tbuckley/cabot-search huggingface dataset:
PDTM-07. DEFINING THE MECHANISMS UNDERLYING NF1 OPTIC GLIOMA PENETRANCE
Authors: Nicole Brossier, Olivia Cobb, David Gutmann
Journal: Neuro-Oncology (2019)

Abstract While most children develop cancer without a clear etiology, some pediatric cancers arise in the context of tumor predisposition syndromes, typically caused by germline mutations in genes that regulate cell growth. The most common of these syndromes, Neurofibromatosis type 1 (NF1), affects ~1:3,000 individuals worldwide, 15% of whom will develop low-grade tumors of the optic pathway (optic pathway gliomas; OPGs). However, it is currently unclear which children with NF1 will develop an OPG, making risk assessment for each individual child difficult. Recent evidence suggests that the specific NF1 germline mutation that each child is born with may be one factor that modulates tumor penetrance. To address the hypothesis that specific germline NF1 gene mutations differentially increase the risk of optic glioma formation through cell-intrinsic effects on the tumor cell of origin, we designed a series of studies to examine the impact of different NF1 germline gene mutations on neuroglial progenitor cell populations in the developing brain. We first defined the putative cells of origin – neuroglial progenitor cells within the third ventricular zone (TVZ) – over normal mouse brain development using Nestin-CFPnuc reporter mice. Three cell populations were identified, and these populations display distinct spatial localizations and are dynamic over the course of late embryonic and early postnatal development. Functional differences were identified between these populations in vitro (e.g., differential clonogenic incidence and proliferation), and additional differences were identified by RNA sequencing. After characterizing these populations, we evaluated their spatiotemporal dynamics in mice genetically engineered to harbor different NF1 patient-derived germline Nf1 gene mutations. Interestingly, some, but not all, Nf1 gene mutations resulted in increased GFAP+ progenitor content and progenitor proliferation. Taken together, these findings provide early experimental evidence for mutational specificity in specific putative brain tumor cells of origin relevant to glioma penetrance.
Ivermectin use in children below 15 kg: potential benefits for onchocerciasis and scabies elimination programmes
Authors: R. Colebunders, S.T. Wafula, A. Hotterbeekx, J. N. Siewe‐Fodjo
Journal: British Journal of Dermatology (2019)

Linked Article: Levy et al. Br J Dermatol 2020; 182:1003–6.
QOLP-35. OUTCOMES AND CORRELATIONS BETWEEN LEGACY QUALITY OF LIFE MEASURES (EORTC-C30/EORTC-BN20) AND THE ELECTRONIC QUALITY OF LIFE MEASURING SYSTEM NIH-PROMIS IN GLIOBLASTOMA PATIENTS
Authors: Tobias Walbert, Lonni Schultz, James Snyder, Aarushi Suneja
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Health-related quality of life (QoL) and patient reported outcomes are essential to guide patient-care. The NIH sponsored electronic Patient-Reported Outcomes Measurement Information System (PROMIS) is well established in multiple cancers but not in Glioblastoma (GBM). The aim of this study was to analyze the association of the PROMIS measures with the European Organization for Research and Treatment of Cancer core instrument (EORTC-QLQ-C30) and the brain tumor specific EORTC QLQ-BN20 questionnaire (EORTC-BN20) in GBM patients. METHODS Newly diagnosed patients with GBM were enrolled prospectively to assess association between both tools. The PROMIS modules were selected to reflect the quality of life domains assessed in the EORTC- QLQ-C30 and EORTC-BN20 questionnaires. Pearson’s correlation coefficients were computed between the PROMIS and EORTC-C30/ EORTC-BN20 measures. Due to multiple responses over time, the p-values for the correlation coefficients were adjusted. Because of the large number of correlations computed and many with p-values less than 0.05, the magnitude of the correlation was considered. Correlations greater than 0.5 or less than -0.5 were consider to be “strong” associations, while correlations between 0.3 and 0.499 (or -0.3 and -0.499) were consider to be “moderate”. RESULTS 43 patients with 124 PROMIS/EORTC responses were included in this analysis. The PROMIS measures had strong associations with the QoL functioning and fatigue measures from the EORTC-C30 and future uncertainty, communication deficit, motor dysfunction, social satisfaction and drowsiness from the EORTC-BN20 (all p&lt; 0.001 and correlation &gt;0.5). CONCLUSIONS There are strong and moderate correlations in the majority of PROMIS assessments and the EORTC tools. The PROMIS toolkit may be used to assess core features of the EORTC surveys. GI symptoms, seizures and itchy skin do not correlate. Given the prior documented shorter assessment time, the PROMIS toolkit may be a feasible alternative to established legacy tools to assess QoL in GBM patients.
GENE-48. ANALYSIS OF HUMAN BRAIN TISSUE TRANSCRIPTOME TO IDENTIFY RISK GENES AND ALTERED MOLECULAR PATHWAYS IN GLIOMA-RELATED SEIZURES
Authors: Anteneh Feyissa, Anna Carrano, Xue Wang, Mariet Allen, Nilufer Ertekin-Taner, Steven Rosenfeld, Hugo Guerrero-Cazares, Alfredo Quinones-Hinojosa
Journal: Neuro-Oncology (2019)

Abstract OBJECTIVE Our goal is to identify new pathways perturbed in and which may lead to GRS. METHODS We collected brain transcriptome levels from healthy controls (n=5), patients with GRS (n=9), glioma without seizures (non-GRS, n=8), and idiopathic temporal lobe epilepsy (iTLE, n=7) using Illumina-based poly-A capture high-throughput RNA sequencing approach. Differential gene expression analysis was conducted to ascertain expression differences between the four groups. We identified molecular pathways enriched for differentially expressed genes (DEG) using Ingenuity Pathway Analysis. DEGs were defined as those with log2 fold change ≥ 2 and q-value &lt; 0.01 when compared to GRS. RESULTS Principal component analysis revealed that diagnostic grouping was the main determinant of the transcriptome variance. We identified 212 DEGs in the GRS vs. non-GRS analysis. Among these, 108 genes were up-regulated and 104 genes were down-regulated. Among the genes that were down‐regulated, there was significant enrichment for those involved in acute phase response signaling and immune cell trafficking (e.g. H19, BMP5, CXCL8). Compared to iTLE samples, there were 1015 DEGs in the GRS samples. Among these 877 genes were up-regulated and 138 genes were down-regulated. There was significant enrichment for genes involved in cell-to-cell signaling among those that were either uniquely up‐regulated (e.g. NRK, RGS10, SLC4A4, and SELPLG) or down‐regulated in the GRS samples (e.g. SLC9A3 –Na+/H+ exchanger; SLC5A5-sodium-glucose co-transporter family). Further, two of the most down-regulated genes in samples with GRS, SCLC17A6- vesicular glutamate transporter 2 and FOSB, have previously been shown to be involved in glutamatergic transmission. CONCLUSIONS Our findings suggest that inflammation-related processes and alterations in cell-to cell signaling may underlie the pathogenesis of GRS. Our results also provide support for perturbations in glutamatergic transmission in GRS. Our findings require replication in larger human cohorts and functional experiments to explore the function of the genes perturbed in GRS.
Phase 1/2 Study of AUTO3 the First Bicistronic Chimeric Antigen Receptor (CAR) Targeting CD19 and CD22 Followed By an Anti-PD1 in Patients with Relapsed/Refractory (r/r) Diffuse Large B Cell Lymphoma (DLBCL): Results of Cohort 1 and 2 of the Alexander Study
Authors: Kirit M. Ardeshna, Maria A V Marzolini, Jane Norman, Muhammad Al-Hajj, Simon Thomas, Jim Faulkner, Ekaterini Kotsopoulou, Martin Pule, Vijay G R Peddareddigari, Nushmia Z Khokhar, Maud Jonnaert, Robert Chen, Wendy Osborne
Journal: Blood (2019)
CBMT-34. MODULATING DIETARY TRYPTOPHAN OR GUT MICROBIOTA LEVELS DOES NOT IMPROVE THE EFFICACY OF COMBINED TREATMENT WITH RADIATION, ANTI-PD-1 mAb, AND AN IDO1 ENZYME INHIBITOR IN A MODEL OF GLIOBLASTOMA
Authors: Erik Ladomersky, Lijie Zhai, Kristen Lauing, Jun Qian, April Bell, Sebastian Otto-Meyer, Rohan Savoor, Derek Wainwright
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION Immunotherapy has failed to improve glioblastoma (GBM) patient survival in all phase III clinical trials to-date. We recently discovered that a combination immunotherapeutic approach that simultaneously administers radiation (RT), anti-PD-1 mAb, and an IDO1 enzyme inhibitor resulted in long-term survival of ~40% of mice intracranially-engrafted (i.c.) with syngeneic GBM (Ladomersky et al., 2018; CCR). In the same study we discovered that the survival benefit depended on the inhibitor of IDO1 in non-GBM cells. Our current study further interrogates the role of non-GBM cell IDO1 and its role in the brain tumor microenvironment. METHODS Mice were engrafted with 2×105 GL261 cells and treated at 14 days post-intracranial injection (i.c.) with RT and/or anti-PD-1 mAb, followed by sampling tissue at 1- and 7-days post treatment. Questioning whether dietary supplementation of Trp would overcome the immunosuppressive activity of the Trp metabolic enzyme, IDO1, mice were placed on ad libitum dietary formulations containing 0–500% normal daily intake. Since Trp is only taken in through the diet, and since bacteria also metabolize Trp, we questioned the role of the gut microbiome on immunotherapy of GBM by injecting mice with an antibiotic cocktail beginning 4 weeks prior to i.c.-injection. RESULTS Both RT and anti-PD-1 treatment increase IDO1 expression in the GBM-draining cervical lymph nodes at day 1 post-ic. (P&lt; 0.001). Mice receiving normal (100%) dietary Trp, but no other supplementation levels, achieve a long-term survival benefit (P&lt; 0.001). Unexpectedly, the depletion of gut microbiota has no effect on therapeutic efficacy (P=0.4808). CONCLUSION These data suggest that although both systemic and tissue-selective alterations in Trp metabolism occur after RT and anti-PD-1 therapy, modulating dietary Trp levels or gut microbiota composition does not alter treatment efficacy against GBM.
CMET-32. DNA METHYLATION ALTERATIONS IN LUNG ADENOCARCINOMAS THAT DEVELOP BRAIN METASTASES
Authors: Jeffrey Zuccato, Yasin Mamatjan, Kenneth Aldape, Gelareh Zadeh
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION The development of brain metastases from primary cancer profoundly impacts patient prognosis. Metastases are the most common adult brain tumor with up to one quarter of lung cancers developing metastases and median overall survival after metastasis being one year. Clinical factors do not reliably predict brain metastasis development and over 90% are identified after symptoms develop. DNA methylation signatures predict outcomes in other cancers and so identifying signatures that predict metastasis development may allow for treatment strategies that prevent development in high risk patients. METHODS Whole genome DNA-methylation profiling was undertaken on N=124 lung adenocarcinoma patients after bisulfite conversion of DNA from formalin-fixed paraffin-embedded tissue. In a randomly selected 70% training cohort, the most differentially methylated CpG sites between patients developing and not developing brain metastases were identified with p&lt; 0.05. A generalized boosted regression model built on these selected features output brain metastasis risk scores for patients in the independent 30% testing cohort. RESULTS Brain metastases developed in 49/124 (39.5%) of patients and 2.3K CpG sites were significantly differentially methylated between patients developing and not developing metastases. Methylation-based brain metastasis risk scores predicted time to brain metastasis in a univariate cox regression model (HR=3.2, 95% CI 1.1–9.4, p=0.03). A corresponding area under the receiver operating characteristic curve at 52 months was 0.64. A multivariate cox analysis including tumor size and nodal status, representing the non-metastatic components of cancer stage, identified methylation score as the only independent predictor of brain metastasis (HR=4.3, 95%CI 1.1–17, p=0.038). CONCLUSIONS DNA methylation signatures in lung adenocarcinoma predict brain metastasis development independent of stage components, which classically predict patient outcome in cancer. Future work developing a comprehensive nomogram utilizing methylation scores together with other clinical factors to determine patient specific risk values may aid in treatment decisions and patient prognosis counselling.
EPID-32. IS THERE ANY EVIDENCE OF REPORTING AND CITATION BIAS AMONG COMPLETED PHASE III INTERVENTIONAL BRAIN TUMOR TRIALS?
Authors: Appaji Rayi, Iyad Alnahhas, Rachel Smith, Pierre Giglio, Vinay Puduvalli
Journal: Neuro-Oncology (2019)

Abstract OBJECTIVE Reporting and citation bias based on positive versus negative outcome among completed phase III interventional brain tumor trials (IBTTs) have not been previously reported. Thus, we aimed to assess the evidence. METHODS Clinicaltrials.gov was used to obtain all phase III IBTTs completed prior to December 31st 2016. Trials closed due to poor accrual or non-phase III were excluded. Data about the funding source, type of intervention, conducted at U.S or Non-U.S locations, patients enrolled, primary completion date, time to dissemination of results in months (either reported on clinicaltrials.gov or published in a journal), citations per year (from web of science) and outcome (positive or neutral/negative) were abstracted. Median time to dissemination was estimated using Kaplan-Meier estimates and a log rank test for statistical significance. The number of citations per year for positive and negative/neutral studies was compared using a t-test. RESULTS 65 studies were analyzed. The median time from primary completion to dissemination of results for trials with a positive outcome was 20 months (n = 20; 95% CI: 12–31) compared to 30 months for trials with a negative outcome (n=35; 95 % CI: 22 – 37) (p = 0.095). The average number of citations per year for trials with a positive outcome is 62.4 (n = 21; range 1.1 – 614.8) compared to 25.0 for trials with a negative outcome (n=35; range 0.14 - 158.8) (p = 0.213). There was no significant difference in time to dissemination based on the funding source, type of intervention or the location where the trial was conducted. CONCLUSION Positive phase III IBTTs results are disseminated earlier and are cited more frequently compared to negative trials. However, there is no statistically significant evidence of reporting or citation bias.
INNV-42. VENOUS THROMBOEMBOLISM RISK ASSESSMENT IN PATIENTS WITH GLIOMA
Authors: Dusten Unruh, Jonathan Lamano, Qazi Haider, Jonathon Judkins, Margaret Schwartz, Yuping Li, Kathleen McCortney, Christina Amidei, Denise Scholtens, Craig Horbinski
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Venous thromboembolism (VTE) is a debilitating and life-threating condition that is common in patients with cancer, especially glioma. Antithrombotic prophylaxis is controversial in glioma patients because of possible intracerebral hemorrhage. Effective VTE prediction models exist for patients with other cancers, but not glioma. Our prior publications suggested a protective role of IDH1 mutations (IDHmut) against VTE, as well as a positive association between elevated circulating Tissue Factor (TF), a procoagulant secreted by cancers, and VTE in glioma patients. Others have recently found a correlation between podoplanin, a platelet activator, and tumor-associated VTE, but this has not been proven in gliomas. Our objective is to develop a multidimensional VTE prediction tool to improve glioma patient care, incorporating clinical, blood-based, histologic, and molecular markers. METHODS The Northwestern University Nervous System Tumor Bank provided preoperative arterial blood, tumor tissue, and clinical-pathologic data from 265 grade II-IV glioma patients over a 3-year interval. Molecular profiling was done by GlioSeq NGS. RESULTS Seventy-seven out of 265 grade II-IV glioma patients (29%) experienced VTE during their disease course. VTE was itself a negative prognostic marker for median overall survival (18 vs. 54 months, P&lt; 0.001). Positive risk factors for VTE included advanced patient age, high body mass index, high tumor grade, prior history of VTE, coronary artery disease, hyperlipidemia, hypertension, and elevated circulating TF activity. While tumor expression of podoplanin positively correlated with VTE, circulating podoplanin did not. Among molecular markers, only IDHmut correlated with VTE risk, and it was associated with greatly reduced risk (OR=0.28; 95% CI=0.12–0.64, P=0.001). CONCLUSIONS This study identified multiple risk factors for glioma-associated VTE. Using these data, we are developing a multivariable prediction calculator that will improve patient care by identifying patients who would benefit most from prophylactic anticoagulation.
FA Gene Carrier Status Predisposes to Myeloid Neoplasms and Bone Marrow Failure in Adults
Authors: Jibran Durrani, Hassan Awada, Wenyi Shen, Cassandra M Kerr, Vera Adema, Sunisa Kongkiatkamon, Ashwin Kishtagari, Samuel Li, Yasunobu Nagata, Sanghee Hong, Aziz Nazha, Bhumika J. Patel, Yogenthiran Saunthararajah, Hetty E. Carraway, Valeria Visconte, Seth J. Corey, Mikkael A. Sekeres, Thomas Laframboise, Jaroslaw P. Maciejewski
Journal: Blood (2019)
Left Atrial Enlargement Could Be Detected on Extended Computed Tomography Angiography Within Initial Stroke Assessment
Authors: Stoyan Popkirov
Journal: JAMA Neurology (2019)

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
Efficacy of Chemotherapy, Phd-Inhibitor Molidustat or BRD4 Inhibitor JQ1 in Combination with Targeted Inhibition of Mutated IDH1 in Human AML In Vivo
Authors: Anuhar Chaturvedi, Charu Gupta, Stefan Kaulfuss, Basem Othman, Kerstin Görlich, Renate Schottmann, Olaf Panknin, Markus Wagner, Arnold Ganser, Michael Jeffers, Andrea Haegebarth, Michael Heuser
Journal: Blood (2019)
Identification of a Chromatin-Splicing Mutational Signature to Define Secondary Acute Myeloid Leukemia: A Report from the Northern Italy Leukemia Group (NILG) Prospective Trial 02/06
Authors: Chiara Caprioli, Federico Lussana, Silvia Salmoiraghi, Roberta Cavagna, Ksenija Buklijas, Lara Elidi, Pamela Zanghì, Anna Michelato, Federica Delaini, Elena Oldani, Dario Ferrero, Ernesta Audisio, Filippo Marmont, Elisabetta Terruzzi, Lorella De Paoli, Chiara Cattaneo, Erika Borlenghi, Irene Cavattoni, Monica Tajana, Anna Maria Scattolin, Daniele Giovanni Mattei, Paolo Corradini, Leonardo Campiotti, Fabio Ciceri, Massimo Bernardi, Elisabetta Todisco, Agostino Cortelezzi, Sergio Cortelazzo, Giacomo Gianfaldoni, Alberto Bosi, Brunangelo Falini, Tamara Intermesoli, Chiara Pavoni, Renato Bassan, Orietta Spinelli, Alessandro Rambaldi
Journal: Blood (2019)
Update on the Management of Constipation
Authors: Arnold Wald
Journal: JAMA (2019)

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 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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
RDNA-07. INCREASING EXTENT OF ABLATION – A SENOLYTIC APPROACH TO PROMOTE APOPTOSIS OF LATENT GLIOBLASTOMA FOLLOWING CHEMORADIATION
Authors: Masum Rahman, Ian Olson, Zhi Tang, Karishma Rajani, Lucas Carlstrom, Terry Burns
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Despite best current therapies, median survival for glioblastoma remains little more than a year. There remains an urgent need for improved treatment strategies. Current therapies, including radiation and temozolomide, are known to induce senescence in tumor cells. Advances in aging research have identified drugs with “senolytic” properties to kill senescent cells. This work tests the hypothesis that induction of senescence pathways following radiation can provide a window of opportunity to eliminate residual glioblastoma cells using drugs that block senescent cell-associated pathways (SCAPs). METHODS Human glioblastoma cells were radiated with 10, 15, or 20 Gy and maintained in culture for 3 to 4 weeks to facilitate maturation of a senescent phenotype. Given existence of multiple SCAPs, we evaluated the IC50 for several senolytic candidates including Dasatinib, Quercetin, Fisetin, AMG-232, Onalespib, A1331852, and Navitoclax in radiated vs non-radiated cells. RESULTS Among these, the Bcl-XL inhibitors A1331852 and Navitoclax both selectively killed multiple lines of radiated, senescent tumor cells at lower concentrations as compared to unirradiated, non-senescent tumor cells. Across multiple GBM cell line, the average IC50 for senescent cells was 12.88 nM (95%CI= 9.068–18.58 nM), as compared to the IC50 of non-senescent cells of 103.2 nM (95%CI= 74.24–143.9 nM; p&lt; 0.005). Such differential sensitivity to Bcl-XL inhibition after radiation was not observed in the non-GBM control cells evaluated to date. CONCLUSION Our findings suggest that blocking the anti-apoptotic pathway Bcl-XL in GBM cells rendered at least transiently senescent following radiation may provide an avenue to selectively ablate residual glioblastoma cells following radiation. Our data provide proof of principle that senolytic therapy may represent a previously untapped window of opportunity to increase extent of tumor ablation following completion of standard cytotoxic therapies.
Abstract 9944: Effects of Smoking Cessation on the Intestinal Microbiota
Authors: Marcus G Sublette, Tzu-wen L Cross, Claudia E Korcarz, Kristin M Hansen, Madeline K Oguss, Federico Rey, James H Stein
Journal: Circulation (2019)

Background: Cigarette smoking and cessation have a wide range of effects on metabolism, oxidant stress, and inflammation, but their effects on the human intestinal microbiota are not well known. We...
Development of a Genetically-Engineered Allogeneic Anti-CD38 T Cell Therapy Utilizing a Novel Antigen Receptor Structure
Authors: Bei Bei Ding, John Dixon Gray, Irina Krapf, Yanliang Zhang, Nan Zhang, Qingdong Mark Deng, Angel Wei, Robert D. Knight, Jerome B. Zeldis, Gunnar F. Kaufmann, Henry Ji, Wenzhong Guo
Journal: Blood (2019)