tbuckley/cabot-search huggingface dataset:
Use of Home Blood Pressure Results for Assessing the Quality of Care for Hypertension
Authors: Kevin O. Hwang, Eric J. Thomas, Laura A. Petersen
Journal: JAMA (2018)

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QOLP-22. THE INTERNATIONAL LOW GRADE GLIOMA REGISTRY: PATIENT-REPORTED QUALITY OF LIFE
Authors: Luke Benz, Joeky Senders, Jeffrey Wefel, Elizabeth Claus
Journal: Neuro-Oncology (2018)

The overarching goal of the International Low Grade Glioma (LGG) Registry is to allow for focused study of LGG (defined as adult grade II astrocytoma, mixed glioma, or oligodendroglioma), including quality of life (QOL). To date, enrollment is completed for 234 patients from 21 states and nine countries (US, France, United Kingdom, Canada, Australia, Hong Kong, New Zealand, Belarus and Spain). Pilot data on QOL (MOS SF-36 scale, measured from 0–100 with higher scores suggesting better QOL) are available for 112 LGG patients for whom we have confirmed treatment via medical record review. Enrolled LGG patients were predominantly White (91.2%), female (56.3%), generally otherwise healthy with only 5% reporting a co-morbid condition) and had a mean age of 36.9 years. A wide range of symptoms were reported by patients: 23.4% reported being unable to drive, 32.4% reported trouble thinking, and 35.1% reported difficulty with getting words out. To date, fifty-two percent of patients have received radiation (XRT): patients not treated with XRT at diagnosis report significantly better physical functioning than do those who received XRT, with persons receiving XRT at time of diagnosis reporting the lowest scores (p=0.003). Interestingly, patients not treated with XRT reported lower emotional and mental health scores than did those receiving XRT (p=0.02). Interpretation of these findings is limited at this point given the small sample and possible selection bias; possibilities include that the no XRT group may be more depressed/anxious for unrelated reasons, or, the absence of treatment may leave them feeling uneasy. When compared to study subjects from our prior meningioma case/control study of QOL, these results suggest significant reduction in QOL for LGG patients and possible variation by XRT treatment and thus the need to better understand these differences.
A core outcome set for clinical trials of chemoradiotherapy interventions for anal cancer (CORMAC): a patient and health-care professional consensus
Authors: Rebecca Fish, Caroline Sanders, Richard Adams, Julie Brewer, Sara T Brookes, Jill DeNardo, Rohit Kochhar, Mark P Saunders, David Sebag-Montefiore, Paula R Williamson, Andrew G Renehan
Journal: The Lancet. Gastroenterology & hepatology (2018)
Facebook ad claiming that vaccines can kill is banned by UK regulator
Authors: Clare Dyer
Journal: BMJ (2018)

The UK’s Advertising Standards Authority (ASA) has ruled that a Facebook advertisement paid for by a US based antivaccination campaign group, which featured a picture of a baby with his eyes closed should not appear again.

The ad, posted for Stop Mandatory Vaccination, founded by Larry Cook, a Los Angeles based author and “natural living” advocate, stated, “Parents, not only can any vaccine given at any age kill your child, but if this unthinkable tragedy does occur, doctors will dismiss it as ‘sudden infant death syndrome’ (SIDS). If you are on the fence about vaccinating, read this story …
Nearly half of older patients stop taking statins within a year, study finds
Authors: Susan Mayor
Journal: BMJ (2018)

Nearly half of older patients prescribed statins stop taking them within a year, a large observational study1 has found.

Researchers analysed data for all adults aged 65 years and older who were dispensed at least one prescription for a statin over the two year period from 1 January 2014 to 31 December 2015. The data came from the Pharmaceutical Benefits Scheme, which collects information on the type, quantity, and timing of drugs dispensed to a randomly selected 10% sample of the Australian population covered by the country’s universal healthcare scheme.

Results, published …
ACTR-20. A SMALL MOLECULE AXL INHIBITOR, BGB324 – FIRST-IN-HUMAN GBM SURGICAL PK TRIAL FOR RECURRENT TUMORS
Authors: Sadashib Ghosh, Hirokazu Sadahiro, Kyung-Don Kang, Justin T Gibson, Mutsuko Minata, Hai Yu, Junfeng Shi, Rishi Chhipa, Zhihong Chen, Songjian Lu, Yannick Simoni, Takuya Furuta, Hemragul Sabit, Suojun Zhang, Soniya Bastola, Shinobu Yamaguchi, Heba Allah Alsheikh, Svetlana Komarova, Jun Wang, Sung-Hak Kim, Dolores Hambardzumyan, Xinghua Lu, Evan W Newell, Biplab Dasgupta, Mitsutoshi Nakada, L James Lee, L Burt Nabors, Lyse A. Norian, Ichiro Nakano
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) remains the deadliest of all primary brain tumors with very few effective treatment options. Recently, we reported that high AXL expression is correlated with poor prognosis in GBM patients and demonstrated the therapeutic benefits of targeting AXL, a member of TAM receptor tyrosine kinase family using a novel small molecule inhibitor, BGB324 in immunocompetent mouse GBM models and xenografts of patient-derived glioma stem cells(GSCs). The promise of BGB324 in tumor burden management prompted us to develop a clinical trial with BGB324 as a single agent therapeutic with the goal to extend it as a combinatorial therapy in the future. Our surgical PK/PD clinical trial with BGB324 in recurrent GBM has been approved by the Brain Malignancy Steering Committee at the National Cancer Institute. Study treatment will consist of 2 cohorts of adult GBM patients, one (Group A) receiving the treatment pre-operatively and the other (Group B) receiving no treatment at all prior to surgery. First 5 patients recruited to Group A will be checked for the desired intra-tumoral drug concentration achieved to continue the trial. Group A will be supplemented by an additional 5 patients bringing the number to n=10 in each arm of the trial. Following surgical resection, patients in both cohorts will receive BGB324 daily in 21-day cycles. Treatment will be continued unless patients exhibit significant toxicity or substantial tumor progression. Our preclinical findings show the upregulation of AXL and its role in apoptosis induction in mesenchymal GBM as well as its association with MLK4, a serine threonine kinase we previously characterized as a mesenchymal GSC molecular target. Inhibition of phosphorylation of AXL and concomitant NF-kB activation in mesenchymal GSCs was found to be the nodal target of the drug action. An up-to-date information of the trial will be presented in detail.
ACTR-21. MANAGEMENT OF OCULAR SIDE EFFECTS IN PATIENTS WITH EGFR-AMPLIFIED GLIOBLASTOMA RECEIVING DEPATUXIZUMAB MAFODOTIN
Authors: Stella Kim, Golnaz Moazami, Erica Gomez, Christopher Ocampo, Earle Bain, Maria Guseva, Marian Macsai
Journal: Neuro-Oncology (2018)

Depatuxizumab mafodotin (depatux-m, formerly ABT-414), is an antibody-drug conjugate comprised of an EGFR-targeted antibody, a non-cleavable linker maleimidocaproyl, and the microtubule inhibitor monomethylauristatin F. Promising antitumor activity of depatux-m was observed in patients with glioblastoma (GBM) in Phase 12 studies. Dosage of depatux-m is limited by ocular side effects (OSE), such as blurred vision, dry eye, and photophobia from corneal epitheliopathy, which are generally reversible after dose reduction or drug discontinuation. This Phase 3b study evaluates depatux-m-related OSE management strategies used in depatux-m clinical trials. This open-label study will enroll approximately 90 patients with newly diagnosed, histologically confirmed, grade IV GBM that is epidermal growth factor receptor (EGFR)-amplified. Patients will receive depatux-m during the chemoradiation phase (radiation and temozolomide [TMZ]), and during adjuvant therapy with TMZ. Patients are randomized to one of three prophylactic ocular treatments: standard steroids (SS), SS with vasoconstrictors and cold compress (VC), or enhanced steroids (ES) with VC. Primary objective is to evaluate these prophylactic strategies for their effect on the proportion of patients requiring a change in OSE management due to inadequate control of OSEs, defined as either a 3-line decline in visual acuity from baseline or Grade 3 OSE severity on the Corneal Epithelial Adverse Event (CEAE) activities of daily living-based scale. Inadequate control with initial prophylactic regimen will trigger a switch to the addition of bandage contact lenses (BCL). Secondary objective assesses change in OSE management due to inadequate control of OSEs by BCL, defined as percentage of patients with Grade 3 CEAE that will trigger transition of patient to investigator discretion regimen (depatux-m interruption/dose reduction, VC prophylaxis, or ES prophylaxis). ClinicalTrials.gov: NCT03419403.
Clinical Application and Potential of Fecal Microbiota Transplantation
Authors: R.E. Ooijevaar, E.M. Terveer, H.W. Verspaget, E.J. Kuijper, J.J. Keller
Journal: Annual Review of Medicine (2018)

Fecal microbiota transplantation (FMT) is a well-established treatment for recurrent Clostridioides difficile infection. FMT has become a more readily available and useful new treatment option as a result of stool banks. The current state of knowledge indicates that dysbiosis of the gut microbiota is implicated in several disorders in addition to C. difficile infection. Randomized controlled studies have shown FMT to be somewhat effective in treating ulcerative colitis, irritable bowel syndrome, and hepatic encephalopathy. In addition, FMT has been beneficial in treating several other conditions, such as the eradication of multidrug-resistant organisms and graft-versus-host disease. We expect that FMT will soon be implemented as a treatment strategy for several new indications, although further studies are needed.
IMMU-09. HETEROGENEOUS INTRA-TUMORAL ANTIGEN EXPRESSION IN RELATION TO IMMUNOTHERAPY OF HIGH GRADE GLIOMA
Authors: Michael Barish, Lihong Weng, Massimo D’Apuzzo, Yubo Zhai, Alfonso Brito, Brenda Chang, Aniee Sarkissian, Renate Starr, Wen-Chung Chang, Brenda Aguilar, Araceli Naranjo, Suzette Blanchard, Russell Rockne, Behnam Badie, Vanessa Jonsson, Dina Awabdeh, Blake Brewster, Stephen Forman, Christine Brown
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) remains an almost universally fatal brain tumor despite numerous on-going efforts to devise novel and efficacious therapies. We are exploring one approach, immunotherapy with genetically modified T cells expressing chimeric antigen receptors (CARs) targeting specific tumor antigens. While adoptive CAR T cell immunotherapy has shown promising efficacy in pre-clinical and clinical studies, tumor relapses nevertheless occur, a reflection of our incomplete understanding of target antigen expression in GBM. We have previously suggested from analysis of inter-tumoral heterogeneity in primary tissues from patients with GBM that, in principle, a multiple antigen approach targeting IL13Rα2, HER2 and EGFR could effectively target approximately 93% of patient tumors. Our most recent observations, working with this same cohort of patient tumor samples, indicate that individual GBM lesions are composed of numerous subpopulations of tumor cells with differing target antigen expression patterns. This high degree of intra-tumoral heterogeneity, evident in the spatial extent (“granularity”) of target antigen expression patterns and their relations to tumor architecture, may complicate single- and multiple-target immunotherapies by contributing to antigen escape and tumor recurrence.
Abstract 17375: In Utero Particulate Matter Exposure Produces Heart Failure and Electrical Remodeling at Adulthood
Authors: Victor P Long, Vineeta Tanwar, Matthew W Gorr, Stephen H Baine, Ingrid M Bonilla, Cynthia A Carnes, Loren E Wold
Journal: Circulation (2015)

Introduction: In utero exposure to particulate matter through perinatal development has been demonstrated to produce cardiac dysfunction during adulthood. It is unknown what effect exposure to air pollution during the in utero period alone has on cardiac dysfunction and electrical remodeling in adulthood. We tested the hypothesis that adult mice exposed to concentrated particulate matter in utero would demonstrate global cardiac dysfunction as well as cellular electrical remodeling at adulthood. Methods: Female FVB mice were exposed either to filtered air (FA) or particulate matter with diameter less than 2.5 μm (PM2.5) at a concentration of ~ 51.69 μg/m3 for 6 h/day, 7 days/wk (consistent with exposure in a large metropolitan city) beginning at plug formation throughout pregnancy. Cardiac function was assessed via ECHO in male offspring at 12 wks of age, followed by sacrifice and isolation of ventricular cardiomyocytes from both groups of mice for electrophysiological recordings. Results: ECHO identified increased LVESd (2.25 ± 0.20 FA, 2.61 ± 0.35 PM2.5, P=0.0001) and LVEDd (3.89 ± 0.03 FA, 3.99 ± 0.038 PM2.5, P=0.04) dimensions and reduced PWTs (1.40 ± 0.05 FA, 1.26 ± 0.04 PM2.5, P=0.04) in mice exposed in utero to PM2.5. Morphological alterations were associated with lower systolic function as indicated by reduced fractional shortening% (43.6 ± 2.1 FA, 33.2 ± 1.6 PM2.5, P=0.0009) in PM2.5 exposed mice compared to FA controls. Electrophysiological recordings revealed significant prolongation of the action potential at 90% repolarization (APD90) in PM2.5 exposed mice compared to FA. (FIGURE) Conclusions: In utero exposure to relevant levels of particulate matter results in dilated cardiomyopathy and electrical remodeling. Future studies are warranted to determine the causes of, and the exposure thresholds resulting in this adverse cardiac remodeling.
RTHP-07. TRANSCRIPTION FACTOR NETWORKS OF OLIGODENDROGLIOMAS (IDH-MUTANT AND 1p/19q CODELETED) TREATED WITH ADJUVANT RADIOTHERAPY OR OBSERVATION INFORMS PROGNOSIS
Authors: Jonathan So, Fabio Moraes, Yasin Mamatjan, Kenneth Aldape, Gelareh Zadeh
Journal: Neuro-Oncology (2018)

Multicentre sequencing efforts have allowed for the molecular characterization of low-grade gliomas (LGG)(The Cancer Genome Atlas (TCGA), 2015). We sought to analyze TCGA gene expression datasets on oligodendrogliomas patients treated with adjuvant radiation (RT) or those observed to discover prognostic markers and pathways. mRNA expression and clinical information of patients with oligodendroglioma were taken from the TCGA “Brain Lower Grade Glioma” provisional dataset. Transcription factor network reconstruction and analysis were performed using the R packages “RTN” and “RTNsurvival”. Elastic net regularization and survival modeling were performed using the “biospear”, “plsRCox”, “survival” packages. From our cohort of 137 patients, 65 received adjuvant RT and 72 were observed. In the cohort that received adjuvant RT, a transcription factor activity signature was generated that was associated with shorter progression-free survival (PFS) (HR = 2.3, p < 0.001). This increased risk was not seen in patients who were observed (HR = 0.8, p = 0.3). Within the observation cohort, transcription factors associated with the circadian clock pathway (ARNTL, ARNTL2, CLOCK) predicted for poorer PFS (HR = 1.6, p < 0.01). A transcription factor activity signature was generated that was associated with poor PFS (HR = 1.8, p < 10–5) and OS (HR = 1.7, p < 0.002) only for those patients who were observed. Median OS in the observation cohort negative for the signature was not reached, but was 70 months for patients positive for the signature. CONCLUSIONS: We identified a transcription factor activity signature associated with poor prognosis in patients with IDH mutated and 1p19q codeleted oligodendroglioma treated with adjuvant radiotherapy. These patients would be potential candidates for treatment intensification. A second signature was generated for patients who were more likely to progress on observation. This potentially identifies a cohort who would benefit from upfront adjuvant radiotherapy.
EXTH-39. DETECTION, MOLECULAR PROFILING AND CULTURE OF CSF-CTCs IN LEPTOMENINGEAL DISEASE (LMDz) IN MELANOMA TO IMPROVE DIAGNOSIS AND TREATMENT STRATEGIES
Authors: Vincent Law, Brittany Evernden, Rajappa Kenchappa, John Puskas, Elena Ryzhova, Inna Smalley, Nam Tran, Arnold Etame, Solmaz Sahebjam, Anthony Magliocco, Keiran Smalley, Peter Forsyth
Journal: Neuro-Oncology (2018)

Approximately 5% of melanoma-associated brain metastasis also develops universally fatal LMDz. The aim of this study was to improve diagnosis and personalized treatment for melanoma-LMDz by enumerating CTCs from CSF. CSF-CTCs were enriched and detected by Veridex CellSearch® System and the circulating melanoma cell kit. Cell-free DNA and cell-associated DNA were extracted, sequenced and profiled. Expanded ex-vivo CSF-CTCs and murine BRAF V600E mutant SM1 cells were labeled with viral fluorophore-NanoLuc BRET and injected into the cisterna magna of immunocomprised mice. These cells were also tested for drug sensitivity in-vitro. CSF-CTCs: 12 patients with definite LMDz and 8 melanoma patients without LMDz were studied. All but 1 LMDz patients (92%) had CSF-CTCs (23 CTCs/ml to 3055 CTCs/ml CSF). In contrast, only 3/8 (37%) melanoma patients without LMDz had CSF-CTCs detected, with significantly lower CTC counts per ml CSF (0.13 CTCs/ml to 0.6 CTCs/ml CSF). CSF-CTCs Profile: LMDz patients showed GNAQ Q209P mutation (uveal melanoma), NRAS Q61R mutation (nasal melanoma) and also BRAF V600E mutation. Ex vivo culture of CSF-CTCs and in-vivo injections: We successfully demonstrated ex-vivo expansion of isolated CSF-CTCs (~25% of samples). Drug treatment revealed Ceritinib could kill BRAF-inhibitor resistant melanoma-CTCs. Mice injected with SM1-GFP-NanoLuc exhibited tumor growth in ~1.5 weeks. Metastasis was detected in the brain and spinal cord regions. Though current patient size is small, this is the first report of the successful culture and drug testing of CSF-CTCs from patients with LMDz. Single cell analysis and in-vivo testing in progress.
CSIG-02. VAL-083 INHIBITS PROLIFERATION OF A PANEL OF EIGHT GLIOBLASTOMA STEM CELL LINES: DOWNREGULATION OF BDR4 AS A NOVEL ANTI-NEOPLASTIC MECHANISM
Authors: Elise Fernandez, Anne Steino, Glenn Lesser, Jeffrey Bacha, Dennis Brown, Madan Kwatra
Journal: Neuro-Oncology (2018)

VAL-083 (Dianhydrogalactitol) is a bi-functional DNA targeting agent that is currently being evaluated in a phase II trial in recurrent glioblastoma (GBM) patients. The goal of the present study was to further elucidate the anti-neoplastic effects and signaling pathways through which VAL-083 functions. We examined the efficacy of VAL-083 against a panel of eight GBM stem cells (GSCs) isolated from newly diagnosed GBM patients. The panel of GSCs were molecularly phenotyped based on the expression of several proteins including EGFR, EGFRvIII, and MGMT as well as several stem cell markers including SOX2, NESTIN, MST1, CD133, TFRC, and OLIG2. The effect of VAL-083 on GSC growth was measured using WST-1 reagent and the effect on GSC’s ability to form neurospheres was assessed by microscopy. Our results show that VAL-083 inhibits neurosphere formation in all eight GSCs. Further, VAL-083 inhibits the growth of GSCs with an IC50 of 200–2000 nM. To identify the molecular pathways affected by VAL-083, control and VAL-083-treated GSCs were subjected to proteomic analysis using reverse phase protein array (RPPA) technology. The RPPA examined the expression of a total of 297 proteins and phosphoproteins. It was found that VAL-083 affects the expression of several proteins and phosphoproteins central to GBM growth. A key protein significantly downregulated by VAL-083 was bromodomain protein 4 (BRD4). This is a salient important finding because BRD4 has been implicated in several cancers including GBM, and agents that target BRD4 are undergoing development as anti-neoplastic agents. In summary, we report that VAL-083 is effective in halting the growth of a panel of GSC isolated from newly diagnosed GBM patients and the underlying mechanism involves downregulation of BRD4.
Abstract P382: Association of Recurrent Common Infections and Subclinical Cardiovascular Disease in Mexican Women
Authors: Priscilla Espinosa-Tamez, Andres Catzin-Kuhlmann, Adriana Monge, Elsa Yunes, Carlos Cantú-Brito, Adrian Marcel, Martín Lajous, Ruy Lopez-Ridaura
Journal: Circulation (2017)

Introduction: Both acute and agent specific chronic infections have been associated with increased cardiovascular risk, however data on the burden of common recurrent infections and cardiovascular disease (CVD) is limited. Hypothesis: Women with greater exposure to uncomplicated common infectious events have an increased risk of subclinical CVD (sCVD) compared to women with no events. Methods: In a cross-sectional study we assessed the relationship of recurrent infections and carotid artery intima-media thickness (IMT) in 1,945 disease-free women from the Mexican Teachers’ Cohort. Through 2012-2016, participants answered questions on respiratory, urinary tract and vaginal infections during the previous year and IMT was measured using ultrasound by standardized neurologists and log-transformed. Total infectious episodes were categorized as “0”, “1 or 2” and “3 or more”. We defined sCVD as mean right and left IMT≥0.8mm or plaque. Multivariable linear and logistic regression analyses were used to evaluate the association of infectious events with IMT and sCVD adjusting for age, sociodemographic, and cardiovascular risk factors. Results: Among participants (50 ±5 years of age) 14% (278 of 1945) reported no infections, 41% (800 of 1945) 1 or 2 infections, and 45% (867 of 1945) 3 or more. Overall prevalence of sCVD was 12% (242 of 1945). Adjusted models for logistic regression showed that women with 3 or more infections had 80% higher odds of subclinical CVD (95% CI 1.1, 2.9) compared to women without infections (p-trend: 0.019). Sub-analyses by type of infection were not significantly associated with sCVD (Image 1). Linear regression analysis did not show a significant association between mean IMT and recurrent infections. Conclusion: Recurrent infectious events in women are associated with greater sCVD, which supports the hypothesis of low grade chronic inflammation in CVD.