tbuckley/cabot-search huggingface dataset:
EPEN-25. KANSL1 GAIN AND FUSION - A NOVEL ALTERATION IN CHILDHOOD EPENDYMOMA
Authors: Yulia Margolin-Miller, Helen Toledano, Lital Sela-Tzuriano, Michal Hameiri-Grossman, Shalom Michowiz, Suzanna Fichman-Horn, Meora Feinmesser, Stefan Pfister, Hendrik Witt, Isaac Yaniv, Smadar Avigad
Journal: Neuro-Oncology (2018)

Ependymoma is a malignant pediatric brain tumor, often incurable with current treatment regimens. We aimed to identify new genes involved in pediatric ependymoma using copy number SNP array analysis. We analyzed 34 primary tumors, in 10 cases we analyzed the paired diagnosis-relapse samples and in 5 of them we also analyzed the corresponding peripheral blood (PB) sample. The most prevalent alterations identified were gain of 8q (18%), deletion of 10q (18%), gain of 11q (12%) and gain of 17q (53%). The locus of the 17q21.31 gain contains only one gene - KANSL1 (KAT8 regulatory NSL complex subunit 1) gene. The gain affected exons 1–4 of the gene. This gain was identified in 9 out of the 10 (90%) relapse samples and in all of the PB samples. The gain was validated at the RNA level and a significant overexpression of KANSL1 mRNA was detected in the samples exhibiting gain versus the samples with normal copy number (p=0.04). KANSL1 is part of the NSL complex which functions as a histone acetyltransferase. The 17q21.31 locus contains a common inversion duplication polymorphism enriched in European populations. Recently, a new fusion was discovered in high frequencies in adult malignancies between KANSL1 and ARL17, termed KANSARL, both located on 17q21.31. KANSARL fusion was detected in 71% of our samples. All the samples that exhibited gain of KANSL1 were positive for the KANSARL fusion. Our results suggest that the gain precedes the formation of the fusion which may be a predisposing event in ependymoma.
Impact of the length of the resection margin on local recurrence after curative endoscopic submucosal dissection for early gastric cancer
Authors: H. Chung, J. Park, S. Shin, S. Lee, Y. Lee
Journal: Annals of Oncology (2018)

Introduction: Little is known about safe resection margin in endoscopic submucosal dissection (ESD) for early gastric cancer (EGC). The aim of this study was to assess the clinical significance of the resection margin. Methods: A total of 1548 patients underwent ESD for EGC between 2007 and 2014, at a tertiary hospital, Seoul, Korea. The curative resection rate was 90.3% (1399/1548). Among them 30 patients (2.14%), 17 adenomas (1.21%) and 13 adenocarcinomas (0.92%), had local recurrence. Data from 90 patients without recurrence, and who were matched by age and gender, were extracted on a 1:3 basis and their clinical and histological parameters were compared. Results: The median time for detection of local recurrence at previous ESD sites was 9.1 months (range, 3–34 months) after ESD, and patients without recurrence had a median follow-up of 43.6 months (range, 26–104 months). The mean tumor-free lateral margin length was 1.38 ± 0.44 mm in patients with recurrence compared to 5.40 ± 2.51 mm in those without recurrence (P < 0.001). No factor other than lateral margin length was statistically different between the two groups. In multivariate analysis, a lateral free margin of less than 1 mm (hazard ratio [HR], 3.075; 95% confidence interval [CI], 1.094–8.646) and EGC arising from an adenoma (HR, 2.761; 95% CI, 1.109–6.875) were related to local recurrence. Conclusion: A tumor-free lateral resection margin less than 1 mm and cancer arising from an adenoma were significantly associated with local recurrence even after curative ESD for EGC. These patients should undergo stricter surveillance endoscopy for early detection of possible local recurrence in the first year after ESD. Further research is required to elucidate the optimal length of resection margin in ESD for EGC.
GERM-02. NOVEL TREATMENT APPROACH FOR PATIENTS WITH CENTRAL NERVOUS SYSTEM (CNS) PURE EMBRYONAL CARCINOMA WITH INTENSIVE INDUCTION AND CONSOLIDATION MARROW-ABLATIVE CHEMOTHERAPY FOLLOWED BY AN ANTI-CD30 ANTIBODY-DRUG CONJUGATE, WITHOUT IRRADIATION
Authors: Mohammad H Abu Arja, Suzanne E Conley, Mohamed S AbdelBaki, Diana S Osorio, Scott Coven, Rolla T Abu-Arja, Daniel Boué, Kevin Ginn, Jeffrey Leonard, Jonathan L Finlay
Journal: Neuro-Oncology (2018)

Primary CNS embryonal carcinoma confers a poor prognosis despite conventional chemotherapy and radiotherapy. We report upon a novel treatment approach to CNS embryonal carcinoma using intensive, including marrow-ablative, chemotherapy followed by maintenance therapy with brentuximab-vedotin without irradiation. Brentuximab-vedotin is an anti-CD30 antibody conjugated to an anti-tubulin synthetic analog. Retrospective review of two patients’ medical records treated since 2015 at Nationwide Children’s Hospital. We report upon the management of two patients with suprasellar pure, CD30-positive embryonal carcinoma. A 17-years-old female with Down syndrome compounded by autism and a 9-years-old male with documented cognitive dysfunction received two cycles of carboplatin/etoposide interspersed with one cycle of cyclophosphamide/etoposide for induction, followed by three cycles of marrow-ablative thiotepa/carboplatin with autologous hematopoietic cell rescue. The first patient achieved complete radiographic and tumor marker response to induction and marrow-ablative chemotherapy, and has completed six cycles of intravenous brentuximab-vedotin, continuing now disease-free 28 months since diagnosis without adverse effects. The second patient had a complete serum and cerebrospinal fluid tumor marker response and a dramatic radiographic response with a small residual abnormality at the end of marrow-ablative chemotherapy that was found at surgery to be composed of predominately reactive changes. Currently, the patient has received the first of six proposed cycles of intravenous brentuximab-vedotin. Intensive, including marrow-ablative chemotherapy followed by maintenance with an anti-CD30 antibody-drug conjugate may provide selective and safe alternative to radiotherapy in the management of patients with CNS embryonal carcinoma especially for patients at high risk of developing irradiation-related complications.
CRAN-20. THE TEN-YEAR EVOLUTIONARY TRAJECTORY OF A HIGHLY RECURRENT PAEDIATRIC HIGH GRADE NEUROEPITHELIAL TUMOUR WITH MN1:BEND2 FUSION
Authors: Anna Burford, Alan Mackay, Sergey Popov, Maria Vinci, Diana Carvalho, Matthew Clarke, Elisa Izquierdo, Aimee Avery, Thomas S Jacques, Wendy J Ingram, Andrew S Moore, Kieran Frawley, Timothy E Hassall, Thomas Robertson
Journal: Neuro-Oncology (2018)

Astroblastomas are rare brain tumours which predominate in children and young adults, and have a controversial claim as a distinct entity, with no established WHO grade. Reports suggest a better outcome than high grade gliomas, though they frequently recur. Recently, they have been described to overlap with a newly-discovered group of tumours described as ‘high grade neuroepithelial tumour with MN1 alteration’ (CNS HGNET-MN1), defined by global methylation patterns and strongly associated with gene fusions targeting MN1. We have studied a rare case of astroblastoma arising in a 6 year-old girl, with multiple recurrences over a period of 10 years, with the pathognomonic MN1:BEND2 fusion. Exome sequencing of eleven surgical interventions allowed for a phylogenetic reconstruction of tumour evolution, which when integrated with clinical, pathological and radiological data provide for a detailed understanding of disease progression, with initial treatment driving tumour dissemination along four distinct trajectories. Infiltration of distant sites was associated with gains of chromosomal arms and later genome doubling. There was evidence of convergent evolution of different lesions acquiring distinct alterations targeting the NF-kB pathway, supported by strong immunohistochemical staining of RELA, and high levels of target gene expression, such as IL8. These data represent an unique opportunity to understand the evolutionary history of a highly recurrent childhood brain tumour, and provide novel therapeutic targets for astroblastoma / CNS HGNET-MN1.
LGG-56. TREATMENT WITH VEMURAFENIB IN PEDIATRIC PATIENTS WITH LOW-GRADE GLIOMAS WITH BRAF V600E MUTATION. REPORT OF 4 CASES
Authors: María Cores, Mariana Nana, Paula Robledo, Blanca Diez, García Lombardi
Journal: Neuro-Oncology (2018)

BRAF mutations, resulting in aberrant activation of the MAPK pathways are critical in low grade gliomas (LGG) pathogenesis. BRAF V600E mutation (BRAF V600E +) is present in 10 - 20% of this tumors, mostly in Pleomorphic Xanthotrocytoma (PXA) and gangliogliomas. Vemurafenib has shown efficacy on patients with LGG by inhibition of BRAF serine-threonine kinase. To report the experience at two institutions, in the use of Vemurafenib for pediatric patients with LGG BRAF V600E+, relapsed or refractory to standard treatments with chemo/radiotherapy. MATERIALS AND Pediatric patients with BRAF V600E + LGG treated with vemurafenib between January 2015 and december 2017 at Hospital de Niños Ricardo Gutierrez and FLENI were included. 4 patients were included. 3 male/1 female. Ages: 1, 2, 4 and 12 years. 2 Pilomyxoid Astrocytomas, 2 gagliogliomas. 3/4 localized disease (1 metastatic patient, ganglioglioma). 2 patients: 3 lines of chemotherapy (vinblastine/ Vincristine- Carboplatin, Temozolomide), 2 patients radiotherapy. Vemurafenib dosis: 240-480 mg twice daily. Median time of treatment: 17 months (r: 18-48). Response (clinical and by MRI): very good in 3 patients and stable disease 1 patient. Toxicity: 4 patients skin (rash/nevus/ photosesitization), 1 patient neurologic (disestesia). Suspend treatment for toxicity: 1 patient (transient suspension). in our experience all patients had response, 3 of them a very good one. Dermatologic toxicity was the most common but is well tolerated.
GERM-07. HISTOLOGICAL DIAGNOSES OF BIFOCAL, DI-NEGATIVE, AND TUMOR MARKER-NEGATIVE TUMORS; AND OUTCOME AFTER NON-CSI STRATEGY FOR CYTOLOGY-POSITIVE GERMINOMAS IN JAPAN. HOMEWORK AFTER DELPHI CONSENSUS
Authors: Ryo Nishikawa, Masayuki Kanamori
Journal: Neuro-Oncology (2018)

The Delphi consensus statements on the management of intracranial germ cell tumors (GCTs) (Murray MJ, et al. Lancet Oncology 16:e470-e477, 2015) left some homework unanswered. One of them was the histological diagnosis of bifocal (pineal and neurohypophyseal), diabetes insipidus (DI)-negative and tumor marker (HCG and AFP) –negative tumors; and the other was justification of craniospinal irradiation (CSI) for CSF cytology-positive germinomas. We performed a survey for 54 institutes in Japan and analyzed the clinical information, histological diagnoses, treatments, and outcome to answer those questions. There were six (6.9%) out of 88 histologically verified bifocal, DI and tumor marker-negative cases that was not germinoma, including two germinomas with teratomatous component, two immature teratomas, an embryonal carcinoma and a granuloma. Among 80 cases with positive CSF cytology, 26 received CSI and 53 received cranial irradiation. The 5 year PFSs were similar (90% and 82%, respectively). However, there was a difference in the pattern of failure; two cases (7.7%) with CSI developed recurrence within the irradiated fields while 6 cases (11.3%) treated with cranial irradiation developed spinal recurrences and two of them were dead because of the recurrent tumors.
CRP/albumin ratio can be a predictor of response to neoadjuvant chemoradiotherapy (CRT) in rectal cancer
Authors: T. Yetisyigit, S. Seber, A. Yolcu
Journal: Annals of Oncology (2018)

Introduction: C-reactive protein to albumin (CRP/Alb) ratio is a surrogate marker of hosts reaction to systemic inflammation generated by tumor microenvironment. Recent studies have reported its efficacy as a prognostic marker in various cancers. However, its association with tumor response to treatment has not been fully elucidated. We aimed to investigate the effect of pretreatment CRP/Albumin ratio on treatment response in rectum cancer patients receiving CRT. Methods: 35 consecutive patients diagnosed with rectum cancer who received neoadjuvant CRT with capecitabine between 2015 - 2017 were included in the study. CRP, Albumin, and hemogram values determined before treatment initiation along with data for other clinical and biochemical factors were retrieved from the medical records. Cut off values for CRP/Alb and neutrophil/lymphocyte ratio (NLR) were taken as 0.1 and 2.6, respectively. Both of the values are reported in meta analysis studies elucidating thresholds of CRP/Alb and NLR ratios. Results: Seven patients (20%) achieved complete response while 26 patients (74%) had ypN0 disease. The distribution of ypT1, ypT2 and yp T3 stage were 13,10,5 patients respectively. Complete responders and patients with ypT1NO disease were grouped as good responders while patients with yp T3 or with post CRT node positive disease were grouped as poor responders. When the correlation between biochemical and clinical parameters with post treatment pathological stage was analyzed in univariate analysis; patients with a low CRP/Alb ratio (OR 1.8, %95 CI 1.00- 3.34, p = 0.001) and distance from anal verge < 4cm (OR 0.2,%95 CI 1.24- 4.23, p = 0.014) were found to independent predictors for good response. Conclusion: CRP/Alb ratio along with tumor distance from the anal verge was shown to be predictive factors for tumor response to therapy. Further prospective studies are needed for validation of our findings for identification of clinical subgroups most likely to benefit from neoadjuvant treatment.
Fri0737-hpr women’s experiences of coping with chronic widespread pain – a qualitative study
Authors: K. Aili, S. Bergman, A. Bremander, E. Haglund, I. Larsson
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background:</h3> Approximately ten percent of the population report chronic widespread pain (CWP), the condition is more common among women than men. For most people, the pain interferes with many aspects of every-day life and implies large consequences. However, the group reporting CWP is heterogeneous and there is a need for better understanding of the different strategies used for coping with pain in every-day life. <h3>Objectives:</h3> The purpose of this study was to describe women's experiences of how to cope with CWP. <h3>Methods:</h3> The study had a descriptive design with a qualitative content analysis approach. Individual interviews were conducted with 19 women, 31–66 of age, who had reported CWP in a survey 2016. CWP was defined according to the 1990 ACR criteria for fibromyalgia. To be considered chronic, the pain should have persisted for more than three months during the last 12 months. A manifest qualitative content analysis was used to analyze the main question "How do you cope with your chronic widespread pain?" The analysis resulted in four categories. <h3>Results:</h3> Women described their coping with CWP in four different ways; to take control, to continue as usual, to follow instructions and to rest. <i>To take control</i> meant to make deliberate decisions to handle everyday day life. It also meant to take care of oneself, to think positive and to exercise at an adequate level. <i>To continue as usual</i> meant not to listen to body signals and either to ignore or accept the pain. <i>To follow instructions</i> meant listening to the health professionals and following advices, but without taking any part of the responsibility for the treatment outcome. <i>To rest</i> meant to perceive an unreasonable need for recovery, to resign and let the pain set the terms for the daily living. <h3>Conclusions:</h3> Women expressed different ways of coping with CWP including both active and passive strategies. The coping strategies included two dimensions, where one ranged from <i>actively taking control over the pain</i>, to <i>passively following instructions</i> and the other from <i>actively continue as usual</i> by either accepting or ignoring the pain to <i>passively rest</i> and being mastered by pain. <h3>Disclosure of Interest:</h3> None declared
LGG-13. RESOLVING TRANSCRIPTIONAL PROFILES IN BRAF-REARRANGED PILOCYTIC ASTROCYTOMA USING SINGLE CELL RNA SEQUENCING
Authors: Zachary Reitman, Brenton Paolella, Guillaume Bergthold, Kristine Pelton, Sarah Becker, Robert Jones, Zach Herbert, Leslie Grimmett, John Daley, Mariella Filbin, Mario Suva, Liliana Goumnerova, Karen Wright, Susan Chi, Mark Kieran, Aviv Regev, Alex Shalek, Keith L Ligon, Rameen Beroukhim, Pratiti Bandopadhayay
Journal: Neuro-Oncology (2018)

Pilocytic astrocytoma (PAs) are pediatric low grade gliomas that frequently harbor oncogenic KIAA1549-BRAF fusions and exhibit low rates of other somatic genetic alterations. Previous transcriptomic profiling of bulk PA tissues sought to uncover gene expression programs that distinguish PA from other tumor types and which may underlie the unique biological features of PA. However, bulk PA transcriptomic data is often confounded by gene signatures thought to be contributed by normal, non-tumor cells. Also, analysis of bulk PA tissue provides incomplete information on whether distinct cell populations exist among the tumor cells. To resolve the cell types contributing to PA transcriptional profiles and to identify gene expression programs that distinguish PA tumor cells from those of higher-grade tumors, we performed RNA sequencing of >1000 single cells (scRNA-seq) collected from six PAs. To confidently distinguish tumor cells from non-tumor cells, we sorted cells by glial progenitor marker A2B5 status and also profiled KIAA1549-BRAF fusion status for every cell. This scRNA-seq approach revealed unique tumor and non-tumor cell populations within PAs. We identified tumor cell populations expressing oligodendrocyte precursor and radial glia gene signatures. Non-tumor cells consisted of populations expressing microglia, T lymphocyte, and endothelial cell gene signatures which accounted for many of the expression patterns seen in bulk PA transcriptional data. In summary, scRNA-seq has revealed the cellular ecosystem and population structure of PA.
MBRS-47. ESTABLISHMENT OF A 3D SPHEROID-BASED MODEL OF MEDULLOBLASTOMA THAT RECAPITULATES TUMOUR GROWTH, DRUG RESPONSE AND MIGRATION
Authors: Sophie J Roper, Paul J Scotting, Beth Coyle
Journal: Neuro-Oncology (2018)

Medulloblastoma is the most common malignant brain tumour, accounting for 15-20% of all childhood brain tumours. Traditional two-dimensional (2D) cell culture fails to recapitulate the multi-dimensional growth and complex microenvironment observed in patient tumours and hence is limited in its ability to predict therapeutic response. There is therefore an urgent need to develop a three-dimensional (3D) in vitro culture technique that can be used to understand underlying tumour biology and evaluate potential therapeutic agents. Here, we optimised seeding densities and a universal culture medium for a highly reproducible 3D spheroid-based assay in a panel of medulloblastoma cell lines representing three molecular subgroups (DAOY, ONS76, UW228-3 [SHH]; HD-MB03 [Group 3]; CHLA-01-MED, CHLA-01R-MED [Group 4]). Medulloblastoma cell lines formed spheroids of different morphologies, reflecting their clinical and molecular characteristics. Culture as 3D spheroids increased resistance to Vincristine treatment relative to 2D (CellTiter-Glo; p≤0.0001). Automated imaging analysis (Celigo® cytometer) confirmed this difference in therapeutic response and identified a subpopulation of live, therapy-resistant cells within the 3D spheroid after treatment. Immunohistochemistry staining of a spheroid array demonstrated expression of key markers of proliferation (Ki67) and stemness (SOX2). Medulloblastoma 3D spheroids displayed different patterns of migration across a Collagen IV or basement membrane extract (Cultrex® BME) matrix. This migration could be inhibited by targeting WIP1 (CCT007093), a metastasis-related marker. We have established a clinically-relevant, optimised 3D spheroid model of medulloblastoma that allows direct comparison across molecular subgroups and is a significant improvement over traditional 2D models.
EPEN-21. SINGLE CELL RNASEQ IDENTIFIES A PUTATIVE CANCER STEM CELL POPULATION IN POSTERIOR FOSSA EPN
Authors: Andrew Donson, Austin Gillen, Kent Riemondy, Jay Hesselberth, Vladimir Amani, Andrea Griesinger, Davis Witt, Todd Hankinson, Michael Handler, Rajeev Vibhakar, Nicholas Foreman
Journal: Neuro-Oncology (2018)

Biological studies of ependymoma (EPN) have advanced our understanding of this tumor, but have relied heavily on bulk-tumor profiling. Intra-tumoral cellular heterogeneity within EPN bulk-tumor samples significantly confounds our understanding of the biology of this tumor, impeding development of effective therapy. We have addressed this problem using single cell RNAseq analysis (scRNAseq) of EPN, to characterize the cellular diversity within EPN tumor microenvironment. Using the 10x Chromium Drop-seq platform we analyzed approximately 3000 cells from 9 posterior fossa EPN patient samples. This approach identified 3 major cell subpopulations that were determined to be tumor based on shared EPN-specific gene expression. Two of these subpopulations exhibited molecular profiles indicative of (i) multiciliated border cells, and (ii) basement membrane cells, corresponding to the 2 major cellular populations present in normal ependymal cells from which EPN are thought to arise. The 3rd subpopulation harbored a cancer stem cell (CSC) gene signature, distinguished by upregulation of established stem-cell marker CD44 and stress-response genes, and low expression of ependymal differentiation genes. The abundance of this EPN subpopulations was estimated in primary tumor samples by deconvolution in a large cohort of clinically annotated EPN bulk-tumor transcriptomic profiles. A higher proportion of CSC or multiciliated cell populations was shown to determine assignment to transcriptomic subgroups PFA and PFB respectively. A higher proportion of CSCs was shown to be associated with a shorter survival than other EPN tumor subpopulations. Collectively, these findings support the hypothesis that this putative CSC subpopulation underlies tumor aggressiveness in posterior fossa EPN.
Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways
Authors: Mats Nagel, Philip R. Jansen, Sven Stringer, Kyoko Watanabe, Christiaan A. de Leeuw, Julien Bryois, Jeanne E. Savage, Anke R. Hammerschlag, Nathan G. Skene, Ana B. Muñoz-Manchado, Tonya White, Henning Tiemeier, Sten Linnarsson, Jens Hjerling-Leffler, Tinca J. C. Polderman, Patrick F. Sullivan, Sophie van der Sluis, Danielle Posthuma
Journal: Nature Genetics (2018)
Incidence and Prevalence of Pediatric Eosinophilic Esophagitis in Utah Based on a 5-Year Population-Based Study
Authors: Jacob Robson, Molly O’Gorman, Amber McClain, Krishna Mutyala, Cassandra Davis, Carlos Barbagelata, Justin Wheeler, Rafael Firszt, Ken Smith, Raza Patel, Kathryn Peterson, Amy Lowichik, Stephen Guthery
Journal: Clinical Gastroenterology and Hepatology (2018)