tbuckley/cabot-search huggingface dataset:
Association of Concomitant Use of Cholinesterase Inhibitors or Memantine With Cognitive Decline in Alzheimer Clinical Trials
Authors: Richard E. Kennedy, Gary R. Cutter, Mackenzie E. Fowler, Lon S. Schneider
Journal: JAMA Network Open (2018)

<h3>Importance</h3> Clinical trials in Alzheimer disease (AD) generally allow participants to continue receiving concomitant medications, including cholinesterase inhibitors (ChEIs) and memantine, if the dose is stable. Previous analysis of observational studies indicates such individuals experience greater rate of decline on cognitive testing than those not receiving such medications. <h3>Objective</h3> To investigate whether concomitant use of ChEIs or memantine is associated with cognitive outcomes in AD clinical trials. <h3>Data Sources</h3> Meta-database of 18 studies from the Alzheimer Disease Cooperative Study and Alzheimer Disease Neuroimaging Initiative. <h3>Study Selection</h3> All studies with data on ChEI and memantine use that included assessment of specified outcome measures. <h3>Data Extraction and Synthesis</h3> The analysis estimated annual rate of decline on the Alzheimer Disease Assessment Scale–cognitive subscale (ADAS-cog) using linear mixed-effects models, and compared rates for participants receiving ChEIs and memantine, alone and combined, with participants not receiving either medication using random-effects meta-analysis. <h3>Main Outcomes and Measures</h3> Annual rate of change on the ADAS-cog. <h3>Results</h3> Across 10 studies, of 2714 participants, the mean (SD) age was 75.0 (8.2) years, 58% were female, and 9% were racial/ethnic minorities. There were 906 participants (33.4%) receiving ChEIs, 143 (5.3%) receiving memantine, 923 (34.0%) receiving both, and 742 (27.3%) receiving neither. Meta-analysis showed those receiving ChEIs or memantine were associated with significantly greater annual rate of decline on the ADAS-cog than those receiving neither medication (1.4 points/y; 95% CI, 0.1-2.7). <h3>Conclusions and Relevance</h3> Similar to observational studies, many participants in AD clinical trials receiving ChEIs or memantine experience greater cognitive decline. This difference is nearly as large as the hypothesized effect sizes of the treatments investigated in the trials. Concomitant use of ChEIs or memantine may be confounded with outcomes on the ADAS-cog and should be considered in design of clinical trials of potential therapeutic agents for AD. Post hoc analyses stratifying by ChEIs or memantine must be interpreted cautiously given the potential for confounding.
Correction: Learning curve and competence for volumetric laser endomicroscopy in Barrett’s esophagus using cumulative sum analysis
Authors: Arvind Trindade, Sumant Inamdar, Michael Smith, Lisa Rosen, Dennis Han, Kenneth Chang, Cadman Leggett, Charles Lightdale, Douglas Pleskow, Divyesh Sejpal, Guillermo Tearney, Rebecca Thomas, Michael Wallace
Journal: Endoscopy (2018)

Correction to:Learning curve and competence for volumetric laser endomicroscopy in Barrett’s esophagus using cumulative sum analysisEndoscopy 2018; 50(05): 471-478DOI: 10.1055/s-0043-121569
HOUT-20. AN ONLINE CALCULATOR FOR THE PREDICTION OF SURVIVAL AND ADJUVANT TREATMENT BENEFIT IN GLIOBLASTOMA PATIENTS
Authors: Joeky Senders, Patrick Staples, William B Gormley, Timothy Smith, Marike L D Broekman, Omar Arnaout
Journal: Neuro-Oncology (2018)

Although survival statistics for glioblastoma patients are well-defined on population-scale, individualizing survival prognostication remains challenging. Furthermore, treatment efficacy proven on group-level does not directly apply to the same extent in each individual patient. This study compares a variety of statistical and machine learning algorithms in their ability to predict the individual survival benefit of adjuvant chemo- and radiotherapy. The best performing model was used to develop an online survival calculator. Patients operated for a histopathologically confirmed glioblastoma were extracted from the Surveillance Epidemiology and End Results database (2005–2015) and split into a training and hold-out test set with an 80/20 ratio. Fifteen statistical and machine learning algorithms were trained based on 13 demographic, socioeconomic, clinical, and radiographic features to predict overall survival, one-year survival status, and subject-level ten-year survival curves. The resultant models were compared based on discriminatory performance and calibration, as well as interpretability, predictive applicability, and computational efficiency. FINDINGS: In total, 20,821 patients met our inclusion criteria. The accelerated failure time (AFT) model demonstrated superior performance in terms of discrimination (concordance index 0.70), calibration, interpretability, predictive applicability, and computational efficiency compared to cox-proportional hazards regression and a variety of competitive machine learning models. The AFT model was, therefore, deployed through a free, publicly-available software. INTERPRETATION: This study provides a framework for the development of outcome prediction tools in cancer patients, as well as an online calculator for the prediction of survival and treatment benefit in glioblastoma patients. Model deployment of survival calculators requires a multidimensional assessment rather than a single metric comparison. Future research efforts should improve the interpretability, predictive applicability, and computational efficiency of existing machine learning algorithms, increase the granularity of population-based registries, and externally validate the proposed prediction tool.
MNGI-11. LONGITUDINAL GENOMIC ANALYSIS OF SPORADIC MENINGIOMAS WITH MULTIPLE RECURRENCES
Authors: Irina Gepfner-Tuma, Praveen Baskaran, Jens Schittenhelm, Juergen Honegger, Saskia Biskup, Florian Heinrich Ebner, Martin Korn, Felix Behling, Kathrin Machetanz, Frank Paulsen, Ulrike Ernemann, Christian La Fougère, Marco Skardelly, Sven Nahnsen, Marcos Tatagiba, Ghazaleh Tabatabai
Journal: Neuro-Oncology (2018)

Recently, genomic patterns and methylation profiles of meningiomas were described as prognostic factors for aggressiveness and recurrence (e.g. TERT, SMO and AKT1 mutations). However, the particular molecular profiles of recurrence and malignant progression of specific meningioma subtypes remain undefined. In this regard, longitudinal molecular studies are very interesting. In this study, we characterized somatic mutations in a cohort of sporadic meningioma patients. We included 9 patients with multiple recurrences and up to 11 subsequent resections of sporadic meningiomas. We performed a comparative whole-exome sequencing (WES). Moreover, we used the whole-exome data to predict the HLA MHC class I peptides of the subsequent tumor samples in silico. Our study included patients with follow-up times accounted for up to 26 years (average: 12.6 years, range 3–26). We detected a TRAF7 mutation (c.1189G>C) in only 2 of 6 recurrent tumor samples of a female patient with a malignant progression from a WHO I to a WHO grade II meningioma. In a male patient with 9 analyzed meningioma tumor samples, recurrent somatic PLEKHG5, AGBL1, ALK, RICTOR, DEPDC5 mutations were detected. This individual pattern remained constantly evident under different treatments, even after systemic treatment with the mTOR inhibitor everolimus. Moreover, unique mutations in HLA-DQA1, OR14J1, PRH1 genes occurred after mTOR inhibition in this male patient. Furthermore, we identified somatic mutations in the tumor suppressor candidate NBPF1 in 7 of 9 patients. HLA allele types were predicted in silico, with A*02:01, B*57:01, C*03:03, C07:01 and B51:01 being most frequent. Neither ubiquitously shared somatic mutations nor shared MHC class I peptides were identified among this cohort. Taken together, our study outlines a heterogeneous molecular profile in this analysis. Since longitudinal samples in sporadic meningioma are rather rare, the ICOM consortium would be an ideal frame for studying the molecular profile of recurrence in meningioma in larger cohorts.
Fremanezumab: First Global Approval
Authors: Sheridan M. Hoy
Journal: Drugs (2018)

Fremanezumab-vfrm (hereafter referred to as fremanezumab) [AJOVY™] is a fully humanized monoclonal antibody (IgG2Δa) developed by Teva Pharmaceuticals to selectively target calcitonin gene-related peptide (a vasodilatory neuropeptide involved in the pathophysiology of migraine). Its use has been associated with significant reductions in migraine frequency, the requirement for acute headache medication use and headache-related disability compared with placebo in multinational, phase III studies, and in September 2018 fremanezumab was approved by the US FDA for the preventive treatment of migraine in adults. A regulatory assessment for fremanezumab as a preventive treatment of migraine in adults is underway in the EU. Fremanezumab is also undergoing phase III development for the preventive treatment of cluster headache (although a phase III chronic cluster headache study has been suspended due to the results of a prespecified futility analysis) and phase II development for the preventive treatment of post-traumatic headache disorder. This article summarizes the milestones in the development of fremanezumab leading to this first approval in the USA for the preventive treatment of migraine in adults.
EXTH-65. BET INHIBITION IN COMBINATION WITH TEMOZOLOMIDE TARGETS MYCN-POSITIVE GLIOBLASTOMA CELLS
Authors: Matko Čančer, Lisa Drews, Gabriela Rosén, Bengt Westermark, Sven Nelander, Karin Forsberg-Nilsson, Lene Uhrbom, Holger Weishaupt, Fredrik Swartling
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the most common malignant brain tumor in adults with a 15 month median survival after diagnosis. Patients receive surgical resection of the tumor, followed by aggressive radio- and chemotherapy with temozolomide (TMZ). Many human cancers including GBM demonstrate addiction to MYC transcription factor signaling and thus become susceptible to inhibition of MYC downstream genes. JQ1 is an effective inhibitor of BET Bromodomains, a class of epigenetic readers regulating expression of MYC genes and their downstream targets. In a panel of 19 patient-derived GBM cell lines, we showed that BET inhibition alone and in combination with TMZ decreases viability by inducing cell cycle arrest, apoptosis and senescence. We propose a distinct expression signature of GBM cells that correlates with a sensitivity to BET inhibition. Cell lines most sensitive to BET inhibition exhibited ten-fold upregulation of MYCN, as compared to resistant cell lines, while we could not find a correlation between MYC expression and sensitivity to the inhibition. Following BET inhibition, JQ1-sensitive cells downregulated MYCN both on mRNA and protein level, while the inhibition of JQ1-resistant cells had no effect on MYCN expression. In JQ1-sensitive cells, we found enrichment of pathways regulating cell cycle, DNA replication, DNA damage response and repair. As DNA repair leads to an acquired chemoresistance to TMZ, JQ1 treatment in combination with TMZ can further inhibit proliferation of TMZ-resistant cells. Intriguingly, JQ1-sensitive cells expressed high levels of OLIG2 and LGR5, suggesting that BET inhibition targets a subset of proneural GBM progenitors. Taken together, we suggest that BET inhibition can increase the potency of TMZ therapy in particular for GBM patients with a MYCN-positive signature. Ongoing in vivo evaluation of JQ1 and TMZ aims to determine the efficacy of the drug combination in inhibiting tumor growth.
High-Deductible Health Plans and Prevention
Authors: Olena Mazurenko, Melinda J.B. Buntin, Nir Menachemi
Journal: Annual Review of Public Health (2018)

High-deductible health plans (HDHPs) are becoming more popular owing to their potential to curb rising health care costs. Relative to traditional health insurance plans, HDHPs involve higher out-of-pocket costs for consumers, which have been associated with lower utilization of health services. We focus specifically on the impact that HDHPs have on the use of preventive services. We critique the current evidence by discussing the benefits and drawbacks of the research designs used to examine this relationship. We also summarize the findings from the most methodologically sophisticated studies. We conclude that the balance of the evidence shows that HDHPs are reducing the use of some preventive service, especially screenings. However, it is not clear if HDHPs affect all preventive services. Additional research is needed to determine why variability in conclusions exists among studies. We describe an agenda for future research that can further inform public health decision makers on the impact of HDHPs on prevention.
Lorcaserin and Renal Outcomes in Obese and Overweight Patients in the CAMELLIA-TIMI 61 Trial
Authors: Benjamin M. Scirica, Erin A. Bohula, Jamie P. Dwyer, Arman Qamar, Silvio E. Inzucchi, Darren K. McGuire, Anthony C. Keech, Steven R. Smith, Sabina A. Murphy, Kyungah Im, Lawrence A. Leiter, Milan Gupta, Tushar Patel, Wenfeng Miao, Carlos Perdomo, Marc P. Bonaca, Christian T. Ruff, Marc S. Sabatine, Stephen D. Wiviott
Journal: Circulation (2019)

Obesity is thought to increase renal hyperfiltration, thereby increasing albuminuria and the progression of renal disease. The effect of pharmacologically mediated weight loss on renal outcomes is not well-described. Lorcaserin, a selective serotonin 2C receptor agonist that promotes appetite suppression, led to sustained weight loss without any increased risk for major adverse cardiovascular (CV) events in the CAMELLIA-TIMI 61 trial (Cardiovascular and Metabolic Effects of Lorcaserin in Overweight and Obese Patients-Thrombolysis in Myocardial Infarction 61).CAMELLIA-TIMI 61 randomly assigned 12 000 overweight or obese patients with or at high risk for atherosclerotic CV disease to lorcaserin or placebo on a background of lifestyle modification. The primary renal outcome was a composite of new or worsening persistent micro- or macroalbuminuria, new or worsening chronic kidney disease, doubling of serum creatinine, end-stage renal disease, renal transplant, or renal death.At baseline, 23.8% of patients had an estimated glomerular filtration rate (eGFR) <60 mL·min-1·1.73 m-2 and 19.0% had albuminuria (urinary albumin:creatinine ratio ≥30 mg/g). Lorcaserin reduced the risk of the primary renal composite outcome (4.2% per year versus 4.9% per year; hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.79-0.96; P=0.0064). The benefit was consistent across subpopulations at increased baseline CV and renal risk. Lorcaserin improved both eGFR and urinary albumin:creatinune ratio within the first year after randomization. The effect of lorcaserin on weight, hemoglobin A1c, and systolic blood pressure was consistent regardless of baseline renal function. Likewise, there was no excess in cardiovascular events in patients assigned to lorcaserin in comparison with placebo, regardless of renal function. After adjustment for baseline characteristics, those with evidence of kidney disease were at increased risk of major CV events. Compared with patients with an eGFR ≥90 mL·min-1·1.73 m-2, those with an eGFR 60-90 and those <60 mL·min-1·1.73 m-2 had HRs of 1.25 (95% CI, 1.01, 1.56) and 1.51 (95% CI, 1.17, 1.95), respectively ( P for trend 0.0015). Likewise, compared with patients with no albuminuria (<30 mg/g), those microalbuminuria and those with macroalbuminuria had HRs of 1.46 (95% CI, 1.22, 1.74) and 2.10 (95% CI, 1.58, 2.80), respectively ( P for trend <0.0001).Renal dysfunction was associated with increased CV risk in overweight and obese patients. When added to diet and lifestyle, lorcaserin reduced the rate of new-onset or progressive renal impairment in comparison with placebo.URL: https://www.clinicaltrials.gov . Unique identifier: NCT02019264.
GENE-06. THE ONCOHISTONE H3.3K27M DRIVES DIFFUSE INTRINSIC PONTINE GLIOMA INDEPENDENT OF FUNCTIONAL EZH2
Authors: Swati Dhar, Oren Becher
Journal: Neuro-Oncology (2018)

Diffuse Intrinsic Pontine Glioma (DIPG) is an incurable childhood brain tumor. Recent studies demonstrate that the replication independent oncohistone H3.3K27M, mutated in 65% of DIPG cases, inhibits Enhancer of zeste homolog 2 (EZH2), the enzymatic component of Polycomb Repressor Complex 2 (PRC2), leading to a global reduction in H3K27me3 levels and gene de-repression. Conflicting data exists supporting both an oncogenic and a tumor suppressor role for EZH2 in cancer. The present work addressed the functional significance of EZH2 and its cross-talk with the mutant histone H3.3K27M, in the context of DIPG pathogenesis. Brainstem tumors were established by intracranial injections of NTv-a; EZH2f/fneonatal pups using Replication Competent Avian Sarcoma leucosis virus long terminal repeat with splice acceptor (RCAS) viruses, expressing PDGF-B p53 shRNA, and RCAS-Cre/Y. Immunohistochemical staining (IHC) for Ki-67, H3K27me3, GFAP, Olig-2 and Nestin were performed on the Discovery ULTRA (Ventana). Cell proliferation assay (BrdU) was performed in neurosphere cultures established from brainstems of NTv-a; EZH2f/fneonates, using the EZH2 inhibitor, EPZ011989 (1mM, Epizyme) for 5 days. Ezh2 deletion in NTv-a; Ezh2f/fmice exacerbated DIPG pathogenesis, indicated by a 2.5-fold higher Ki-67 immunostaining (pEzh2deletion in neurospheres from Ntv-a; Ezh2f/fneonates enhanced cell proliferation as did the addition of EPZ011989. Superimposition of the H3.3K27M mutant histone in this background, significantly shortened tumor latency, with a median survival of 54 days compared to 70 days in H3.3 wild type histone control group (p<0.05) and 50% incidence of Grade IV tumors. These results suggest that H3K27M may be oncogenic even in the absence of EZH2. FUTURE Current studies aim to analyze the genetic and epigenetic landscape of these tumors using RNA-Seq and functional assays to determine whether EZH2 inhibitors will be a viable option for children with DIPG in the clinic.
CADD-56. INTRA-ARTERIAL NEO100 TRANSIENTLY OPENS THE BLOOD BRAIN BARRIER
Authors: Thomas Chen, Weijun Wang, Florence Hofman, Axel Schonthal
Journal: Neuro-Oncology (2018)

NEO100 is a GMP grade highly purified version of perillyl alcohol (POH), a monoterpene with cell cycle inhibitor properties. It is currently administered intranasally in Phase I/IIa IND trial in the United States for patients with recurrent GBM. Recently, we have found that NEO100 may be administered in a vitro setting, resulting in transient opening of the blood brain barrier. We have confirmed this finding in-vivo using an intracardiac injection of NEO100; intracardiac injection is used as an intra-arterial model for small rodents. Evans Blue injected intravenously after intracardiac NEO100 leads to staining throughout the whole brain. This effect is seen for up to 6 hours after injection; after that time, no Evans Blue stain is seen in the brain. We then injected a small molecule (dopamine), which normally does not cross the blood brain barrier. We were able to detect dopamine in the brain via HPLC after intracardiac injection of NEO100, followed by intravenous dopamine. Having demonstrated that non BBB permeable small molecules can cross into the brain with intra-arterial NEO100, we then tested fluorescent antibodies. Again, intracardiac injection of NEO100 followed by intravenous fluorescent antibodies allowed the antibodies to be detected in the normal brain. An in-vivo intracranial model of GL26 tumor was created. The checkpoint inhibitor antibody (anti-PD1) was used. Four groups (6 animals per group) were treated: Group 1-saline alone Group 2-NEO100 alone Group 3-anti-PD1 alone Group 4-NEO100 followed by anti-PD1. Kaplan Meier survival curves were constructed. All animals in Group 1 and Group 2 passed away within one week. Group 3 had one survivor, Group 4-all six animals survived and are still doing well. We will be translating this study into a clinical trial using interventional neuroradiology to deliver NEO100, followed by intravenous administration of anti-PD1.
Effect on longevity of one-third reduction in premature mortality from non-communicable diseases by 2030: a global analysis of the Sustainable Development Goal health target
Authors: Bochen Cao, Freddie Bray, André Ilbawi, Isabelle Soerjomataram
Journal: The Lancet Global Health (2018)

To curb the rising global burden of non-communicable diseases (NCDs), the UN Sustainable Development Goals (SDGs) include a target to reduce premature mortality from NCDs by a third by 2030. A quantitative assessment of the effect on longevity of meeting this target is one of the many important measures needed to advocate and inform national disease control policies. We did a global analysis to estimate improvements in average expected years lived between 30 and 70 years of age that would result from meeting the SDG target.We estimated age-specific mortality in 183 countries in 2015, for the four major NCDs (cardiovascular diseases, cancers, chronic respiratory diseases, and diabetes) and all NCDs combined, using data from WHO Global Health Estimates. We then estimated the potential gains in average expected years lived between 30 and 70 years of age (LE[30-70)) by eliminating all or a third of premature mortality from specific causes of death in countries grouped by World Bank income groups. The feasibility of reducing mortality to the targeted level over 15 years was also assessed on the basis of historical mortality trends from 2000 to 2015.Reducing a third of premature mortality from NCDs over 15 years is feasible in high-income and upper-middle-income countries, but remains challenging in countries with lower income levels. National longevity will improve if this target is met, corresponding to an average gain in LE[30-70) of 0·64 years worldwide from reduced premature mortality for the four major NCDs and 0·80 years for all NCDs. According to major NCD type, the largest gains attributable to cardiovascular diseases would be in lower-middle-income countries (a gain of 0·45 years), whereas gains attributable to cancer would be in low-income countries (0·33 years).A one-third reduction in premature mortality from the major NCDs in 2015-30 would have substantial effects on longevity. High-level political commitments to effective and equitable national surveillance and prioritised prevention, early detection, and treatment programmes tailored to the major NCD types are needed urgently in lower-resourced settings if this SDG target is to be met by 2030.None.