tbuckley/cabot-search huggingface dataset:
Alirocumab Reduces Total Nonfatal Cardiovascular and Fatal Events
Authors: Michael Szarek, Harvey D. White, Gregory G. Schwartz, Marco Alings, Deepak L. Bhatt, Vera A. Bittner, Chern-En Chiang, Rafael Diaz, Jay M. Edelberg, Shaun G. Goodman, Corinne Hanotin, Robert A. Harrington, J. Wouter Jukema, Takeshi Kimura, Robert Gabor Kiss, Guillaume Lecorps, Kenneth W. Mahaffey, Angèle Moryusef, Robert Pordy, Matthew T. Roe, Pierluigi Tricoci, Denis Xavier, Andreas M. Zeiher, Ph. Gabriel Steg
Journal: Journal of the American College of Cardiology (2018)

The ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial compared alirocumab with placebo, added to high-intensity or maximum-tolerated statin treatment, after acute coronary syndrome (ACS) in 18,924 patients. Alirocumab reduced the first occurrence of the primary composite endpoint and was associated with fewer all-cause deaths.This pre-specified analysis determined the extent to which alirocumab reduced total (first and subsequent) nonfatal cardiovascular events and all-cause deaths in ODYSSEY OUTCOMES.Hazard functions for total nonfatal cardiovascular events (myocardial infarction, stroke, ischemia-driven coronary revascularization, and hospitalization for unstable angina or heart failure) and death were jointly estimated, linked by a shared frailty accounting for patient risk heterogeneity and correlated within-patient nonfatal events. An association parameter also quantified the strength of the linkage between risk of nonfatal events and death. The model provides accurate relative estimates of nonfatal event risk if nonfatal events are associated with increased risk for death.With 3,064 first and 5,425 total events, 190 fewer first and 385 fewer total nonfatal cardiovascular events or deaths were observed with alirocumab compared with placebo. Alirocumab reduced total nonfatal cardiovascular events (hazard ratio: 0.87; 95% confidence interval: 0.82 to 0.93) and death (hazard ratio: 0.83; 95% confidence interval: 0.71 to 0.97) in the presence of a strong association between nonfatal and fatal event risk.In patients with ACS, the total number of nonfatal cardiovascular events and deaths prevented with alirocumab was twice the number of first events prevented. Consequently, total event reduction is a more comprehensive metric to capture the totality of alirocumab clinical efficacy after ACS.
Comparison of Local Control of Brain Metastases With Stereotactic Radiosurgery vs Surgical Resection
Authors: Thomas M. Churilla, Imran H. Chowdhury, Elizabeth Handorf, Laurence Collette, Sandra Collette, Yanqun Dong, Brian M. Alexander, Martin Kocher, Riccardo Soffietti, Elizabeth B. Claus, Stephanie E. Weiss
Journal: JAMA Oncology (2018)

Brain metastases are a common source of morbidity for patients with cancer, and limited data exist to support the local therapeutic choice between surgical resection and stereotactic radiosurgery (SRS).To evaluate local control of brain metastases among patients treated with SRS vs surgical resection within the European Organization for the Research and Treatment of Cancer (EORTC) 22952-26001 phase 3 trial.This unplanned, exploratory analysis of the international, multi-institutional randomized clinical trial EORTC 22952-26001 (conducted from 1996-2007) was performed from February 9, 2017, through July 25, 2018. The EORTC 22952-26001 trial randomized patients with 1 to 3 brain metastases to whole-brain radiotherapy vs observation after complete surgical resection or before SRS. Patients in the present analysis were stratified but not randomized according to local modality (SRS or surgical resection) and treated per protocol with 1 to 2 brain metastases and tumors with a diameter of no greater than 4 cm.Surgical resection or SRS.The primary end point was local recurrence of treated lesions. Cumulative incidence of local recurrence was calculated according to modality (surgical resection vs SRS) with competing risk regression to adjust for prognostic factors and competing risk of death.A total of 268 patients were included in the analysis (66.4% men; median age, 60.7 years [range, 26.9-81.1 years]); 154 (57.5%) underwent SRS and 114 (42.5%) underwent surgical resection. Median follow-up time was 39.9 months (range, 26.0-1982.0 months). Compared with the SRS group, patients undergoing surgical resection had larger metastases (median 28 mm [range, 10-40 mm] vs 20 mm [range, 4-40 mm]; P < .001), more frequently had 1 brain metastasis (112 [98.2%] vs 114 [74.0%]; P < .001), and differed in location (parietal, 21 [18.4%] vs 61 [39.6%]; posterior fossa, 30 [26.3%] vs 12 [7.8%]; P < .001). In adjusted models, local recurrence was similar between the SRS and surgical resection groups (hazard ratio [HR], 1.15; 95% CI, 0.72-1.83). However, when stratified by interval, patients with surgical resection had a much higher risk of early (0-3 months) local recurrence compared with those undergoing SRS (HR, 5.94; 95% CI, 1.72-20.45), but their risk decreased with time (HR for 3-6 months, 1.37 [95% CI, 0.64-2.90]; HR for 6-9 months, 0.75 [95% CI, 0.28-2.00]). At 9 months or longer, the surgical resection group had a lower risk of local recurrence (HR, 0.36; 95% CI, 0.14-0.93).In this exploratory analysis, local control of brain metastases was similar between SRS and surgical resection groups. Stereotactic radiosurgery was associated with improved early local control of treated lesions compared with surgical resection, although the relative benefit decreased with time.ClinicalTrials.gov Identifier: NCT00002899.
Results from a Prospective, Dose Escalating, Prophylaxis Study in Young Boys with Severe Hemophilia a in China: The China Hemophilia Individualized Prophylaxis Study (CHIPS) (NCT02999308)
Authors: Runhui Wu, Wanru Yao, Xiaobo Luo, Ling Tang, Min Zhou, Yan Wang, Ping Ding, Ningning Zhang, Sheng Yang, Pamela Hillard, Koyo Usuba, Nancy Young, Andrea Doria, Audrey Abad, Zhenping Chen, Yun Peng, Junde Wu, Koon-Hung Luke, Victor S. Blanchette, Xiaojing Li, Qing Zhang
Journal: Blood (2017)
Medicaid expands and drug prices are on the agenda after US midterm elections
Authors: Owen Dyer
Journal: BMJ (2018)

Voters in three of America’s most conservative states passed ballot measures that will implement provisions of “Obamacare” and extend Medicaid to tens of thousands of working citizens who earn too much to qualify under the old rules but not enough to afford private insurance.

The electorates of Utah, Nebraska, and Idaho chose to expand coverage as laid down by the Affordable Care Act, even as they largely elected representatives opposed to Barack Obama’s signature healthcare law.

The changes should extend coverage to about 150 000 people in Utah, 90 000 in Nebraska, and 62 000 in Idaho. Thirty three other states have already expanded Medicaid. Such expansion was meant to be automatic under the original law, but in 2012 the Supreme Court ruled that states had the right to …
CADD-42. EFFICACY OF MUTANT INTERLEUKIN-13 ALPHA-2 RECEPTOR–TARGETED LIPOSOMAL DOXORUBICIN IN THE INTRACRANIAL BRAIN TUMOR MODEL
Authors: Darya Nesterova, Achuthamangalam Madhankumar, Oliver Mrowczynski, Becky Sue Webb, James Connor
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the most common primary central nervous system (CNS) tumor in the United States and yet despite aggressive treatment, the median survival remains at 8 months. About 75% of human glioblastoma tumors selectively overexpress the α2 subtype of interleukin 13 (IL-13Rα2), considered a “decoy receptor” for GBM, allowing it to evade apoptosis normally induced by IL-13 binding. Our laboratory and others have developed targeting strategies to take advantage of IL-13Rα2 expression on GBMs. We showed that wildtype IL-13 targeted nanoliposomes delivering doxorubicin (WT-IL13-Dox), resulted in over 5-fold reduction of orthotopic tumors, with 60% of mice surviving for >200 days compared to mice treated with unconjugated liposomes. WT-IL13, however, also binds to the shared IL-13/IL-4 receptor α1 subunit found in multiple organs, including the heart and lungs, suggesting potential cross-reactivity with surrounding tissues. To address off-target effects, a mutant version of IL-13 was developed known as Targeted Quadruple Mutant-13 (TQM), which display improved binding affinity to the IL-13Rα2 receptor, and decreased affinity to the IL-13/IL-4 receptor α1 subunit. Twenty mice were normalized by tumor burden into two groups, one treated with WT-IL13-Dox and the other group with TQM-13-conjugated liposomal doxorubicin (TQM-13-Lip-Dox). Each group received 5mg/kg of doxorubicin in the liposomes for 4 weeks. Mice treated with TQM-targeted liposomes had slower tumor growth, smaller tumor burden, and prolonged survival (33 vs 23 days, p=0.009) than those treated with WT-IL13 liposomes. WBC counts in WT-IL13 mice suggested they were immunocompromised in comparison to TQM mice (p=0.02), which may contribute to worse survival. These findings suggest that TQM-13 bound nanoliposomes may enable the development of targeted therapy with a decreased side effect profile for delivery of chemotherapeutic agents to GBMs.
DDIS-04. COMPOUNDS IDENTIFIED BY STRUCTURE BASED VIRTUAL SCREENING DECREASE GBM BTIC GROWTH AND GLUCOSE UPTAKE
Authors: Catherine Libby, Sixue Zhang, Sajina Gc, Gloria Benavides, Sarah Scott, Vibha Pathak, Omar Moukha-Chafiq, Yanjie Li, Matthew Redmann, Anh Tran, Arphaxad Otamias, Victor Darley-Usmar, Marek Napierala, Jianhua Zhang, Corinne Augelli-Szafran, Wei Zhang, Anita Hjelmeland
Journal: Neuro-Oncology (2018)

Patient prognosis for individuals diagnosed with GBM remains incredibly poor with a median survival of only 15 months despite aggressive treatment with surgical tumor resection, chemotherapy, and radiation therapy. Therapeutic development to prolong survival has been hampered by a high degree of inter- and intra-tumoral heterogeneity. Contributing to tumor heterogeneity is a subset of highly tumorigenic cells, termed brain tumor initiating cells (BTICs), that can self-renew and have been shown to be highly invasive and resistant to therapy. BTICs can survive under nutrient poor conditions due to their increased expression of glucose transporter 3 (GLUT3). In a recently accepted study, we utilized structure based virtual screening (SBVS) using a GLUT3 homology model to identify two novel GLUT inhibitors. We are now generating a structure-activity relationship profile based on a highly efficacious compound (IC50= ~300 nM) with the same backbone structure identified in the initial screen and seek to improve the potency, selectivity and drug-like properties of the GLUT inhibitors. We have tested several novel analogs and identified four that have maintained efficacy against BTICs in vitro (IC50= 300–600 nM). Importantly, these analogs have displayed less toxicity to astrocytes than lead compounds in addition to improved stability in mouse liver microsomes. As proof of concept, we have begun to test the GLUT inhibitors alone and in combination with chemotherapy in vivo. Thus far, our work has demonstrated that targeting glucose transport is a promising therapeutic avenue to explore.
CSIG-21. THE ROLE OF miR-219a-2-3p AS A TUMOR SUPPRESSOR IN IDH1/2-WILD-TYPE GRADE II/III GLIOMAS
Authors: Jessica Fleming, Erica Hlavin Bell, Zhen-yue Tong, Ivana Grozdic, Joseph McElroy, Sasha Beyer, Denise Fabian, Tiantian Cui, Ilinca Popp, Ori Staszewski, Marco Prinz, Saikh Jaharul Haque, Anca-Ligia Grosu, Arnab Chakravarti
Journal: Neuro-Oncology (2018)

IDH1/2 mutation status can accurately stratify distinct groups of lower-grade glioma (LGG) patients with IDH1/2 non-mutant patients having significantly worse survival rates. A better understanding of the molecular alterations in IDH1/2 mutant versus non-mutant patients may lead to new therapeutic options for the high-risk non-mutant population. We conducted a global microRNA (miRNA) expression analysis using the NanoString array to identify miRNAs differentially expressed in IDH1/2 mutant versus non-mutant grade II/III glioma patients. Of the miRNAs differentially expressed, we performed additional validation experiments confirming miR-219a-2-3p, which provided strong rationale to characterize this miRNA in gliomas. miR-219a-2-3p was significantly upregulated 3.4-fold (FDR p = 0.026) in IDH1/2 mutant versus non-mutant tumors (n=56) and was validated in the TCGA LGG cohort. Upon univariable Cox-regression analysis, miR-219a-2-3p was significantly associated with better overall survival (HR = 0.73 (0.55–0.96); p = 0.03). We hypothesized that miR-219a-2-3p may act as a tumor suppressor in IDH1/2 non-mutant gliomas. Overexpression of miR-219a-2-3p in LN18 (PTEN wild-type) and U87 (PTEN mutated) glioma cell lines harboring wild-type IDH1/2 resulted in a significant inhibition of cell proliferation, colony formation, and cell invasion. We also observed a significant radiosensitizing effect of miR-219a-2-3p. Using an in silico approach, we identified four putative targets of miR-219a-2-3p. Overexpression of miR-219a-2-3p significantly downregulated each target at the mRNA and protein levels. These targets have been shown to play a role in tumor progression by activating the PI3K-AKT and Ras-ERK pathways. Accordingly, we observed a significant decrease in AKT phosphorylation when miR-219a-2-3p was overexpressed. These data suggest that miR-219a-2-3p and/or its targets may be potential candidates to pursue as novel therapeutic options in IDH1/2 wild-type gliomas. Currently, in vivo experiments for miR-219a-2-3p are in progress. FUNDING: R01CA108633, R01CA169368, RC2CA148190, U10CA180850-01(NCI), Brain Tumor Funders Collaborative Grant, and the Ohio State University Comprehensive Cancer Center (all to AC).
PDTM-11. A NOVEL EX VIVO MODEL FOR HUMAN MEDULLOBLASTOMA: A NEW PERSONALIZED MEDICINE TOOL
Authors: James Felker, Abhinev Dey, Anshu Malhotra, Jingbo Liu, Matthew Schniederjan, Anna Kenney, Tobey MacDonald
Journal: Neuro-Oncology (2018)

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Current treatment involves multi-agent chemotherapy and/or radiation, but this one-size-fits-all treatment often results in long term side effects. The development of novel therapeutics has been slowed, limited by the lack of representative samples of individual patient MB; therefore, we adapted a novel drug testing assay to address this issue: organotypic ex vivo brain tumor slice culture (OSC). We hypothesize that OSC can be a robust real-time screening tool for evaluating drug efficacy for individual MB patients. We tested novel inhibitors for STAT3 (WP1066) and YB1 (fisetin) in an OSC assay, with cisplatin and DMSO vehicle as positive and negative controls respectively. OBJECTIVES: To determine the feasibility of performing our OSC on human MB and to evaluate WP1066 and fisetin on patient-derived samples. MB was taken directly from the OR at time of initial resection. Tumors were sectioned into 300-μm-thick slices with a vibratome. The slices were cultured, treated with WP1066, fisetin, cisplatin, or vehicle and after 48hrs, the slices were fixed in 4% paraformaldehyde. The slices were immunostained with antibodies against cleaved caspase 3, and confocal images were obtained. Analysis and quantification of staining was done with FIJI and IMARIS imaging software. We were able to perform our assay on three patient samples: two non-WNT/non-SHH and one SHH tumor. WP1066 and fisetin treatment induced cell death in all three samples, similar to cisplatin, and significantly more than vehicle. We also found increased cell death in the nestin positive tumor stem-like cells. We correlated phenotypic response with gene expression, as determined by single-cell RNA-sequencing performed on one MB and whole exome sequencing of another MB. CONCLUSIONS: We have successfully performed a novel OSC assay for real-time drug testing, thus illustrating a possible new personalized medicine tool in MB.
A brain-penetrant triazolopyrimidine enhances microtubule-stability, reduces axonal dysfunction and decreases tau pathology in a mouse tauopathy model
Authors: Bin Zhang, Yuemang Yao, Anne-Sophie Cornec, Killian Oukoloff, Michael J. James, Pyry Koivula, John Q. Trojanowski, Amos B. Smith, Virginia M.-Y. Lee, Carlo Ballatore, Kurt R. Brunden
Journal: Molecular Neurodegeneration (2018)

Alzheimer's disease (AD) and related tauopathies are neurodegenerative diseases that are characterized by the presence of insoluble inclusions of the protein tau within brain neurons and often glia. Tau is normally found associated with axonal microtubules (MTs) in the brain, and in tauopathies this MT binding is diminished due to tau hyperphosphorylation. As MTs play a critical role in the movement of cellular constituents within neurons via axonal transport, it is likely that the dissociation of tau from MTs alters MT structure and axonal transport, and there is evidence of this in tauopathy mouse models as well as in AD brain. We previously demonstrated that different natural products which stabilize MTs by interacting with β-tubulin at the taxane binding site provide significant benefit in transgenic mouse models of tauopathy. More recently, we have reported on a series of MT-stabilizing triazolopyrimidines (TPDs), which interact with β-tubulin at the vinblastine binding site, that exhibit favorable properties including brain penetration and oral bioavailability. Here, we have examined a prototype TPD example, CNDR-51657, in a secondary prevention study utilizing aged tau transgenic mice. 9-Month old female PS19 mice with a low amount of existing tau pathology received twice-weekly administration of vehicle, or 3 or 10 mg/kg of CNDR-51657, for 3 months. Mice were examined in the Barnes maze at the end of the dosing period, and brain tissue and optic nerves were examined immunohistochemically or biochemically for changes in MT density, axonal dystrophy, and tau pathology. Mice were also assessed for changes in organ weights and blood cell numbers. CNDR-51657 caused a significant amelioration of the MT deficit and axonal dystrophy observed in vehicle-treated aged PS19 mice. Moreover, PS19 mice receiving CNDR-51657 had significantly lower tau pathology, with a trend toward improved Barnes maze performance. Importantly, no adverse effects were observed in the compound-treated mice, including no change in white blood cell counts as is often observed in cancer patients receiving high doses of MT-stabilizing drugs. A brain-penetrant MT-stabilizing TPD can safely correct MT and axonal deficits in an established mouse model of tauopathy, resulting in reduced tau pathology.
ACTR-61. LONG-TERM ANALYSES OF THE NOA-08 RANDOMIZED PHASE III TRIAL
Authors: Tobias Kessler, Antje Wick, Michael Platten, Christoph Meisner, Michael Bamberg, Ulrich Herrlinger, Jörg Felsberg, Astrid Weyerbrock, Clemens Seidel, Joachim Steinbach, Michael Sabel, Jan Vesper, Jürgen Debus, Felix Sahm, Jürgen Meixensberger, Ralf Ketter, Regine Mayer-Steinacker, Andreas von Deimling, Guido Reifenberger, Michael Weller, Wolfgang Wick
Journal: Neuro-Oncology (2018)

Optimal treatment and role of O6-methylguanine DNA-methyl transferase (MGMT) status in elderly patients is still not defined. This is the long-term update (LT) of the NOA-08 trial (NCT01502241) that compared efficacy and safety of RT to TMZ in elderly patients with anaplastic astrocytoma (AA) or glioblastoma (GB) using overall survival (OS) as primary endpoint and event-free survival (EFS) as well as efficacy according to MGMT status as major secondary endpoints. FINDINGS: In the LT with a data cut-off Apr 1 2018 median OS was 8·2 [7·0–10·0] months for TMZ treatment versus 9·4 [8·1–10·4] months for RT; hazard ratio (HR)=0·93 (95% CI: 0·76-1·15)] of TMZ versus RT did not differ between both arms. Also, median EFS [3·4 [3·2–4·1] months versus 4·6 [4·2–5·0] months 3did not differ with a HR=1·02 (0·83-1·25)]. MGMT promoter methylation tested in tumor tissue (82/221 patients, 37·1%) was associated with prolonged OS [13·6 [10·1–16·5] versus 8·0 [6·9-9·9] months; HR=0·53 (0·40-0·70), p<0·0001]. Patients with MGMT promoter methylation had longer OS and EFS when treated with TMZ (18·4 [13·9–24·4] months and 8·5 [6·9–13·3] months) versus RT (9·6 [6·4–13·7] months and 4·8 [4·3–6·2] months, HR 0·44 [0.27–0.70], p<0·001 for OS and 0·46 [0.29–0.73], p=0·001 for EFS). Patients without MGMT promoter methylation had shorter EFS and a shorter OS with the usual testing not significant when treated with TMZ (6·7 [5·6–8·2] months and 3·0 [2·6-3·3] months) versus with RT (10·2 [8·0–12·0] months and 4·6 [3·7-6·4] months), HR 1·33 [0·95-1·87], p=0·099 for OS and 1·86 [1·32-2·62], p<0·001 for EFS). INTERPRETATION: LT of NOA-08 confirms the non-inferiority of TMZ compared with RT in the treatment of elderly patients with AA or GB. To improve OS and EFS, MGMT promoter methylation is a strong predictive biomarker for the choice between RT and TMZ and offers unexpectedly favorable long-term outcome with initial TMZ monotherapy.
HGG-11. GERMLINE GENETIC PREDISPOSITION TO PEDIATRIC GLIOMA
Authors: Ivo Muskens, Kyle Walsh, Chenan Zhang, Adam de Smith, Libby Morimoto, Xiaomei Ma, Joseph Wiemels
Journal: Neuro-Oncology (2019)

INTRODUCTION: Gliomas constitute a majority of pediatric brain tumors. While some advances have been made over recent years with regards to pediatric glioma etiology, most studies have evaluated a limited set of known cancer-predisposition genes. In the current study, the impact of rare germline variants on risk of pediatric glioma was evaluated in 320 patients (predominantly high-grade) derived with a population-based sampling strategy using whole-exome sequencing by evaluating 162 known cancer-related genes and by gene-burden testing. METHODS: DNA was extracted from neonatal dried blood spots from 320 pediatric glioma patients born and diagnosed in California and sequenced using the Personalis ACE whole-exome sequencing platform. 63 patients were diagnosed with a glioblastoma (GBM). Sequencing data were analyzed according to the Broad best practice guidelines. Variants with an allele frequency < 0.0001 in the Genome Aggregation Database (gnomAD) that were nonsense mutations, frameshift mutations, or mutations previously described in ClinVar as pathogenic were considered putatively causal. Additionally, gene-burden testing was performed for nonsense mutations, frameshift mutations, and mutations with a CADD score > 20 using gnomAD as a control dataset. RESULTS: All samples passed quality control and the mean read depth was 41.4. Thirty-one (9.7%) samples harbored a variant that was deemed putatively causal, of which 6 were located in TP53. GBM patients harbored 4 of the TP53 mutations (6.4%). Gene-burden testing also revealed that the frequency of rare and predicted functional TP53 variants was significantly higher in pediatric glioma patients than in controls, reaching exome-wide significance (p=2.87x10-7). CONCLUSION: This study identified several putatively pathogenic germline mutations that may contribute to pediatric glioma risk. Variants in TP53 were associated with pediatric glioma on an exome-wide significance level, and most of these variants occurred in pediatric GBM patients. Pediatric GBM patients may, therefore, benefit from targeted sequencing of TP53 and adjusted treatment strategies.