Low-depth whole genome with long-read single-molecule nanopore sequencing was used to simultaneously assess copy number profile and MB subgrouping based on DNA methylation. The DNA methylation data generated by Nanopore sequencing were compared to a publicly available reference cohort comprising over 2,800 brain tumors including the four subgroups of MB (Capper et al. Nature; 2018) to generate a score that estimates a confidence with a tumor group assignment. Among the 24 MB analyzed with nanopore sequencing (six WNT, nine SHH, five group 3, and four group 4), all of them were classified in the appropriate subgroup established by expression-based Nanostring subgrouping. In addition to the subgrouping, we also examine the genomic profile. Furthermore, all previously identified clinically relevant genomic rearrangements (mostly MYC and MYCN amplifications) were also detected with our assay. In conclusion, we are confirming the full reliability of nanopore sequencing as a novel rapid and cheap assay for methylation-based MB subgrouping. We now plan to implement this technology to other embryonal tumors of the central nervous system.
MBRS-60. THE ACTIONABLE GENOMIC LANDSCAPE OF RELAPSED MEDULLOBLASTOMA IS DEFINED BY MAINTENANCE AND ACQUISITION OF DRIVER EVENTS
Authors: Richardson Stacey , Hill Rebecca M , Kui Christopher , Lindsey Janet C , Grabovska Yura , Schwalbe Edward C , Hicks Debbie , Williamson Daniel , Crosier Stephen , Joshi Abjhit , Wharton Stephen B , Hansford Jordan , Pizer Barry , Vinci Maria , Mastronuzzi Angela , Carai Andrea , Michalski Anthony , Jacques Thomas S , Bailey Simon , Clifford Steven C 
Published: December 2020

Abstract
Medulloblastoma relapse (rMB) occurs in 30–40% of patients and is almost universally fatal. Understanding the genomic landscape of rMB, and its relationship to disease characteristics at diagnosis, will be essential to underpin the development of improved therapeutic strategies, delivered at both diagnosis and relapse. Utilising NGS and Illumina DNA methylation arrays, we interrogated the molecular landscape of &gt;100 rMBs, alongside matched diagnostic samples (n&gt;80), encompassing molecular subgroup, novel subtypes, copy number (CNV) and mutational variants. Molecular subgroup and novel subtypes were stable over disease-course. The majority of genomic aberrations were also maintained (total arm-level CNVs at relapse, 60% maintained/40% acquired; deleterious/driver mutations, 75% maintained/25% acquired). Importantly, however, the landscape of alterations differed markedly at relapse, through both selective maintenance and acquisition of specific gene and pathway aberrations. For instance, we observed significant enrichment of subgroup-specific events at relapse, including focal CDK6/CDK14 amplifications (4/26 (15%) of MBGroup4) and CDKN2A/CDKN2B deletions (3/48 (6%) of MBSHH). In contrast, mutations in DNA damage response pathways were commonly enriched across all molecular subgroups, most significantly in MBSHH (~40% of rMBSHH; TP53, 9/36 (25%); ATM, 5/36 (14%)). Driver events in rMB are characterised by both selective maintenance and acquisition across disease-course, and together combine to define its actionable genetic landscape. Evaluation of their clinical and biological significance will be essential to establish their potential (i) as biomarkers to direct disease management and (ii) as a basis for therapeutic strategies targeted against medulloblastoma relapse.
MBRS-62. CURAXIN CBL0137 INHIBITS THE VIABILITY OF CANCEROUS CELLS IN PRE-CLINIC MODELS OF MYC-AMPLIFIED MEDULLOBLASTOMA
Authors: Wang Jiajia , Wang Baocheng , Zhao Yang , Ma Jie 
Published: December 2020

Abstract
Medulloblastoma is a malignant brain tumour that mostly occurs in children, and MYC-amplified medulloblastoma is characterized by pronounced invasiveness and dismal prognosis. There is no effective treatment for Medulloblastoma and its precise pathological mechanism remains obscure. Previous studies indicated that the altered epigenetic machinery manifested in the neoplastic transformation of MYC-amplified MB has become increasingly evident. It is hypothesized that epigenetic genes dependencies associated with small molecule inhibitors that have been approved or are in advanced development may help identify the potential therapeutic targets. By integrating mRNA expression profiles and the corresponding clinic-pathologic information of patients suffering from medulloblastoma, and analysing prior CRISPR screening results, we demonstrated that SSRP1 is a negative prognostic factor that functions to stimulate the viability of MB cells. SSRP1 is a subunit of the FACT complex, an important histone chaperone required for transcriptional regulation, DNA replication and damage repair. Its biological effect on tumour proliferation was assessed by using RNA interference and administering CBL0137, a small molecular inhibitor of FACT. Gene expression analysis also demonstrated that CBL0137 selectively downregulated the expression of MYC and NEUROD1. Furthermore, the administration of CBL0137 suppressed tumour growth in mouse xenograft models. This pharmacological method to selectively target MYC transcription was demonstrated in our study, and therefore can be applied as a promising treatment strategy for MYC-amplified medulloblastoma. In Conclusion, we identified an attractive strategy of selectively downregulating MYC transcription by applying inhibitor CBL0137, thereby revealing the potential clinical utility of CBL0137 to improve the prognosis of MYC-amplified medulloblastoma patients.
MBRS-70. FUNCTIONAL DEPENDENCY BETWEEN REST AND DNMT1 IN MEDULLOBLASTOMA
Authors: Maegawa Shinji , Dobson Tara , Lu Yue , Estecio Marcos , Harmanci Arif , Gopalakrishnan Vidya 
Published: December 2020

Abstract
Medulloblastomas exhibit poor neuronal lineage specification. Expression of RE1 Silencing Transcription Factor (REST), a repressor of neurogenesis, is aberrantly elevated in human sonic hedgehog (SHH) medulloblastomas. Constitutive REST expression in mice (RESTTG) drives medulloblastoma genesis and promotes tumor progression in the context of Ptch1 haploinsufficiency (Ptch+/−), implicating it as a driver of tumorigenesis. Tumor formation in Ptch+/−/RESTTG mice showed significantly decreased latency and increased penetrance compared to that in Ptch+/− mice. Since REST silences gene expression by chromatin remodeling, we sought to identify cooperating epigenetic events that contributed to its oncogenic activity. To this end, we performed a loss of function screen employing a bar-coded library of short hairpin RNAs against epigenes, to identify candidates whose loss could create a proliferative vulnerability in the context of REST-elevation. This screen identified DNA methyltransferase 1 (DNMT1) as a high-priority epigenetic modifier. DNMT1 and the Ubiquitin like with PHD and Ring finger domain 1 (UHRF1) proteins are essential for methylation of hemi-methylated DNA at the replication fork during S-phase. Their expression is downregulated during neuronal differentiation. In human SHH-medulloblastoma tumors, REST and UHRF1 expression are positively correlated with higher levels of both genes noted specifically in the SHH-beta subtype, and is associated with poor prognosis. The requirement for DNMT1/UHRF1 in the context of REST elevation, was established by RNA-Seq and Reduced Representation Bisulfite Sequencing (RRBS), which revealed hypermethylation and downregulated expression of REST-target genes needed for neurogenesis. Thus, DNMT1/UHRF1 is a functional and potential therapeutic vulnerability in REST-elevated SHH medulloblastomas.
MODL-01. SAFETY IN CONCOMITANT USE OF MEK AND BRAF INHIBITORS WITH BEVACIZUMAB
Authors: Winzent Shelby , Sabus Ashley , Hemenway Molly , Nellan Anandani , Mulcahy-Levy Jean 
Published: December 2020

Abstract

BACKGROUND
MEK and BRAF inhibitors are increasingly common treatments for pediatric nervous system tumors. While effective in blocking Ras/Raf/MEK/ERK pathway activation driving tumor progression, the side effect profile differs from traditional cytotoxic chemotherapies. Little data exists on overlapping toxicities with other targeted agents like bevacizumab despite their potential combined therapeutic benefit.

METHODS
A retrospective review of patients treated with MEK +/- BRAF inhibitors and bevacizumab from 2015–2019 was conducted. Data collected included demographics, tumor type, neurofibromatosis status, treatment duration, reason for concurrent treatment, and toxicities.

RESULTS
Fifteen patients aged 3–24 years old (median age 14 years) were identified. Diagnoses included five high-grade gliomas, four low-grade gliomas, four benign nerve sheath tumors, and one ependymoma. Nearly half (46.7%) were positive for neurofibromatosis type 1. Three patients were treated with a BRAF + MEK inhibitor and twelve were treated with a MEK inhibitor combined with bevacizumab. Duration of treatment ranged from 16–420 days (median 119 days). Reasons for concomitant therapy included progressive disease with neurologic decline (46.7%), painful benign nerve sheath tumors (26.7%), and visual loss with optic pathway gliomas (26.7%). Toxicities while on concurrent therapy included one episode of grade 1 left ventricular dysfunction, one grade 1 bleeding episode, and one grade 2 wound complication. There were no episodes of hypertension, thrombosis, GI perforations, or cytopenias.

CONCLUSIONS
Our preliminary experience suggests bevacizumab in combination with MEK and BRAF inhibitors can be used safely across a variety of pediatric nervous tumors. Larger studies are needed to confirm these findings.
MODL-16. ABEMACICLIB, A SELECTIVE CDK4/6 INHIBITOR, RESTRICTS GROWTH OF PEDIATRIC GLIAL-LINEAGE TUMORS IN VITRO AND IN VIVO
Authors: Liang Muh-Lii , Hsieh Tsung-Han , Wong Tai-Tong 
Published: December 2020

Abstract

BACKGROUND
Glial-lineage tumors constitute a heterogeneous group of neoplasms, comprising gliomas, oligodendrogliomas, and ependymomas, which account for 40%–50% of all pediatric central nervous system tumors. Advances in modern neuro-oncological therapeutics are aimed at improving neoadjuvant chemotherapy and deferring radiotherapy because radiation exposure may cause long-term side effects on the developing brain in young children. Despite aggressive treatment, more than half the high-grade gliomas (pHGGs) and one-third of ependymomas exhibit recurrence within 2 years of initial treatment.

METHODS
By using integrated bioinformatics and through experimental validation, we found that at least one gene among CCND1, CDK4, and CDK6 was overexpressed in pHGGs and ependymomas.

RESULTS
The use of abemaciclib, a highly selective CDK4/6 inhibitor, effectively inhibited cell proliferation and reduced the expression of cell cycle–related and DNA repair–related gene expression, which was determined through RNA-seq analysis. The efficiency of abemaciclib was validated in vitro in pHGGs and ependymoma cells and in vivo by using subcutaneously implanted ependymoma cells from patient-derived xenograft (PDX) in mouse models. Abemaciclib demonstrated the suppression of RB phosphorylation, downstream target genes of E2F, G2M checkpoint, and DNA repair, resulting in tumor suppression.

CONCLUSION
Abemaciclib showed encouraging results in preclinical pediatric glial-lineage tumors models and represented a potential therapeutic strategy for treating challenging tumors in children.
NFB-05. AN UNUSUAL PRESENTATION OF RECURRENT LANGERHANS CELL HISTIOCYTOSIS OF THE CRANIOFACIAL BONES IN A PATIENT WITH NEUROFIBROMATOSIS TYPE I
Authors: Chaffee Blake , Judd Alexis , Rush Sarah , Wright Erin 
Published: December 2020

Abstract
Neurofibromatosis type 1 (NF1), predisposes patients to benign and malignant tumors due to lack of suppression of the mitogen activated protein kinase (MAPK) signaling pathway. Langerhans cell histiocytosis (LCH) manifests in numerous ways, from localized lesions to multisystem organ involvement secondary to a constitutively active MAPK signaling cascade often driven by BRAF mutations. While both LCH and NF1 are characterized by overactive MAPK signaling, there are few reports of the two diseases occurring simultaneously. We report a novel case of a patient with underlying NF1 and recurrent LCH without a BRAFV600E mutation. She initially presented at 2 years of age with an aggressive appearing mass of the left temporal bone found on surveillance imaging. Pathology was consistent with Langerhans histiocytosis and she was treated with the LCH-III protocol for patients with high-risk LCH due to the location of her lesion. Five years after completion of therapy, MRI demonstrated development of a calvarial mass consistent with relapsed LCH in a new risk site. Lesional curettage was performed and pathology confirmed recurrence of LCH with juvenile xanthogranulomatous features. BRAF testing of blood and the lesion were negative for any BRAF alterations. Further genomic evaluation of the tumor is in progress at this time to evaluate for other known mutations associated with LCH. The patient is currently receiving monthly cytarabine treatment which she has tolerated to date. Our patient represents a unique presentation of recurrent LCH in a patient with NF1 and further molecular evaluation may help identify other drivers of LCH activation.
NFB-13. TRAMETINIB FOR PLEXIFORM NEUROFIBROMA AND RECURRENT LOW-GRADE GLIOMA
Authors: Sato Aimee , Millard Nathan , Perez Francisco , Vitanza Nicholas , Leary Sarah 
Published: December 2020

Abstract

BACKGROUND
Based on early clinical efficacy data, Seattle Children’s established a standard clinical practice for MEK inhibitor therapy for children with plexiform neurofibroma (PN) or recurrent low-grade glioma (LGG).

METHODS
Data were collected under an IRB-approved retrospective chart review. Trametinib was prescribed off-label at 0.025 mg/kg daily for up to two years. Physical exam and laboratory monitoring were monthly for 3 months, then every 3 months. Retinal examination, ECHO/ECG were every 3 months. Tumor response was evaluated by MRI every 3 months for LGG; imaging for PN was dependent on tumor location.

RESULTS
30 patients received trametinib; 17 LGG, 16 PN (3 both); 22 with Neurofibromatosis, Type-1 (NF1); 16 female/15 male; median age 11 (range 4.1–22.6). Most common tumor location was optic pathway (n=11) and face/neck (n=10). Most common adverse events (AE) were dermatologic and gastrointestinal. Ten had dose interruption/reduction, only one discontinued therapy for AE. Six received dermatology specialty care for AE. With median follow-up of 12 months, only 3 patients had progression, one with NF1. One-year EFS was 100% for PN and 88%+7 for LGG. Driver mutations were identified in 9 of 10 tumors tested (5 BRAF fusion, 1 BRAFV600E, 1 FGFR1+NF1, 1 FGFR1+PTPN11, 1 NF1). Radiology review of response will be presented.

CONCLUSIONS
This real-world pediatric cohort supports efficacy and tolerability of MEK inhibitor therapy for short-term control of plexiform neurofibroma and low-grade glioma with and without NF1. Further studies are warranted to evaluate comparative efficacy, combination therapy and duration of therapy.