Citations

Abstract Background: Regular use of nonsteroidal anti-inflammatory drugs (NSAID) is associated with lower risk of colorectal cancer. Genome-wide interaction analysis on single variants (G × E) has identified several SNPs that may interact with NSAIDs to confer colorectal cancer risk, but variations in gene expression levels may also modify the effect of NSAID use. Therefore, we tested interactions between NSAID use and predicted gene expression levels in relation to colorectal cancer risk. Methods: Genetically predicted gene expressions were tested for interaction with NSAID use on colorectal cancer risk among 19,258 colorectal cancer cases and 18,597 controls from 21 observational studies. A Mixed Score Test for Interactions (MiSTi) approach was used to jointly assess G × E effects which are modeled via fixed interaction effects of the weighted burden within each gene set (burden) and residual G × E effects (variance). A false discovery rate (FDR) at 0.2 was applied to correct for multiple testing. Results: Among the 4,840 genes tested, genetically predicted expression levels of four genes modified the effect of any NSAID use on colorectal cancer risk, including DPP10 (PG×E = 1.96 × 10−4), KRT16 (PG×E = 2.3 × 10−4), CD14 (PG×E = 9.38 × 10−4), and CYP27A1 (PG×E = 1.44 × 10−3). There was a significant interaction between expression level of RP11-89N17 and regular use of aspirin only on colorectal cancer risk (PG×E = 3.23 × 10−5). No interactions were observed between predicted gene expression and nonaspirin NSAID use at FDR < 0.2. Conclusions: By incorporating functional information, we discovered several novel genes that interacted with NSAID use. Impact: These findings provide preliminary support that could help understand the chemopreventive mechanisms of NSAIDs on colorectal cancer.

Linitis plastica (LP), a subset of gastric adenocarcinoma (GA), has been considered as a fatal disease with few management options. Little evidence has been reported regarding the role for surgical therapy in treating LP. A retrospective review of GA patients with LP from the surveillance, epidemiology, and end results database (2004–2009) was performed. 29,440 patients with GA were identified, of whom 948 (3.2%) had LP. After matching for American Joint Commission on Cancer (AJCC) stage, LP patients had significantly worse 5-year disease specific survival (DSS) compared with GA (6 vs 34%, P < 0.001). For potentially resectable LP patients (i.e., stage I–III), 5-year DSS was 0 per cent for no treatment and for radiation therapy alone, 18 per cent for both and surgery and radiation, and 20 per cent for surgery alone(P < 0.001). LP is a marker of poor survival in patients with GA. However, surgical resection provides the best oncologic outcomes in these patients with a 20 per cent 5-year DSS in patients with loco-regional disease.

The interrelationships between atrial fibrillation (AF) and heart failure (HF) are complex and poorly understood, yet the number of patients with AF and HF continues to increase worldwide. Thus, there is a need for initiatives that prioritize research on the intersection between AF and HF. This article summarizes the proceedings of a virtual workshop convened by the US National Heart, Lung, and Blood Institute to identify important research opportunities in AF and HF. Key knowledge gaps were reviewed and research priorities were proposed for characterizing the pathophysiological overlap and deleterious interactions between AF and HF; preventing HF in people with AF; preventing AF in individuals with HF; and addressing symptom burden and health status outcomes in AF and HF. These research priorities will hopefully help inform, encourage, and stimulate innovative, cost-efficient, and transformative studies to enhance the outcomes of patients with AF and HF.

LBA3 Background: Bortezomib (btz) combined with lenalidomide (len) and dexamethasone (dex) (VRd) is a standard initial therapy for NDMM. Carfilzomib (cfz), a next-generation proteasome inhibitor, in combination with len-dex (KRd) has shown higher efficacy in phase II trials. This randomized phase III trial was designed to examine if KRd improves progression free survival (PFS) compared to VRd in NDMM (current results), and whether indefinite maintenance with len improves OS compared with two-year maintenance (to be analyzed once data matures). Methods: Patients (Pts) with NDMM, were randomized to receive VRd or KRd in a 1:1 fashion for 36 weeks followed by a second randomization (1:1) to indefinite versus two years of len maintenance. Pts without del17p, t (14;16), t(14;20), plasma cell leukemia or high-risk GEP70 profile, were enrolled. VRd arm included btz 1.3 mg/m2 on days(d) 1, 4, 8, and 11 (d 1, 8 for cycles 9-12), len 25 mg d 1-14, and dex 40 mg d 1, 2, 4, 5, 8, 9, 11, 12 of a 3-week (wk) cycle for 12 cycles, while pts in the KRd arm received cfz 36 mg/m2 d 1, 2, 8, 9, 15, 16 with len 25 mg daily on d 1-21 and dex 40 mg wkly, in 4 wk cycles for 9 cycles. Maintenance included len 15mg d 1-21 every 4 wks. The study was designed to detect a hazard ratio (HR)=0.75 with 80% power at 1-sided 2.5% alpha and 399 PFS events (progression or death regardless of intervening therapy). Results: The study accrued 1087 pts (VRd=542, KRd=545). The median age was 65y. Treatment, efficacy, and toxicity data are in the table. At the second of 3 planned interim analyses, with PFS HR=1.04 (95% CI, 0.8 to 1.3, p=0.74), futility was met. Median PFS was VRd=34.4m and KRd=34.6m; no differences were seen based on age (<65 or ≥65), presence or absence of t(4;14) or ISS stage. The three-year OS (95% CI) was similar: VRd 84% (80 to 88) and KRd 86% (82 to 89). Conclusions: In this randomized phase 3 trial, KRd did not improve PFS compared with VRd in NDMM. A significantly higher rate of cardio-pulmonary and renal toxicity was observed with KRd, while neuropathy rates were higher with VRd. VRd remains the standard triplet induction regimen in standard and intermediate risk NDMM, and a suitable backbone for 4 drug combinations. Clinical trial information: NCT01863550 . [Table: see text]