tbuckley/cabot-search huggingface dataset:
EPEN-07. OVEREXPRESSION AND MUTATIONS OF CXORF67 IN ‘INFANT-TYPE’ POSTERIOR FOSSA TYPE-A (PFA) EPENDYMOMAS
Authors: Wilda Orisme, Ji Wen, Bo Tang, Jens-Martin Hübner, Gang Wu, Sujuan Jia, John Easton, Kelly Haupfear, Brian D Freibaum, Hong Joo Kim, Anthony High, BaoHan Vo, Ruth G Tatevossian, Junmin Peng, Stefan M Pfister, Jinghui Zhang, J Paul Taylor, Martine Roussel, Kristian W Pajtler, Marcel Kool, David W Ellison
Journal: Neuro-Oncology (2018)

Ependymomas are classified into nine molecular groups by DNA methylation profiling. PFA tumors are most prevalent, present mainly in infants and have poor outcomes. Genomic studies have not identified a recurrent driver mutation in PFA ependymomas. However, PFA ependymomas are characterized by lack of H3 K27 trimethylation (H3K27-me3) and overexpression of CXorf67, a novel gene of unknown function. A review of PF ependymoma sequencing data revealed recurrent mutations in CXorf67. Subsequent analysis of a large series of ependymomas (n=263) showed that CXorf67 mutations occur in PFA ependymomas at a frequency of 9.4%, but not in non-PFA ependymomas. Targeted sequencing also revealed H3 K27M mutations in PFA ependymomas at a frequency of 3.9%. H3 and CXorf67 mutations were mutually exclusive. We used immunoprecipitation (IP) / mass spectrometry (MS) to study proteins bound to CXorf67 in the Daoy cell line, which overexpresses CXorf67. EZH2, SUZ12, and EED, core components of the PRC2 complex were identified among enriched peptides and validated through complementary SUZ12 IP/MS. We also showed that modulation of CXorf67 influences H3K27-me3 levels downstream of PRC2, suggesting a link between overexpression of CXorf67 and the altered global epigenetic state in PFA ependymomas through its interaction with PRC2. Enforced reduction of CXorf67 in Daoy cells restored H3K27-me3 levels, while enforced expression of CXorf67 in HEK293T and neural stem cells reduced H3K27-me3 levels. Our results suggest that CXorf67 overexpression may have an oncogenic role in PFA ependymomas, but the selective advantage of CXorf67 mutations is yet to be explained.
Abstract B24: Molecular and functional dissection of the CIC-DUX4 fusion in undifferentiated round cell sarcoma
Authors: Ross A. Okimoto, Wei Wu, Trever G. Bivona
Journal: Clinical Cancer Research (2018)

Abstract CIC-DUX4 soft-tissue tumors are an aggressive subset of undifferentiated round cell sarcomas that arise in children and young adults. The cytogenetic hallmark, (t(4;19) or t(10;19)), of this tumor is a chromosomal translocation that fuses the transcription factor, Capicua (CIC), with the double homeobox 4 protein, DUX4. Despite morphologic similarities to Ewing sarcoma, CIC-DUX4 sarcomas are clinically distinct with rapid development of lethal metastatic disease and chemoinsensitivity. The unique cytogenetic and clinical features that distinguish CIC-DUX4 sarcomas from other small round cell tumors provide a unique opportunity to identify and rationally target this population to improve clinical outcomes. To meet this need, we are taking a systematic functional approach to identify critical CIC-DUX4 targets that promote tumor progression and metastasis. Leveraging a comparative transcriptional analysis between cytogenetically distinct small round cell sarcomas, we reveal that the CIC-DUX4 fusion activates highly conserved molecular networks to control tumor growth and metastatic capacity. Using an orthotopic soft-tissue sarcoma model, we show that CIC-DUX4 induces ETV4 expression to drive invasion and metastasis. Genetic silencing of ETV4 in CIC-DUX4 expressing tumors limits tumor dissemination without a profound impact on tumor cell growth. These findings suggest that CIC-DUX4 enhances metastasis and tumor growth through distinct transcriptional repertoires. Consistent with this, we identify multiple components of the cell cycle machinery that are transcriptionally regulated by CIC-DUX4 expression. Specifically, the CIC-DUX4 fusion co-opts native CIC-binding specificity to transcriptionally activate these cell cycle target genes. Altogether, our molecular and functional dissection of the CIC-DUX4 fusion reveals highly conserved CIC-regulated transcriptional targets that promote tumor growth and metastasis. We aim to pharmacologically exploit these key CIC-DUX4-dependent transcriptional nodes to improve outcomes for this population with few therapeutic options. Citation Format: Ross A. Okimoto, Wei Wu, Trever G. Bivona. Molecular and functional dissection of the CIC-DUX4 fusion in undifferentiated round cell sarcoma [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr B24.
QOL-17. ERRORS ON BEDSIDE TESTING OF ANTI-SACCADES MAY PREDICT COGNITIVE DYSFUNCTION
Authors: Raja Khan, Thomas Merchant, Kathryn Russell, Zsila Sadighi, Jason Ashford, Heather Conklin
Journal: Neuro-Oncology (2018)

Anti-saccade is a voluntary contraversive rapid eye movement that is produced exactly opposite to a presented target. It involves inhibition of a reflexive target seeking saccade and voluntary production of a counter saccade. Abnormalities on anti-saccade tests associate with impaired attention and processing speed (PS), but testing anti-saccades requires cumbersome laboratory procedures. We have developed a bedside method to test anti-saccades that takes 3 minutes to complete. We aimed to test if errors on bedside testing of anti-saccades will associate with impaired attention, impulsivity and PS. Seventy-three consecutive participants (ages 5-17) on our craniopharyngioma protocol of proton therapy were evaluated over 1-3-time points. A total of 115 data points were available. Conners’ Continuous Performance Test II was used to measure sustained attention and subsets from the Wechsler Intelligence Scales were used to measure PS and working memory. In univariate generalized estimating equation (GEE) analyses, ≥ 20% error rate on anti-saccade test associated with impairment of PS (p=0.001), attention (p=0.03) and impulsivity (p=0.01). Working memory, age at testing, and time point in treatment did not associate with anti-saccade errors. In a multivariable logistic GEE model including PS, attention, and impulsivity, only increased impulsivity (p=0.04) remained significantly associated with ≥ 20% anti-saccade error rate. Our data suggests that for children with brain tumors, bedside measurement of anti-saccades may identify those with impaired attention, impulsivity and PS. These children may then be assessed with formal neuropsychological testing. Anti-saccades testing, if confirmed in validating studies, may become a useful tool in resource limited settings.
CRAN-27. PAEDIATRIC EXTRAVENTRICULAR NEUROCYTOMA: A SERIES AND A RARE COMPLICATION
Authors: Alexandra Johnson, Annie Bye, David Ziegler, Andrew Gifford, Erica Jacobsen, Richard Cohn
Journal: Neuro-Oncology (2018)

Paediatric extraventricular neurocytoma (EVN) is a rare central nervous system (CNS) tumour accounting for 0.1% of CNS tumours (Liu et al 2013). Limited data exists regarding presentation and outcome of paediatric EVN. A retrospective review of patients presenting with EVN to Sydney Children’s Hospital was conducted between 2007 and 2015 inclusively. Demographic data, presenting symptoms, seizure type and post-surgical outcome were examined. Four patients presented with EVN. Age at presentation ranged between 6–15 years (median 9.75), with follow-up of 2–10 years (median 6.6). Presenting features included focal seizures (n=2), generalised seizures (n=1) and headache (n=2). Two patients had focal neurological signs, one with homonymous hemianopia and another with sudden decline including dysarthria, hemiparesis and ipsilateral facial palsy accompanied by impaired consciousness. This latter patient had an intratumoral haemorrhage, cerebral oedema and enhancement of tumour periphery on magnetic resonance imaging / angiogram (MRI/MRA). MRA showed tortuous branching vessels from middle cerebral artery and AV shunting in the tumour bed. All patients had a gross total resection, and histopathology showed Ki67 <2% in all, though microvascular proliferation was noted (n=2, including the patient with haemorrhage). Recurrence including cerebellar metastasis and localised nodules occurred in the patient with haemorrhage. Focal seizures developed 4 years post-operatively, responding to carbamazepine. All other patients remained seizure free without recurrence post-operatively. Haemorrhage is a rare finding in EVN with 6 adults previously reported, including one with sudden hemiparesis (Ritz et al 2005). Clinicians should be aware of rare dramatic presentations in EVN due to intratumoral haemorrhage.
DEV-06. OUTCOME OF CHILDREN WITH MEDULLOBLASTOMA TREATED IN A TERTIARY REFERRAL CENTRE IN MALAYSIA
Authors: Mukhtaar Shaalih Tsai Ei Chan, Siti Nuraihan Nordin, Sing Yee Hiew, Eni Juraida Abdul Rahman, Hishamshah Mohd Ibrahim, Zulaiha Muda, Ida Shahnaz Othman, Bina Sharine Menon, Yin Sear Lim, Kok Hoi The
Journal: Neuro-Oncology (2018)

Medulloblastoma is the most common childhood malignant brain tumour. A retrospective review of all children diagnosed with medulloblastoma referred and treated at the Paediatric Haematology & Oncology unit, Hospital Kuala Lumpur, Malaysia over a 20 year period between January 1997 and December 2016 was conducted. Patients were identified through an electronic patient database kept by the treating Paediatric Haematologist & Oncologist in the centre. A total of 66 patients were identified. Boys (43 patients, 65%) outnumbered girls (23 patients, 35%) at a ratio of 2:1. The mean age at diagnosis is 6.8 years old. Thirty five patients (52%) are classified as high risks based only on age (less than 3 years old at diagnosis) and presence of metastatic disease at diagnosis. The estimated 5 year survival rates for the whole group, children in the standard risk group and the high risk group are 64%, 86% and 44% respectively. Complete current information is only available for 30 survivors. Amongst them, thirteen patients (43%) has various neurological deficits, seven (23%) developed endocrine complications and eight (27%) have both neurological & endocrine complications. Only two patients (7%) are free from long term neurological & endocrine complications. Survival outcome of children with standard risk medulloblastoma treated in Hospital Kuala Lumpur is comparable with that in developed countries. However, the outcome of children with high risk medulloblastoma should be further improved.
Haemoglobin scavenging in intracranial bleeding: biology and clinical implications
Authors: Diederik Bulters, Ben Gaastra, Ardalan Zolnourian, Sheila Alexander, Dianxu Ren, Spiros L. Blackburn, Mark Borsody, Sylvain Doré, James Galea, Koji Iihara, Paul Nyquist, Ian Galea
Journal: Nature Reviews Neurology (2018)
Self-Reported Concussions from Playing a Sport or Being Physically Active Among High School Students — United States, 2017
Authors: Lara DePadilla, Gabrielle F. Miller, Sherry Everett Jones, Alexis B. Peterson, Matthew J. Breiding
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Increased susceptibility to concussions and longer recovery times among high school athletes compared with older athletes (1) make concussions among youths playing a sport or being physically active an area of concern. Short-term and long-term sequelae of concussions can include cognitive, affective, and behavioral changes (1). Surveillance methods used to monitor concussions among youths likely underestimate the prevalence. Estimates assessed from emergency departments miss concussions treated outside hospitals, those generated using high school athletic trainer reports miss concussions sustained outside of school-based sports (2), and both sources miss medically untreated concussions. To estimate the prevalence of concussions among U.S. high school students related to playing a sport or being physically active, CDC analyzed data from the 2017 national Youth Risk Behavior Survey (YRBS). Overall, 15.1% of students (approximately 2.5 million*) reported having at least one of these concussions during the 12 months before the survey, and 6.0% reported two or more concussions. Concussion prevalence was significantly higher among male students than among female students and among students who played on a sports team than among students who did not. Among all sex, grade, and racial/ethnic subgroups, the odds of reporting a concussion increased significantly with the number of sports teams on which students played. These findings underscore the need to 1) foster a culture of safety in which concussion prevention and management is explicitly addressed; 2) expand efforts to educate students, parents, coaches, and health care providers regarding the risk for concussion; and 3) identify programs, policies, and practices that prevent concussions.
A Mediastinal Mass in a Young Man
Authors: Snigdha Jain, Arjun Gupta, Srikanth Nagalla
Journal: JAMA (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
The outcome of patients (pts) with metastatic colorectal cancer (mCRC) based on site of metastases (mets) and the impact of molecular markers and site of primary cancer on metastatic pattern.
Authors: Thiruvarudsothy Prasanna, Paul Stanley Craft, Yu Jo Chua, Christos Stelios Karapetis, Peter Gibbs, Rachel Wong, Jeanne Tie, David Roder, Timothy Jay Price, Rob Padbury, Cynthia Piantadosi, Desmond Yip
Journal: Journal of Clinical Oncology (2017)

3560 Background: Although liver is the commonest site of mets in pts with CRC, pattern of spread is variable and may reflect different biology in different subsets of pts. Methods: This is a retrospective analysis to explore the outcome of pts with mCRC based on their site of mets at diagnosis and to identify tumor characteristics which could predict the site of mets. Pts from 2 Australian databases, BioGrid (BG) and South Australian Cancer Registry (SA), from 01/2006 to 12/2015 were grouped into 5 cohorts; lung only, liver only or any pts with brain, bone or peritoneal mets. Overall survival (OS) for each group was compared with the rest of the sample using Kaplan Meier analysis and the log rank test separately in each dataset. Mantel-Haenszel Chi-squared test was performed in pooled data to assess the association between KRAS, BRAF, Micro satellite instability (MSI), site of primary and site of mets. Results: 5967 pts were included. In both datasets median OS was significantly higher when mets were limited to lung or liver and shorter for those with brain, bone or peritoneal mets. BRAF, KRAS and MSI data were available for 20%, 37% and 21% of the sample. In the pooled analysis BRAF mutation was associated with brain (Relative Risk=5.2) and peritoneal mets (RR=1.8) with lower incidence of lung (RR=0.3) and liver (RR=0.7) limited mets. KRAS mutation was associated with lung only mets(RR=1.4). Left colon tumors were associated with bone (RR=1.6) and lung only mets (RR=2.3) while peritoneal spread was less frequent compared with right colon tumors(RR=0.6). Rectal cancer was strongly associated with brain, bone and lung mets (RR=1.7, 1.7, 2.0). MSI status was not associated with site of mets though liver only mets was less frequent in MSI high tumors. Conclusions: Survival duration with mCRC is related to the site of mets. OS was significantly better when mets were confined to either lung or liver. BRAF mutation and primary rectal cancer were associated with poor prognostic metastatic sites like brain and bone. [Table: see text]
Comment on Stiermaier et al. Prevalence and Prognostic Impact of Diabetes in Takotsubo Syndrome: Insights From the International, Multicenter GEIST Registry. Diabetes Care 2018;41:1084–1088
Authors: Marco Giuseppe Del Buono, Salvatore Carbone, Antonio Abbate
Journal: Diabetes Care (2018)

We read with great interest the article by Stiermaier et al. (1) in the May issue of Diabetes Care . The authors reported the prevalence of type 2 diabetes (T2D) and its prognostic role in patients diagnosed with Takotsubo syndrome (TTS) using the multicenter international GErman Italian STress cardiomyopathy (GEIST) registry. Of the patients with TTS, 21% had T2D, and they had 66% higher all-cause mortality compared with patients without T2D.

We found great inspiration from their work (1) and retrospectively …
RONC-15. CYSTIC DYNAMIC EVALUATION AND EARLY LATE TOXICITY IN TWO PEDIATRIC LOW GRADE GLIOMAS TREATED WITH ACTIVE SCANNING PROTON BEAM RADIOTHERAPY
Authors: Barbara Rombi, Mino Zucchelli, Sabina Vennarini, Mirko Lipparini, Soraia Micò, Ilario Ammendolia, Daniele Zama, Arcangelo Prete, Silvia Cammelli, Francesco Toni, Letizia Ronchi, Alessio G Morganti, Andrea Pession, Maurizio Amichetti, Fraia Melchionda
Journal: Neuro-Oncology (2018)

To evaluate cystic dynamics in two pediatric low grade gliomas during proton beam therapy (PBT) by weekly MRI and in the follow up (FU) time. Early late toxicity was also reported. Both solid and cystic tumor’s components were drown in weekly MRI performed during proton radiation and in the FU phase. P1 case was a multiple partially resected 5 yo girl with hypothalamic pylocitic Astrocytoma no-responding after second line of chemotherapy, who acutely lost visual acuity due to cystic tumor’s progression. P2 case was a 13 yo boy with progressive mesencephalic pylocitic Astrocytoma previously treated with multi-agents chemotherapy and several surgeries. After cystic drainage both were treated with PBT at 54 Gy GCE. During proton therapy # 7 MRI for P1 and # 6 MRI for P2 patient were performed and didn’t shown cyst growth which required intervention; P1 developed two episodes of severe acute headache and both developed partial alopecia. In P1 patient both cystic and solid component progressively reduced (cyst/solid-1w +2/-15%, cyst/solid-2w -9/-22%, cyst/solid-3w -17/-28%, cyst/solid-4w -18/-38%, cyst/solid-5w -30/-43%, cyst/solid-6w -34/-44%, cyst/solid-1FU -43/-50%, cyst/solid-2FU -51/-63%). In P2 patient only cyst part progressively increased (cyst/solid-2w +7/-4%, cyst/solid-3w +36/-10%, cyst/solid-4w +58/-12%, cyst/solid-5w +73/-15%, cyst/solid-6w +90/-15%, cyst/solid-7w +94/-16%, cyst/solid-1FU +126/-37%, cyst/solid-2FU -18/-45%). P2 had transient cyst growth after PT with significant volume reduction on the second FU. After 10 months of median FU, no late side effects were noted however P1 improved visual acuity.
Emergence of KRAS mutation may play a major role in the secondary resistance to EGFR blockade
Authors: T. Yamada, G. Takahashi, T. Iwai, K. Takeda, H. Furuki, M. Koizumi, S. Shinji, A. Matsuda, Y. Yokoyama, M. Hotta, K. Hara, H. Yoshida
Journal: Annals of Oncology (2018)

Introduction: Oncogenic KRAS mutations are negative biomarkers of response to epidermal growth factor receptor (EGFR) blockade. KRAS mutation is usually detected in biopsies of primary colorectal tumors. However, the genomic profiles of primary tumors and metastases are not always concordant, and chemotherapeutic agents and targeted drugs can alter the tumor molecular landscape. Circulating tumor DNA (ctDNA) is a novel tool to detect molecular heterogeneity. In this study, we tried to clarify the mechanism of primary or secondary resistance to EGFR blockade as first-line treatment of metastatic colorectal cancer. Methods: We enrolled 33 chemotherapy-naïve patients with metastatic CRC and no RAS mutations in their primary tumors. Patients with BRAF mutation in a primary tumor or ctDNA were excluded. Patients were treated with first-line systemic chemotherapy that included EGFR blockade. We obtained ctDNA from each patient before they started chemotherapy, and every 2–3 months during chemotherapy until disease progression. We detected KRAS (codons 12, 13, 61, and 146), BRAF (V600E) and EGFR (S492R) mutations using digital polymerase chain reaction. Results: KRAS mutations were detected in the ctDNA of 5 of the 33 patients (15%) before chemotherapy. Twenty-seven of the 28 patients (96%) without ctDNA KRAS mutations achieved early tumor shrinkage (ETS). Two patients achieved a complete response (CR), 24 achieved a partial response (PR), and two patients experienced stable disease (SD). The five patients with ctDNA KRAS mutations did not achieve ETS. One patient had SD and four experienced disease progression (PD). Of the 26 initial responders, 17 (65%) acquired resistance. Emerging KRAS mutations were detected in the ctDNA of 16 of these 17 patients (94%); ten of these patients had multiple mutations. BRAF mutations were also detected in seven patients (39%). Eight patients (44%) had S492R mutations; none of the patients had solo S492R mutations. One patient, who had no KRAS mutation, had S492R mutations. Conclusion: KRAS mutation was detected in 5 of 7 patients who had no response by EGFR blockade. Emerging KRAS mutations were detected in most of the patients (94%) who acquired resistance. This indicates that emergence of KRAS mutation may play a major role in the primary and secondary resistance to EGFR blockade.