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This multicenter, phase 4, Prospective Randomized Open, Blinded End‐point (PROBE) study aimed to evaluate safety and efficacy of telmisartan/rosuvastatin single‐pill combination (SPC) therapy on lowering central blood pressure (BP) compared with telmisartan monotherapy in hypertensive patients with dyslipidemia in Korea. Study was terminated earlier than planned due to COVID‐19 pandemic, thus should be considered as a pilot study. Among 125 patients who met the inclusion criteria of hypertension and dyslipidemia (defined as 10‐year Atherosclerotic Cardiovascular Disease risk score over 5%), 80 patients went through 4‐week single‐group run‐in period with telmisartan 40–80 mg, then randomized to telmisartan 80 mg + rosuvastatin (10 or 20 mg) SPC group or telmisartan 80 mg monotherapy group. The central/brachial BP, brachial‐ankle pulse wave velocity (baPWV), and augmentation index (AIx) were assessed at baseline and 16 weeks later. Mean brachial SBP changed from 135.80 ± 14.22 mmHg to 130.69 ± 13.23 mmHg in telmisartan/rosuvastatin group and from 134.37 ± 12.50 mmHg to 133.75 ± 12.30 mmHg in telmisartan monotherapy group without significant difference (between‐group difference p = .149). Mean central SBP were reduced significantly in the telmisartan/rosuvastatin group with change from 126.72 ± 14.44 mmHg to 121.56 ± 14.56 mmHg while telmisartan monotherapy group showed no significant change (between‐group difference p = .028). BaPWV changed from 1672.57 ± 371.72 m/s to 1591.75 ± 272.16 m/s in telmisartan/rosuvastatin group and from 1542.85 ± 263.70 m/s to 1586.12 ± 297.45 m/s in telmisartan group with no significance (between‐group difference p = .078). Change of AIx had no significant difference (between‐group difference p = .314). Both groups showed excellent compliance rate of 96.9 ± 4.5% with no significant difference in adverse rate. Telmisartan/rosuvastatin SPC therapy was more effective in lowering central BP compared with the telmisartan monotherapy. The results of this study showed benefit of additive statin therapy in hypertensive patients combined with dyslipidemia.

Author's summary We investigated the association between body mass index and clinical outcomes of peripheral artery disease (PAD) after endovascular therapy (EVT). A total of 2914 PAD patients undergoing EVT were participated according to body mass index groups. Underweight was significantly associated with increased risk of major adverse cardiovascular events (MACE) (adjusted hazard ratio [HR], 1.540; 95% confidence interval [CI], 1.091–2.173) and major adverse limb events (MALE) (adjusted HR, 1.523; 95% CI, 1.066–2.177) compared with normal weight. Plus, overweight was associated with lower risk of MACE and not with MALE. However, obesity showed no significant association with MACE or MALE., Background and Objectives Few studies have investigated the obesity paradox in clinical outcomes of peripheral artery disease (PAD). We investigated the association between body mass index (BMI) and clinical outcomes in PAD patients undergoing endovascular therapy (EVT). Methods Patients (n=2,914) from the retrospective Korean Vascular Intervention Society Endovascular Therapy in Lower Limb Artery Disease registry were categorized according to BMI: underweight (

AIMS The aim of this trial was to compare the safety and efficacy of a thin-strut biodegradable polymer sirolimus-eluting cobalt-chromium stent (Orsiro) to a thick-strut biodegradable polymer biolimus-eluting stent (BioMatrix). METHODS AND RESULTS This randomised, open-label, non-inferiority trial was conducted among patients undergoing percutaneous coronary intervention. The primary endpoint was target lesion failure (TLF). Between July 2014 and September 2017, we randomly assigned 2,341 patients to BioMatrix stents (n=1,166) or Orsiro stents (n=1,175). We analysed 2,327 patients who completed 18-month follow-up. The mean patient age was 63.5 years, and 1,565 (67.3%) patients presented with acute coronary syndrome. At 18 months, 34 (2.9%) patients with BioMatrix stents and 24 (2.1%) with Orsiro stents experienced TLF (hazard ratio [HR] 0.70, upper limit of one-sided 95% confidence interval: 1.18, p for non-inferiority

Background and objectives The EPIC™ stent is a self-expanding, nitinol stent that has been designed to enhance flexibility and provide expansion within vessels. The aim of the present study was to investigate the clinical efficacy and safety of the EPIC™ stent when used to treat iliac artery diseases in a prospective Korean multicenter registry. Methods A total of 138 patients with iliac artery diseases who received endovascular treatment with EPIC™ stents at 9 Korean sites were enrolled in a prospective cohort and followed for 1 year. The primary endpoint was the 1-year freedom from target lesion revascularization (TLR). The secondary endpoints were 1-year clinical patency and freedom from major adverse events (MAEs). Results The mean age of the study subjects was 66.8±8.5 years and most subjects were male (86.2%). The most frequent lesion type was Trans-Atlantic Inter-Society Consensus B (43.5%) and the majority (56.5%) of the target lesions were located in the common iliac artery. Procedural success was obtained in 99.3% of patients. The freedom from TLR and the clinical patency at 1-year follow-up were 94.9% and 92.3%, respectively. The 1-year rate of MAEs was 5.1%. Combined coronary artery disease (hazard ratio [HR], 5.91; 95% confidence interval [CI], 1.13-30.89; p=0.035) and smaller stent diameter (HR, 0.38; 95% CI, 0.17-0.88; p=0.023) were identified as independent risk factors of TLR after EPIC™ stent implantation. Conclusions The EPIC™ stents demonstrated excellent immediate and 1-year efficacy and safety outcomes in iliac artery lesions in this multicenter, prospective, registry-based study.

The self-renewal transcription factor Nanog and the phosphoinositide 3-kinase (PI3K)–Akt pathway are known to be essential for maintenance of mesenchymal stem cells. We evaluated their contribution to the maintenance of CD133(+) cancer stem-like cells (CSCs) and spheroid-forming cells in patient-derived cell lines from three human sarcoma subtypes: HT1080 fibrosarcoma, SK-LMS-1 leiomyosarcoma, and DDLS8817 dedifferentiated liposarcoma. Levels of Nanog and activated Akt were significantly higher in sarcoma cells grown as spheroids or sorted for CD133 expression to enrich for CSCs. shRNA knockdown of Nanog decreased spheroid formation 10- to 14-fold, and reversed resistance to both doxorubicin and radiation in vitro and in H1080 flank xenografts. In the HT1080 xenograft model, doxorubicin and Nanog knockdown reduced tumor growth by 34% and 45%, respectively, and the combination reduced tumor growth by 74%. Using a human phospho-kinase antibody array, Akt1/2 signaling, known to regulate Nanog, was found to be highly activated in sarcoma spheroid cells compared with monolayer cells. Pharmacologic inhibition of Akt using LY294002 and Akt1/2 knockdown using shRNA in sarcoma CSCs decreased Nanog expression and spheroid formation and reversed chemotherapy resistance. Akt1/2 inhibition combined with doxorubicin treatment of HT1080 flank xenografts reduced tumor growth by 73%. Finally, in a human sarcoma tumor microarray, expression of CD133, Nanog, and phospho-Akt were 1.8- to 6.8-fold higher in tumor tissue compared with normal tissue. Together, these results indicate that the Akt1/2–Nanog pathway is critical for maintenance of sarcoma CSCs and spheroid-forming cells, supporting further exploration of this pathway as a therapeutic target in sarcoma.

The poor prognosis of gastric cancer (GC) results largely from metastasis and chemotherapy resistance. Toward novel therapeutic strategies that target or evade these phenomena, we evaluated the function of the transcriptional regulator transducin (β)-like 1 X-linked receptor 1 (TBL1XR1) in GC cells, including stem-like cells. In this study, the correlation of expression of TBL1XR1 and clinical features and GC patients' outcomes was evaluated. Knockdown or exogenous expression of TBL1XR1 was combined with in vitro (2D and 3D cultures) and in vivo (mouse lung and lymphatic metastasis models) assays to evaluate the function of TBL1XR1. TBL1XR1's downstream signaling was delineated by phospho-kinase array and knockdown of candidate mediators. Analysis of clinical data showed that TBL1XR1 overexpression was correlated with worse prognosis. Functional assays showed that TBL1XR1 promoted stemness, epithelial-mesenchymal transition (EMT), and lung and lymphatic metastasis in GC cells. TBL1XR1 activated ERK1/2-Sox2 signaling and was dependent on signaling via PI3K/AKT, in GC stem-like cells distinguished by CD44 expression. Moreover, inhibition of these signaling proteins reversed chemoresistance in in vitro and in vivo models. Taken together, our results indicate that TBL1XR1 promotes stemness and metastasis in GC, making it a potential prognostic indicator. The PI3K/AKT-TBL1XR1-ERK1/2-Sox2 axis may represent a target for the treatment of GC.

Background Toward identifying new strategies to target gastric cancer stem-like cells (CSCs), we evaluated the function of the tumour suppressor CDK5 regulatory subunit-associated protein 3 (CDK5RAP3) in gastric CSC maintenance. Methods We examined the expression of CDK5RAP3 and CD44 in gastric cancer patients. The function and mechanisms of CDK5RAP3 were checked in human and mouse gastric cancer cell lines and in mouse xenograft. Results We show that CDK5RAP3 is weakly expressed in gastric CSCs and is negatively correlated with the gastric CSC marker CD44. CDK5RAP3 overexpression decreased expression of CSC markers, spheroid formation, invasion and migration, and reversed chemoresistance in gastric CSCs in vitro and vivo. CDK5RAP3 expression was found to be regulated by extracellular-related kinase (ERK) signalling. ERK inhibitors decreased spheroid formation, migration and invasion, and the expression of epithelial-to-mesenchymal transition (EMT)-related proteins in both GA cells and organoids derived from a genetically engineered mouse model of GA. Finally, CDK5RAP3 expression was associated with reduced lymph-node metastasis and better prognosis, even in the presence of high expression of the EMT transcription factor Snail, among patients with CD44-positive GA. Conclusions Our results demonstrate that CDK5RAP3 is suppressed by ERK signalling and negatively regulates the self-renewal and EMT of gastric CSCs.

We have shown that activation of the receptor tyrosine kinase (RTK)-RAS pathway in gastric adenocarcinoma (GA) promotes acquisition of cancer stem-like cell (CSC) phenotypes including metastasis and chemotherapy resistance. Here, we evaluated the prognostic value of the CSC marker CD44 and the RTK-RAS activation marker phosphorylated MEK (p-MEK) in patients with resectable GA. CD44 and p-MEK were measured in tumors from GA patients who underwent curative-intent gastrectomy at Fujian Medical University Union Hospital (FMUUH, n = 134) and Memorial Sloan Kettering Cancer Center (MSKCC, n = 56). Overall survival (OS) was estimated by the Kaplan-Meier method, and multivariate analysis was performed by Cox proportional hazards regression modeling. Despite multiple significant differences in clinicopathologic characteristics between the FMUUH and MSKCC cohorts, high CD44 and high p-MEK expression were both independent negative prognostic factors for OS on univariate analysis in both cohorts (p

Aims We compared long-term clinical outcomes between patients treated with Orsiro sirolimus-eluting stent (O-SES) and those treated with durable biocompatible polymer Resolute Integrity zotarolimus-eluting stent (R-ZES). Methods and results The ORIENT trial was a randomized controlled noninferiority trial to compare angiographic outcomes between O-SES and R-ZES. We performed a post hoc analysis of 3-year clinical outcomes and included 372 patients who were prospectively enrolled and randomly assigned to O-SES (n = 250) and R-ZES (n = 122) groups in a 2:1 ratio. The primary endpoint was target lesion failure defined as a composite of cardiac death, nonfatal myocardial infarction, and target lesion revascularization. At 3 years, target lesion failure occurred in 4.7% and 7.8% of O-SES and R-ZES groups, respectively (hazard ratio, 0.58; 95% confidence intervals, 0.24-1.41; p = .232 by log-rank test). Secondary endpoints including cardiac death, myocardial infarction, and target lesion revascularization showed no significant differences between the groups. Stent thrombosis occurred in two patients in R-ZES group (0.0% vs. 1.6%, p = .040). Conclusion This study confirms long-term safety and efficacy of the two stents. We found a trend for lower target lesion failure with O-SES compared to R-ZES, although statistically insignificant.

To evaluate the effect of β-blockers according to heart rate in patients with acute myocardial infarction (AMI) without heart failure (HF) or left ventricular systolic dysfunction (LVSD).We enrolled patients with AMI without HF or LVSD between June 1, 2003, and February 28, 2015, from Seoul National University Hospital Acute Myocardial Infarction Registry. Patients were categorized according to discharge heart rate recorded on electrocardiographs and β-blocker use. Low heart rate was defined as less than 75 beats/min. The primary end point was 5-year all-cause mortality according to discharge heart rate and β-blocker use.Of 2271 patients, 1696 (74.7%) received β-blockers and 1427 (62.8%) had low heart rates. At 5 years after discharge, 205 patients died. Overall, patients with low heart rates (P.001) and those with β-blocker treatment had lower mortality (P.001). After adjustment for covariates, β-blocker use was associated with 48% reduced risk for 5-year mortality in patients with high heart rates (hazard ratio, 0.52; 95% CI, 0.35-0.76), but not in those with low heart rates (P=.97). In an inverse-probability treatment-weighted cohort, β-blocker use was also associated with improved mortality in those with a high heart rate. Findings were similar for 5-year cardiovascular mortality.Among survivors with AMI without HF or LVSD, β-blocker use was associated with reduced 5-year all-cause mortality in patients who have high heart rates, but not in those with low heart rates.

Intestinal-type gastric cancer often results from Helicobacter pylori infection through intestinal metaplasia, a transdifferentiated premalignant phenotype. Because H. pylori virulence factor CagA has been associated with aberrant expression of the transcription factor CDX1, which regulates intestinal differentiation, we explored its relationship with H. pylori infection and function during gastric carcinogenesis in normal gastric epithelial cells and gastric cancer cell lines. Infection of HFE 145 cells with CagA+ H. pylori increased expression of CDX1, as well as the epithelial-to-mesenchymal transition (EMT) markers Snail and Slug, increased invasion and migration, but those effects were not found in HFE 145 cells infected with CagA-deficient H. pylori. CDX1 overexpression increased expression of the intestinal markers Villin, sucrose isomaltase (SI), and MUC2, induced spheroid formation, and enhanced expression of the stem cell markers CD44, SOX2, Oct4, and Nanog, while CDX1 knockdown inhibited proliferation and intestinal stemness. Treatment of CDX1-expressing cells with metformin, an antidiabetic drug known to decrease the risk of gastric cancer, decreased expression of EMT and stemness markers, and reduced spheroid formation. In a murine xenograft model, combining metformin or shCDX1 with cisplatin reduced tumor growth, increased caspase-3 cleavage, and reduced expression of CD44 and MMP-9 to a greater degree than cisplatin alone. Patients with more advanced intestinal metaplasia staging exhibited higher CDX1 expression than those with earlier intestinal metaplasia staging (P = 0.039), and those with H. pylori tended to have more CDX1 expression than noninfected patients (P = 0.061). Finally, human tissue samples with higher CDX1 levels showed prominent CD44/SOX2 expression. Our findings indicate CagA+ H. pylori–induced CDX1 expression may enhance gastric cancer tumorigenesis and progression, and support therapeutic targeting of CDX1 in gastric cancer. Implications: This study shows that CDX1 contributes to the tumorigenesis and progression of gastric cancer and suggests the potential of targeting CDX1 to treat this malignancy.

To identify drivers of sarcoma cancer stem-like cells (CSCs), we compared gene expression using RNA sequencing between HT1080 fibrosarcoma and SK-LMS-1 leiomyosarcoma spheroids (which are enriched for CSCs) compared with the parent populations. The most overexpressed survival signaling-related gene in spheroids was phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3), a regulatory subunit of PI3K, which functions in tumorigenesis and metastasis. In a human sarcoma microarray, PIK3R3 was also overexpressed by 4.1-fold compared with normal tissues. PIK3R3 inhibition using shRNA in the HT1080, SK-LMS-1, and DDLS8817 dedifferentiated liposarcoma in spheroids and in CD133+ cells (a CSC marker) reduced expression of CD133 and the stem cell factor Nanog and blocked spheroid formation by 61–71%. Mechanistic studies showed that in spheroid cells, PIK3R3 activated AKT and ERK signaling. Inhibition of PIK3R3, AKT, or ERK using shRNA or inhibitors decreased expression of Nanog, spheroid formation by 68–73%, and anchorage-independent growth by 76–91%. PIK3R3 or ERK1/2 inhibition similarly blocked sarcoma spheroid cell migration, invasion, secretion of MMP-2, xenograft invasion into adjacent normal tissue, and chemotherapy resistance. Together, these results show that signaling through the PIK3R3/ERK/Nanog axis promotes sarcoma CSC phenotypes such as migration, invasion, and chemotherapy resistance, and identify PIK3R3 as a potential therapeutic target in sarcoma.

There are limited data evaluating conformation of antithrombotic therapy usage to the guideline recommendations. We investigated clinical trends and prognoses of patients with atrial fibrillation (AF) according to anticoagulants and antiplatelet agents beyond 1 year after percutaneous coronary intervention (PCI). We analyzed the records of patients with AF who underwent PCI using the Korean National Health Insurance Service database. The primary endpoint was a composite of major adverse cardiac events (MACE). The safety outcome was bleeding complications. Of 4193 participants, 81.6% received antiplatelet therapy, whereas 27.3% had oral anticoagulant (OAC)-based therapy at 18 months after PCI. The dominant therapy was dual antiplatelet therapy (37.2%), and only 3.3% of participants had OAC monotherapy. At the 1-year follow-up, the incidence of MACE was significantly lower among those receiving a combination of OAC and single antiplatelet therapy (SAPT) than among those receiving OAC monotherapy (4.78% vs. 9.42%, p = 0.017). Bleeding complication events (5.01% vs. 5.80%, p = 0.587) did not differ between the groups. In clinical practice, most patients with AF who underwent PCI continued to receive antiplatelet agents beyond 1-year post-PCI. OAC with SAPT seemed to be more effective than OAC monotherapy, without a difference in safety.

Background UFM1 has been found to be involved in the regulation of tumor development. This study aims to clarify the role and potential molecular mechanisms of UFM1 in the invasion and metastasis of gastric cancer. Methods Expression of UFM1 in gastric tumor and paired adjacent noncancerous tissues from 437 patients was analyzed by Western blotting, immunohistochemistry, and realtime PCR. Its correlation with the clinicopathological characteristics and prognosis of gastric cancer patients was analyzed. The effects of UFM1 on the invasion and migration of gastric cancer cells were determined by the wound and trans-well assays, and the effect of UFM1 on subcutaneous tumor formation was verified in nude mice. The potential downstream targets of UFM1 and related molecular mechanisms were clarified by the human protein kinase assay and co-immunoprecipitation technique. Results Compared with the corresponding adjacent tissues, the transcription level and protein expression level of UFM1 in gastric cancer tissues were significantly downregulated (P P Conclusion UFM1 suppresses the invasion and metastasis of gastric cancer by increasing the ubiquitination of PDK1 through negatively regulating PI3K/AKT signaling.

Our previous work showed that in a mouse model of gastric adenocarcinoma with loss of p53 and Cdh1 that adding oncogenic Kras (a.k.a. Tcon mice) accelerates tumorigenesis and metastasis. Here, we sought to examine KRAS activation in epithelial-to-mesenchymal transition (EMT) and generation of cancer stem–like cells (CSC). Transduction of nontransformed HFE-145 gastric epithelial cells with oncogenic KRASG12V significantly decreased expression of the epithelial marker E-cadherin, increased expression of the mesenchymal marker vimentin and the EMT transcription factor Slug, and increased migration and invasion by 15- to 17-fold. KRASG12V also increased expression of self-renewal proteins such as Sox2 and increased spheroid formation by 2.6-fold. In tumor-derived organoids from Tcon mice, Kras knockdown decreased spheroid formation, expression of EMT-related proteins, migration, and invasion; similar effects, as well as reversal of chemoresistance, were observed following KRAS knockdown or MEK inhibition in patient tumor-derived gastric adenocarcinoma cell lines (AGS and KATOIII). KRAS inhibition in gastric adenocarcinoma spheroid cells led to reduced AGS flank xenograft growth, loss of the infiltrative tumor border, fewer lung metastases, and increased survival. In a tissue microarray of human gastric adenocarcinomas from 115 patients, high tumor levels of CD44 (a marker of CSCs) and KRAS activation were independent predictors of worse overall survival. In conclusion, KRAS activation in gastric adenocarcinoma cells stimulates EMT and transition to CSCs, thus promoting metastasis. Implications: This study provides rationale for examining inhibitors of KRAS to block metastasis and reverse chemotherapy resistance in gastric adenocarcinoma patients.

Background/aims After a study comparing drug-eluting stents (DESs) to sequential treatment with drug-eluting balloons (DEBs) and bare metal stents (BMSs), we retrospectively analysed strut malapposition and neointimal hyperplasia in de novo coronary lesions using optical coherence tomography (OCT) or intravascular ultrasonography (IVUS). Methods We obtained OCT data from 16 patients (eight per group) and IVUS data from 40 patients (20 per group). OCT or IVUS was performed after the index procedure and after 9 months. Parameters including obstruction volume due to neointimal hyperplasia (neointimal hyperplasia volume/stent volume, %), strut malapposition (% of malapposed struts), and intra-individual inhomogeneity of in-stent restenosis were compared. Results Although obstruction volume due to neointimal hyperplasia was significantly higher in the DEB-BMS group (14.90 ± 15.36 vs. DES 7.03 ± 11.39, p = 0.025), there was no difference in strut malapposition between the two groups (DEB-BMS 1.99 ± 5.37 vs. DES 0.88 ± 2.22, p = 0.856). The DEB-BMS group showed greater intra-individual inhomogeneity of in-stent restenosis pattern than the DES group. Conclusion Treatment with DEB followed by BMS failed to improve strut malapposition despite higher in-stent neointimal growth, probably because of the inhomogeneous inhibition of in-stent neointimal hyperplasia by DEB. DEB technology should be improved to obtain even drug delivery to the vessel wall and homogeneous prevention of neointimal growth comparable to contemporary DES.

Background Some studies comparing minimally invasive direct coronary artery bypass (MIDCAB) and percutaneous coronary intervention (PCI) have reported MIDCAB's superiority, but they did not investigate contemporary PCI with newer generation drug-eluting stents (DES). We compared clinical outcomes after MIDCAB with previously reported outcomes after PCI with second-generation DES.Methods and Results:We retrospectively reviewed the records of patients treated with MIDCAB. Baseline characteristics and clinical outcomes after MIDCAB were compared with those for left anterior descending artery disease treated via PCI. The primary outcomes were major adverse cardiovascular and cerebrovascular events (MACCE), a composite of cardiovascular death, non-fatal myocardial infarction, ischemic stroke, and target vessel revascularization (TVR). A propensity score-matching (PSM) analysis was conducted to adjust for between-group differences in baseline characteristics. We analyzed 77 patients treated with MIDCAB and 2,206 treated with PCI. The MIDCAB group was older and had more severe coronary disease and a higher incidence of left ventricular dysfunction. Over a 3-year follow-up, the PCI group had favorable MACCE outcomes. After PSM, there were no between-group differences in MACCE (MIDCAB, 15.6% vs. PCI, 23.4%; hazard ratio [HR], 0.80; 95% CI: 0.38-1.68, P=0.548) or TVR (MIDCAB, 2.6% vs. PCI, 5.2%; HR, 0.51; 95% CI: 0.10-3.09, P=0.509). Conclusions Clinical outcomes were similar between MIDCAB and PCI using second-generation DES over 3 years of follow-up.

Background Neoadjuvant chemotherapy followed by gastrectomy with D2 lymphadenectomy is commonly used for patients with locally advanced gastric adenocarcinoma. The eighth AJCC ypTNM staging system was validated based on patients undergoing more limited lymphadenectomy (less than D2). The aim of this study was to develop a system for accurate staging of patients with locally advanced gastric adenocarcinoma who receive neoadjuvant chemotherapy followed by gastrectomy with D2 lymphadenectomy. Methods A modified system of ypTNM was developed, based on overall survival (OS) of patients receiving neoadjuvant chemotherapy followed by gastrectomy with D2 lymphadenectomy at Memorial Sloan Kettering Cancer Center, and validated using data from an international cohort of patients who had similar treatment. Results Of 325 patients in the derivation cohort, 33 (10·2 per cent) had ypT0 N0/+ tumours, which are not classifiable under the AJCC system. The 5-year OS rate for modified ypTNM stages I, II, IIIA and IIIB was 89, 71, 42·3 and 10 per cent respectively, compared with 82, 65·2 and 24·1 for AJCC stages I, II and III respectively. The concordance index (0·730 versus 0·709), estimated area under the curve (0·765 versus 0·740) and time-dependent receiver operating characteristic (ROC) curve throughout the observation period were all superior for modified ypTNM staging. For the validation cohort of 186 patients, the modified system was again better at separating patients into prognostic groups for OS. Conclusion The modified ypTNM staging system improves the accuracy of OS prediction for patients treated with neoadjuvant chemotherapy followed by gastrectomy with D2 lymphadenectomy.

Previous clinical studies have shown inconsistent results regarding the effect of erythropoietin in ST-segment elevation myocardial infarction (STEMI). This study investigated whether directed intracoronary infusion of darbepoetin-α into ischemic myocardium before reperfusion would reduce infarct size or post-infarct remodeling in STEMI patients.Eighty STEMI patients received one of the following treatments simultaneously with the first balloon inflation: intracoronary darbepoetin-α 300 μg (n = 40) or saline (n = 40), administered via the over-the-wire balloon system. The primary endpoint was infarct size estimated by serial cardiac enzyme levels after procedure. The secondary endpoints were (1) infarct size and proportion of salvaged myocardium measured with cardiac magnetic resonance (CMR) at baseline; (2) post-infarct remodeling (PIR), defined as an increase in left ventricular end-diastolic volume more than 20% at 4 months compared to the baseline on CMR; and (3) composite cardiovascular endpoints assessed at 4 months.The peak CK-MB [median 270.0 (interquartile range 139.8-356.3) versus 231.5 (131.0-408.5) ng/mL, P = 0.55] and troponin-I [128.5 (63.5-227.8) versus 109.0 (43.8-220.0) ng/mL, P = 0.52) ] did not differ between the darbepoetin-α and control group. Fifty-seven patients completed the baseline and 4-month follow-up CMR. There were no differences in infarct size [30.6 (18.1-49.8) versus 31.5 (22.5-47.3) cm3, P = 0.91), proportion of salvaged myocardium [26.7% (15.9-42.6%) versus 35.8% (22.4-48.8%), P = 0.12) or PIR (8.0% versus 6.7%, P = 0.62) between the two groups. Composite cardiovascular outcomes did not differ between the two groups.In conclusion, administration of intracoronary darbepoetin-α before reperfusion did not reduce infarct size or post-infarct remodeling in STEMI patients.

Atrial fibrillation is a common cardiac arrhythmia and an important risk factor for stroke and cardiovascular morbidity. However, there is limited evidence regarding the association of air pollution with atrial fibrillation. This study aimed to compare the short-term and long-term effects of air pollution on atrial fibrillation.A nationwide cohort from the Korean general population.Different analytical approaches were used for short-term and long-term effects. For the analysis of short-term effects, the daily incidence of emergency admissions for atrial fibrillation was identified. The relationship of atrial fibrillation with air pollutants, including PMDuring the study period, 1137 emergency visits were identified in Seoul as being associated with atrial fibrillation. A 10-μg/mThis study suggests that short-term exposure to PM

Background High-intensity statin therapy is typically used in patients with acute myocardial infarction (AMI) for secondary prevention. However, there have been consistent concerns regarding its association with diabetes mellitus. We investigated the effect of high-intensity atorvastatin and rosuvastatin on new-onset diabetes mellitus (NODM) and cardiovascular outcomes over a 3-year follow-up period. Methods Data from the Korea Acute Myocardial Infarction Registry were collected from November 2011 to October 2015, and 13,104 patients with AMI were enrolled from major cardiovascular centers. Among them, 2221 patients without diabetes who had been administered with high-intensity atorvastatin (40–80 mg) and rosuvastatin (20 mg) were investigated. The atorvastatin and rosuvastatin groups were evaluated for the incidence of NODM and major adverse cardiac events (MACE) including death, myocardial infarction, and revascularization cases in the following 3 years. Results Baseline characteristics were comparable between the two groups. Event-free survival rate of NODM was not significantly different between the atorvastatin and rosuvastatin groups (92.5% vs. 90.8%, respectively; Log-rank P-value = 0.550). The event-free survival rate of MACE was also not significantly different between atorvastatin and rosuvastatin groups (89.0% vs. 89.6%, respectively; Log rank P-value = 0.662). Multivariate Cox analysis revealed that statin type was not a prognostic factor in the development of NODM and MACE. Conclusions Administering high-intensity atorvastatin and rosuvastatin in patients with AMI produced comparable effects on NODM and clinical outcomes, suggesting their clinical equivalence in secondary prevention.

Background Although electrocardiography and cardiac troponin play important roles in the diagnosis of acute coronary syndrome (ACS), there remain unmet clinical needs. Heart-type fatty acid-binding protein (H-FABP) has been identified as an early diagnostic marker of acute myocardial infarction (AMI). In this study, we examined the diagnostic and prognostic value of H-FABP in patients suspected with ACS. Methods We conducted an observational single-center cohort study, including 89 adults aged 30 years or older, who presented to the emergency room (ER) within 24 hours after the onset of chest pain and/or dyspnea. We performed laboratory analysis and point-of-care testing (POCT) for cardiac markers, including H-FABP, troponin I, and creatine kinase-myocardial band. We also evaluated the correlation between cardiac markers and left ventricular (LV) dysfunction and extent of coronary artery disease (CAD). Results In patients presented to ER within 4 hours after symptom onset (n = 49), the diagnostic accuracy of H-FABP for AMI, as quantified by the area under the receiver operating characteristic curve, was higher (0.738; 95% confidence interval [CI], 0.591–0.885) than other cardiac markers. In POCT, the diagnostic accuracy of H-FABP (56%; 95% CI, 45–67) was significantly higher than other cardiac markers. H-FABP was correlated with not extent of CAD but post-AMI LV dysfunction. Conclusion H-FABP is a useful cardiac marker for the early diagnosis of AMI and prediction of myocardia injury. Difference in the circulatory release timeline of cardiac markers could explain its utility in early-stage of myocardial injury., Graphical Abstract

Background: This study aimed to present the development process and characteristics of the Korean Registry of Acute Myocardial Infarction for Regional Cardiocerebrovascular Centers (KRAMI-RCC). Methods: We developed KRAMI-RCC, a web-based registry for patients with AMI. Patients from 14 RCCs were registered for more than three years from July 2016. It includes an automatic error-checking system, and user training and on-site monitoring are performed to manage data quality. Results: A total of 11,700 AMI patients were registered in KRAMI-RCC over three years (73.9% men). The proportions of patients with ST-elevation and non-ST-elevation myocardial infarction at discharge were 43.4% and 56.6%, respectively. Of the total three-year patients, 5.6% died in the hospital, and 4.4% died 12 months after discharge. The case fatality within 12 months was 9.7%. Pre-hospital care data showed delayed arrival time after onset of symptoms (median 153 min) and low transportation rate by public ambulance (25.2%). Post-hospital care data showed lower participation rate in the second rehabilitation program (16.8%). Conclusions: The recently developed KRAMI-RCC registry has been more focused on pre-hospital and post-hospital data, which will be helpful in understanding the current state of AMI disease management and in making policy decisions to reduce case fatality in Korea.

Congenital interatrial shunt can unload the left atrium (LA) and may lower the risk of new-onset heart failure (HF) or atrial fibrillation (AF). We evaluated the risk of new-onset HF or AF in patients with and without interatrial shunt. We enrolled 2660 consecutive patients with acute stroke or transient ischemic attack (TIA) who underwent transesophageal echocardiography at Seoul National University Bundang Hospital from January 1, 2006 to December 31, 2018. The primary outcomes were 10-year new-onset HF, new-onset AF, and new-onset HF or AF composite. Overall, 466 (17.5%) patients with an interatrial shunt had smaller E velocity (0.66 ± 0.21 vs. 0.69 ± 0.22 m/s, P = 0.037) and smaller E/e′ (9.1 ± 4.0 vs. 10.0 ± 5.0, P = 0.001) than 2194 (82.5%) patients without an interatrial shunt. The 10-year incidence of AF, HF, and AF or HF composite was lower in patients with an interatrial shunt (10-year AF, 11.2 vs. 17.8%, P

ObjectiveTo investigate the long-term prognostic implications of transient new-onset atrial fibrillation (AF) in patients with acute myocardial infarction (AMI).DesignRetrospective observational study.SettingSingle tertiary centre.ParticipantsThis study included 2523 patients who presented with AMI from 3 June 2003 to 24 February 2015, after the exclusion of those with prior AF or in-hospital death.Outcome measuresPatients were divided into three groups according to the occurrence and type of new-onset AF: (1) sinus rhythm (SR) group; (2) paroxysmal AF (PaAF: AF converted to SR prior to discharge) group and (3) persistent AF (PeAF: AF persisted during the hospitalisation) group. Post-discharge all-cause mortality and stroke incidences were compared between the groups.ResultsNew-onset AF was observed in 271 patients (10.7%; PaAF: 230, PeAF: 41). The median follow-up period was 7.2 years (IQR: 5.2–9.4). The incidence of all-cause death and stroke was highest in the PeAF group, followed by the PaAF and SR groups (all-cause mortality: 48.8% vs 26.5% vs 14.7%, pConclusionsNew-onset AF following AMI is associated with poor long-term outcomes. Even when AF episodes are brief and are converted to SR, new-onset AF remains associated with an increased risk of recurrent AF and stroke.

IntroductionCoronary CT angiography (CCTA) is widely used for non-invasive coronary artery evaluation, but it is limited in identifying the nature of functional characteristics that cause ischaemia. Recent computational fluid dynamic (CFD) techniques applied to CCTA images permit non-invasive computation of fractional flow reserve (FFR), a measure of lesion-specific ischaemia. However, this technology has limitations, such as long computational time and the need for expensive equipment, which hinder widespread use.Methods and analysisThis study is a prospective, multicentre, comparative and confirmatory trial designed to evaluate the diagnostic performance of HeartMedi V.1.0, a novel CT-derived FFR measurement for the detection of haemodynamically significant coronary artery stenoses identified by CCTA, based on invasive FFR as a reference standard. The invasive FFR values ≤0.80 will be considered haemodynamically significant. The study will enrol 184 patients who underwent CCTA, invasive coronary angiography and invasive FFR. Computational FFR (c-FFR) will be analysed by CFD techniques using a lumped parameter model based on vessel length method. Blinded core laboratory interpretation will be performed for CCTA, invasive coronary angiography, invasive FFR and c-FFR. The primary objective of the study is to compare the area under the receiver–operator characteristic curve between c-FFR and CCTA to non-invasively detect the presence of haemodynamically significant coronary stenosis. The secondary endpoints include diagnostic accuracy, sensitivity, specificity, positive predictive value, negative predictive value and correlation of c-FFR with invasive FFR.Ethics and disseminationThe study has ethic approval from the ethics committee of Seoul National University Bundang Hospital (E-1709/420-001) and informed consent will be obtained for all enrolled patients. The result will be published in a peer-reviewed journal.Trial registration numberKCT0002725; Pre-results.

Little clinical evidence supports the strict implementation of glycemic control for diabetic patients with AMI. We aimed to demonstrate the effect of long-term glycemic control on mortality in patients with diabetes mellitus after acute myocardial infarction (AMI). Eight hundred and twenty-four consecutive diabetic patients were divided into three groups according to the mean hemoglobin (HbA1c) value

Objectives The aim of this study was to evaluate the effect of ticagrelor versus clopidogrel on left ventricular (LV) remodeling after reperfusion of ST-segment elevation myocardial infarction (STEMI) in humans. Background Animal studies have demonstrated that ticagrelor compared with clopidogrel better protects myocardium against reperfusion injury and improves remodeling after myocardial infarction. Methods In this investigator-initiated, randomized, open-label, assessor-blinded trial performed at 10 centers in Korea, patients were enrolled if they had naive STEMI successfully treated with primary percutaneous coronary intervention (PCI) and at least 6-month planned duration of dual-antiplatelet treatment. The coprimary endpoints were LV remodeling index (LVRI) (a relative change of LV end-diastolic volume) measured on 3-dimensional echocardiography and N-terminal pro–B-type natriuretic peptide level at 6 months. Results Among initially enrolled patients with STEMI (n = 336), 139 in each group completed the study. LVRI at 6 months was numerically lower with ticagrelor versus clopidogrel (0.6 ± 18.6% vs. 4.5 ± 16.5%; p = 0.095). Ticagrelor significantly reduced the 6-month level of N-terminal pro–B-type natriuretic peptide (173 ± 141 pg/ml vs. 289 ± 585 pg/ml; p = 0.028). These differences were prominent in patients with pre-PCI TIMI (Thrombolysis In Myocardial Infarction) flow grade 0. By multivariate analysis, ticagrelor versus clopidogrel reduced the risk for positive LV remodeling (LVRI >0%) (odds ratio: 0.56; 95% confidence interval: 0.33 to 0.95; p = 0.030). The LV end-diastolic volume index remained unchanged during ticagrelor treatment (from 54.7 ± 12.2 to 54.2 ± 12.2 ml/m2; p = 0.629), but this value increased over time during clopidogrel treatment (from 54.6 ± 11.3 to 56.4 ± 13.9 ml/m2; p = 0.056) (difference −2.3 ml/m2; 95% confidence interval: −4.8 to 0.2 ml/m2; p = 0.073). Ticagrelor reduced LV end-systolic volume index (from 27.0 ± 8.5 to 24.7 ± 8.4 ml/m2; p Conclusions Ticagrelor was superior to clopidogrel for LV remodeling after reperfusion of STEMI with primary PCI. (High Platelet Inhibition With Ticagrelor to Improve Left Ventricular Remodeling in Patients With ST Segment Elevation Myocardial Infarction [HEALING-AMI]; NCT02224534 )

Background The influence of intensive glucose control in diabetic patients on the macrovascular outcomes is controversial. Thus, this study aimed to elucidate the effect of preprocedural hemoglobin A1c (HbA1c) on clinical outcomes after endovascular therapy for lower extremity artery disease (LEAD) in diabetic patients. Methods Diabetic patients were enrolled from the retrospective cohorts of a Korean multicenter endovascular therapy registry and were divided according to the HbA1c level during index admission into the optimal ( Results Of the 1103 patients enrolled (897 men, mean age 68.2 ± 8.9 years), 432 (39.2%) were classified into the optimal glycemic control group and 671 (60.8%) into the suboptimal glycemic control group. In-hospital events and immediate procedural complications were not different between the two groups. The suboptimal group showed a trend towards a higher incidence of MALE than the optimal group (log-rank p = 0.072). Although no significant differences were found between the two groups in terms of overall survival or amputation, the risk of reintervention was significantly higher in the suboptimal group (log-rank p = 0.048). In the multivariate Cox regression model, suboptimal glycemic control was one of the independent predictors for reintervention. When our data were analyzed according to the initial presentation, suboptimal preprocedural HbA1c significantly increased the incidence of MALE compared with optimal preprocedural HbA1c only in patients with intermittent claudication. Conclusion In diabetic patients undergoing endovascular therapy for LEAD, suboptimal preprocedural HbA1c is associated with an increased risk of adverse limb events, especially in patients with intermittent claudication. Further prospective research will be required to validate the role of more intensive glycemic control on the reduction of adverse limb events in diabetic patients undergoing endovascular therapy for LEAD.

Background Detection of arrhythmias is crucial for the treatment of cardiovascular diseases. However, conventional devices do not provide sufficient diagnostic accuracy while patients should suffer from bothersome diagnostic process. We sought to evaluate diagnostic capability and safety of the new adhesive electrocardiogram (ECG) monitoring device in patients who need ECG monitoring during admission. Methods We enrolled 10 patients who admitted to Seoul National University Bundang Hospital and required continuous ECG monitoring between October 31, 2019 and December 18, 2019. New adhesive ECG monitoring device and conventional ECG monitoring device were simultaneously applied to the patients and maintained for 48 hours. From each patient, 48 pairs of ECG signal were collected and analyzed by two cardiologists independently. Discrepancy of diagnosis and frequency of noise or signal loss were compared between the two devices. Results From analyzable ECG data, discrepancy of arrhythmia diagnosis was not observed between the two devices. Noise rate was higher in conventional ECG monitoring device (2.5% vs. 17.3%, P < 0.001) and signal loss was not observed in new adhesive device while there was 9.4% of signal losses in conventional Holter recorder group. The new device was well-tolerated among 48 hours of monitoring period and no adverse event was observed. Conclusion A newer adhesive ECG monitoring device demonstrated similar diagnostic accuracy compared to conventional ECG monitoring device., Graphical Abstract

The aim of this study was to compare gastric cancer (GC) patients aged 80 years or older undergoing gastrectomy at two high-volume cancer centers in the US and China. Patients aged ≥ 80 years who underwent R0 resection at Memorial Sloan Kettering Cancer Center (MSKCC) in New York, USA (n = 159), and Fujian Medical University Union Hospital (FMUUH) in Fujian, China (n = 118) from January 2000 to December 2013 were included. Demographic, surgical, and pathologic variables were compared, and factors associated with survival were determined via multivariate analysis. The number of patients increased annually in the FMUUH cohort but not in the MSKCC cohort. Patients at MSKCC were slightly older (mean age 83.7 vs. 82.7 years), more commonly female (38 vs. 19%), and had higher average body mass index (BMI; 26 vs. 23). Treatment at FMUUH more frequently employed total gastrectomy (59 vs. 20%) and laparoscopic surgery (65 vs. 7%), and less frequently included adjuvant therapy (11 vs. 18%). In addition, FMUUH patients had larger tumors of more advanced T, N, and TNM stage. Morbidity (35 vs. 25%, p = 0.08) and 30-day mortality (2.5 vs. 3.3%, p = 0.67) were similar between the cohorts. For each TNM stage, there was no significant difference between MSKCC and FMUUH patients in 5-year overall survival and disease-specific survival (DSS). TNM stage was the only independent predictor of DSS for both cohorts. Patients ≥ 80 years of age selected for gastrectomy for GC at MSKCC and FMUUH had acceptable morbidity and mortality, and DSS was primarily dependent on TNM stage.

Structured Abstract Background Percutaneous coronary intervention (PCI) for true ostial left anterior descending artery (LAD)-chronic total occlusion (CTO) lesions poses technical challenges owing to its inherent anatomical features. Methods In total, 270 consecutive patients who underwent PCI for ostial LAD-CTO at 13 major cardiac centers in South Korea were included. Ostial LAD-CTO was strictly defined as a LAD-CTO lesion the proximal cap of which was confined within 1 mm from the carina of the distal left main coronary artery (LMCA) bifurcation. Results Ostial LAD-CTOs were frequently accompanied by stumpless lesion entry (43.4%), whereas significant bending within the occluded segment was less frequent (14.4%). The overall technical success rate was 85.9%, and serious in-hospital adverse events occurred in 5.6%. The retrograde approach tended to contribute more frequently to success in patients with concomitant LMCA disease, stumpless CTO, interventional collaterals, and higher Japanese-CTO scores. Apparent dissection or hematoma requiring rescue procedure at the LMCA or left circumflex artery occurred in 14 patients (5.2%), with a higher tendency in patients who had LMCA disease (12.1% vs. 4.2%) and stumpless entry (9.4% vs. 2.0%) than in those without. Among patients who were successfully treated with an average number of 1.7 stents, target-vessel failure occurred in 23 patients (9.9%) during a median 3.3 years of follow-up. Conclusions In this first, large-scale analysis of true ostial LAD-CTO, PCI was feasible with a high technical success rate and favorable mid-term outcomes. Clinically relevant inflow vessel injury can occur during PCI and should be an important technical consideration regarding safety.

Background: TARGIT-A trial showed that intraoperative radiotherapy (IORT) using Intrabeam® concurrent with lumpectomy within a risk-adapted approach could be considered as an option for eligible patients with early breast cancer. To introduce IORT in clinical practice for Korean breast cancer patients, safety profiles for this new technique from clinical trial with Korean are required due to ethnic (anatomical) difference. Acute toxicity is a key hurdle for patients receiving IORT, because IORT may affect wound healing and increase wound complications. We conducted a phase II study as a feasibility test of IORT at the dose of 20 Gy for the replacement of boost-EBRT in Korean women who are candidates for breast-conserving treatment. Methods: This single-arm trial aimed to investigate acute toxicity occurred within 6 months after IORT. In 1,119 patients receiving EBRT from TARGIT-A trial, the incidence of acute toxicity within 6 months is 15%. Compared with WBRT, we aim to prove a non-inferiority of IORT with 20 Gy. A sample size of 195 achieves 80% power to detect a non-inferiority proportion (P0) of 0.2300 using a one-sided binomial test for non-inferiority. These results assume that the actual proportion (P1) is 0.1500. Considering a drop-out rate of 10%, the trial would need to enroll 215 patients in total. This trial is registered with ClinicalTrials.gov, number NCT02213991. Results: From August 2014 to November 2016, 233 women with early breast cancer were screened, and 215 undergoing IORT were enrolled. In 36 women, clinically significant complications during acute period are noted. The rate of patients experiencing acute toxicity was 16.7% (95% CI, 11.8-21.7%). The actual non-inferiority margin of our trial was 21.7% under the pre-specified margin as 23.0%. In details, There are 31 with seroma collection (more than 3 times when aspiration volume is over 10cc), 2 with wound infection, and 5 with skin break down. At a median follow-up of 17.8 months, there is no local recurrence. Conclusions: Targeted intraoperative radiotherapy using Intrabeam® is a safe procedure for Korean breast cancer patients with acceptable toxicity profile in acute period. Citation Format: Lee HW, Yoon C, Ahn SG, Kim JW, Cha YJ, Lee IJ, Jeong J. A prospective phase II study of TARGeted Intraoperative radioTherapy boost plus whole breast irradiation in breast cancer patients undergoing breast-conserving treatment [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-11-21.

Objective Chest pain is one of the most common complaints in the emergency department (ED). Cardiac computed tomography angiography (CCTA) is a frequently used tool for the early triage of patients with low- to intermediate-risk acute chest pain. We present a study protocol for a multicenter prospective randomized controlled clinical trial testing the hypothesis that a low-dose CCTA protocol using prospective electrocardiogram (ECG)-triggering and limited-scan range can provide sufficient diagnostic safety for early triage of patients with acute chest pain. Methods The trial will include 681 younger adult (aged 20 to 55) patients visiting EDs of three academic hospitals for acute chest pain or equivalent symptoms who require further evaluation to rule out acute coronary syndrome. Participants will be randomly allocated to either low-dose or conventional CCTA protocol at a 2:1 ratio. The low-dose group will undergo CCTA with prospective ECG-triggering and restricted scan range from sub-carina to heart base. The conventional protocol group will undergo CCTA with retrospective ECG-gating covering the entire chest. Patient disposition is determined based on computed tomography findings and clinical progression and all patients are followed for a month. The primary objective is to prove that the chance of experiencing any hard event within 30 days after a negative low-dose CCTA is less than 1%. The secondary objectives are comparisons of the amount of radiation exposure, ED length of stay and overall cost. Results and conclusion Our low-dose protocol is readily applicable to current multi-detector computed tomography devices. If this study proves its safety and efficacy, dose-reduction without purchasing of expensive newer devices would be possible.

Rac1, a Rho GTPase family member, is dysregulated in a variety of tumor types including gastric adenocarcinoma, but little is known about its role in cancer stem-like cells (CSCs). Therefore, Rac1 activity and inhibition were examined in gastric adenocarcinoma cells and mouse xenograft models for epithelial-to-mesenchymal transition (EMT) and CSC phenotypes. Rac1 activity was significantly higher in spheroid-forming or CD44+ gastric adenocarcinoma CSCs compared with unselected cells. Rac1 inhibition using Rac1 shRNA or a Rac1 inhibitor (NSC23766) decreased expression of the self-renewal transcription factor, Sox-2, decreased spheroid formation by 78%–81%, and prevented tumor initiation in immunodeficient mice. Gastric adenocarcinoma CSCs had increased expression of the EMT transcription factor Slug, 4.4- to 8.3-fold greater migration, and 4.2- to 12.6-fold greater invasion than unselected cells, and these increases could be blocked completely with Rac1 inhibition. Gastric adenocarcinoma spheroid cells were resistant to 5-fluorouracil and cisplatin chemotherapy, and this chemotherapy resistance could be reversed with Rac1 shRNA or NSC23766. The PI3K/Akt pathway may be upstream of Rac1, and JNK may be downstream of Rac1. In the MKN-45 xenograft model, cisplatin inhibited tumor growth by 50%, Rac1 inhibition by 35%, and the combination by 77%. Higher Rac1 activity, in clinical specimens from gastric adenocarcinoma patients who underwent potentially curative surgery, correlated with significantly worse survival (P = 0.017). In conclusion, Rac1 promotes the EMT program in gastric adenocarcinoma and the acquisition of a CSC state. Rac1 inhibition in gastric adenocarcinoma cells blocks EMT and CSC phenotypes, and thus may prevent metastasis and augment chemotherapy. Implications: In gastric adenocarcinoma, therapeutic targeting of the Rac1 pathway may prevent or reverse EMT and CSC phenotypes that drive tumor progression, metastasis, and chemotherapy resistance. Mol Cancer Res; 15(8); 1106–16. ©2017 AACR.

Objective The pathophysiology and natural course of coronary nonculprit plaques remain unclear. We investigated whether the short-term natural course of nonculprit plaques differs between ST-segment elevation myocardial infarction (STEMI) and chronic total occlusion (CTO) patients. Methods We performed serial virtual histology intravascular ultrasound on nonculprit plaques in 26 STEMI and 11 CTO lesions at baseline and the 6-month follow-up. Results At baseline, more lesions in the STEMI group were virtual histology intravascular ultrasound-derived thin-cap fibroatheromas (TCFA; 76.9 vs. 18.1%, P=0.002). During the follow-up period, the plaque composition changed dynamically in the STEMI group (fibrofatty: 9.8±1.9 to 17.3±2.9%, P=0.030; dense calcium: 12.7±1.8 to 8.1±1.7%, P=0.026; necrotic core: 21.1±1.8 to 15.4±2.2%, P=0.052), with a consistent plaque size. In the CTO group, the plaque composition and plaque size remained consistent without a significant change. Also, more lesions in the STEMI group remained as or progressed to TCFA, compared with the CTO group (67 vs. 11%, P=0.089). Factors associated with a persistent TCFA or with a new development of TCFA were a large necrotic core volume index and the diagnosis of STEMI, whereas new statin usage was a protective factor. Conclusion Nonculprit lesions in STEMI patients were more unstable at the baseline compared with those in CTO patients. During follow-up, nonculprit lesions in STEMI and CTO patients showed a distinct pattern of change; the former were stabilized in plaque composition, whereas the latter remained consistent. The diagnosis of STEMI and a large necrotic core volume were predictors of evolution to a TCFA, and new statin usage was a protective factor.

The biological functions of circular RNAs (circRNAs) in gastric cancer (GC) remain largely unexplored. Here, we identified that circ-RanGAP1 was significantly upregulated in both GC tissues and exosomes from the plasma of GC patients. High circ-RanGAP1 expression was closely associated with an advanced TNM stage, lymph node metastases, and worse survival. Inhibition of circ-RanGAP1 decreased GC cell invasion and migration in vitro. Overexpression of circ-RanGAP1 had the opposite effect. Additionally, circ-RanGAP1 silencing remarkably suppressed tumor growth and metastasis of GC in vivo. Mechanistically, circ-RanGAP1 sponged miR-877-3p to upregulate VEGFA expression. Overexpression of miR-877-3p reversed the biological functions mediated by circ-RanGAP1 in GC cells. Interestingly, we demonstrated that circ-RanGAP1 was upregulated in plasma exosomes from preoperative GC patients. More importantly, the plasma exosomes derived from these patients enhanced the migration and invasion potential of GC cells. Overall, the circ-RanGAP1-mediated miR-877-3p/VEGFA axis promotes GC progression. Our findings suggest that circ-RanGAP1 might act as a potential prognostic biomarker and therapeutic target for GC treatment.

Background To evaluate the association between retinal artery occlusion (RAO) and subclinical coronary artery disease (CAD). Methods We studied 41 patients with non-arteritic RAO without any history or symptoms of CAD, who had undergone coronary computed tomographic angiography (CCTA) for systemic atherosclerotic evaluation between 2007 and 2012. The age- and gender-matched control group comprised 4-fold subjects who were randomly selected from asymptomatic subjects who underwent CCTA during general health evaluation. Medical records and CCTA findings were compared between RAO patients and control groups. Multiple logistic regression analysis was carried out to assess the risk factors associated with CAD. Results Cardiovascular risk factors were not significantly different between RAO patients and control groups. RAO patients showed higher coronary artery calcium score than did control subjects (267.9 ± 674.9 vs. 120.2 ± 289.5). On CCTA, the prevalence of obstructive CAD (diameter stenosis ≥ 50%) in RAO patients was significantly higher than that in controls (29% vs. 15%; odds ratio [OR], 3.0). RAO patients demonstrated a significantly higher segment-involvement score (SIS) (2.6 ± 3.0 vs. 1.6 ± 2.4) and segment-stenosis score (SSS) (3.6 ± 4.8 vs. 2.0 ± 3.3) than did controls. After adjustment of associated factors, RAO showed significant association (OR, 3.0) with obstructive CAD and extensive CAD (SIS > 4: OR, 2.8; SSS > 8: OR, 3.4). Conclusion Patients with RAO had a higher prevalence of subclinical obstructive CAD with a more extensive and heavier burden of coronary artery plaques than did age- and gender-matched controls. Physicians should understand the potential risk of CAD in RAO patients., Graphical Abstract

Background/Introduction Physical activity has been shown to reduce mortality in a dose-response fashion. Current guidelines recommend 500 to 1,000 MET-min per week of regular physical activity. However, evidence is limited regarding the specific dose-response relationship in patients with cardiovascular disease. Purpose Our aim was to compare the impact of physical activity on mortality in primary versus secondary cardiovascular prevention. Methods We analyzed 441,798 individuals with complete information on physical activity levels between 2009 and 2015 were extracted from a population-based cohort (National Health Insurance Service-National Health Screening cohort). Physical activity measured by self-report questionnaires. A rating of 2.9, 4.0, and 7.0 METs were assigned for light-intensity, moderate-intensity, and vigorous-intensity activities, respectively. Physical activity-related energy expenditure (MET-min/week) was calculated by summing the product of frequency, intensity, and duration. The level of physical activity was classified into 0, 0 to 499, 500 to 999, 1,000 to 1,499, and ≥1,500 MET-min/week. Study participants were stratified by the presence of cardiovascular disease, defined as prior myocardial infarction, ischemic heart disease, prior stroke, and/or chronic heart failure. The main study outcome was all-cause mortality. The median follow-up duration was 5.9 years. Results Individuals with cardiovascular disease had lower physical activity levels and a higher risk of mortality than those without cardiovascular disease. There was an inverse relationship between the physical activity level and the mortality risk in both groups. The benefit in the secondary prevention group was shown to be greater than that in the primary prevention group: every 500 MET-min/week increase in physical activity resulted in a 14% and 7% risk reduction in mortality in the secondary and primary prevention groups, respectively (interaction P Adjusted risk of mortality Conclusion Individuals with cardiovascular disease may benefit from physical activity to a greater extent than do healthy subjects without cardiovascular disease. Clinicians should encourage patients with cardiovascular disease to maintain a physically active lifestyle as much as possible.

This study aimed to determine the association between achieved blood pressure at 6-month follow-up and cardiovascular outcomes at 2 years in patients treated with β-blockers and renin-angiotensin-aldosterone blockers after acute myocardial infarction (AMI).We analyzed data from 5503 patients enrolled in the national AMI registry. Patients with myocardial reinfarction (MrI), rehospitalization for heart failure (rHHF), or stroke before 6-month follow-up were excluded. Achieved blood pressures were categorized into 10-mm Hg increments. The primary outcome was all-cause death. The secondary outcome was a composite of all-cause death, MrI, and rHHF. Hazard ratios (HRs) were estimated with multivariable-adjusted Cox hazards models using 125- to 134-mm Hg systolic blood pressure (SBP) and 75- to 84-mm Hg diastolic blood pressure (DBP) subgroups as reference.After a median follow-up of 2.1 years, SBP115 mm Hg was associated with increased risks for all-cause death (adjusted HR: 2.202 [1.158-4.188]) and for a composite outcome (HR: 1.682 [1.075-2.630]). Likewise, DBP75 mm Hg tended to be associated with an increase in all-cause death (HR: 2.078 [0.998-4.327] for DBP of 65 to 74 mm Hg; HR: 2.610 [1.256-5.423] for DBP65 mm Hg). Even in patients75 years, the risk of a composite outcome was increased for DBP65 mm Hg (HR: 2.492 [1.401-4.434]).Low blood pressure achieved with β-blocker and renin-angiotensin-aldosterone blocker at 6 months was associated with an increased risk of all-cause mortality independently of confounding factors in patients with AMI. This finding suggests that caution should be taken for patients with AMI who use blood-pressure-lowering treatments.

Abstract Head and neck squamous cell carcinomas (HNSCCs) harbor a subset of cells that are CD44(+) and present with malignancy and radiotherapy resistance. As a key regulator of self-renewal, Nanog expression not only determines cell fate in pluripotent cells but also mediates tumorigenesis in cancer cells; thus, we examined the role of Nanog in CD44(+) HNSCC. Three HNSCC cell lines, tumor xenografts, and patient tumors were examined. Nanog levels were significantly higher in CD44(+) HNSCC spheroids than in CD44(−) spheroids, and further increased when grown as spheroids to enrich for CSCs. CD44(+) spheroids showed a 3.4–7.5-fold increase in migration and invasion compared with CD44(−) spheroids and were resistant to radiation therapy, which was reversed by inhibiting Nanog. Nanog knockdown also decreased spheroid formation by 66.5–68.8%. Moreover, a phosphokinase array identified upregulated ERK1/2 signaling in CD44(+) HNSCC cells compared with that in CD44(−) cells. ERK1/2 signaling was found to regulate Nanog expression, aiding tumor progression, metastasis, and radiotherapy resistance. In xenograft models, the combination of radiation and Nanog or ERK1/2 inhibition inhibited tumor growth by 75.6% and 79.1%, respectively. In lung metastasis models, CD44(+) cells injected into the tail vein of mice led to significantly more lung metastases and higher Nanog expression level compared with that by ERK1/2-knockdown CD44(+) cells. Finally, in tumor tissues, CD44 and Nanog expression levels were correlated with tumorigenesis in HNSCC patients. Thus, targeting Nanog and the ERK1/2 signaling pathway may prevent or reverse CSC phenotypes and epithelial–mesenchymal transition that drive tumor progression, metastasis, and radiotherapy resistance in HNSCC.

BACKGROUND Self-expandable stents, Absolute Pro® (ABS) and Complete SE® (COM), demonstrated safety and efficacy in previous studies. We aimed to determine which stent is more effective for the endovascular treatment of femoropopliteal artery disease. METHODS We enrolled patients who underwent endovascular intervention from 2010 to 2015 in our hospital. The primary endpoint was clinical primary patency, which is a composite of freedom from restenosis or clinically driven target lesion revascularization (TLR). RESULTS A total of 197 patients and 210 limbs were analyzed, with 96 limbs of 88 patients assigned to the ABS group and 114 limbs of 109 patients assigned to the COM group. Baseline and lesion characteristics were similar between the two groups. The number of stents per limbs were 1.28±0.55 and 1.29±0.51 in the ABS and COM groups, respectively (P=0.92). The postprocedure ankle-brachial index was significantly improved in both groups compared with the preprocedural one (P

ObjectivesTo date, no research has investigated the association between cardiac complication and electrical injury; hence, we aimed to assess the consequences and relating factors of cardiac complications from electrical injuries in South Korea.DesignRetrospective single-centre study.Participants721 patients who had electrical injury–related admission during 2007–2017. An electronic medical record system was used to extract records of patients admitted for electrical injury treatment.ResultsCardiac complications included abnormal parameters of myocardial damage, abnormal regional wall motion detected via echocardiogram, dysrhythmia (eg, bradycardia, atrial flutter/fibrillation) and ventricular tachycardia or fibrillation. Overall, 107 patients (14.8%) experienced cardiac complications. The average admission duration and intensive care unit stay duration were significantly longer in patients with cardiac complications than in those without them (75.0±45.3 vs 56.6±48.0 days and 19.3±24.1 vs 10.4±15.5 days, respectively, p=0.01). All deaths occurred within 32 days, and the most common cause of death was septic shock. Total body surface area (TBSA) was only positively related factor to cardiac complications.ConclusionThis study is the first in South Korea to reveal that electrical accident patients with cardiac complications experience poorer in-hospital prognosis, and TBSA was the only risk factor of cardiac complications. And initial treatment for infection and inflammations could be important in electrical injury.

AIMS The aim of this study was to compare the outcomes between multivessel and infarct-related artery (IRA)-only percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI), multivessel disease (MVD), and severe renal dysfunction (RD) using the nationwide AMI registry. METHODS AND RESULTS Among 13,104 patients, 537 diagnosed with AMI and MVD who had severe RD at presentation (estimated glomerular filtration rate [GFR]

Background/aims Whether the presence of chronic total occlusion (CTO) affects patency after stenting in femoropopliteal lesions is unknown. We determined the effects of plain balloon angioplasty (POBA) in comparison with those of stenting on patency for femoropopliteal CTO and stenosis (non-CTO). Methods We analyzed data from the Korean Vascular Intervention Society Endovascular Therapy in Lower-Limb Artery Diseases Registry, a multicenter cohort of patients with lower extremity peripheral arterial disease. Data from 1,329 patients and 1558 limbs treated with endovascular intervention for at least one femoropopliteal lesion were evaluated. Results Among the 1,558 limbs, 345, 432, 275, and 506 were in the non-CTO-POBA, non-CTO-stent, CTO-POBA, and CTO-stent groups, respectively. During follow-up, loss of clinical primary patency, a composite of freedom from restenosis or clinically driven target lesion revascularization, occurred in 65 (18.8%), 68 (15.7%), 62 (22.5%), and 113 limbs (22.3%) in the non-CTO-POBA, non-CTO-stent, CTO-POBA, and CTO-stent groups, respectively. The patients in the non-CTO-stent group showed a significantly better clinical primary patency than those in the no-CTO-POBA group, whereas those in the CTO-stent and CTO-POBA groups showed no significant differences. After inverse probability of treatment weighting to balance the differences among covariates between the non-CTO-stent and non-CTO-POBA groups, the non-CTO-stent group still showed superior clinical primary patency as compared with the non-CTO-POBA group. Conclusion In the patients with femoropopliteal stenosis without CTO, stenting resulted in better clinical outcomes than balloon angioplasty. The presence of CTO in the femoropopliteal lesion should be considered when selecting a suitable device for performing endovascular procedures.

Background Diabetes mellitus (DM) causes macro- and microvasculopathy, but data on cardiac microvascular changes in large animals are scarce. We sought to determine the effect of DM on macro- and microvascular changes in diabetic pigs and humans. Methods Eight domestic pigs (4 with type I diabetes and 4 controls) underwent coronary angiography with optical coherence tomography (OCT; at baseline and 1 and 2 months), coronary computed tomography angiography, cardiac magnet resonance (CMR) imaging, and histologic examination. Results The diabetic pigs had more irregular capillaries with acellular capillaries and a smaller capillary diameter (11.7 ± 0.33 μm vs. 13.5 ± 0.53 μm; P < 0.001) than those of the control pigs. The OCT showed no significant epicardial stenosis in either group; however diabetic pigs had a greater intima-media thickness. CMR results showed that diabetic pigs had a lower relative upslope at rest (31.3 ± 5.9 vs. 37.9 ± 8.1; P = 0.011) and during stress (18.0 ± 3.0 vs. 21.6 ± 2.8; P = 0.007) than the control pigs, implying decreased myocardial perfusion. Among the 79 patients with ST elevation myocardial infarction, 25 had diabetes and they had lower myocardial perfusion on CMR as well. Conclusion DM causes microvascular remodeling and a decrease in myocardial perfusion in large animals at a very early stage of the disease course. Early and effective interventions are necessary to interrupt the progression of vascular complications in diabetic patients., Graphical Abstract

Tobacco smoking causes cardiovascular diseases, lung disease, and various cancers. Understanding the population-based characteristics associated with smoking and the cause of death is important to improve survival. This study sought to evaluate the differential impact of smoking on cardiac or non-cardiac death according to age. Data from 514,866 healthy adults who underwent national health screening in South Korea were analyzed. The participants were divided into three groups: never-smoker, ex-smoker or current smoker according to the smoking status. The incidence rates and hazard ratios (HRs) of cardiac or non-cardiac deaths according to smoking status and age groups during the 10-year follow-up were calculated to evaluate the differential risk of smoking. Over the follow-up period, 6,192 and 24,443 cardiac and non-cardiac deaths had occurred, respectively. The estimated incidence rate of cardiac and non-cardiac death gradually increased in older age groups and was higher in current smokers and ex-smokers than that in never-smokers among all age groups. After adjustment of covariates, the HRs for cardiac death of current smokers compared to never-smokers were the highest in individuals in their 40’s (1.82; 95% CI, 1.45–2.28); this gradually decreased to 0.96 (95% CI, 0.67–1.38) in individuals >80 years. In contrast, the HRs for non-cardiac death peaked in individuals in their 50’s, (HR 1.69, 95% CI 1.57–1.82) and was sustained in those >80 years (HR 1.40, 95% CI 1.17–1.69). Ex-smokers did not show elevated risk of cardiac death compared to never-smokers in any age group, whereas they showed significantly higher risk of non-cardiac death in their 60’s and 70’s (HR, 1.29; 95% CI, 1.19–1.39; HR 1.22, 95% CI, 1.12–1.32, respectively). Acute myocardial infarction and lung cancer showed patterns similar to those of cardiac and non-cardiac death, respectively. Smoking was associated with higher relative risk of cardiac death in the middle-aged group and non-cardiac death in the older age group. Ex-smokers in the older age group had elevated risk of non-cardiac death. To prevent early cardiac death and late non-cardiac death, smoking cessation should be emphasized as early as possible.

Objective Although chronic kidney disease (CKD) and diabetes are important prognostic factors in patients with peripheral artery disease, there are limited data regarding the outcomes of endovascular treatment (EVT) according to the severity of CKD, especially in the presence of diabetes. This study sought to compare clinical outcomes of lower limb EVT between patients with and patients without CKD according to the presence of diabetes. Methods Patients were enrolled from the Korean multicenter EVT registry and were divided according to the presence of diabetes, then further stratified by CKD (estimated glomerular filtration rate 2 ). The primary outcome was major adverse limb events (MALEs; a composite of reintervention for target limb, reintervention for target vessel, and unplanned major amputation) at 2 years. Results A total of 3045 patients were eligible for analysis: 1277 nondiabetic patients (944 without CKD, 333 with CKD) and 1768 diabetic patients (951 without CKD, 817 with CKD). CKD was associated with a significantly increased risk of MALEs after EVT in diabetic patients (14.4% vs 9.9%; adjusted hazard ratio, 1.60; 95% confidence interval, 1.28-2.01; P P = .203; interaction P = .018). In analysis stratified by the severity of CKD among diabetic patients, end-stage renal disease was significantly associated with an increased risk of MALE. Conclusions CKD was associated with a significantly higher risk of MALEs after EVT in diabetic patients but not in nondiabetic patients. The increased risk of MALEs was mainly driven by patients with end-stage renal disease.

Several studies have reported a high rate of RHOA mutations in the Lauren diffuse-type gastric adenocarcinoma (GA) but not in intestinal-type GA. The aim of this study was to determine if RhoA activity is prognostic for overall survival (OS) in patients with resectable GA.Retrospective review was performed on a prospective database of GA patients who underwent potentially curative resection between 2003 and 2012 at a single institution. Tissue microarrays were constructed from surgical specimens and analyzed for phosphorylated RhoA, a marker of inactive RhoA signaling. OS was estimated by the Kaplan-Meier method, and multivariate analysis was performed by Cox proportional hazards regression modeling.One hundred thirty-six patients with diffuse-type GA and 129 patients with intestinal-type GA were examined. Compared to intestinal-type GA, diffuse-type GA tumors were significantly associated with increased tumor size and advanced tumor, node, metastasis (TNM) classification system stage. In patients with diffuse-type GA, high RhoA activity was associated with significantly worse OS when compared to low RhoA activity (5-year OS 52.5 vs. 81.0 %, p = 0.017). This difference in OS was not observed in patients with intestinal-type GA (5-year OS 83.9 vs. 81.6 %, p = 0.766). On multivariate analysis of diffuse-type GA patients, high RhoA activity was an independent negative prognostic factor for OS (hazard ratio 2.38, 95 % confidence interval 1.07-5.28).Increased RhoA activity is predictive of worse OS in patients with diffuse-type GA who undergo potentially curative surgical resection. Along with findings from genomic studies, these results suggest RhoA may be a novel therapeutic target in diffuse-type GA.

Background and Purpose Left ventricular (LV) diastolic dysfunction, developed in relation to myocardial dysfunction and remodeling, is documented in 15%-25% of the population. However, its role in functional recovery and recurrent vascular events after acute ischemic stroke has not been thoroughly investigated. Methods In this retrospective observational study, we identified 2,827 ischemic stroke cases with adequate echocardiographic evaluations to assess LV diastolic dysfunction within 1 month after the index stroke. The peak transmitral filling velocity/mean mitral annular velocity during early diastole (E/e’) was used to estimate LV diastolic dysfunction. We divided patients into 3 groups according to E/e’ as follows