Citations

Background— Daily physical activity assessed by accelerometers represents a novel method to assess the impact of interventions on heart failure (HF) patients’ functional status. We hypothesized that daily activity varies by patient characteristics and correlates with established measures of HF severity in HF with preserved ejection fraction. Methods and Results— In this ancillary study of the NEAT-HFpEF trial (Nitrate’s Effects on Activity Tolerance in HF With Preserved Ejection Fraction), average daily accelerometer units (ADAU) and hours active per day were assessed during a 14-day period before starting isosorbide mononitrate or placebo (n=110). Baseline ADAU was negatively associated with age, female sex, height, and body mass index, and these variables accounted for 28% of the variability in ADAU ( P <0.007 for all). Adjusting for these factors, patients with lower ADAU were more likely to have had an HF hospitalization, orthopnea, diabetes mellitus and anemia, be treated with β-blockers, have higher ejection fraction, relative wall thickness and left atrial volume, and worse New York Heart Association class, HF-specific quality of life scores, 6-minute walk distance, and NT-proBNP (N-terminal pro-B-type natriuretic peptide; P <0.05 for all). Associations between hours active per day and clinical characteristics were similar. Relative to baseline, there were no significant associations between changes in ADAU or hours active per day and changes in standard functional assessments (New York Heart Association, quality of life, 6-minute walk distance, and NT-proBNP) with isosorbide mononitrate. Conclusions— Daily activity is a measure of HF-related and global functional status in HF with preserved ejection fraction. As compared with intermittently assessed standard HF assessments, change in daily activity may provide unique information about the impact of HF interventions on functional status. Clinical Trial Registration— URL: https://www.clinicaltrials.gov/ . Unique identifier: NCT02053493

Abstract Germline and somatic mutations in BRCA1 and BRCA2 (BRCA) confer PARP inhibitor sensitivity. Promoter hypermethylation is an alternate mechanism of gene down-regulation, and BRCA1 promoter methylation is relatively common in sporadic ovarian cancer. The clinical significance of BRCA1 methylation is less clear than for mutations, as the Cancer Genome Atlas (TCGA) and others have failed to show improved survival in ovarian carcinomas with BRCA1 methylation. No one has previously tested whether BRCA1 methylation confers in vivo sensitivity to PARP inhibitors in patients with ovarian cancer. ARIEL2 is a phase 2 study of the PARP inhibitor rucaparib in patients with recurrent platinum sensitive high-grade ovarian, peritoneal or fallopian tube carcinoma. At enrollment, ARIEL2 required pre-treatment tumor biopsies with the goal of developing tissue predictors of PARP inhibitor sensitivity other than BRCA mutations. The number of women with known germline mutations was capped at 15 patients in order to predominantly enroll BRCA wildtype cases. As presented at ASCO 2016, in cases with no BRCA mutations, a high fraction of genomic loss of heterozygosity (LOH) significantly predicted a better progression-free survival (the primary endpoint), longer duration of response, and a higher fraction of responders compared to cases with low LOH. We assessed BRCA1 and RAD51C promoter hypermethylation using methylation-sensitive polymerase chain reaction in paired archival and pre-treatment biopsies from patients on ARIEL2. Of 165 cases for which methylation analyses were completed, 21 (12.7%) were methylated at the BRCA1 promoter and four (2.4%) at the RAD51C promoter. Methylation of BRCA1 and RAD51C was mutually exclusive with mutation in BRCA or other homologous recombination genes. All four cases with RAD51C methylation and 15/19 (78.9%) with BRCA1 methylation were associated with high LOH. In 90 paired samples archival and pre-treatment tissues, RAD51C methylation was 100% concordant and BRCA1 methylation was highly concordant (p&lt;0·001). For 13 cases with BRCA1 methylation in the archival specimen, 4 (30·8%) were unmethylated in the paired pretreatment tumor, but for 77 unmethylated archival specimens, gain of methylation in the pretreatment biopsy was observed just once. Confirmed RECIST responses were seen in 52.4% (11/21) BRCA1 methylated and 75.0% (3/4) RAD51C methylated cases. In conclusion, BRCA1 and RAD51C methylation in ovarian carcinomas correlates with a high response rate to PARP inhibitors. If methylation was to be used as a predictor of PARP inhibitor sensitivity, it would need to be assessed in a pre-treatment (not archival) specimen. The loss of BRCA1 methylation in recurrent ovarian carcinoma, which was common even in these platinum sensitive cases, could explain why BRCA1 methylation is associated with similar survival to methylated cases, despite initial improved therapeutic sensitivity. Citation Format: Elizabeth Swisher, Maria Harrell, Kevin K. Lin, Clare Scott, Sandra Goble, Amit Oza, Robert L. Coleman, Gottfried Konecny, Anna V. Tinker, David M. O'Malley, Rebecca Kristeleit, Ling Ma, James Brenton, Katherine Bell-McGuinn, Ana Oaknin, Alexandra Leary, Elaina Mann, Heidi Giordano, Mitch Rapon, Iain McNeish, Scott H. Kaufmann. BRCA1 and RAD51C Promoter Hypermethylation Confer Sensitivity to PARP Inhibitors in Patients with Platinum Sensitive Ovarian Carcinoma [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP28.

Abstract High-grade epithelial ovarian carcinomas containing mutated BRCA1 or BRCA2 (BRCA1/2) homologous recombination (HR) genes are sensitive to platinum-based chemotherapy and PARP inhibitors (PARPi), while restoration of HR function due to secondary mutations in BRCA1/2 has been recognized as an important resistance mechanism. We sequenced core HR pathway genes in 12 pairs of pretreatment and postprogression tumor biopsy samples collected from patients in ARIEL2 Part 1, a phase II study of the PARPi rucaparib as treatment for platinum-sensitive, relapsed ovarian carcinoma. In 6 of 12 pretreatment biopsies, a truncation mutation in BRCA1, RAD51C, or RAD51D was identified. In five of six paired postprogression biopsies, one or more secondary mutations restored the open reading frame. Four distinct secondary mutations and spatial heterogeneity were observed for RAD51C. In vitro complementation assays and a patient-derived xenograft, as well as predictive molecular modeling, confirmed that resistance to rucaparib was associated with secondary mutations. Significance: Analyses of primary and secondary mutations in RAD51C and RAD51D provide evidence for these primary mutations in conferring PARPi sensitivity and secondary mutations as a mechanism of acquired PARPi resistance. PARPi resistance due to secondary mutations underpins the need for early delivery of PARPi therapy and for combination strategies. Cancer Discov; 7(9); 984–98. ©2017 AACR. See related commentary by Domchek, p. 937. See related article by Quigley et al., p. 999. See related article by Goodall et al., p. 1006. This article is highlighted in the In This Issue feature, p. 920

AbstractIntroductionCardiac pacing from the right ventricular apex is associated with detrimental long‐term effects and nonapical pacing locations may be associated with improved outcomes. There is little data regarding complications with nonapical lead positions. The aim of this study was to assess long‐term outcomes and lead‐related complications associated with differing ventricular lead tip position.Methods and resultsAll adult patients who underwent dual‐chamber pacemaker implantation from 2004 to 2014 were included if they had postprocedure chest radiographs amenable to lead position determination. Long‐term outcomes and lead‐related complication rates were recorded. These were compared at 5 years between: (1) apical and septal leads, (2) apical and nonseptal nonapical (NSNA), and (3) apical and septal with >40% ventricular pacing. We retrospectively evaluated 3,450 patients, which included 238 with a septal position and 733 with NSNA lead positions. Septal lead position was associated with a lower mortality compared to apical leads (24% vs. 31%, P = 0.02). In patients with greater than 40% pacing, septal leads were associated with significantly higher rates of incident atrial fibrillation compared to apical leads (49% vs. 34%, P = 0.04). NSNA positions were associated with a significantly higher rate of lead dislodgement (4% vs. 2%, P = 0.005) and need for revision (8% vs. 5%, P = 0.005).ConclusionsSeptal pacemaker lead position is associated with a lower mortality compared to apically placed leads, but a higher incidence of atrial fibrillation with higher percentage ventricular pacing. NSNA lead locations are associated with more complications and should be avoided.

AbstractMedical devices increasingly depend on software. While this expands the ability of devices to perform key therapeutic and diagnostic functions, reliance on software inevitably causes exposure to hazards of security vulnerabilities. This article uses a recent high‐profile case example to outline a proactive approach to security awareness that incorporates a scientific, risk‐based analysis of security concerns that supports ongoing discussions with patients about their medical devices.