Citations

Abstract Purpose: Gastric adenocarcinoma is the third most common cause of cancer mortality worldwide. Accurate and affordable noninvasive detection methods have potential value for screening and surveillance. Herein, we identify novel methylated DNA markers (MDM) for gastric adenocarcinoma, validate their discrimination for gastric adenocarcinoma in tissues from geographically separate cohorts, explore marker acquisition through the oncogenic cascade, and describe distributions of candidate MDMs in plasma from gastric adenocarcinoma cases and normal controls. Experimental Design: Following discovery by unbiased whole-methylome sequencing, candidate MDMs were validated by blinded methylation-specific PCR in archival case–control tissues from U.S. and South Korean patients. Top MDMs were then assayed by an analytically sensitive method (quantitative real-time allele-specific target and signal amplification) in a blinded pilot study on archival plasma from gastric adenocarcinoma cases and normal controls. Results: Whole-methylome discovery yielded novel and highly discriminant candidate MDMs. In tissue, a panel of candidate MDMs detected gastric adenocarcinoma in 92% to 100% of U.S. and South Korean cohorts at 100% specificity. Levels of most MDMs increased progressively from normal mucosa through metaplasia, adenoma, and gastric adenocarcinoma with variation in points of greatest marker acquisition. In plasma, a 3-marker panel (ELMO1, ZNF569, C13orf18) detected 86% (95% CI, 71–95) of gastric adenocarcinomas at 95% specificity. Conclusions: Novel MDMs appear to accurately discriminate gastric adenocarcinoma from normal controls in both tissue and plasma. The point of aberrant methylation during oncogenesis varies by MDM, which may have relevance to marker selection in clinical applications. Further exploration of these MDMs for gastric adenocarcinoma screening and surveillance is warranted. Clin Cancer Res; 24(22); 5724–34. ©2018 AACR.

AbstractBackgroundQuadripolar left ventricular (LV) leads provide a more optimal pacing configuration for cardiac resynchronization therapy (CRT) than conventional bipolar leads. The objective of this study is to determine the clinical outcomes of CRT using quadripolar leads.MethodsThis study included 516 CRT patients who received bipolar LV leads (n = 278) or quadripolar LV leads (n = 238) from January 2013 to June 2016. Data were retrospectively collected from a prospective CRT database and electronic health records. CRT response to CRT was defined as >5% improvement in the LV ejection fraction (LVEF) from baseline. Baseline characteristics and outcomes were compared between groups.ResultsNew York Heart Association Functional Classification and LVEF significantly improved in the quadripolar and bipolar groups after CRT. There was no difference in the all‐cause mortality rate. The implant success rate was significantly higher in the quadripolar group (100% vs 97.8%; P = 0.02). Quadripolar lead placement was an independent predictor of CRT response at 12 months (hazard ratio, 0.76; 95% confidence interval, 0.58–0.98; P = 0.04). The rate of LV lead–related complications requiring invasive lead revision or abandonment was significantly higher in the bipolar group (11.2% vs 4.6%; P = 0.007).ConclusionsQuadripolar leads achieve similar CRT outcomes as bipolar LV leads but with a higher implant success rate and fewer procedure‐related complications.

SummaryBackgroundHepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma (HCC) worldwide. It remains incompletely understood in the real world how anti‐viral therapy affects survival after HCC diagnosis.MethodsThis was an international multicentre cohort study of 2518 HBV‐related HCC cases diagnosed between 2000 and 2015. Cox proportional hazards models were utilised to estimate hazard ratios (HR) with 95% (CI) for anti‐viral therapy and cirrhosis on patients' risk of death.ResultsApproximately, 48% of patients received anti‐viral therapy at any time, but only 17% were on therapy at HCC diagnosis (38% at US centres, 11% at Asian centres). Anti‐viral therapy would have been indicated for >60% of the patients not on anti‐viral therapy based on American criteria. Patients with cirrhosis had lower 5‐year survival (34% vs 46%; P < 0.001) while patients receiving anti‐viral therapy had increased 5‐year survival compared to untreated patients (42% vs 25% with cirrhosis and 58% vs 36% without cirrhosis; P < 0.001 for both). Similar findings were seen for other patient subgroups by cancer stages and cancer treatment types. Anti‐viral therapy was associated with a decrease in risk of death, whether started before or after HCC diagnosis (adjusted HR 0.62 and 0.79, respectively; P < 0.001).ConclusionsAnti‐viral therapy improved overall survival in patients with HBV‐related HCC across cancer stages and treatment types but was underutilised at both US and Asia centres. Expanded use of anti‐viral therapy in HBV‐related HCC and better linkage‐to‐care for HBV patients are needed.

Abstract Lung cancer remains the leading cause of cancer-related death, partly due to the fact that most patients are diagnosed with metastatic disease, which is the main cause of death, yet effective therapeutics are lacking. Utilizing mouse models of metastatic lung adenocarcinomas, we report that the transcription factor GATA3 and its cofactor FOG2 play critical roles in lung adenocarcinoma metastasis by promoting the expression of the lysyl hydroxylase (LH) family members, which in turn regulate the tumorigenicity and motility of lung tumor cells through both EMT and EMT-independent mechanisms. In vivo, LHs are elevated in human lung adenocarcinomas and are associated with worse patient survival. Collectively, our data suggest that targeting LHs may be useful for treating metastatic lung cancer. Citation Format: Wei Liu, Ting Zhang, Lixia Guo, Yuanyuan Wang, Yanan Yang. Role of lysyl hydroxylases in metastatic lung cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B07.

ABSTRACT Osteoclasts are bone‐resorbing cells differentiated from macrophage/monocyte precursors in response to macrophage colony‐stimulating factor (M‐CSF) and receptor activator of NF‐κB ligand (RANKL). In vitro models are principally based on primary bone marrow macrophages (BMMs), but RAW 264.7 cells are frequently used because they are widely available, easy to culture, and more amenable to genetic manipulation than primary cells. Increasing evidence, however, has shown that the vastly different origins of these two cell types may have important effects on cell behavior. In particular, M‐CSF is a prerequisite for the differentiation of BMMs, by promoting survival and proliferation and priming the cells for RANKL induction. RAW 264.7 cells readily form osteoclasts in the presence of RANKL, but M‐CSF is not required. Based on these key differences, we sought to understand their functional implications and how it might affect osteoclast differentiation and related signaling pathways. Using a robust and high‐throughput proteomics strategy, we quantified the global protein changes in osteoclasts derived from BMMs and RAW 264.7 cells at 1, 3, and 5 days of differentiation. Data are available via ProteomeXchange with the identifier PXD009610. Correlation analysis of the proteomes demonstrated low concordance between the two cell types ( R 2 ≈ 0.13). Bioinformatics analysis indicate that RANKL‐dependent signaling was intact in RAW 264.7 cells, but biological processes known to be dependent on M‐CSF were significantly different, including cell cycle control, cytoskeletal organization, and apoptosis. RAW 264.7 cells exhibited constitutive activation of Erk and Akt that was dependent on the activity of Abelson tyrosine kinase, and the timing of Erk and Akt activation was significantly different between BMMs and RAW 264.7 cells. Our findings provide the first evidence for major discrepancies between BMMs and RAW 264.7 cells, indicating that careful consideration is needed when using the RAW 264.7 cell line for studying M‐CSF‐dependent signaling and functions. © 2018 American Society for Bone and Mineral Research. © 2018 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Objectives/HypothesisOver the past decade, thoracic slide tracheoplasty (TST) has become the principal operation in the management of congenital tracheal stenosis. The purpose of this report was to describe our experience with revision TST following unsuccessful prior tracheal reconstruction.Study DesignRetrospective analysis at an academic children's hospital.MethodsPatients undergoing TST on cardiopulmonary bypass between January 2005 and May 2014 were reviewed. Patients with a history of prior airway surgery were extracted for further analysis. Preoperative patient variables and postoperative outcomes were evaluated and compared between patients undergoing revision slide tracheoplasty (RTST) and a control group of 26 matched patients undergoing primary surgery TST.ResultsTwenty‐six revision patients (25 referrals, one primary patient) of 162 patients reviewed over the study period met inclusion criteria. Twenty‐three patients had a history of complete tracheal rings, and three patients had cartilaginous deficiency. A total of 41 airway reconstruction procedures had been performed prior to RTST. When compared to primary TST, patients undergoing RTST required fewer cardiac procedures intraoperatively, and fewer mean ventilator hours (P = .01) postoperatively. There was no significant difference in the median length of stay, requirement of >48 hours ventilation, or postoperative complications between groups. There was one nonsurgical postoperative mortality following RTST.ConclusionsDespite some differences in the postoperative management when compared to nonrevision cases, revision TST can be successfully performed after prior tracheal reconstruction with good postoperative outcomes.Level of Evidence4. Laryngoscope, 128:2181–2186, 2018

Objectives The ability to determine the severity of renal fibrosis, which is involved in most chronic kidney diseases, may be beneficial for monitoring disease progression and management. The aim of this study was to assess a new method involving gold nanoparticles conjugated to an anti-collagen-I antibody (Co-I-AuNPs) as a computed tomography (CT) imaging contrast for the evaluation of renal fibrosis in situ. Materials and Methods Gold nanoparticles conjugated to an anti-collagen-I antibody were prepared using gold chloride reduction with sodium citrate and coated with polyethylene glycol (PEG), and their size was determined by electron microscopy and nanoparticle tracking analysis. Anti-collagen-I antibody was then conjugated to PEG-SH/COOH on the AuNP surface. The success of antibody conjugation was tested in vitro using collagen-coated plate and mouse stenotic kidney sections and in vivo using micro-CT and multidetector CT imaging. Results Bare AuNPs were 18.7 ± 0.6 nm and PEG-coated AuNPs were 45.3 ± 0.1 nm in size. In vitro, Co-I-AuNPs specifically bound to both a collagen-coated plate and mouse fibrotic kidneys. Furthermore, the stenotic mouse kidney showed increased Co-I-AuNPs retention compared with the contralateral kidney (59.3 ± 5.1 vs 45.1 ± 1.7 HU, P = 0.05), which correlated with its collagen deposition. Micro-CT also detected gold signals in situ in the Co-I-AuNP-injected kidney, which colocalized with histological trichrome staining. Conclusion Gold nanoparticles conjugated to an anti-collagen-I antibody are able to visualize kidney fibrosis in vitro and in situ and may be useful for nondestructive quantification of tissue fibrosis.

Objective Synovitis is a prevalent feature in patients with knee osteoarthritis ( OA ) and meniscal tear and is associated with pain and cartilage damage. Patient‐reported swelling is also prevalent in this population. The aim of this study was to investigate the cross‐sectional association between patient‐reported swelling and effusion‐synovitis detected by magnetic resonance imaging ( MRI ) in patients with OA and meniscal tear. Methods We used baseline data from a multicenter, randomized controlled trial, Meniscal Tear in Osteoarthritis Research ( METEOR ). MRI ‐identified effusion‐synovitis, a proxy for effusion and synovitis on noncontrast MRI s, was graded as none/small versus medium/large. Using MRI ‐identified effusion‐synovitis as the gold standard, we assessed the sensitivity, specificity, and positive predictive value of patient self‐reported swelling in the previous week (none, intermittent, constant) to detect effusion and synovitis. Results We analyzed data from 276 patients. Twenty‐five percent of patients reported no swelling, 40% had intermittent swelling, and 36% had constant swelling. Fifty‐two percent had MRI ‐identified medium/large–grade effusion‐synovitis. As compared with MRI ‐identified effusion‐synovitis, any patient‐reported swelling (versus none) had a sensitivity of 84% (95% confidence interval [95% CI ] 77–89), a specificity of 34% (95% CI 26–43), and a positive predictive value of 57% (95% CI 54–61). A history of constant swelling (versus none or intermittent) showed a sensitivity of 46% (95% CI 37–54), a specificity of 75% (95% CI 67–82), and a positive predictive value of 66% (95% CI 58–74). Conclusion We found that the sensitivity and specificity of patient‐reported swelling were modest when compared with effusion‐synovitis detected by MRI . These data urge caution against using patient‐reported swelling as a proxy of inflammation manifesting as effusion‐synovitis.