tbuckley/cabot-search huggingface dataset:
What is the place of pancreatic endoscopic ultrasound elastography in 2018?
Authors: Marc Giovannini
Journal: Endoscopy (2018)

Sonoelastography is based on the knowledge that some diseases, such as cancer, lead to a change in tissue hardness. Elastography examines the elastic properties of tissues by applying a slight compression to the tissue and comparing an image obtained before and after this compression. Endoscopic ultrasound (EUS) is the best technique available today to diagnose small pancreatic masses and to obtain histology from such lesions. However, in around 10 % – 15 % of cases, the EUS-guided fine needle aspiration (EUS-FNA) is non-contributory; since 2006 (date of the first publication on EUS elastography), the majority of published studies have tried to prove that EUS elastography should replace EUS-FNA.
RTHP-38. BNCT COMBINED WITH EARLY SUCCESSIVE BEVACIZUMAB TREATMENTS FOR RECURRENT MALIGNANT GLIOMAS
Authors: Shin-Ichi Miyatake, Hiroyuki Shiba, Shinji Kawabata, Toshihiko Kuroiwa, Natsuko Kondo, Yoshinori Sakurai, Minoru Suzuki, Koji Ono
Journal: Neuro-Oncology (2018)
QOLP-16. CAPTURING THE PRIMARY BRAIN TUMOR (PBT) PATIENT’S EXPERIENCE OF BODY IMAGE DISSATISFACTION: REPORT FROM THE NEURO-ONCOLOGY BRANCH-NATURAL HISTORY STUDY (NOB-NHS)
Authors: Alvina Acquaye, Elizabeth Vera, Orwa Aboud, Terri Armstrong, Lisa Boris, Miranda Brown, Sonja Crandon, Nancy Garren, Ming Ji, Jason Levine, Carlos Romo, Jennifer Reyes, Christine Siegel, Jing Wu, Megan Mackey, Kevin Camphausen, Peter Mathan, DeeDee Smart, María Fletcher Ruiz, Tito Mendoza, Mark Gilbert, Lindsay Rowe
Journal: Neuro-Oncology (2018)
CADD-48. microRNA-34a PACKAGED IN BACTERIAL NANOCELLS OVERCOMES THERAPEUTIC RESISTANCE IN GLIOBLASTOMA
Authors: Muhammad Babar Khan, Rosamaria Ruggieri, Nhan Tran, Jann Sarkaria, Jennifer MacDiarmid, Himanshu Brahmbhatt, John Boockvar, Marc Symons
Journal: Neuro-Oncology (2018)

microRNA-34a could serve as a novel therapeutic agent since it is under-expressed in Glioblastoma and modulates the expression of multiple genes in the deregulated p53, Rb and receptor tyrosine kinase networks which confer selective growth advantage and represent significant intra-tumoral heterogeneity, a major cause of therapeutic resistance. We studied the effects of microRNA-34a transfection in three primary patient-derived lines (GBM 6, GBM118 and GBM 126, respectively belonging to classical, mesenchymal and proneural subtypes), four established cell lines (T98G, U251, A172, LN229; where T98G and U251 show primary resistance to treatment while A172 and LN229 are sensitive) and two cell lines with acquired resistance to temozolomide (A172TR, LN229TR). microRNA-34a reduced proliferation and sensitized to temozolomide (Combination Index< 0.2–0.6) and radiation (dose enhancement factor 1.7–2.2) treatment, regardless of baseline treatment resistance in all studied cell lines. We identified broadly conserved microRNA-34a binding sites in the 3’UTR of multiple mRNAs in the Glioblastoma deregulated networks and genes known to confer therapeutic resistance and validated the direct downregulation of Bcl-2 protein as a major contributor to temozolomide sensitization. Nanocells (400nm diameter), termed EDV, were derived from genetically modified bacteria, provided with a bispecific antibody targeting EGFR and loaded with microRNA-34a. EDVs were injected intravenously while temozolomide was administered by oral gavage in GBM6 orthotopic mouse model. We observed significant increases in miR-34a expression, downregulation of oncogenes and reduction in tumor growth in mice treated with microRNA-34a EDV relative to control EDV(p=0.021). Further, microRNA-34a EDV significantly improved survival and synergized with temozolomide therapy [p<0.001, median survival of control EDV, microRNA-34a EDV, control EDV with temozolomide and microRNA-34a EDV with temozolomide was 44, 48, 86 and 165+ days respectively]. In conclusion, microRNA-34a EDV counteracts therapeutic resistance and intra-tumor heterogeneity.
Abstract 17138: Emergence of a Unique Biomarker Signature in Pediatric Patients With Developing Chemotherapy Cardiotoxicity
Authors: Olga H Toro-Salazar, Eileen Gillan, Michael O’Loughlin, Joanna Ferranti, Kia N Zellars, Paige E Perreault, Kathryn Mason, Bruce Liang, Shailendra Upadyay, Wojciech Mazur, Subba Raman, Kan Hor, Francis G Spinale
Journal: Circulation (2016)

Background: A class of chemotherapeutics commonly used in pediatric cancer is the anthrycylines (ACs), but often is associated with left ventricular dysfunction: i.e. chemotherapy induced cardiotoxicity (CIC). The goal of this project was to examine whether a specific set of plasma biomarkers could be identified in pediatric patients undergoing initial AC treatment and at risk for CIC as well as examined in relationship to referent normal pediatric patients. Methods and Results: AC treated pediatric patients (n=17, diagnosed with cancer (most commonly Hodgkin’s Lymphoma) with set dosing intervals and maximal AC doses of 325 mg/m2)) underwent cardiac MRI 24-48 hours after AC therapy for LV ejection fraction (LVEF) and plasma obtained at baseline (initial AC treatment) and with repeat studies (up to 12 mos). Plasma was also collected from referent normal pediatric subjects (n=66). Multiplex arrays quantified signatures from the inflammatory (8 unique cytokines) and matrix remodeling (13 unique matrix metall...
Considerations on Retrospective Identification and Classification of Learning Disabilities—Reply
Authors: Zachary A. Miller
Journal: JAMA Neurology (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 Neurology HomeNew OnlineCurrent IssueFor Authors Podcast 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 Neurology journal
Force awakens: a new hope for athletic shoulder strength testing
Authors: Ben Ashworth, Daniel Dylan Cohen
Journal: British Journal of Sports Medicine (2018)

> ‘Lucas [real identity hidden] came through the training session yesterday with no issues. It is now ten weeks since his posterior shoulder repair (non-dominant) and he is pushing to play this Saturday, but his goalkeeper coach says he still looks apprehensive at full stretch and when he has to react or land from a dive. Clinically, his shoulder instability tests are all normal and he has full range of motion. Upper body strength in the gym and all grip strength and hand-held dynamometer scores are back to preinjury levels.

> However, there remain meaningful differences in peak landing force when he performs a plyometric push up (17% offload asymmetry), and the ‘ASH test’ shows a 23% lower rate of force development in a T-position on the affected left shoulder (445 N/s vs 580 N/s, table 1). This suggests that when he has to stabilize quickly, his shoulder is not ready yet. In my opinion he is a risk for the weekend.’

View this table:

Table 1 
Shoulder strength tests



At present, there are few objective markers to support return to performance decisions in athletes following shoulder operation or injury.1 2 The athlete with a shoulder injury requires a testing protocol that is appropriately challenging, yet sensitive enough to inform decisions along the full return to play …
High-Dimensional Single-Cell Analysis Identifies Organ-Specific Signatures and Conserved NK Cell Subsets in Humans and Mice
Authors: Adeline Crinier, Pierre Milpied, Bertrand Escalière, Christelle Piperoglou, Justine Galluso, Anaïs Balsamo, Lionel Spinelli, Inaki Cervera-Marzal, Mikaël Ebbo, Mathilde Girard-Madoux, Sébastien Jaeger, Emilie Bollon, Sami Hamed, Jean Hardwigsen, Sophie Ugolini, Frédéric Vély, Emilie Narni-Mancinelli, Eric Vivier
Journal: Immunity (2018)

Natural killer (NK) cells are innate lymphoid cells (ILCs) involved in antimicrobial and antitumoral responses. Several NK cell subsets have been reported in humans and mice, but their heterogeneity across organs and species remains poorly characterized. We assessed the diversity of human and mouse NK cells by single-cell RNA sequencing on thousands of individual cells isolated from spleen and blood. Unbiased transcriptional clustering revealed two distinct signatures differentiating between splenic and blood NK cells. This analysis at single-cell resolution identified three subpopulations in mouse spleen and four in human spleen, and two subsets each in mouse and human blood. A comparison of transcriptomic profiles within and between species highlighted the similarity of the two major subsets, NK1 and NK2, across organs and species. This unbiased approach provides insight into the biology of NK cells and establishes a rationale for the translation of mouse studies to human physiology and disease.
INNV-19. PLASMA EXTRACELLULAR VESICLE GLIAL FIBRILLARY ACIDIC PROTEIN AND TAU AS BIOMARKERS FOR BRAIN CANCER
Authors: Ali Alattar, Jean Lewis, Johnny Akers, Michael Heller, Clark Chen
Journal: Neuro-Oncology (2018)

Early detection of brain cancer remains a challenging proposition. We applied a novel alternating current electrokinetic (ACE) chip device that relies on the dielectrophoretic (DEP) force to isolate and analyze the proteomic content of extracellular vesicles (EV) derived from undiluted patient plasma to identify biomarkers for early detection of brain tumors. EVs derived from cultured cells or plasma samples were isolated using the ACE chip. The concentration of intra-vesicular glial fibrillary acidic protein (GFAP) and Tau was determined using immunofluorescence staining. Improvement in model prognostication was quantified using net reclassification improvement (NRI>0) and integrated discrimination improvement (IDI). EVs secreted by cultured brain tumor cells (brain metastasis, meningioma, and glioma) harbored high levels of GFAP and Tau. We isolated EVs from plasma collected from brain tumor patients (5 meningiomas, 5 metastases, 6 gliomas) and 17 non-cancer controls. Compared to controls, plasma EVs from brain tumor patients exhibited greater fluorescence for GFAP (1.94 ± 0.139 vs. 1.28 ± 0.042, p<0.0001) and Tau (4.92 ± 0.43 vs. 1.79 ± 0.11, p<0.0001). Immunofluorescence did not differ between tumor types. Elevated EV GFAP was associated with a sensitivity of 88%, a specificity of 92%, and a AUC of 0.931 (95% CI 0.84–1.022) for brain tumor detection. Similarly, elevated EV Tau was associated with sensitivity of 94%, specificity of 94%, and AUC of 0.948 (95% CI 0.846–1.05) for brain tumor detection. The combination of EV GFAP and Tau improved test discrimination relative to GFAP alone (NRI>0 1.66, 95% CI 1.19–2.13, p<0.001; IDI 0.26, 95% CI 0.11–0.41, p<0.001) or Tau alone (NRI>0 1.54, 95% CI 1.03–2.05, p<0.001; IDI 0.18 0.038-0.32, p=0.013). We have provided proof-of-principle studies to demonstrated the utility of a novel DEP-based technology for minimally invasive brain cancer detection using undiluted patient plasma.
PDTM-33. ATRX LOSS CONFERS ENHANCED SENSITIVITY TO COMBINED PARP INHIBITION AND RADIOTHERAPY IN PAEDIATRIC GLIOBLASTOMA MODELS
Authors: Janat Fazal Salom, Lynn Bjerke, Diana Carvalho, Jessica Boult, Alan Mackay, Helen Pemberton, Valeria Molinari, Matthew Clarke, Maria Vinci, Fernando Carceller, Lynley Marshall, Andrew Moore, Angel Montero Carcaboso, Chris Lord, Simon Robinson, Darren Hargrave, Chris Jones
Journal: Neuro-Oncology (2018)

Paediatric high grade glioma (pHGG) are defined by recurrent mutations in H3 histones, as well as frequent alterations in the SWI/SNF chromatin remodelling gene ATRX (α-thalassemia mental retardation X-linked), although the precise role of ATRX in tumorigenesis remains unclear. We sought to explore this using genomic analysis of patient samples, CRISPR-Cas9 engineered isogenic ATRX knockout (KO) cell lines and primary-patient-derived cultures. In combined retrospective and prospective cohorts of pHGG samples, we found ATRX mutations in 95/510 (18.6%) cases (27% hemispheric glioblastoma, 13% diffuse midline glioma), with the majority of truncating mutations found in the ADD domain, and missense mutations almost exclusively in the helicase domain. ATRX mutations commonly co-segregate with H3.3G34 and TP53 mutations, and define a subgroup of patients with a longer overall survival, though with a greater number of somatic mutations and copy number alterations than wild-type cases. CRISPR/Cas9-mediated ATRX KO targeting the ADD domain in TP53 mutant paediatric glioblastoma cells lead to loss of imprinting at the H19 locus in concert with upregulation of a pro-invasive transcriptional programme, though a slower rate of orthotopic tumour growth in vivo. ATRX deficient cells showed an abrogated DNA damage response, with prolonged accumulation of gH2AX foci after irradiation, and an increased dependency on PARP1 through persistent parylation and stalled replication forks. Screening ATRX-deficient isogenics and patient-derived cells against a library of >400 chemotherapeutics and small molecules identified a specific dependency for ATRX loss and sensitivity to distinct PARP inhibitor chemotypes, including catalytic inhibitors (olaparib, rucaparib), and PARP trappers (talazoparib). ATRX deficiency further conferred an enhanced radiosensitization of olaparib in vitro and a prolonged survival of mice treated with combined PARP inhibition and radiotherapy in vivo. These data suggest a synthetic lethality for PARP inhibitors in ATRX-deficient pHGG, and may represent a novel therapeutic strategy for these highly aggressive tumours.
EXTH-43. EFFECTIVE TREATMENT OF CANINE SPONTANEOUS GLIOMAS WITH A CYTOTOXIC COCKTAIL TARGETING IL-13RA2 AND EphA2 RECEPTORS
Authors: John Rossmeisl, Denise Herpai, John Robertson, Peter Dickinson, Stephen Tatter, Waldemar Debinski
Journal: Neuro-Oncology (2018)

Malignant gliomas are incurable tumors and canine spontaneous gliomas are the closest model to human disease. In our Phase I canine clinical trial we are delivering a cocktail targeting IL-13RA2 and EphA2 receptors containing modified bacterial cytotoxins using convection enhanced delivery (CED). Dogs with forebrain gliomas demonstrating IL-13RA2 and EphA2 positivity were included. Using a 3 + 3 dose-escalation design, cohorts were administered 0.05, 0.1, 0.2, 0.4, or 0.8 µg of each cytotoxin/ml of infusate. CED was planned using a shape-fitting algorithm. Cytotoxins were co-administered with gadolinium through reflux preventing catheters to allow intraoperative MRI visualization of infusions. Clinical examinations, adverse events (AE), and volumetric tumor responses were evaluated on days 14, 28, 42, 84, 180, 270, and 365 following treatment. Grades 3, 4, or 5 AE developing within 28 days of infusion were considered dose-limiting toxicities (DLT). Sixteen CED infusions were performed in fourteen dogs with gliomas (astrocytomas, n=5; oligodendrogliomas, n=7; mixed gliomas, n=2). The median target volume was 5.47 cm3 (0.69 to 11.4 cm3). The median target coverage was 77% (38–96%). MRI monitoring facilitated correction of technical complications observed in 5/16 infusions that allowed continued target coverage. The 3-, 6-, 9-, and 12-month progression-free survival rates were 57% (8/14), 38% (5/13), 23% (3/13), and 0% (0/12), respectively. Major tumor responses (52–95% volumetric decreases) associated with clinical improvement have been observed in 5/8 dogs with ≥3 months of follow-up. Tumor necrosis in infused regions was evident in post-mortem examinations in 5 dogs dying of progressive disease. DLT have not been observed. The use of therapeutic planning, intraoperative MRI, and reflux-preventing catheters allowed for safe and effective CED of IL-13RA2 and EphA2 targeted cytotoxins. This study provides evidence of efficacy of the cocktail and warrants further clinical evaluation in humans.
DDIS-28. GENE THERAPY WITH oHSV-1 CD/5-FC EXHIBIT ENHANCED ANTITUMOR EFFICACY IN GLIOMA CELL LINE AND INTRACRANIAL MURINE GLIOMA MODEL
Authors: Fusheng Liu, Sheng Fang, Bo Zhang, Guishan Jin, Ruifang Mi, Mengmeng Zhang, Junwen Zhang
Journal: Neuro-Oncology (2018)

Glioblastoma is one of the most common and lethal types of primary brain tumor. The current standard therapy for GBM consists of surgical followed by combination of radiotherapy and chemotherapy with TMZ. However, median survival following surgery, radiotherapy and TMZ remains dismal. Thus, there is an urgent demand to develop novel, effective therapies for this malignancy. Oncolytic herpes simplex virus 1 (oHSV-1) was one of the first genetically-engineered oncolytic virus. After modifications, oHSV-1 selectively replicated in and killed tumor cells while sparing normal cells. In our study, oHSV was armed with the suicide gene cytosine deaminase (CD) and then we test the efficacy of oHSV-CD/5-FC in glioma cell lines and intracranial murine glioma model. First, we performed MTT assay to inspect the oncolytic activity of oHSV-CD/5-FC in glioma cell lines. U87-Luc cells were implanted stereotactically into the striatum to generate intracranial tumors. 18 days after tumor implantation, mice were randomly divided into groups and intratumorally (IT) injected (same stereotactic coordinates) with oHSV-CD or PBS. 5-FC was administered 3 times intraperitoneally (i.p.). Tumour growth was monitored via bioluminescent imaging using IVIS Spectrum system and magnetic resonance imaging (MRI) once a week after virus injection. We treated four cell lines and two primary cultured GBM cells in a 48-hour MTT assay. All cell lines tested showed sensitivity to oHSV-CD. IC50 ranged from 0.01 (U87 MG) to 0.12 (U251 MG) MOI. And together with 5-FC in all cell lines, IC50 was lower. The results manifested that 5-FC can promote the oncolytic efficacy of oHSV-CD. In U87-Luc tumor model, bioluminescent imaging and MRI results demonstrated majority of injected tumors showed complete regression by treating with oHSV-CD or oHSV-CD together with 5-FC. Median survival was significantly increased compared with vehicle. Taken together, oHSV-CD/5-FC may be a promising therapeutic approach for glioblastoma treatment.
RARE-22. FREQUENT HIGH TUMOR MUTATIONAL BURDEN (TMB) AND PD-L1 EXPRESSION IN PRIMARY CNS LYMPHOMA (PCNSL)
Authors: Ashley Sumrall, Surasak Phuphanich, David Spetzler, Zoran Gatalica, Joanne Xiu, Aaron Provenzano, Andrew J. Brenner, Deepa Subramaniam, Majari Pandey, Amy Heimberger, Santosh Kesari, W Michael Korn, Sandeep Mittal
Journal: Neuro-Oncology (2018)

PD-1 and PD-L1 expression has not been well-described in PCNSL. In one report of 20 PCNSL tumors, PD-1 and PD-L1 expression on tumor cells (TC), tumor-infiltrating lymphocytes (TIL), or tumor-associated macrophages (TAM) was seen in 90% (Clin Neuropathol 2014;PMID:24359606). Another report of 4 patients with relapsed PCNSL showed clinical and radiographic responses to PD-1 blockade (Blood 2017;PMID:28356247). Samples from 36 subjects with large B-cell PCNSL submitted to Caris Life Sciences from 20132018 were tested by NextGen Sequencing (NGS, 592-gene panel [n=30] or 45-gene panel [n=6]) for mutations and gene amplification. RNA sequencing (Archer FusionPlex) was used to detect gene fusions. TMB was calculated using somatic nonsynonymous missense mutation, and microsatellite instability (MSI) was tested by NGS. PD-L1 IHC (SP142) was tested on tumor cells and PD-1 was determined on TIL. High PD-L1 expression (>5% staining) was seen in 14 cases (39%), and low expression (15% staining) was noted in 11 cases (31%). Another 11 cases (30%) showed absent PD-L1 expression. PD-1 expression (>1 cell/high-power field) was seen in 10/12 tumors (83%) without correlation with PD-L1. TMB of 5 mutations per megabase (mt/MB) was seen in all 30 tumors tested with the 592-gene panel, with 27% (n=8) exhibiting high TMB (17 mt/MB). No samples had high level MSI. Overall, 18/30 tumors (60%) had high PD-L1 or high TMB. Mutations in 25 genes were seen; the most frequent were MYD88 (26/30, 87%, all L265P), PIM1 (16/30, 60%), and CD79B (15/30, 50%, all Y196). Among 7 cases tested with RNA-sequencing, one recently reported ETV6-IGH fusion was found (Neuro-Oncology 2018;PMID:29432597). CONCLUSIONS: We found high TMB and PD-L1 expression in PCNSL with no correlation. Nearly two thirds of PCNSL tumors harbor favorable biomarker profiles with anticipated responsiveness to checkpoint inhibitors. Further studies are needed to validate initial results.
IMMU-06. ABSENCE OF THE AMINO ACID STRESS-SENSOR GCN2 REDUCES SUPPRESSIVE EFFECTS OF MDSCs IN GLIOMA
Authors: Aida Rashidi, Jason Miska, Catalina Lee-Chang, Deepak Kanojia, Wojciech Panek, Aurora Lopez-Rosas, Yu Han, Julius Kim, Katarzyna Pituch, Maciej Lesniak
Journal: Neuro-Oncology (2018)

Regulation of nutrient availability is a critical way by which tumors exert their immunosuppressive effects on the host. The glioblastoma microenvironment, in particular, is enriched in expression of indoleamine 2,3- dioxygenase 1 (IDO1), which depletes tryptophan from the microenvironment. Upon depletion of tryptophan, the amino acid stress kinase, general control non-derepressible 2 (GCN2), inhibits general protein synthesis, and upregulates a number of genes to promote the cellular survival. In this study, we explored the effects of a deficiency of the GCN2 pathway on infiltrating immune cells in the context of the glioma. Interestingly after GL-261 (Glioma mouse model cell line) injections in GCN2 knock out (KO), and wild type (WT) mice, GCN2 KO mice survived significantly (pvalue:0.0066) longer compared to WT mice. In-vivo flow cytometric analyses of these mice, showed significant reduction in CD45hiCD11b+ (myeloid cell marker) and Ly6C (monocytic MDSC marker) population in GCN2 KO mice. To study the mechanisms responsible for this, we generated in-vitro bone-marrow-derived MDSCs from both WT and GCN2KO mice. Surprisingly, the in-vitro T-cell suppressive effects of GCN2 KO MDSCs were significantly attenuated, with a decrease in arginase-1 (Arg-1) expression as a potential mechanism for this observation. To validate this phenomena in-vivo, we injected GCN2 KO and WT mice with GL-261 tumor cells, and after 18 days post tumor injection, we isolated Gr-1 (pan-MDSC marker) positive cells from tumor bearing brains, and checked for Arg-1 level by RNA and protein. Our data, both by protein and RNA demonstrated significant reduction in Arg-1 levels. Importantly, ex-vivo isolated Gr-1 myeloid cells from tumor bearing brain of GCN2 KO and WT mice shows dramatically reduced suppressive capabilities. In conclusion, our data demonstrate the importance of GCN2 pathway on MDSC functionality, and provide insight on how amino acid sensing enzymes may regulate immunity in glioblastoma.