tbuckley/cabot-search huggingface dataset:
PATH-02. ASSOCIATION OF IDH1 MUTATION WITH HISTOLOGICAL TYPE IN INDONESIAN GLIOMA
Authors: Rusdy Malueka, Ery Dwianingsih, Rachmat Hartanto, Bethadina Dewi, Fitria Fitria, Halwan Bayuangga, Andre Panggabean, Adiguno Wicaksono, Kusumo Dananjoyo, Ismail Setyopranoto, Ahmad Asmedi
Journal: Neuro-Oncology (2018)

Glioma is the most common primary central nervous system (CNS) tumor in adults. One of molecular biomarkers of significant interest for glioma is isocitrate dehydrogenase (IDH) mutation. IDH1 C.395G>A (R132H) mutation are reported to occur in 55–80% of grade II and III oligodendroglioma and astrocytomas. IDH mutations have an important role in many aspects of glioma, including glioma genesis, patients prognosis, and development of therapeutic strategies. However, information on IDH mutations in gliomas is not yet available in Indonesian population. Seventy-four glioma patients in a reference hospital in Yogyakarta, Indonesia who underwent surgery were recruited. Glioma tissues in the form of paraffin tissue blocks or fresh samples were sliced for hematoxylin eosin staining and immunohistochemical examination. Genomic DNA was extracted from the samples and IDH1 mutation status was analyzed by PCR and nucleotide sequencing. IDH1 C.395G>A (R132H) mutations were detected in 16 (21.6%) of the samples. This mutation rate is lower than the rate previously reported in Asian population. This study also found that 17.5% of astrocytic type of gliomas harboring this mutation compared to 45.45 % in other tumor types. This difference is statistically significant (p=0.037). In conclusion, IDH 1 mutation is found less frequently in Indonesian glioma, and is associated with the histological subtypes.
MNGI-30. RADIOLOGIC FEATURES ARE PROGNOSTIC FOR CLINICAL OUTCOMES OF CHORDOID MENINGIOMA
Authors: William Chen, Calixto-Hope Lucas, Joe Baal, Stephen Magill, Ashley Wu, Jared Hara, Olivier Morin, Chetna Gopinath, Steve Braunstein, Nancy Ann Oberheim Bush, Michael McDermott, Arie Perry, David Solomon, Javier Villanueva-Meyer, David Raleigh
Journal: Neuro-Oncology (2018)
IMMU-14. THERAPEUTIC MODULATION OF THE PHAGOCYTIC AXIS SPARKS ANTI-TUMOR CD8 T CELL RESPONSES IN GLIOBLASTOMA
Authors: Christina von Roemeling, Yaqing Qie, Wen Jiang, Yuanxin Chen, Kevin Shih, Xiujie Liu, Joshua Knight, Rong Tian, Charles Chan, Betty Kim
Journal: Neuro-Oncology (2018)

As the most common primary brain tumor in adults, Glioblastoma (GBM) remains a major unmet medical need. With current treatment strategies, the median survival remains approximately 15 months, and recurrence occurs in nearly all cases. In this study we examine a novel role for the DNA-methylating agent temozolomide (TMZ) as an activator of innate immunogenicity in GBM. TMZ-mediated DNA damage promotes calreticulin (CRT) translocation to the plasma membrane of cancer cells where it functions as a driver of phagocytosis. Ancillary blockade of anti-phagocytic signaling through Cluster of Differentiation 47 (CD47) further enhances tumor cell uptake by bone-marrow derived macrophages (BMDM). Together these agents promote maturation of BMDM into antigen presenting cells (APCs), capable of initiating effector T cell responses in vitro. We recapitulate these findings in immune-competent preclinical models of GBM, where combination therapy significantly prolongs survival in a cytotoxic CD8+ T cell dependent manner. The results of this study indicate that phagocytic axis modulation is a novel strategy to reprogram the innate immune microenvironment, shifting the dynamic towards an ‘inflamed’ tumor phenotype. This novel approach to immunotherapy in GBM is highly translational and warrants further investigation in the clinical setting.
Single Doses of Antibody Drug Conjugates (ADCs) Targeted to CD117 or CD45 Have Potent In Vivo Anti-Leukemia Activity and Survival Benefit in Patient Derived AML Models
Authors: Jennifer L Proctor, Sharon L. Hyzy, Hillary L Adams, Melissa L. Brooks, Andrew D Gabros, Sean M McDonough, Lena Kien, Sharon Aslanian, Bradley R Pearse, Rahul Palchaudhuri, Qing Li, Nathan M Kallen, Ganapathy Sarma, Molly A McShea, Danielle Ladwig, Junia Dushime, Rajiv Panwar, Charlotte F McDonagh, Anthony E. Boitano, Michael P. Cooke
Journal: Blood (2018)
Metabolic reprogramming of natural killer cells in obesity limits antitumor responses
Authors: Xavier Michelet, Lydia Dyck, Andrew Hogan, Roisin M. Loftus, Danielle Duquette, Kevin Wei, Semir Beyaz, Ali Tavakkoli, Cathriona Foley, Raymond Donnelly, Cliona O’Farrelly, Mathilde Raverdeau, Ashley Vernon, William Pettee, Donal O’Shea, Barbara S. Nikolajczyk, Kingston H. G. Mills, Michael B. Brenner, David Finlay, Lydia Lynch
Journal: Nature Immunology (2018)
<sup>68</sup> Ga-DOTA-GGNle-CycMSH <sub>hex</sub> targets the melanocortin-1 receptor for melanoma imaging
Authors: Jianquan Yang, Jingli Xu, Rene Gonzalez, Thomas Lindner, Clemens Kratochwil, Yubin Miao
Journal: Science Translational Medicine (2018)

68 Ga-DOTA-GGNle-CycMSH hex , a radiolabeled melanocortin-1 receptor–targeting imaging probe, detects melanoma in first-in-human testing.
Bone Cements: An Additive to PMMA Bone Cement Enables Postimplantation Drug Refilling, Broadens Range of Compatible Antibiotics, and Prolongs Antimicrobial Therapy (Adv. Healthcare Mater. 21/2018)
Authors: Erika L. Cyphert, Greg D. Learn, Sara K. Hurley, Chao‐yi Lu, Horst A. von Recum
Journal: Advanced Healthcare Materials (2018)

Insoluble polymerized cyclodextrin microparticles entrap antibiotics in bone cement. The cement is then implanted into total joint replacements and is used to treat prolonged infections. In article 1800812, Horst A. von Recum and co-workers show that this cyclodextrin-based system has the ability to be refilled with drugs to extend therapy after implantation.
IMMU-03. DEVELOPMENT OF CYTOMEGALOVIRUS (CMV) BASED DNA VACCINES FOR GBM USING THE UNITE PLATFORM
Authors: Amit Adhikari, Ido Weiss, Anthony Marketon, Barbara Toll, Teri Heiland
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) remains an aggressive, deadly disease in brain cancer, with the median survival of 15 months remaining unchanged for decades. Using our investigational UNITE platform, we are developing a DNA vaccine using CMV antigens. The UNITE platform is based, in part, on a lysosomal targeting technology which can result in increased antigen presentation, a balanced T cell response, and subsequent immunologic benefit. The presence of CMV proteins in GBM offers a unique opportunity to specifically target tumor cells, unlike other cancers. This targeting approach, in the vaccination of mRNA transfected autologous dendritic cells, was employed by Drs. John Sampson and Duane Mitchell, at Duke University in a Phase I trial. Additionally, an ongoing phase II trial, run by Dr. Mitchell at University of Florida, is leveraging the same targeting approach. Promising results were observed using pp65 (a CMV structural protein) loaded dendritic cells in the phase I clinical trial (Clinical Cancer Research, 2014, Pg-2684). Our objective to develop the DNA vaccine is to achieve both a lower cost and quick turnaround time by eliminating need to isolate and culture autologous dendritic cells and to explore other ways of vaccine improvement. We have tested CMV antigens with UNITE platform in mice using intradermal injection followed by electroporation and found robust T cell response. We are also developing orthotopic GBM model in syngeneic mice and to closely mimic human GBM where tumor cells express CMV proteins, we have made stable murine glioma cell lines expressing pp65 or pp65 and gB fused with luciferase as reporter. Therapeutic studies are ongoing in the intracranial GBM mouse models. We believe that if successful, DNA vaccines using CMV proteins as targets, either alone or in combination with other therapies, will be a powerful and cost effective treatment to fight this dreadful cancer.
NCMP-02. MULTIPLE SCLEROSIS OUTCOMES AFTER CANCER IMMUNOTHERAPY
Authors: Catherine Garcia, Val Adams, Lowell Anthony, John Villano
Journal: Neuro-Oncology (2018)

Multiple sclerosis as an adverse event of immune checkpoint inhibitors (ICI) is rare and the outcomes remain largely unknown with limited descriptions in the literature. We analyzed the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database, our institutional records, and the literature for pembrolizumab, atezolizumab, nivolumab, ipilimumab, avelumab, and durvalumab two years prior their FDA approval to December 31, 2017, for all cases of newly diagnosed or MS relapse. We identified 14 cases; 11 cases from FAERS, 1 case was identified from our institution, and 2 cases from the literature. The median age was 52.5 years, with 42.8% males and 42.8% females. Indications for ICI included melanoma (6 patients), non-small cell lung carcinoma (2 cases), pleural mesothelioma (1 case), renal cell carcinoma (1 case), colorectal cancer (1 case), and was not reported in 2 cases. Two cases were identified from pembrolizumab use, 6 cases with nivolumab, 1 case with atezolizumab, and 5 cases after ipilimumab use. No cases were reported with the use of avelumab or durvalumab. History of multiple sclerosis was confirmed in 8 cases. Mean time to beginning of symptoms was 29 days (3 cycles). The median time to beginning of symptoms was longer in patients receiving ipilimumab (45 days, 4 cycles). Median time for symptom resolution in all the patients was 2 months. All cases required hospitalization, further treatment, and close follow up. Two patients died after starting therapy. MS may be associated with overall state deterioration, significant disability, and death. The benefits of ICI should be carefully assessed prior to beginning therapy in patients with a history of MS.
A Regulatory Role of Apoptosis Antagonizing Transcription Factor in the Pathogenesis of Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma
Authors: Divya P. Kumar, Prasanna K. Santhekadur, Mulugeta Seneshaw, Faridoddin Mirshahi, Cora Uram‐Tuculescu, Arun J. Sanyal
Journal: Hepatology (2018)

Hepatocellular carcinoma (HCC) is increasing as a cause of liver‐related mortality largely because of the growing burden of nonalcoholic steatohepatitis (NASH). The mechanisms of HCC development in nonalcoholic fatty liver disease (NAFLD) are incompletely understood. We initially identified apoptosis antagonizing transcription factor (AATF) to be associated with HCC in a mouse model of NASH that develops HCC without the addition of specific carcinogens. AATF, also called che‐1, is a transcriptional factor that is highly conserved among eukaryotes. AATF is known to be a central mediator of the cellular responses as it promotes cell proliferation and survival by inducing cell cycle arrest, autophagy, DNA repair, and inhibition of apoptosis. However, the role of AATF in NASH and HCC remains unknown. Here, we provide evidence for AATF as a contributory factor for HCC in NAFLD. AATF overexpression was further verified in human NASH and HCC and multiple human HCC cell lines. Tumor necrosis factor‐α (TNFα), known to be increased in NASH, induced AATF expression. Promoter analysis of AATF revealed a sterol regulatory element binding transcription factor 1‐c (SREBP‐1c) binding site; inhibition of SREBP‐1 by using specific inhibitors as well as small interfering RNA decreased TNFα‐induced AATF expression. AATF interacted with signal transducer and activator of transcription 3 to increase monocyte chemoattractant protein‐1 expression. AATF knockdown decreased cell proliferation, migration, invasion, colony formation, and anchorage‐dependent growth in HCC cell lines. Xenograft of QGY‐7703 HCC cells with AATF stably knocked down into nonobese diabetic scid gamma mice demonstrated reduced tumorigenesis and metastases. Conclusion: AATF drives NAFLD and hepatocarcinogenesis, offering a potential target for therapeutic intervention.
PATH-22. THE DEVELOPMENT OF A NEW ASSAY TO MEASURE 2-HYDROXYGLUTARATE (2-hg) ENANTIOMER LEVELS AND THE UTILITY OF 2-hg AS A BIOMARKER FOR MANAGEMENT OF IDH MUTANT GLIOMAS
Authors: Shinji Strain, Morris Groves, Mark Emmett
Journal: Neuro-Oncology (2018)

The isocitrate dehydrogenase (IDH) gene is mutated in a large percentage of gliomas and produces the oncometabolite, (R)-2-hydroxgylutarate [(R)-2hg]. However, no correlation between total 2hg levels and clinical parameters, like tumor burden, in glioma patients has been identified. This lack is likely due to the presence of significant levels of the enantiomer, (S)-2-hydroxyglutarate [(S)-2hg]. (S)-2hg is normally produced in the body and during hypoxic conditions. Past studies measuring 2hg via mass spectrometry methods either do not differentiate between (R)-and (S)-2hg, both which are normally detectable in serum, or use LC-MS based assays that lack the sensitivities needed to detect changes in (R)-2hg when an IDH mutant glioma is present. In this study, a novel gas chromatography-mass spectrometry method was built to measure 2hg enantiomers and used to determine if serum levels of (R)-2hg:(S)-2hg, or absolute levels of (R)-2hg, could provide clinical utility as a biomarker in patients with IDH mutant gliomas. The derivatization, fragmentation, and quantitation scheme was optimized for sensitive detection of basal 2hg enantiomers using normal human serum. Serum was then collected from patients with IDHmut and IDHwt gliomas and analyzed to measure levels of 2hg enantiomers before and during the course of treatment. The ratio of (R)-2hg:(S)-2hg was increased in a number of patients with actively growing IDHmut tumors, but not in patients with stable IDHmut tumors or IDHwt tumors. These preliminary results demonstrate the utility of the GC-MS assay for measurement of 2hg enantiomers and their ratio as a biomarker for active disease in patients with IDHmut gliomas.
Abstract 20069: Two Ventricles Are Not Better Than One in the Fontan Circulation: Equivalent Late Outcomes
Authors: Supreet P Marathe, William Shi, Charlotte Verrall, Jascha Kehr, Gopinath Perumal, Jessica Sun, Thomas L Gentles, Nelson Alphonso, David Andrews, Julian Ayer, Diana Zannino, Karin Du Plessis, Yves d'Udekem, David S Winlaw
Journal: Circulation (2017)

Introduction: A subset of Fontan patients have two adequate-sized ventricles, but a biventricular circulation cannot be achieved due to complex morphology or technical reasons. This situation is mo...
Abstract 16514: Interpretation of Whole Genome Sequences for Risk of Early-Onset Myocardial Infarction
Authors: Amit V Khera, Seyedeh M Zekavat, Mark Chaffin, Carolina Roselli, Pradeep Natarajan, Derek Klarin, Judith Lichtman, Gail D'Onofrio, Jennifer Mattera, John Spertus, Wayne Sheu, Kent Taylor, Shih-Yi Lin, Jun-Sing Wang, Tzung-Dau Wang, Jyh-Ming J Juang, Ana Dopazo, Hector Bueno, Bruce Psaty, Stephen S Rich, Wendy Post, Namrata Gupta, Eric Lander, Stacey Gabriel, Jerome Rotter, Yii-Der I Chen, Harlan Krumholz, Sekar Kathiresan
Journal: Circulation (2017)

Introduction: Whole genome sequencing enables ascertainment of the complete spectrum of genetic variation - common and rare, coding and noncoding. Rapid declines in cost have led to enthusiasm that such testing will permit DNA-based population risk stratification. Here, we explore this hypothesis as it relates to early-onset myocardial infarction. Methods: We performed high-coverage whole genome sequencing in a multiethnic cohort of 2,369 individuals with early-onset myocardial infarction and 4,218 controls. We tested single variants as well as the cumulative burden of rare variants (in either protein-coding or non-coding regulatory regions) for disease association. We determined the prevalence and clinical impact of monogenic (single large-effect mutation) and polygenic (cumulative effect of many variants of small effect) risk pathways. Results: Single variant testing confirmed known associations at the 9p21 and LPA risk loci and rare-variant burden testing confirmed a signal in the gene encoding the low...
ACTR-37. SHORT-TERM BEVACIZUMAB FOR RECURRENT GLIOBLASTOMAS
Authors: Tomoo Matsutani, Seiichiro Hirono, Yasuo Iwadate
Journal: Neuro-Oncology (2018)

Survival benefit of bevacizumab (BEV) could not be confirmed for recurrent glioblastomas in EORTC 26101, while BEV is commonly chosen at recurrence due to its positive effect in daily life. BEV is usually repeated until tumor progression or adverse events, but the benefit of continuation of BEV is not known. Recently, short-term BEV has been administrated in our institute to avoid from adverse events, and to reduce medical costs. The survival data of the patients treated with short-term BEV are retrospectively analyzed. Thirty-two patients, who presented recurrence of primary glioblastoma, received short-term BEV, which is 10 mg/kg of BEV bi-weekly administration for 2–6 courses. BEV was discontinued after favorable response in MRI and social functioning, and was resumed for further progression. When the tumor progressed after short-term BEV, it was continued to delay neurological deterioration. Twenty-three of 32 patients could discontinue BEV in the first administration, and 13 of 23 patients were treated with second short-term BEV for further progression. Six of 13 could discontinue BEV again. In our retrospective cohort, median post-recurrent survival was 8.0 months, and 9- and 12-months survivals are 39.8% and 31.8%. The patients, who were able to discontinue BEV, showed statistically longer survival than the patients, who were not, 11.0 months and 3.5 months (p=0.0002, Log-rank). BEV could be safely discontinued for the patients, who respond well for the first administration, and the initial response to BEV might be a good prognostic factor at recurrence.
Daratumumab for Delayed Red-Cell Engraftment after Allogeneic Transplantation
Authors: Claudia I. Chapuy, Richard M. Kaufman, Edwin P. Alyea, Jean M. Connors
Journal: New England Journal of Medicine (2018)

Daratumumab, a human IgG1κ monoclonal antibody targeting CD38, is used to treat multiple myeloma. We describe successful treatment with daratumumab in a case of treatment-refractory pure red-cell aplasia after ABO-mismatched allogeneic stem-cell transplantation. The patient was a 72-year-old man with the myelodysplastic syndrome who received a transplant from an HLA-matched, unrelated donor with a major ABO incompatibility (blood group A in the donor and blood group O in the recipient). The patient had persistent circulating anti-A antibodies and no red-cell recovery 200 days after transplantation. Standard treatments had no effect. Within 1 week after the initiation of treatment with daratumumab, he no longer required transfusions.
Bortezomib, lenalidomide, and dexamethasone (VRd) followed by autologous stem cell transplant for multiple myeloma
Authors: M. Hasib Sidiqi, Mohammed A. Aljama, Irbaz Bin Riaz, Angela Dispenzieri, Eli Muchtar, Francis K. Buadi, Rahma Warsame, Martha Q. Lacy, David Dingli, Nelson Leung, Wilson I. Gonsalves, Prashant Kapoor, Taxiarchis V. Kourelis, William J. Hogan, S. Vincent Rajkumar, Shaji K. Kumar, Morie A. Gertz
Journal: Blood Cancer Journal (2018)

We retrospectively reviewed all patients (n = 243) receiving bortezomib, lenalidomide, and dexamethasone (VRd) induction followed by autologous stem cell transplantation (ASCT) for multiple myeloma at the Mayo Clinic between January 2010 and April of 2017. Median age was 61 (interquartile range, 55-67) with 62% of patients being male. High-risk cytogenetic abnormalities (HRA) were present in 34% of patients. A total of 166 (68%) patients received some form of maintenance/other therapy post transplant (no maintenance (NM, n = 77), lenalidomide maintenance (LM, n = 108), bortezomib maintenance (BM, n = 39), and other therapy (OT, n = 19)). Overall response rate at day 100 post ASCT was 99% (CR 42%) with CR rate increasing to 62% at time of best response post transplant. Two year and 5 year overall survival rates were 90% and 67%, respectively, with an estimated median overall survival (OS) and progression-free survival (PFS) of 96 and 28 months, respectively. HRA was associated with a worse OS but not PFS (median OS: not reached for standard risk vs 60 months for HRA, P = 0.0006; median PFS: 27 months for standard risk vs 22 months for HRA, P = 0.70). The combination of VRd followed by ASCT is a highly effective regimen producing deep and durable responses in many patients.
Emergency care in England faces “year round crisis,” BMA warns
Authors: Gareth Iacobucci
Journal: BMJ (2018)

Emergency care services in England are struggling to cope with a “year round crisis” that is damaging patient care, the BMA has warned.

A new BMA analysis of official NHS England data shows that services fared worse on key performance indicators in summer 2018 than in five of the past eight winters.

It examines NHS trusts’ performance against three key indicators: emergency admissions, trolley waits of over four hours (the time spent between the decision to admit and the admission), and the percentage of emergency attendances completed within four hours.

The analysis shows that …
Facility and Geographic Variation in Rates of Successful Community Discharge After Inpatient Rehabilitation Among Medicare Fee-for-Service Beneficiaries
Authors: Addie Middleton, James E. Graham, Janet Prvu Bettger, Allen Haas, Kenneth J. Ottenbacher
Journal: JAMA Network Open (2018)

<h3>Importance</h3> The Improving Medicare Post–Acute Care Transformation (IMPACT) Act of 2014 mandated a quality measure of successful community discharge for postacute care services. Examining variation in performance nationally can help identify opportunities for improving patient-centered quality of care. <h3>Objective</h3> To examine US facility-level and geographic variation in rates of successful community discharges after inpatient rehabilitation. <h3>Design, Setting, and Participants</h3> This retrospective cohort study of Medicare claims data from December 31, 2013, through October 1, 2015, included 1154 inpatient rehabilitation facilities submitting claims to the Centers for Medicare &amp; Medicaid Services and a total of 487 862 Medicare fee-for-service beneficiaries discharged from inpatient rehabilitation facilities. Analyses were performed from December 8, 2017, through September 11, 2018. <h3>Main Outcomes and Measures</h3> Successful community discharge as defined for the Discharge to Community—Post–Acute Care Inpatient Rehabilitation Facility Quality Reporting Program measure. To be considered a successful community discharge, patients had to discharge from the inpatient rehabilitation facility to the community (ie, home or self-care) and remain there without experiencing an unplanned rehospitalization or dying within the following 31 days. Centers for Medicare &amp; Medicaid Services specifications were followed to identify the cohort, define the outcome, and calculate risk-standardized facility and state rates. <h3>Results</h3> Among the 487 862 patients included in the cohort, mean (SD) age was 76.4 (10.8) years, and 56.9% were female. The overall rate of successful community discharge after inpatient rehabilitation was 63.7% (95% CI, 63.6%-63.8%). Risk-standardized rates ranged from 42.9% to 83.6% across inpatient rehabilitation facilities. Two hundred sixteen facilities (18.7%) performed significantly better than the mean national rate and 203 (17.6%) performed significantly worse (<i>P</i> &lt; .05). Risk-standardized state rates ranged from 55.9% to 73.3%. Rates were lowest in the Northeast (Massachusetts, 55.9%; New Hampshire, 57.0%) and highest in the West (Oregon, 70.3%; Hawaii, 73.3%). <h3>Conclusions and Relevance</h3> The observed variation suggests opportunities exist for improving this important, patient-centered national quality measure. Future research is needed to identify the aspects of care delivery and the community services and supports that facilitate successful community discharge. These findings can be used to guide care improvement efforts and further improve the consistency and quality of postacute care.