tbuckley/cabot-search huggingface dataset:
MBCL-11. CONCURRENT IDH1 AND SMARCB1 MUTATIONS IN A PEDIATRIC MEDULLOBLASTOMA: A CASE REPORT
Authors: Moatasem El-Ayadi, Doron Merkler, Kristof Egervari, Thomas Alexander Mckee, Fabienne Gumy-Pause, David Capper, Torsten Pietsch, Marc Ansari, André O von Bueren
Journal: Neuro-Oncology (2018)

Isocitrate Dehydrogenase-1 (IDH1) is a driver gene in several cancers including brain tumors such as low-grade and high-grade gliomas. Mutations of SMARCB1 were described in atypical teratoid rhabdoid tumors and to date have not been associated with the pathogenesis of medulloblastoma. We report concurrent IDH1 and SMARCB1 mutations in a medulloblastoma patient. We searched the catalogue of somatic mutations in cancer (COSMIC) database and other mutation databases and -to our knowledge- this is the first reported case of medulloblastoma harboring both mutations together. Our patient is a thirteen-year-old male presenting with headache and vomiting at diagnosis. MRI revealed left cerebellar expansive lesion with no evidence of metastasis. A histopathological diagnosis of desmoplastic medulloblastoma was made after complete resection of the tumor. Nuclear INI-1 staining was preserved. FISH analysis showed no evidence of NMYC or CMYC amplification. Next generation sequencing of a panel of 400 genes revealed heterozygous somatic IDH1(p.R132C), SMARCB1(p.R201Q), and CDH11(p.L625T) mutations. Analysis of the tumor using the Illumina Human Methylation 850 (850k) array revealed highest resemblance to the methylation class medulloblastoma, subclass SHH A with no relevant copy number aberrations. The patient was treated according to the HIT-SIOP PNET 4 protocol. He is in complete remission 1.5 years after diagnosis. In conclusion, increasing use of high throughput sequencing will certainly increase the frequency with which rare mutations or mutation combinations are identified. The exact frequency of this mutation combination and whether it has any particular therapeutic implications or prognostic relevance requires further investigation.
Estimating and Interpreting the Overall Survival Benefit of Checkpoint Inhibitors via Meta-analysis—Reply
Authors: Val Gebski, James Chih-Hsin Yang, Chee Khoon Lee
Journal: JAMA Oncology (2018)

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Association of Chronic Opioid Use With Presidential Voting Patterns in US Counties in 2016
Authors: James S. Goodwin, Yong-Fang Kuo, David Brown, David Juurlink, Mukaila Raji
Journal: JAMA Network Open (2018)

<h3>Importance</h3> The causes of the opioid epidemic are incompletely understood. <h3>Objective</h3> To explore the overlap between the geographic distribution of US counties with high opioid use and the vote for the Republican candidate in the 2016 presidential election. <h3>Design, Setting, and Participants</h3> A cross-sectional analysis to explore the extent to which individual- and county-level demographic and economic measures explain the association of opioid use with the 2016 presidential vote at the county level, using rate of prescriptions for at least a 90-day supply of opioids in 2015. Medicare Part D enrollees (N = 3 764 361) constituting a 20% national sample were included. <h3>Main Outcomes and Measures</h3> Chronic opioid use was measured by county rate of receiving a 90-day or greater supply of opioids prescribed in 2015. <h3>Results</h3> Of the 3 764 361 Medicare Part D enrollees in the 20% sample, 679 314 (18.0%) were younger than 65 years, 2 283 007 (60.6%) were female, 3 053 688 (81.1%) were non-Hispanic white, 351 985 (9.3%) were non-Hispanic black, and 198 778 (5.3%) were Hispanic. In a multilevel analysis including county and enrollee, the county of residence explained 9.2% of an enrollee's odds of receiving prolonged opioids after adjusting for individual enrollee characteristics. The correlation between a county's Republican presidential vote and the adjusted rate of Medicare Part D recipients receiving prescriptions for prolonged opioid use was 0.42 (<i>P</i> &lt; .001). In the 693 counties with adjusted rates of opioid prescription significantly higher than the mean county rate, the mean (SE) Republican presidential vote was 59.96% (1.73%), vs 38.67% (1.15%) in the 638 counties with significantly lower rates. Adjusting for county-level socioeconomic measures in linear regression models explained approximately two-thirds of the association of opioid rates and presidential voting rates. <h3>Conclusions and Relevance</h3> Support for the Republican candidate in the 2016 election is a marker for physical conditions, economic circumstances, and cultural forces associated with opioid use. The commonly used socioeconomic indicators do not totally capture all of those forces.
Transplanted Mesenchymal Stem Cells Reduce Autophagic Flux in Infarcted Hearts via the Exosomal Transfer of miR-125b
Authors: Changchen Xiao, Kan Wang, Yinchuan Xu, Hengxun Hu, Na Zhang, Yingchao Wang, Zhiwei Zhong, Jing Zhao, Qingju Li, Dan Zhu, Changle Ke, Shuhan Zhong, Xianpeng Wu, Hong Yu, Wei Zhu, Jinghai Chen, Jianyi Zhang, Jian’an Wang, Xinyang Hu
Journal: Circulation Research (2018)

Rationale : Autophagy can preserve cell viability under conditions of mild ischemic stress by degrading damaged organelles for ATP production, but under conditions of severe ischemia, it can promote cell death and worsen cardiac performance. Mesenchymal stem cells (MSCs) are cardioprotective when tested in animal models of myocardial infarction, but whether these benefits occur through the regulation of autophagy is unknown. Objective: To determine whether transplanted MSCs reduce the rate of autophagic degradation (autophagic flux) in infarcted hearts and if so, to characterize the mechanisms involved. Methods and Results: Treatment with transplanted MSCs improved cardiac function and infarct size while reducing apoptosis and measures of autophagic flux (bafilomycin A1-induced LC3-II [microtubule-associated protein 1 light chain 3] accumulation and autophagosome/autolysosome prevalence) in infarcted mouse hearts. In hypoxia and serum deprivation–cultured neonatal mouse cardiomyocytes, autophagic flux and cell death, as well as p53-Bnip3 (B-cell lymphoma 2–interacting protein 3) signaling, declined when the cells were cultured with MSCs or MSC-secreted exosomes (MSC-exo), but the changes associated with MSC-exo were largely abolished by pretreatment with the exosomal inhibitor GW4869. Furthermore, a mimic of the exosomal oligonucleotide miR-125b reduced, whereas an anti-miR-125b oligonucleotide increased, autophagic flux and cell death, via modulating p53-Bnip3 signaling in hypoxia and serum deprivation–cultured neonatal mouse cardiomyocytes. In the in vivo mouse myocardial infarction model, MSC-exo, but not the exosomes obtained from MSCs pretreated with the anti-miR-125b oligonucleotide (MSC-exo anti-miR-125b ), recapitulated the same results as the in vitro experiments. Moreover, measurements of infarct size and cardiac function were significantly better in groups that were treated with MSC-exo than the MSC-exo anti-miR-125b group. Conclusions: The beneficial effects offered by MSC transplantation after myocardial infarction are at least partially because of improved autophagic flux through excreted exosome containing mainly miR-125b-5p.
Drugs policy will not change as long as UK government refuses to acknowledge the need for change
Authors: Roy Robertson, Andrew McAuley, John Macleod, John Strang, Alison McCallum
Journal: BMJ (2018)

The Royal College of Physicians calls for drug policy to shift from criminal justice to public health,1 but the recent response from the Home Office to the government’s own advisory committee refuses to contemplate the introduction of safe injecting environments for the most damaging drug use.2 As well as relying only on criminal justice information, and without acknowledging the …
Safety and tolerability of a single administration of AR-301, a human monoclonal antibody, in ICU patients with severe pneumonia caused by Staphylococcus aureus: first-in-human trial
Authors: Bruno François, Emmanuelle Mercier, Céline Gonzalez, Karim Asehnoune, Saad Nseir, Maud Fiancette, Arnaud Desachy, Gaëtan Plantefève, Ferhat Meziani, Paul-André de Lame, Pierre-François Laterre
Journal: Intensive Care Medicine (2018)
A novel collaborative approach to endoscopic double bypass in concomitant gastric outlet and biliary obstruction
Authors: Ahmad Hashim, Corey Miller, Ali Bessissow, David Valenti, Alan Barkun, Jeffrey Barkun, Yen-I Chen
Journal: Endoscopy (2018)

Endoscopic ultrasound (EUS)-guided double bypass (EUS-DB) is a novel technique in the management of concomitant biliary and gastric outlet obstruction [1] [2] [3]. It involves the creation of both an EUS-guided gastroenterostomy and a hepatogastrostomy. We describe the first reported case in the literature (with video) of EUS-DB performed in collaboration with interventional radiology.
Response to: ‘Drug-induced lupus erythematosus following immunotherapy with anti-programmed death-(ligand) 1’ by Michot et al and ‘Checkpoint inhibitor-associated immune arthritis’ by Arnaud <i>et al</i>
Authors: Marie Kostine, Christophe Richez, Thierry Schaeverbeke
Journal: Annals of the Rheumatic Diseases (2018)

We thank Michot et al for their comments1 on our original paper entitled ‘Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer-clinical aspects and relationship with tumour response: a single-centre prospective cohort study’.2 We also appreciate the information added in the letter by Arnaud et al also reporting data from the WHO database.3

By adding this series of programmed death-(ligand) 1 (PD-(L)1)-induced lupus erythematosus, the authors contribute to our better knowledge of the wide spectrum of immune-related adverse events (irAEs).

Indeed, since PD-1-deficient mice spontaneously developed lupus-like autoimmune diseases with arthritis and glomerulonephritis,4 such clinical phenotypes could be expected in patients treated with anti PD-(L)1 agents. However, only a few cases of lupus-like cutaneous reaction have yet been reported with anti-PD-1 agents and, more surprisingly, one lupus-like …
Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials
Authors: Vlado Perkovic, Dick de Zeeuw, Kenneth W Mahaffey, Greg Fulcher, Ngozi Erondu, Wayne Shaw, Terrance D Barrett, Michele Weidner-Wells, Hsiaowei Deng, David R Matthews, Bruce Neal
Journal: The Lancet Diabetes & Endocrinology (2018)
EMBR-13. FAVORABLE OUTCOMES IN CHILDREN WITH PINEOBLASTOMA TREATED WITH RISK-ADAPTED CRANIOSPINAL IRRADIATION AND CHEMOTHERAPY: RESULTS AND MOLECULAR ANALYSIS FROM THE SJYC07 AND SJMB03 TRIALS
Authors: Anthony Liu, Brent Orr, Tong Lin, Eric Bouffet, Sridharan Gururangan, John Crawford, Stewart J Kellie, Murali Chintagumpala, Michael Fisher, Daniel C Bowers, Tim Hassall, David Ellison, Giles Robinson, Amar Gajjar
Journal: Neuro-Oncology (2018)

Pineoblastoma (PB) is an aggressive embryonal tumor that has been uniformly treated with high-dose craniospinal irradiation (CSI). Herein, we describe patients diagnosed with PB treated on 2 multi-center, prospective trials with risk-adapted radiation regimens. Patients <3yr received chemotherapy with/without focal irradiation (SJYC07). Patients ≥3yr received risk-adapted CSI (23.4Gy for localized disease, 36–39.6Gy for metastatic) and chemotherapy (SJMB03). DNA methylation was performed using Infinium MethylationEPIC BeadChip and profiled on DKFZ molecularneuropathology2.0 classifier. 40 patients were enrolled (SJMB03=28; SJYC07=12) with 6.07yr median age (range: 0.37–20.4) and 3.8yr median follow-up (range: 0.37–13.1). Twenty-two were stratified as high-risk (HR). All 28 SJMB03 patients received CSI; 6 SJYC07 patients received focal RT and 6 were not irradiated. All but one patient received chemotherapy (parental refusal). On SJMB03, 10/11 non-HR patients receiving 23.4Gy CSI survived without progression (5yr-PFS 100%) as compared to 8/17 HR patients (5yr-PFS 56.3 ± 12.4%). On SJYC07, 11/12 progressed (5yr-PFS 8.3 ± 8.0%). 23/40 tumors (58%) were methylation profiled into the following categories: PBgroupB (N=11), PBgroupA(N=2), pineal parenchymal tumor (N=1), choroid plexus tumor (CPT) (subclass pediatric B) (N=1), with 6 samples having calibrated score <0.9 (associated with medulloblastomagroup3=4, CPT=1, PBgroupB=1, no-match=2). All patients with PB-B were aged ≥3yr with 67% (8/12) surviving progression-free. Patients <3yr had PBgroupA/medulloblastoma/CPT and only 14% (1/7) survived progression-free. Non-metastatic PB in children ≥3yr has excellent survival with average-risk medulloblastoma therapy. The poor survival of young children and HR-PB might be explained by underlying molecular heterogeneity, and clustering of pineal tumors with MBgroup3 or CPT warrants further investigation.
Opioid Prescribing for Low Back Pain
Authors: Jennifer F. Waljee, Chad M. Brummett
Journal: JAMA Network Open (2018)

Dora H. Lin, MHS; Christopher M. Jones, PharmD, MPH; Wilson M. Compton, MD, MPE; James Heyward, MPH; Jan L. Losby, PhD, MSW; Irene B. Murimi, PhD, MA; Grant T. Baldwin, PhD, MPH; Jeromie M. Ballreich, PhD, MHS; David A. Thomas, PhD; Mark Bicket, MD; Linda Porter, PhD; Jonothan C. Tierce, CPhil; G. Caleb Alexander, MD, MS
IMMU-12. T-CELL THERAPIES DEMONSTRATE EFFICACY WITHOUT TOXICITY IN IMMUNOCOMPETENT MODELS OF BRAINSTEM TUMORS
Authors: Matt Schuelke, Laura Evgin, Phonphimon Wongthida, Jill Thompson, Tim Kottke, Luis Sanchez-Perez, John Sampson, Richard Vile
Journal: Neuro-Oncology (2018)

Diffuse intrinsic pontine glioma (DIPG) is a pediatric brainstem tumor with a dismal prognosis and no curative treatments. Immunotherapy has been considered as a treatment for these tumors because of its ability to provide specific and sustained tumor killing. By nature, this approach is inflammatory and remains controversial due to the potential for catastrophic inflammatory toxicity in the brainstem. In order to address whether this approach should be considered as a clinical option, we characterized the efficacy/toxicity profile of transgenic and chimeric antigen receptor (CAR) T-cell therapies in the brainstem using immunocompetent, syngeneic mouse models. We first adoptively transferred naïve transgenic T-cells recognizing the model tumor antigens gp100 or ovalbumin to treat established aggressive, transplantable murine tumors in the brainstem. Encouragingly, this therapy significantly extended median survival (16 to 32 days; p<.001) with no signs of therapeutic toxicity. We plan to expand these studies by incorporating hgp100 into a spontaneously-occurring, engineered model of DIPG, followed by transgenic T-cell treatment. Lastly and most clinically-relevant, we have used CAR T-cell therapy to treat B16 melanoma engineered to express EGFRvIII and implanted into the brainstem. This therapy extended median survival from 14 to 30 days (p<.001). We plan to evaluate whether combinatorial approaches using checkpoint inhibitors or oncolytic viruses can further enhance survival. Together these data from immunocompetent mouse models demonstrate that T-cell immunotherapies are well- tolerated and efficacious against tumors located in the brainstem, opening the door for future clinical trials.
EPID-08. THE CURRENT LANDSCAPE OF THERAPEUTIC CLINICAL TRIALS IN PEDIATRIC BRAIN TUMORS: A REVIEW OF CLINICALTRIALS.GOV
Authors: Eugene Hwang, Sandeep Kuril, Joanne Salcido
Journal: Neuro-Oncology (2018)

Despite substantial investment in clinical trials for pediatric brain tumors, significant therapeutic improvements have been slow for most CNS malignancies. In order to better understand the landscape of clinical trial design, execution, and involved investigator/patient populations, we conducted an examination of all trials registered on clinicaltrials.gov. All trials from 2000-2017 were included if involving therapeutic intervention for children (age 0-18yrs) with CNS tumors only. A total of 182 clinical trials were identified and categorized into targeted therapy (n=67,37%), combination chemotherapy with/without radiation (n=48,26%), immunotherapy (n=22,12%), chemotherapy only (n=14,8%), radiation only (n=11,6%) and other therapies which included biologic or various other agents (n=20,11%). They included patients with newly diagnosed (n=73, 40%), recurrent/refractory/progressive (n=83, 45.6 %), combined (n=24,13%) and other (n=2, 1%) disease settings. The majority of the trials were phase 1 (n=81, 40%) or phase 2 (n=88,44%), and enrolled patients with DIPG (n=97,23%), high grade glioma (n=93,22%), medulloblastoma (n=82,19%), ependymoma (n=64,15%), low grade glioma (n=39,9%) and other types of brain tumors (n=49,12%). As of January 5 2018, included trials were completed (n=76,42%), active (not recruiting and recruiting (n=102,56%)), or neither (n=4,2%). Only four trials were withdrawn prior to initiation. Additional parameters and trends will be analyzed for presentation. This overview provides investigators, providers, patients/families, and foundations a summary of pediatric brain tumor clinical trials over the past one and a half decades. It may help to identify areas of relative lack of trial focus or potential areas of improvement for trial collaboration and execution.
TBIO-01. TARGETING TRANSCRIPTIONAL ADDICTION FOR GBM THERAPY THROUGH CDK7 INHIBITION
Authors: Wei Meng, Jiajia Wang, Qifeng Li, Fang Liu, Meng Li, Wenyan Jiang, Li Lin, Xiaomin Dai, Hongxiang Wang, Chenran Zhang, Baocheng Wang, Juxiang Chen, Liye Zhang, Yujie Tang, Jie Ma
Journal: Neuro-Oncology (2018)

GBM remains to be one of the top lethal cancer types for adult to date. Current GBM therapies suffer greatly from the highly heterogeneous and adaptable nature of GBM cells, indicating an urgent need of alternative therapeutic options. In this study we focused on identifying novel epigenetic targeted strategy against GBM that could potentially overcome these problems. A collection of epigenetic modulating small molecules were subjected to anti-GBM screening and the inhibitory effect of identified agent was validated both in vitro and in vivo. Genetic targeting approaches were also used to verify the on-target inhibitory effect of identified agent. Furthermore, the inhibitory mechanism of identified agent was investigated by integrative analyses of drug-treated GBM cells and GBM tumor databases. The covalent CDK7 inhibitor THZ1 was one of the top hits in our screening and its anti-GBM activity was confirmed both in vitro and in vivo. CDK7 inhibition through CRISPR-Cas9orRNA interference also markedly disrupted GBM cell growth. Mechanistically, THZ1 treatment led to profound disruption of gene transcription in GBM cells, preferentially targeting genes associated with super-enhancers. Furthermore, integrative analyses of multiple GBM tumor databases revealed a consistent up regulation of CDK7 in GBM. Higher CDK7 expression is correlated with worse prognosis for both glioma and GBM, and associated with hyper-transcription of numerous oncogenic gene signatures that were dramatically down regulated in THZ1-treated GBM cells. Our study demonstrates targeting CDK7-associated transcriptional addiction could be an effective therapeutic strategy against GBM, especially for overcoming tumor heterogeneity and plasticity issues.
Acute and Repeated Treatment with 5-PAHSA or 9-PAHSA Isomers Does Not Improve Glucose Control in Mice
Authors: Elsa Pflimlin, Maximilian Bielohuby, Marcus Korn, Kristin Breitschopf, Matthias Löhn, Paulus Wohlfart, Anish Konkar, Michael Podeschwa, Felix Bärenz, Anja Pfenninger, Uwe Schwahn, Till Opatz, Marcel Reimann, Stefan Petry, Norbert Tennagels
Journal: Cell Metabolism (2018)
Association of Multifocal Fibromuscular Dysplasia in Elderly Patients With a More Benign Clinical Phenotype
Authors: Imad Bagh, Jeffrey W. Olin, James B. Froehlich, Eva Kline-Rogers, Bruce Gray, Esther S. H. Kim, Aditya Sharma, Ido Weinberg, Bryan J. Wells, Xiaokui Gu, Heather L. Gornik
Journal: JAMA Cardiology (2018)

Fibromuscular dysplasia (FMD) is a nonatherosclerotic arterial disease that predominately affects women and is most commonly diagnosed in middle age. The natural history of FMD among patients diagnosed at an older age is not well understood.To examine the differences in clinical presentation, arterial bed involvement, vascular events, and need for vascular procedures between younger and older patients with FMD.Analysis of baseline data for patients enrolled in the US Registry for FMD as of December 15, 2016, at referral centers participating in the US Registry for FMD. Patients 18 years and older at the time of enrollment and those with only confirmed multifocal (string of beads type) FMD were included. Patients were categorized according to age at the time of diagnosis (≥65 years vs <65 years).Prevalence of specific symptoms, vascular events, and prior vascular procedures at the time of enrollment in the registry.A total of 1016 patients were included in the analysis, of whom, 170 (16.7%) were 65 years or older at the time of diagnosis. Older patients with FMD were more likely to be asymptomatic at the time of diagnosis (4.2% vs 1.4%; P = .02). Headache and pulsatile tinnitus, both common manifestations of FMD, were less common in older patients (40.5% vs 69.1%; P < .001 and 30% vs 44.6%; P < .001, respectively). Extracranial carotid arteries were more commonly involved in patients 65 years or older at time of diagnosis (87% vs 79.4%; P = .03). There was no difference in prevalence of renal artery involvement, number of arterial beds involved, or diagnosis of any aneurysm. Patients 65 years or older were less likely to have had a major vascular event (37.1% vs 46.1%; P = .03) and fewer had undergone a therapeutic vascular procedure (18.5% vs 33.1%; P < .001).In the US Registry for FMD, patients 65 years or older at the time of diagnosis of multifocal FMD were more likely to be asymptomatic, had lower prevalence of major vascular events, and had undergone fewer therapeutic vascular procedures than younger patients. Patients with multifocal FMD diagnosed at an older age may have a more benign phenotype and fewer symptoms.