Citations

535 Background: Prior ARIES analyses showed that BV-treated mCRC patients (pts) receiving chemotherapy (CT)/biologics + BV within 2 months (mo) after 1st progressive disease (PD) had longer post-progression survival (PPS) than pts receiving only CT/biologics. The present analysis evaluated whether this effect of BV was consistent when used with common 2L CT regimens— irinotecan- (iri-) and oxaliplatin- (ox-) based—in mCRC pts exposed to 1L BV in ARIES. Methods: ARIES enrolled mCRC pts receiving 1L CT + BV. No tx regimens or assessments were protocol specified. This analysis evaluated 1L BV-treated mCRC pts who had PD, survived ≥2 mo after PD, and received 2L iri- or ox-based tx. PPS was estimated by Kaplan-Meier methods. Cox regression was used to estimate hazard ratios (HRs), while adjusting for covariates (eg, 1L time to progression). Results: Of 1550 1L pts in ARIES, 1074 had 1st PD and survived ≥2 mo after PD. Of these 1074, 390 and 114 received 2L iri- and ox-based tx, respectively, ± BV ( table ). Baseline characteristics were generally similar between groups. The incidence of targeted adverse events (TAEs) was as expected and similar between the BV and No BV groups over time. In pts receiving 2L iri- or ox-based CT tx, PPS in BV-treated pts was longer compared to those not on BV. Analyses may be limited by small pt numbers in some groups. Conclusions: Consistent with prior ARIES analyses, the continued use of BV after 1st PD was associated with prolonged PPS regardless of the 2L CT backbone used. [Table: see text]

Background— Ventricular tachycardia and premature ventricular complexes (PVCs) most frequently occur in the context of structural heart disease. However, the burden of idiopathic ventricular arrhythmias (IVA) in the general population is unknown. Methods and Results— We identified incident cases of IVA between 2005 and 2013 from Olmsted County, Minnesota, using the Rochester Epidemiology Project database. For PVC cohorts, we included those with frequent (defined as ≥100 PVC/24 hours) symptomatic PVCs. We defined IVA-associated cardiomyopathy as a drop in ejection fraction of ≥10% from baseline. Between 2005 and 2013, we identified 614 individuals with incident IVA (229 [37.3%] were male; average age was 52.1±17.2 years). Of these, 177 (28.8%) had idiopathic ventricular tachycardia, 408 (66.5%) had symptomatic PVCs, and 29 (4.7%) had IVA-associated cardiomyopathy. The age- and sex-adjusted incidence rates in 2005 to 2007, 2008 to 2010, and 2011 to 2013 were 44.9 per 100 000 (95% confidence interval [CI], 38.0–51.8), 47.6 per 100 000 (95% CI, 40.8–54.5), and 62.0 per 100 000 (95% CI, 54.4–69.6), respectively. In idiopathic ventricular tachycardia, there was an increase in incidence rate with ages ( P <0.001) but not between sexes ( P =0.12). The age-adjusted incidence of symptomatic PVC was higher in females than in males (46.2 per 100 000 [95% CI, 40.9–51.6] versus 20.5 per 100 000 [95% CI, 16.8–24.3]; P <0.001). The small number of individuals with IVA-associated cardiomyopathy precluded any formal testing. Conclusions— The incidence of IVA is increasing. Furthermore, overall incidence increases with age. Although the rate of idiopathic ventricular tachycardia is similar across sexes, women have a higher incidence of symptomatic PVC.

BackgroundMagnetic resonance imaging (MRI) in patients with non‐MRI‐conditional cardiac implantable electronic devices (CIEDs) has been shown to be safe when performed under closely monitored protocols. However, the safety of MRI in patients with devices with a nearly depleted battery has not been reported.MethodsProspective data were collected between January 2008 and May 2015 in patients with non‐MRI‐conditional CIEDs undergoing clinically indicated MRI under institutional protocol. Patients who were pacemaker dependent were excluded. Patients whose devices were at elective replacement indicator (ERI) at the time of MRI or close to ERI (ERI or replacement for battery depletion within 3 months of scan) were identified through database review and analyzed for clinical events.ResultsMRI scans (n = 569) were performed in 442 patients. Of these, we identified 13 scans performed with a nearly depleted battery in nine patients. All scans with implantable cardioverter defibrillators (ICDs, n = 9) were uneventful. However, two scans with pacemakers close to ERI resulted in a power‐on‐reset (PoR) event. One scan with a pacemaker close to ERI that was programmed to DOO mode reached ERI during MRI and automatically changed to VVI mode. Additionally, one scan with a pacemaker at ERI did not allow programming. All pacemakers with events were implanted before 2005.ConclusionPatients with pacemakers and ICDs with a nearly depleted battery can safely undergo MRI when patients are not pacemaker dependent. Attention should be paid because old devices can result in PoR or ERI during MRI, which may lead to oversensing and inhibition of pacing.

Purpose Long-term occlusion of coiled aneurysms frequently fails, probably because of poor intrasaccular healing and inadequate endothelialization across the aneurysm neck. The purpose of this study was to determine if attachment of autologous mesenchymal stem cells (MSCs) to platinum coils would improve the healing response in an elastase-induced aneurysm model in rabbits. Materials and methods With approval from the institutional animal care and use committee, aneurysms were created in rabbits and embolized with control platinum coils (Axium; Medtronic) (n=6) or coils seeded ex vivo with autologous adipose-tissue MSCs (n=7). Aneurysmal occlusion after embolization was evaluated at 1 month with angiography. Histological samples were analyzed by gross imaging and graded on the basis of neck and dome healing on H&E staining. Fibrosis was evaluated using a ratio of the total area presenting collagen. Endothelialization of the neck was quantitatively analyzed using CD31 immunohistochemistry. χ2 and Student's t-test were used to compare groups. Results Healing score (11.5 vs 8.0, p=0.019), fibrosis ratio (10.3 vs 0.13, p=0.006) and endothelialization (902 262 μm2 vs 31 810 μm2, p=0.041) were significantly greater in the MSC group. The MSC group showed marked cellular proliferation and thrombus organization, with a continuous membrane bridging the neck of the aneurysm. Angiographic stable or progressive occlusion rate was significantly lower in the MSC group (0.00, 95% CI 0.00 to 0.41) compared with controls (0.67, 95% CI 0.22 to 0.96) (p=0.02). Conclusions Autologous MSCs attached to platinum coils significantly improve histological healing, as they result in improved neck endothelialization and collagen matrix formation within the aneurysm sac.

Pediatric cancers rarely exhibit recurrent mutational events when compared to most adult cancers. This poses a challenge in understanding how cancers initiate, progress, and metastasize in early childhood. Also, due to limited detected driver mutations, it is difficult to benchmark key genes for drug development. In this review, we use neuroblastoma, a pediatric solid tumor of neural crest origin, as a paradigm for exploring “big data” applications in pediatric oncology. Computational strategies derived from big data science–network- and machine learning-based modeling and drug repositioning—hold the promise of shedding new light on the molecular mechanisms driving neuroblastoma pathogenesis and identifying potential therapeutics to combat this devastating disease. These strategies integrate robust data input, from genomic and transcriptomic studies, clinical data, and in vivo and in vitro experimental models specific to neuroblastoma and other types of cancers that closely mimic its biological characteristics. We discuss contexts in which “big data” and computational approaches, especially network-based modeling, may advance neuroblastoma research, describe currently available data and resources, and propose future models of strategic data collection and analyses for neuroblastoma and other related diseases.

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium ( n Stage1 : 111,666; n Stage2 : 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea ( PPM1J , EDEM3, ACP1, SPEG, EYA4, CYP1A1 , and ATXN2L ; P Stage1 <3.7×10 −7 ), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 ( P =5.4×10 −8 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2 -knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

Abstract Motivation Testing SNP–SNP interactions is considered as a key for overcoming bottlenecks of genetic association studies. However, related statistical methods for testing SNP–SNP interactions are underdeveloped. Results We propose the SNP Interaction Pattern Identifier (SIPI), which tests 45 biologically meaningful interaction patterns for a binary outcome. SIPI takes non-hierarchical models, inheritance modes and mode coding direction into consideration. The simulation results show that SIPI has higher power than MDR (Multifactor Dimensionality Reduction), AA_Full, Geno_Full (full interaction model with additive or genotypic mode) and SNPassoc in detecting interactions. Applying SIPI to the prostate cancer PRACTICAL consortium data with approximately 21 000 patients, the four SNP pairs in EGFR-EGFR, EGFR-MMP16 and EGFR-CSF1 were found to be associated with prostate cancer aggressiveness with the exact or similar pattern in the discovery and validation sets. A similar match for external validation of SNP–SNP interaction studies is suggested. We demonstrated that SIPI not only searches for more meaningful interaction patterns but can also overcome the unstable nature of interaction patterns. Availability and Implementation The SIPI software is freely available at http://publichealth.lsuhsc.edu/LinSoftware/. Supplementary information Supplementary data are available at Bioinformatics online.