tbuckley/cabot-search huggingface dataset:
RARE-03. AGGRESSIVE RESECTION FOR PEDIATRIC CRANIOPHARYNGIOMAS VIA ENDOSCOPIC ENDONASAL APPROACH
Authors: Hiroki Morisako, Takeo Goto, Hiroki Ohata, Hiroaki Sakamoto, Kenji Ohata
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE In recent years, the endoscopic endonasal approach (EEA) has been increasingly used for pediatric craniopharyngiomas. We here present our experience and the outcomes of the EEA resection of pediatric craniopharyngiomas. MATERIALS AND METHODS Between April 2014 and December 2019, 16 cases of pediatric craniopharyngiomas were operated at the Osaka city university (OCU) hospital. Eight patients were diagnosed with primary craniopharyngiomas while 8 had a recurrent tumor. There were 5 males and 11 females, with a mean age of 10.7 years (3–17 years). EEA was selected in all patients and a case of large muti-lobulated tumor was resected by combination of microscopic transcranial approach. RESULTS Gross total resection was achieved in 14 patients and near total resection in other 2. Post-op CSF leak occurred in 3 patients, which was treated with re-exploration. Pituitary stalk was preserved intraoperatively in 4 cases, and 15 patients developed diabetes insipidus and anterior hormonal replacement therapy was required in 15 patients at last follow-up. Visual improvement was noted in 4 patients while vision remained unchanged in the rest. Neuropsychological function status was preserved in all patients, and there was no new-onset obesity postoperatively. The mean follow-up duration was 35.1 months (2 – 69 months) and 4 of 8 recurrent cases had re-recurrence during this period, however there was no recurrent in 8 primary cases. CONCLUSIONS EEA should be the surgical modality of choice for treating pediatric craniopharyngiomas. It results in better visual and cognitive outcomes with a significantly increased extent of resection.
PATH-10. PROGNOSTIC RELEVANT IMMUNOPHENOTYPES OF PEDIATRIC HIGH-GRADE NON-BRAINSTEM GLIOMAS
Authors: Taisiya Mikhaleuskaya, Natalya Konoplya, Alena Valochnik
Journal: Neuro-Oncology (2020)

Abstract Pediatric diffuse astrocytomas comprise a wide range of malignancies with variable prognosis. The 4th grading system used now not always correctly characterizes the biological behavior of these tumors. We collected 24 pediatric supratentorial non-brainstem high grade glioma cases. Patient age ranged from 1 to 18 years old (median 11y). Main tumor locations were as follows: parietal lobe 8 cases; temporal lobe, 10 cases; frontal lobe, 3 cases; occipital lobe 3 cases. Eight of them were totally removed. All patients were treated with standard CT and RT. The main objective was to assess the prognostic impact of histopathological and molecular criteria on progression-free(PFS) and overall survival (OS) of high grade gliomas. The following criteria were analyzed: IDH1 R132H, BRAF V600E expression, ALT-phenotype, CDKN2A deletion, 1p/19q co-deletion, glial and neuronal markers expression. RESULTS: IDHR132H mutation was identified in 3 cases. 4 cases carried BRAFV600E mutation with CDKN2A deletion and displayed PXA phenotype. 5 cases showed undifferentiated glial morphology and ALT–phenotype. Also there was a group of tumors without any of the above mentioned genetic changes. Interestingly 3 of them were post radiation tumors. Statistical analysis showed that low OS correlated with ALT-phenotype(p-0.015), absence of neuronal markers expression and absence of molecular changes (p-0.03). Mutation of IDH1R132H was a favorable prognostic factor as in the adult population. PFS was affected only by the presence of neuronal expression (p-0.015). Employing immunohistochemical analysis with surrogate molecular markers in complex with FISH can provide additional prognostic information in case of pediatric high grade gliomas.
STEM-29. THE HISTONE VARIANT macroH2A2 ORCHESTRATES AN ACTIONABLE CHROMATIN PROGRAM OF STEMNESS IN GLIOBLASTOMA
Authors: Ana Nikolic, Anna Bobyn, Katrina Ellestad, Xueqing Lun, Michael Johnston, Christopher Gafuik, Franz Zemp, Nicoletta Ninkovic, Daniel Berger, Duncan Brownsey, Peter Dirks, Darren Derksen, Donna Senger, Jennifer Chan, Douglas Mahoney, Marco Gallo
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma cells with the crucial stemness property of self-renewal constitute therapy-resistant reservoirs that seed tumor relapse. Effective targeting of these cells in clinical settings has been hampered by their relative quiescence, which invalidates the cell replication bias of most current treatments. Furthermore, although their dependence on specific chromatin and transcriptional states for the maintenance of stemness programs has been proposed as a vulnerability, these nuclear programs have been challenging to target pharmaceutically. Therefore the identification of targetable chromatin paradigms regulating self-renewal would represent a significant advancement for this incurable malignancy. Here we report a new role for the histone variant macroH2A2 in modulating a targetable epigenetic network of stemness in glioblastoma. By integrating transcriptomic, bulk and single-cell epigenomic datasets we generated from patient-derived models and surgical specimens, we show that macroH2A2 represses a transcriptional network of stemness through direct regulation of chromatin accessibility at enhancer elements. Functional assays in vitro and in vivo further showcase that macroH2A2 antagonizes self-renewal and stemness in glioblastoma preclinical models. In agreement with our experimental findings, high expression of macroH2A2 is a positive prognostic factor in clinical glioblastoma cohorts. Reasoning that increasing macroH2A2 levels could be an effective strategy to repress stemness programs and ameliorate patient outcome, we embarked on a screen to identify compounds that could elevate macroH2A2 levels. We report that an inhibitor of the chromatin remodeler Menin increases macroH2A2 levels, which in turn repress self-renewal. Additionally, we provide evidence that Menin inhibition induces viral mimicry programs and the demise of glioblastoma cells. Menin inhibition is being tested in clinical trials for blood malignancies (NCT04067336). Our preclinical work therefore reveals a novel and central role for macroH2A2 in an epigenetic network of stemness and suggests new clinical approaches for glioblastoma.
GCT-73. EXPRESSION PROFILING OF INTRACRANIAL GERM CELL TUMORS REVEALS UPREGULATION OF RAS THROUGH mRNA-microRNA SIGNALING PATHWAY
Authors: Aaron M Taylor, Jianhe Shen, Lingzhao Ren, Keita Terashima, Lei Huang, Elizabeth M Snyder, Adekunle Adesina, Jack Su, Ryo Nishikawa, Hideo Nakamura, Ho-Keung Ng, Stephen T C Wong, Robert E Braun, Tsz-Kwong Man, Ching C Lau
Journal: Neuro-Oncology (2020)

Abstract Intracranial germ cell tumors (IGCTs) account for 3% of CNS tumors in children in the U.S. and 11% in Japan and East Asian countries. IGCTs are separated into two distinct subtypes based on histology: germinomas and non-germinomatous germ cell tumors (NGGCTs). The deep central location of IGCTs makes surgical resection and therefore molecular subtype classification difficult, and previous gene expression studies are limited. We performed mRNA expression profiling (Human Genome U133 Plus 2.0) and microRNA expression profiling (ABI TaqMan) with 36 and 49 IGCTs, respectively. Sample stratification using non-negative matrix factorization clustering of gene expression revealed two distinct subgroups that delineated germinomas from NGGCTs. Employing stepwise model building in each data set separately, we were able to separate these groups using only mRNA probes for the LIN28B and L1TD1 genes, and two microRNA, microRNA-26a and microRNA-373. MicroRNA26a suppresses the LIN28B gene and is down-regulated in germinoma. LIN28B directly binds and suppresses the let-7 microRNA family, which suppress the KRAS oncogene, previously found to be mutated in ~19% of IGCTs. L1TD1 is required for human stem cell renewal and directly interacts with LIN28B for its RNA binding function. LIN28B and L1TD1 are both known to be upregulated in other systemic germ cell tumors, but this has not yet been documented in IGCTs. In conclusion, these results show that intracranial germinomas have similar gene expression compared to systemic seminoma, and suggest a mechanism by which activation of LIN28B and L1TD1 downregulates the let-7 microRNA and subsequently upregulates KRAS.
RARE-01. MANAGEMENT AND OUTCOMES OF PAEDIATRIC CRANIOPHARYNGIOMA: A 15-YEAR EXPERIENCE IN SINGAPORE
Authors: Mervyn Jun Rui Lim, Sherry Jiani Liu, Cindy Wei Li Ho, Kejia Teo, Sein Lwin, Ning Chou, Tseng Tsai Yeo, Miriam Kimpo, Vincent Diong Weng Nga
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Craniopharyngiomas are rare embryonic malformations of the sellar region with high survival rates but high morbidity due to long-term sequelae caused by the location of the tumour. We summarise our institution’s experience on the management and outcomes of paediatric craniopharyngiomas in Singapore. METHODS This was a retrospective review of all paediatric patients (18 years and below) with histologically diagnosed craniopharyngioma managed by the National University Hospital, Singapore from January 2002 to June 2017. Data on clinical presentation, imaging, treatments, and outcomes were extracted from the electronic medical records using a standardized data collection form. Data analysis was conducted using RStudio (Version 1.2.5033). Institutional ethics approval was obtained for the study. RESULTS We identified 12 cases of paediatric craniopharyngiomas. The majority of cases were male (8, 66.7%) and the median age at presentation was 6.0 (IQR 3.8 – 9.5). Initial surgical management was tumour excision (11, 91.7%) or insertion of a reservoir into the cyst cavity (1, 8.3%). All cases had diabetes insipidus, 10 (83.3%) had endocrine dysfunction, and 8 (66.7%) had visual impairment on long term follow up. 7 (58.3%) cases had recurrence, and 3 (25.0%) had demised. Cox-regression showed that females (HR=33.9, p=0.049), and Chinese race (HR=13.3, p=0.034) were at higher risk for recurrence, but age at diagnosis and residual tumor on post-operative MRI was not significant. CONCLUSION The management of craniopharyngioma is complex as it is complicated by high recurrence rates and significant long-term morbidity. Further research on treatment strategies focusing on maintaining quality of life is important.
CTNI-23. IDH1/2wt ANAPLASTIC GLIOMAS OF THE EORTC RANDOMIZED PHASE III INTERGROUP CATNON TRIAL: OVERALL SURVIVAL RELATED TO TREATMENT, MGMT STATUS AND MOLECULAR FEATURES OF GLIOBLASTOMA
Authors: C Mircea S Tesileanu, Pim French, Sarah Erridge, Michael Vogelbaum, Anna Nowak, Marc Sanson, Alba Brandes, Wolfgang Wick, Paul Clement, Jean Baurain, Warren Mason, Helen Wheeler, Michael Weller, Kenneth Aldape, Pieter Wesseling, Johan M Kros, Vassilis Golfinopoulos, Thierry Gorlia, Brigitta Baumert, Martin van den Bent
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The phase III CATNON trial randomized 751 adult patients with newly diagnosed 1p/19q non-codeleted anaplastic glioma to 59.4 Gy radiotherapy +/- concurrent and/or adjuvant TMZ. Here, we present the molecular analysis of the IDH1/2wt subgroup, and associations between molecular characteristics and patient outcomes. METHODS CNV data and MGMT promoter methylation status were assessed from EPIC methylation array data. IDH1/2 and H3F3A mutation status were determined with a glioma tailored next-generation sequencing panel and TERT promoter mutation status using a SNaPshot assay. Overall survival (OS) was measured from date of randomization. RESULTS Of 654 assessed tumors, 211 (32%) were IDH1/2wt. An H3F3A mutation was present in 14 tumors (K27M: n=10; G34R: n=4). Of the remaining 197 patients, 154 tumors had molecular features of glioblastoma according to cIMPACT-NOW 3 criteria (‘IDH1/2wt astrocytomas WHO IV’), 39 tumors did not (‘IDH1/2wt astrocytomas WHO III’), and 4 had inconclusive molecular data. IDH1/2wt astrocytomas WHO III patients had significantly better survival than WHO IV patients: median OS of 2.83 yrs vs 1.43 yrs respectively [log-rank test: p&amp;lt; 0.001]. Of the 154 IDH1/2wt astrocytoma WHO IV, 55 (36%) were found MGMT promoter methylated. MGMT promoter methylation was prognostic in IDH1/2wt astrocytomas WHO IV patients, with a median OS of 1.86 yrs for methylated vs 1.34 yrs for unmethylated [HR 1.62, p=0.006]. In the IDH1/2wt astrocytomas WHO IV, no effect of concurrent and/or adjuvant TMZ was observed; the HR for OS after RT with any TMZ vs RT alone was 1.31 [95% CI 0.73–2.36, p=0.4] for MGMT promoter methylated and 0.90 [95% CI 0.55–1.45, p=0.7] for unmethylated glioma patients. CONCLUSIONS Our study validated the prognostic value of the cIMPACT-NOW 3 criteria. MGMT promoter methylation is prognostic but not predictive for outcome to TMZ treatment in this cohort of IDH1/2wt anaplastic gliomas with molecular features of glioblastoma.
LINC-08. INCREASED TREATMENT TOXICITIES AND INFERIOR OUTCOMES IN UNDERNOURISHED CHILDREN WITH BRAIN TUMOURS
Authors: Maya Prasad, Ekta Chheda, Girish Chinnaswamy, Tejpal Gupta, Rahul Krishnatry, Tushar Vora, Jayant Godashastri
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Children on treatment for brain tumours are known to be at high risk of undernutrition, the impact on outcome and toxicity is not well understood. METHODS Retrospective audit of children(&amp;lt;18 years)diagnosed January 2017-December 2018 with embryonal brain tumours (medulloblastoma, primitive neuro-ectodermal tumors, pinealoblastoma, atypical teratoid/rhabdoid tumour) and treated at our centre. Data was retrieved from case records and electronic medical records. Nutritional status(NS) was defined as per World Health Organization (WHO) into severe malnutrition (SAM),moderate malnutrition (MAM),well nourished (WN) and overweight. Undernutrition(UN) was defined as SAM/MAM.Toxicity was documented till end of treatment,defined as treatment delay&amp;gt;1week,significant infection or toxic death. RESULTS Of 124 eligible patients who received entire chemotherapy at our centre, NS data was available in 73 at diagnosis and 58 at follow-up. At diagnosis-29,16,26 and 2 and at follow-up-20,16,22 and 0 were SAM,MAM,WN and overweight. During treatment, weight gain was documented in 26%, stable weight in 55% and weight loss in 19%. Those UN at diagnosis had worse outcomes at follow-up with 70% alive in remission compared to 88% of WN(p-0.14). There was increased toxicity in UN group(50%) compared to WN(24%),p-0.04.All 3 toxic deaths were in UN. Those who lost weight during treatment had higher toxicities(70%) compared to those with stable weight (30%)or weight gain(20%),p-0.02. CONCLUSIONS In spite of nutritional intervention, children on treatment for brain tumours tend to lose weight. Increased treatment toxicities and inferior outcomes in undernourished children with brain tumours necessitates proactive and aggressive nutritional monitoring and intervention.
HGG-37. PAEDIATRIC GLIOBLASTOMA CELLS SHOW CRITICAL DEPENDENCIES ON EPIGENOMIC AND EPITRANSCRIPTOMIC CONTROL OF GENE EXPRESSION BY H3.3G34R/V MUTATIONS
Authors: Lynn Bjerke, Alan Mackay, Rebecca Rogers, Yura Grabovska, Valeria Molinari, Sara Temelso, Kristina Cole, Angela Waanders, Angel Montero Carcaboso, Maria Vinci, Chris Jones
Journal: Neuro-Oncology (2020)

Abstract H3.3G34R/V mutations are restricted to glioblastomas of the cerebral hemispheres, and occur predominantly in adolescents and young adults. We had previously shown these mutations to result in a global re-organisation of the activating mark H3K36me3 to drive transcription of key developmental transcription factors and oncogenes such as MYCN, however the precise mechanism was unclear. Using multiple H3G34R/V samples and ChIP-seq with antibodies specific to both wild-type and mutant histone H3.3, we show a high degree of incorporation of mutant histone into nucleosomes, with only a minority (&amp;lt;15%) remaining wild-type only. Heterogenous G34-mutant nucleosomes displayed significantly elevated H3K36me3 binding, the majority apparently in trans to the mutation on the wild-type H3.3, and expression signatures associated with chromatin modification, cell cycle progression, DNA repair and gene transcription. Super-enhancer analysis by H3K27ac ChIP-Seq highlighted lineage-dependent transcription factors and previously identified targets MYCN and NOTCH1 (both stabilised by FBXW7, down-regulated by loss of chromosome 4q), as well as specific H3K36 lysine demethylases and splicing factors. Whole-genome CRISPR-Cas9 screening of patient-derived H3.3G34R/V cells identified critical dependencies on these latter targets, in addition to a general essentiality for genes involved in RNA processing. Assessment of RNA methylation by MeRIP-seq revealed a strong concordance of m6A-modified RNA and H3K36me3 binding, with differentially modified transcripts in mutant cellsassociated with the 3’-UTR but also the promoter and gene bodies. These data highlight the critical nature of the epitranscriptome in H3.3G34R/V-mutant paediatric glioblastoma, and highlight novel targets for therapeutic intervention.
QOL-19. PARENT-REPORTED COGNITIVE PROBLEMS AND DIRECT ASSESSMENT OF COGNITION IN CHILDREN TREATED FOR A BRAIN TUMOR
Authors: Jurgen Lemiere, Charlotte Sleurs, Linde Van den Wyngaert, Karen Vandenabeele, Josefien Vandereydt, Trui Vercruysse, Sandra Jacobs
Journal: Neuro-Oncology (2020)

Abstract The Pediatric Perceived Cognitive Function (PedsPCF) item bank is a short parent and self-reported cognitive screening questionnaire developed in the context of pediatric oncology. The PedsPCF demonstrated satisfactory psychometric properties and the scores of the PedsPCF are found to be associated with clinical outcomes. Today little research is available to evaluate whether the PedsPCF is correlated with direct assessments of neurocognitive domains. The aim of the current study is to investigate whether important cognitive domains, such as different aspects of intelligence, memory, visuomotor integration can predict the PedsPCF score. We obtained 100 PedsPCF filled in by parents from children treated for a brain tumor. All these children completed a comprehensive neuropsychological battery. Mean age at diagnosis was 7.47 years and mean age at completion of PedsPCF and testing 13.84. The most common diagnoses were pilocytic astrocytoma (n=43) and medulloblastoma (n=14). A linear regression model with verbal comprehension, perceptual reasoning, processing speed, visuomotor integration as predictors for overall PedsPCF score was significant (p.005), but the overall model fit was limited (adjusted R2: 14%). Visuomotor integration and processing speed were significant predictors (beta = 0.56 and -0.29). Our results are in line with the overall finding that the correlation between questionnaires assessing quality of survival and direct assessments of cognition are low. For clinical practice these results are important as the PedsPCF can’t be used to replace direct cognitive assessments or vice versa.
Evolving Concepts in the Diagnosis and Staging of Multiple Myeloma
Authors: Jens Hillengass
Journal: Journal of the National Comprehensive Cancer Network (2020)

Until recently, treatment for multiple myeloma was only initiated in symptomatic disease. Greater understanding of the underlying biology and the development of new biomarkers, however, has led to changes in diagnosis, and with the help of improved imaging techniques, clinicians are increasingly identifying patients with early myeloma who may benefit from treatment. One major development in diagnostic imaging is the replacement of radiography with CT. PET/CT imaging is also useful for treatment response assessment, because the disappearance of focal lesions is an important prognostic factor. Finally, the Revised International Staging System for multiple myeloma has incorporated additional prognostic markers of aggressive disease, and risk-adapted treatment has been shown to improve survival.
NIMG-12. 18F-FLUORETHYLTYROSINE POSITRON EMISSION TOMOGRAPHY VERSUS MAGNETIC RESONANCE SPECTROSCOPY IN PREOPERATIVE DETECTION OF NEWLY DIAGNOSED GLIOMAS BY USING MACHINE LEARNING
Authors: Lazaros Lazaridis, Sied Kebir, Manuel Weber, Teresa Schmidt, Kathy Keyvani, Daniela Pierscianek, Martin Stuschke, Gearald Antoch, Michael Forsting, Ulrich Sure, Christoph Kleinschnitz, Ken Herrmann, Lale Umutlu, Cornelius Deuschl, Martin Glas
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Advanced imaging techniques entered the field of neurooncology. In this analysis we compare the diagnostic potential of 18F-fluorethyltyrosine (FET) positron emission tomography (PET) and magnetic resonance spectroscopy (MRS) in their potential to preoperatively predict certain glioma subtypes. AIMS Goal of this analysis ist the evaluation of FET PET and MRS regarding the preoperative prediction of glioma subtypes. METHODS We analyzed 33 patients with histopathologically confirmed newly diagnosed glioma. The patients received FET PET and MRS during one single preoperative diagnostic session. According to the molecular portfolio patients were subdivided in IDH wildtype glioblastoma patients (GBM), IDH wildtype WHO grade II/III glioma patients (Astro_IDHwt), IDH mutant WHO grade II/III glioma patients without 1p/19q codeletion (Astro_IDHmut) and with 1p/19q codeletion (ODG). Mean and maximum tumor-to-brain ratio (TBRmean and TBRmax), N-acetylaspartate, choline and creatine peaks were correlated with postoperative tumor diagnosis. To gain generalizable implications we subdivided the study cohort into a development and validation subcohort. A support vector machine model was fitted to the development subcohort and evaluated on the validation subcohort. Receiver operating characteristic curve served to assess model performance. RESULTS GBM patients had highest TBRmax and TBRmean values (mean: 3.5 and 3.8) and the ODG patients showed the second highest TBRmax and TBRmean values (mean: 2.6 and 3). The distribution of MRS markers exhibited to clear trend. The performance of glioma subtyping was comparatively low for the TBR values (AUC: 0.68) and even lower for the MRS markers (AUC: 0.60). These results are in line with preliminary investigations performed by our institute for the comparison of 11C-methionine PET with MRS in preoperative glioma subtyping. CONCLUSIONS FET PET and MRS bear limited potential in glioma subgrouping. However, FET PET appears to be slightly superior. Investigation in a larger cohort is required to draw definite conclusions.
MBCL-30. NOVEL SMO MUTATION IN DESMOPLASTIC/NODULAR MEDULLOBLASTOMA: A CASE REPORT
Authors: Avery Wright, Ana Aguilar-Bonilla, Emily Owens Pickle, Amy A Smith
Journal: Neuro-Oncology (2020)

Abstract Smoothened (SMO) is a transmembrane protein which is regulated by SHH (Sonic hedgehog) protein binding to PTCH1. SMO activation controls GLI which then translocates into the nucleus and activates target genes. The SHH subtype of medulloblastoma has been extensively studied to have mutations within the SHH signaling pathway, often in PTCH1, SUFU, and SMO. We present a case of desmoplastic/nodular medulloblastoma with the mutation SMO c.1810G&amp;gt;A. The patient presented at 11 years old with a two-week history of headaches and morning vomiting. His neuroimaging revealed a T2 hyperintense, enhancing mass centered at the fourth ventricle. He underwent gross total resection and had no metastatic spread. There were no alterations in PTCH1, SUFU, Tp53, GLI2, MYC/MYCN, CTNNB1, or the WNT pathway. The SMO c.1810G&amp;gt;A alteration has not been previously identified as a somatic mutation in a CNS tumor. The functional effect of this mutation has not been studied. It is known that desmoplastic/nodular histology in medulloblastoma is associated with the SHH subtype and given the fact that SMO is regulated by SHH signaling, this patient was ultimately diagnosed with SHH subtype medulloblastoma. Findings of novel somatic mutations in patients raises the question of whether the mutation is in fact the driver of neoplasia.