bluuebunny/crossref_metadata_2025_split huggingface dataset:
HGG-20. DIAGNOSTIC AND BIOLOGICAL ROLE OF METHYLATION PATTERNS IN REPLICATION REPAIR DEFICIENT HIGH GRADE GLIOMAS
Authors: Dodgshun Andrew , Fukuoka Kohei , Edwards Melissa , Bianchi Vanessa , Sexton-Oates Alexandra , Larouche Valerie , Magimairajan Vanan , Lindhorst Scott , Yalon Michal , Mason Gary , Crooks Bruce , Constantini Shlomi , Massimino Maura , Chiaravalli Stefano , Ramdas Jagadeesh , Mason Warren , Shamvil Ashraf , Farah Roula , Van Damme An , Opocher Enrico , Hamid Syed Ahmer , Ziegler David , Samuel David , Cole Kristina A , Tomboc Patrick , Stearns Duncan , Thomas Gregory , Lossos Alexander , Sullivan Michael , Hansford Jordan R , Jones David , Mackay Alan , Jones Chris , Ramaswamy Vijay , Hawkins Cynthia , Bouffet Eric , Tabori Uri 
Published: December 2020

Abstract
Replication repair deficiency (RRD) is an important driving mechanism of pediatric high grade glioma (pHGG) occurring predominantly in the context of germline mutations in RRD-associated genes. Although pHGG present specific patterns of DNA methylation corresponding to driving oncogenic processes, methylation patterns have not been well studied in RRD tumors. We analyzed 52 RRD pHGG using either 450k or 850k methylation arrays. These arrays were compared with 234 PHGG driven by other genetic or epigenetic mechanisms and 10 additional pHGG samples known to be hypermutant. RRD pHGG displayed a methylation pattern corresponding to specific secondary mutations such as IDH1 and H3K27M. Strikingly, RRD pHGG lacking these known secondary mutations largely clustered together with a poorly described group previously labelled Wild type-C. Most of the hypermutant tumors clustered in a similar location suggesting undiagnosed RRD may be a driving force for tumors clustering in this location. Analysis of methylation patterns revealed that RRD pHGG displayed a unique CpG Island Demethylator Phenotype in contrast to the Methylator Phenotype described in other cancers. This effect was most concentrated at gene promotors. Prominent demethylation was observed in genes and pathways critical to cellular survival including cell cycle, gene expression, cellular metabolism and cellular organization. These data suggest that methylation profiles may provide diagnostic information for the detection of RRD pHGG. Furthermore, our findings highlight the unique natural selection pressures in these highly dysregulated, hypermutant cancers and provide novel impact of hypermutation and RRD on the cancer epigenome.
HGG-50. TWO CASES OF H3 K27M-MUTANT DIFFUSE MIDLINE GLIOMA OF CERVICAL SPINAL CORD
Authors: Kuroha Masae , Tamura Kaoru , Inaji Motoki , Hashimoto Satoka , Kobayashi Daisuke , Tanaka Yoji , Nariai Tadashi , Maehara Taketoshi 
Published: December 2020

Abstract

BACKGROUND
“Diffuse midline glioma, H3 K27M-mutant’ was newly categorized as a separate pathological entity in the 2016 WHO classification, based on recently discovered mutation. Spinal cord glioma with H3 K27M-mutant is rare, so we reported the clinical course of two cases. CASE 1: A 17-year-old male presented with posterior headache and right limbs paralysis. MRI showed cervical spinal cord with expansion, T2-weighted high intensity and a part of enhancement. The biopsy revealed a diffuse midline glioma, H3 K27M-mutant. He received bevacizumab plus radiotherapy-temozolomide. In a few months, he had quadriplegia and cranial nerve paralysis and needed respirator. There was not expansion of mass, but intracranial dissemination. CASE 2: A 16-year-old male presented with posterior neck pain and right limbs paralysis. On brain stem and cervical spine, MRI findings were same to case 1. The biopsy was undergone and revealed H3 K27M mutation. He received bevacizumab in addition to radiotherapy-temozolomide. Although he also had quadriplegia, the progression of tumor has stopped. He has received chemotherapy with respirator at home.

DISCUSSION
It was previously reported that the prognostic factors for diffuse midline glioma were tumor location, H3 K27M-mutation and age, but there are few relevant studies. The consensus on the treatment is also not clearly determined. Because the cervical spinal cord gliomas are rapidly advanced miserably, we added bevacizumab to standard radiotherapy-temozolomide for initial treatment. In addition, whole brain and spine radiation may be considered to avoid dissemination. Multicenter study is important to collect information and improve treatment of H3 K27M-mutant glioma.
IMG-17. RADIOMICS CHARACTERIZATION OF FOUR PEDIATRIC BRAIN TUMOR SUBTYPES IN PDX MOUSE MODELS
Authors: Serkova Natalie , Stukova Marina , Henehan Samuel , Steiner Jenna , Pierce Angela , Griesinger Andrea , Veo Bethany , Alimova Irina , Venkataraman Sujatha , Green Adam , Dahl Nathan , Foreman Nicholas , Vibhakar Rajeev 
Published: December 2020

Abstract

BACKGROUND
Previously, we have reported on the development of advanced magnetic resonance imaging (MRI) protocols for mouse brain tumors. The goal of this follow-up pre-clinical study was to develop a machine-learning MRI classifier (radiomics) for four subtypes of childhood brain tumor in patient-derived xenograft (PDX) mice.

METHODS
MRI scans on orthotopic medulloblastoma, ependymoma, ATRT and DIPG PDX (each n=12 animals) were performed on the animal 9.4 Tesla scanner with an in-plane resolution of 47 microns. Image segmentation, as well as shape and texture based radiomics descriptors were modeled using a modified COLIAGE software for tumor classification and to characterize tumor habitat of each tumor subtype.

RESULTS
The mean tumor volumes were 11.2 mm3. Each MRI scan was segmented into three regions: (i) well defined tumor (including distant metastases); (ii) peritumoral edema; (iii) tumor necrosis. 360 radiomics features (capturing co-occurrence, grey-level dependence and directional gradients) were obtained for each region. The model classified four subtypes with high accuracy while achieving sufficient segmentation accuracy despite the small lesion size. A subset of fourteen tumoral, six peritumoral and five distant MRI radiomics features were found to be predictive of the tumor sub-type (p=0.0017) independently of tumor anatomical location.

CONCLUSIONS
MRI protocols followed by radiomics feature analysis discriminated among specific radiological features for four distinct orthotopic PDX models: medulloblastomas exhibit low ADC values, high angiogenesis and cortical metastases as compared to ependymomas (high levels of edema and olfactory bulb metastases), ATRT (the highest level of necrosis) and DIPG (highest T2 signal intensities and spinal metastases).
IMMU-09. NIVOLUMAB THERAPY FOR A PEDIATRIC-ONSET PRIMARY INTRACRANIAL MELANOMA
Authors: Oba Utako , Koga Yuhki , Kawaguchi Riichiro , Nakashima Kentaro , Akagi Yojiro , Hata Nobuhiro , Yamamoto Nanae , Kohashi Kenichi , Masuda Satohiro , Iihara Koji , Oda Yoshinao , Ohga Shouichi 
Published: December 2020

Abstract
Primary intracranial malignant melanoma (PIMM) is an uncommon cancer in childhood, that accounts for approximately 1% of melanoma, and 0.07% of brain tumors even in all age group. Because extracranial malignant melanoma usually occurs as a cutaneous lesion, affected patients have a chance to receive the early diagnosis and curable resection of the isolated tumor. However, unresectable metastatic cases have a poor prognosis with a median overall survival of 8 months. We report a 12-year-old girl with PIMM who received nivolumab therapy after an administration of dacarbazine. The tumor harbored no BRAF mutation. After the intravenous administration of nivolumab, cerebrospinal fluid 5-S-cysteinyldopa levels declined and circulating CD8+HLA-DR+T cells increased, indicating the initial effect of nivolumab on PIMM. However, multiple lesions progressed for two month-immunotherapy, during which cerebrospinal fluid nivolumab concentrations attained to 1.2% of serum ones. The present case demonstrated the safety and modest effect of nivolumab for CNS melanoma. Nivolumab is a tolerable first-line therapy for diffuse PIMM, but pediatric patients need a more intensified CNS-specific immunotherapy.
IMMU-26. DISEASE CONTROL IN A PEDIATRIC PATIENT WITH NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME (GBM) AND SOMATIC HIGH MICROSATELLITE INSTABILITY (MSI-H) WITH PD-1 INHIBITOR NIVOLUMAB (NIVO) ONLY AND NO FOCAL RADIOTHERAPY (RT)
Authors: Larkin Trisha , Blatt Jason , Gururangan Sridharan 
Published: December 2020

Abstract
Immune checkpoint inhibitors that target programmed death receptor-1 (PD-1) have recently been shown to be a promising option for the management of recurrent mismatch repair (MMR) deficient GBM following radiotherapy. We report a case of a 9-year-old boy who presented with a 6 week history of frontal headaches and was found to have a left frontal lobe mass. Pathology obtained from a gross total resection (GTR) was consistent with classic GBM, WHO Grade IV. Neuroimaging four weeks following initial resection was remarkable for local recurrence. The patient underwent another GTR of the tumor at our center. While pathology again confirmed GBM, GlioSequencing of tumor tissue from second resection showed MSI-H, NF2 mutation p.R338H, NF1 mutations p.R2450* and pI193Yfs*11, TP53 mutations p.R213* and p.R273C, EGFR mutation, and multiple variants of uncertain significance. Germline testing was negative for MMR deficiency or other deleterious mutations. Parents opted to defer radiotherapy and consented to monotherapy treatment with Nivolumab (Opdivo, BMS pharmaceuticals, USA), a PD-1 inhibitor, at a dose of 3 mg/kg administered every two weeks. Our patient is now 22 months post-second resection and continues to receive Nivolumab without evidence of recurrent disease or adverse autoimmune effects from PD-1 blockade. He has remained in school with good academic performance and has exhibited no regression of functional status during the entirety of his treatment course. This case provides evidence of possible efficacy of PD-1 blockade without focal radiotherapy in this child with GBM and somatic MSI instability.
IMMU-28. IMMUNOGENOMIC ANALYSIS REVEALS LGALS1 CONTRIBUTES TO THE IMMUNE HETEROGENEITY AND IMMUNOSUPPRESSION IN GLIOMA
Authors: Chen Qun , Cai Jinquan , Han Bo , Meng Xiangqi 
Published: December 2020

Abstract
Mutualistic and dynamic communication between tumour cells and the surrounding microenvironment accelerates the initiation, progression, chemoresistance and immune evasion of glioblastoma (GBM). However, the immunosuppressive mechanisms of GBM has not been thoroughly elucidated to date. We enrolled six microenvironmental signatures to identify glioma microenvironmental genes. The functional enrichment analysis such as ssGSEA, ESTIMATE algorithm, Gene Ontology, Pathway analysis is conducted to discover the potential function of microenvironmental genes. In vivo and in vitro experiments are used to verify the immunologic function of LGALS1 in GBM. We screen eight glioma microenvironmental genes from glioma databases, and discover a key immunosuppressive gene (LGALS1 encoding Galectin-1) exhibiting obviously prognostic significance among glioma microenvironmental genes. Gliomas with different LGALS1 expression have specific genomic variation spectrums. Immunosuppression is a predominate characteristic in GBMs with high expression of LGALS1. Knockdown of LGALS1 remodels the GBM immunosuppressive microenvironment by down regulating M2 macrophages and myeloid-derived suppressor cells (MDSCs), and inhibiting immunosuppressive cytokines. Our results thus implied an important role of microenvironmental regulation in glioma malignancy and provided evidences of LGALS1 contributing to immunosuppressive environment in glioma and that targeting LGALS1 could remodel immunosuppressive microenvironment of glioma.
LGG-12. TRAMETINIB FOR PEDIATRIC LOW GRADE GLIOMAS: A SINGLE INSTITUTION EXPERIENCE
Authors: Barbour Mustafa , Huang Michael Angelo 
Published: December 2020

Abstract

INTRODUCTION
Low grade gliomas (LGG) are the most common pediatric brain tumors. Tumors not amenable to resection can recur or progress despite treatment with chemotherapy and/or radiation. Recent discovery of the activation of the mitogen-activated-protein-kinase (MAPK) pathway as the primary oncogenic driver for this group of tumors has led to a shift towards the use of BRAF and MEK inhibitors.

METHODS
Herein we performed a chart review of seven pediatric LGG treated with trametinib, a MEK inhibitor. While most were treated in the relapse setting, one patient was treated for de novo LGG as a result of experiencing multiple severe adverse effects to conventional agents.

RESULTS
Median age was 14 years old (range: 5 to 17 years). Six of seven patients had tissue for molecular characterization. The 2 patients with Neurofibromatosis Type 1 (NF-1) carried no other molecular aberrations. Two had the BRAF V600e mutation (1 had a concurrent PTPN11 mutation) and 2 were positive for the KIAA1549-BRAF fusion. Average duration on treatment was 8 months (range: 3 to 31 months). Disease control was achieved in 6 of 7 subjects, with one PR as best response. One patient with concurrent BRAF V600e and PTPN11 mutations progressed on trametinib and was switched to dual BRAF and MEK inhibitor therapy. Most common toxicities were acne (57.1%), oral mucositis (42.9%), skin rash, and paronychia (both 28.6%). Three patients required dose reduction and/or intermittent dose interruption.

CONCLUSION
Our data supports the use of trametinib for both upfront and relapsed/refractory pediatric LGG.
LINC-07. PREVALENCE AND SPECTRUM OF EARLY ENDOCRINE DISORDERS IN SURVIVORS OF PEDIATRIC EMBRYONAL BRAIN TUMORS (PEBT): EXPERIENCE FROM INDIA
Authors: Prasad Maya , Nair Kalasekhar Vijayasekharan , Krishnatry Rahul , Chinnaswamy Girish , Gupta Tejpal , Rao Sudha 
Published: December 2020

Abstract

BACKGROUND
Survivors of pediatric brain tumors are at high risk of developing endocrine disorders, potentially impacting growth,development and quality of life.

METHODS
etrospective audit of 2-year survivors of PEBT(3-18years at diagnosis)viz. medulloblastoma(MB),Central nervous system Primitive neuro-ectodermal tumors(CNS-PNET) and atypical teratoid/rhabdoid tumor(ATRT) treated January 2006-December 2017 at Tata Memorial Centre,Mumbai, with surgery, cranio-spinal irradiation(CSI; 35Gy in high-risk MB,CNS-PNET,ATRT and 23.4Gy in average-risk MB with tumor boost 19.8Gy)and six cycles of adjuvant chemotherapy(cyclophosphamide,cisplatin and vincristine).Patients were followed up by a paediatric endocrinology team specialized in management of PEBT.

RESULTS
Of 249 PEBT treated during this period,88 are alive in remission &gt;2 years (69-MB, 15-CNS PNET,4-ATRT),median age at diagnosis 6 years. At a median follow-up of 5.6 years (range 3- 12.5years),63 patients(72%) had at least one endocrine disorder,26(29.%)≥2 hormonal deficiencies. The most common endocrine disorders were central hypothyroidism(57%),growth hormone deficiency(40%), central hypogonadism(5%)and central hypoadrenalism (3.5%).The median time to develop hypothyroidism was 2.8 years(range 5months to 8.5 years) from CSI. Growth hormone replacement therapy began after a median period of 4.2 years(range-1.5 to 11.5years) from CSI. Higher dose of CSI was associated with development of endocrine disorder (odds ratio [OR] 2.71; 95% CI, 1.03 to 7.04,p-0.04).

CONCLUSIONS
The high incidence of endocrine deficits in survivors of PEBT necessitates early and lifelong monitoring. Early and appropriate management is crucial to achieve full growth potential.
LINC-20. INFANT BRAIN TUMOURS IN HONG KONG
Authors: Shing Matthew M K , Ku Dennis T L , Chan Godfrey C F , Luk C W , Yau Jeffrey P W , Fu Eric , Yan Carol L S , Ling Alvin S C 
Published: December 2020

Abstract

OBJECTIVES
To review the clinical features, pathology and survivals of infants with brain tumours.

METHODS
A retrospective review of the clinical findings, pathology, treatment and survival outcome in infants with brain tumours.

RESULTS
From 1999 to 2018, there were 507 children (&lt;18 years) who were diagnosed to have brain tumours in Hong Kong. The patients were treated in five public hospitals. The clinical data were collected by the Hong Kong Paediatric Haematology and Oncology Study Group, and were cross-checked with the data of the Hong Kong Cancer Registry. In this group of patients, there were 36 infants (birth to 365 days of age) i.e. 7.1% of the whole group. Both benign and malignant brain tumours were included, while non-neoplastic lesions were excluded. On average, there was 1.89 cases per year. The pathology of the tumours were astrocytoma (n= 8), medulloblastoma (n=6), germ cell tumour (n=6), PNET (n=5), ATRT (n=4), choroid plexus tumours (n=3), ependymoma (n=2), craniopharyngioma (n= 1) and ganglioglioma (n= 1). These infants were treated according to their clinical conditions and prognosis, with operation, chemotherapy or both. Radiotherapy was withheld or postponed to older age. Some patients only received palliative care due to the poor neurological status or prognosis. The overall survivals of children younger than 18 years old vs infants were 67.3% (±2.3) vs 50.5%(±9.2) respectively, while the event free survivals were 64.4% (±2.4) and 43.5% (±8.8) at 10-years respectively.

CONCLUSION
Infants with brain tumours have different pathology and inferior outcome.
MBCL-21. GERMLINE ELONGATOR MUTATIONS IN SONIC HEDGEHOG MEDULLOBLASTOMA
Authors: Robinson Giles W , Waszak Sebastian M , Gudenas Brian L , Smith Kyle S , Forget Antoine , Kojic Marija , Jesus Garcia-Lopez , Hadley Jennifer , Hamilton Kayla V , Indersie Emilie , Buchhalter Ivo , Jager Natalie , Sharma Tanvi , Rausch Tobias , Kool Marcel , Sturm Dominic , Jones David T W , Tatevossian Ruth , Lombard Berangere , Loew Damarys , Bowers Daniel , Bendel Anne , Partap Sonia , Chintagumpala Murali , Crawford John , Gottardo Nicholas G , Smith Amy , Dufour Christelle , Rutkowski Stefan , Grotzer Michael , Remke Mark , Puget Stephanie , Pajtler Kristian W , Milde Till , Witt Olaf , Ryzhova Marina , Korshunov Andrey , Orr Brent A , Ellison David W , Brugieres Laurence , Lichter Peter , Nichols Kim E , Gajjar Amar , Wainwright Brandon J , Ayrault Olivier , Korbel Jan O , Northcott Paul A , Pfister Stefan M 
Published: December 2020

Abstract

BACKGROUND
Our previous analysis of established cancer predisposition genes in medulloblastoma (MB) identified pathogenic germline variants in ~5% of all patients. Here, we extended our analysis to include all protein-coding genes.

METHODS
Case-control analysis performed on 795 MB patients against &gt;118,000 cancer-free children and adults was performed to identify an association between rare germline variants and MB.

RESULTS
Germline loss-of-function variants of Elongator Complex Protein 1 (ELP1; 9q31.3) were strongly associated with SHH subgroup (MBSHH). ELP1-associated-MBs accounted for ~15% (29/202) of pediatric MBSHH cases and were restricted to the SHHα subtype. ELP1-associated-MBs demonstrated biallelic inactivation of ELP1 due to somatic chromosome 9q loss and most tumors exhibited co-occurring somatic PTCH1 (9q22.32) alterations. Inheritance was verified by parent-offspring sequencing (n=3) and pedigree analysis identified two families with a history of pediatric MB. ELP1-associated-MBSHH were characterized by desmoplastic/nodular histology (76%; 13/17) and demonstrated a favorable clinical outcome when compared to TP53-associated-MBSHH (5-yr OS 92% vs 20%; p-value=1.3e-6) despite both belonging to the SHHα subtype. ELP1 is a subunit of the Elongator complex, that promotes efficient translational elongation through tRNA modifications at the wobble (U34) position. Biochemical, transcriptional, and proteomic analyses revealed ELP1-associated-MBs exhibit destabilization of the core Elongator complex, loss of tRNA wobble modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response.

CONCLUSIONS
We identified ELP1 as the most common MB predisposition gene, increasing the total genetic predisposition for pediatric MBSHH to 40%. These results mark MBSHH as an overwhelmingly genetically-predisposed disease and implicate disruption of protein homeostasis in MBSHH development.
MBCL-22. EFFICACY OF DOUBLE-CONDITIONING REGIMEN COMPRISING THIOTEPA AND MELPHALAN FOR RELAPSED MEDULLOBLASTOMA – A SINGLE INSTITUTION EXPERIENCE
Authors: Yamasaki Kai , Tanimura Kazuki , Okuhiro Yuki , Hira Kota , Nitani Chika , Okada Keiko , Fujisaki Hiroyuki , Kunihiro Noritsugu , Matsusaka Yasuhiro , Sakamoto Hiroaki , Hara Junichi 
Published: December 2020

Abstract

BACKGROUND
The prognosis of relapsed medulloblastoma was dismal. Recently, we published the promising outcome of metastatic medulloblastomas treated with a double-conditioning regimen comprising high-dose thiotepa and melphalan (HD-TM). Here, we report a single-center study of HD-TM for relapsed medulloblastomas.

MATERIALS AND METHODS
From April 2006 to January 2019, 17 consecutive medulloblastoma patients with the first relapse were identified, and of which 10 received HD-TM were retrospectively reviewed.

RESULTS
The median age at first relapse was 11.9 years (range 1.8–31.7). The median follow-up period was 23.5 months after 1st relapse. Four localized relapses at the posterior fossa and 6 metastatic relapses including 3 with multiple sites were observed. Surgical resection and re-irradiation were administered in 5 and 9 patients, respectively. Two-year PFS and OS after relapse were 21±18.1% and 60±21.9%, respectively, and significantly better than in patients who did not receive HD-TM. Among 7 evaluable patients, tumor shrinkage was observed in 6 after HD-TM administration including 3 patients who were resistant to prior chemotherapy. At the present time, 5 patients are alive with no evidence of disease (NED). The last 5 patients received re-irradiation including 12 Gy craniospinal irradiation (CSI), and 4 are alive with NED. In multivariate analysis for all patients, both HD-TM and re-irradiation were associated with improved OS and PFS, but disseminated relapse had no prognostic value (p=0.56).

CONCLUSION
HD-TM contributes to prolonged survival when combined with re-irradiation. HD-TM might become a curative approach for relapsed medulloblastoma, especially when combined with CSI.