Objectives The aim of this study was to test the hypothesis that angiotensin (Ang)-converting enzyme-2 (ACE2) overexpression may inhibit myocardial collagen accumulation and improve left ventricular ...(LV) remodeling and function in diabetic cardiomyopathy. Background Hyperglycemia activates the renin-Ang system, which promotes the accumulation of extracellular matrix and progression of cardiac remodeling and dysfunction. Methods Ninety male Wistar rats were divided randomly into treatment (n = 80) and control (n = 10) groups. Diabetes was induced in the treatment group by a single intraperitoneal injection of streptozotocin. Twelve weeks after streptozotocin injection, rats in the treatment group were further divided into adenovirus-ACE2, adenovirus–enhanced green fluorescent protein, losartan, and mock groups (n = 20 each). LV volume; LV systolic and diastolic function; extent of myocardial fibrosis; protein expression levels of ACE2, Ang-converting enzyme, and Ang-(1-7); and matrix metalloproteinase–2 activity were evaluated. Cardiac myocyte and fibroblast culture was performed to assess Ang-II and collagen protein expression before and after ACE2 gene transfection. Results Four weeks after ACE2 gene transfer, the adenovirus-ACE2 group showed increased ACE2 expression, matrix metalloproteinase–2 activity, and LV ejection fractions and decreased LV volumes, myocardial fibrosis, and ACE, Ang-II, and collagen expression in comparison with the adenovirus–enhanced green fluorescent protein and control groups. ACE2 was superior to losartan in improving LV remodeling and function and reducing collagen expression. The putative mechanisms may involve a shift in balance toward an inhibited fibroblast-myocyte cross-talk for collagen and transforming growth factor–beta production and enhanced collagen degradation by matrix metalloproteinase–2. Conclusions ACE2 inhibits myocardial collagen accumulation and improves LV remodeling and function in a rat model of diabetic cardiomyopathy. Thus, ACE2 provides a promising approach to the treatment of patients with diabetic cardiomyopathy.
Long-term outcomes are imperative to confirm safety of drug-eluting stents. There have been 2 randomized controlled trials comparing everolimus-eluting stents (EESs) and Resolute zotarolimus-eluting ...stents (ZES-Rs). To date, long-term clinical outcomes of these stents were limited to only 1 report, which has recently reported 4-year comparisons of these stents. Therefore, more evidence is needed regarding long-term clinical outcomes of the second-generation stents. This study compared the long-term clinical outcomes of EES with ZES-R in “all-comer” cohorts up to 3-year follow-up. The EXCELLENT and RESOLUTE-Korea registries prospectively enrolled 3,056 patients treated with EES and 1,998 with ZES-R, respectively, without exclusions. Stent-related composite outcomes (target lesion failure) and patient-related composite events up to 3-year follow-up were compared in crude and propensity score–matched analyses. Of 5,054 patients, 3,830 patients (75.8%) had off-label indication (2,217 treated with EES and 1,613 treated with ZES-R). The stent-related outcome (189 6.2% vs 127 6.4%, p = 0.812) and the patient-related outcome (420 13.7% vs 250 12.5%, p = 0.581) did not differ between EES and ZES-R, respectively, at 3 years, which was corroborated by similar results from the propensity score–matched cohort (hazard ratio HR 0.92, 95% confidence interval CI 0.70 to 1.20, p = 0.523 and 0.85, 95% CI 0.70 to 1.02, p = 0.081, for stent- and patient-related outcomes, respectively). The rate of definite or probable stent thrombosis up to 3 years (22 0.7% vs 10 0.5%, p = 0.370) was also similar. The rate of very late definite or probable stent thrombosis was very low and comparable between the 2 stents (3 0.1% vs 1 0.1%, p = 0.657). In multivariate analysis, chronic renal failure (adjusted HR 3.615, 95% CI 2.440 to 5.354, p <0.001) and off-label indication (adjusted HR 1.782, 95% CI 1.169 to 2.718, p = 0.007) were the strongest predictors of target lesion failure at 3 years. In conclusion, both stents showed comparable safety and efficacy at 3-year follow-up in this robust real-world registry with unrestricted use of EES and ZES-R. Overall incidences of target lesion failure and definite stent thrombosis, including very late stent thrombosis, were low, even in the patients with off-label indications, suggesting excellent long-term safety and sustained efficacy of both types of second-generation drug-eluting stents.
Background and Aims Although fully covered self-expandable metal stents (FCSEMSs) have been commonly used for EUS-guided biliary drainage (EUS-BD), FCSEMS migration is a main limitation of this ...procedure. In the present study we evaluated the technical and clinical success rates, adverse events, and long-term outcomes of a newly developed hybrid stent that has been customized for EUS-BD. Methods From September 2011 to May 2015, 54 consecutive patients with biliary obstruction were enrolled in this prospective, observational study. These patients were candidates for alternative BD techniques because of failed ERCP. The hybrid metal stent used for EUS-BD in this study was partially covered, had anchoring flaps, and is commercially available in Korea. Results EUS-guided hepaticogastrostomy (EUS-HGS) was performed in 21 patients and EUS-guided choledochoduodenostomy (EUS-CDS) in 33 patients. The technical and clinical success rates of EUS-BD were 100% (54/54) and 94.4% (51/54), respectively. Immediate adverse events developed after EUS-BD in 9 patients (16.6%; cholangitis in 3, bleeding in 2, self-limited pneumoperitoneum in 3, and abdominal pain in 1). Proximal or distal stent migration was not observed during the follow-up period (median, 148.5 days; IQR, 79.7-244), and the mean stent patency duration was 166.3 days and 329.1 days in the EUS-HGS and EUS-CDS groups, respectively. Conclusions EUS-BD with the hybrid metal stent is technically feasible and can effectively treat biliary obstruction after failed ERCP. EUS-BD with the hybrid metal stent can reduce stent-related adverse events, especially stent migration.
To evaluate the effects of combining the assessment of circulating high-sensitivity C-reactive protein (hs-CRP) with that of Epstein-Barr virus DNA (EBV DNA) in the pretherapy prognostication of ...nasopharyngeal carcinoma (NPC).
Three independent cohorts of NPC patients (training set of n=3113, internal validation set of n=1556, and prospective validation set of n=1668) were studied. Determinants of disease-free survival, distant metastasis-free survival, and overall survival were assessed by multivariate analysis. Hazard ratios and survival probabilities of the patient groups, segregated by clinical stage (T1-2N0-1M0, T3-4N0-1M0, T1-2N2-3M0, and T3-4N2-3M0) and EBV DNA load (low or high) alone, and also according to hs-CRP level (low or high), were compared.
Elevated hs-CRP and EBV DNA levels were significantly correlated with poor disease-free survival, distant metastasis-free survival, and overall survival in both the training and validation sets. Associations were similar and remained significant after excluding patients with cardiovascular disease, diabetes, and chronic hepatitis B. Patients with advanced-stage disease were segregated by high EBV DNA levels and high hs-CRP level into a poorest-risk group, and participants with either high EBV DNA but low hs-CRP level or high hs-CRP but low EBV DNA values had poorer survival compared with the bottom values for both biomarkers. These findings demonstrate a significant improvement in the prognostic ability of conventional advanced NPC staging.
Baseline plasma EBV DNA and serum hs-CRP levels were significantly correlated with survival in NPC patients. The combined interpretation of EBV DNA with hs-CRP levels led to refinement of the risks for the patient subsets, with improved risk discrimination in patients with advanced-stage disease.
To investigate the clinical implications of frailty in chronic kidney disease patients undergoing maintenance hemodialysis and chronic peritoneal dialysis.
In this prospective study, all of the ...participants completed the Short Form of the Kidney Disease Quality of Life questionnaire, Korean version, to determine their frailty phenotype. We also obtained blood chemistry and demographic data at enrollment. Data regarding the history of hospitalization and death were collected during the follow-up period.
We recruited 1,658 patients (1,255 maintenance hemodialysis and 403 chronic peritoneal dialysis) from multidialysis units (n = 27). We excluded patients who had been hospitalized in the previous 3 months.
Hospitalization and survival rate during study period.
The participants' mean age was 55.2 ± 11.9 years old, and 55.2% were male. Among the participants, 34.8% were rated as frail and 45.7% as prefrail. Multivariate analysis demonstrated significant associations of frailty with age, comorbidity, disability, unemployment, higher body mass index, and a lower educational level. During the follow-up period (median 17.1 months), 608 patients (79 not frail, 250 prefrail, and 279 frail) were hospitalized, and 87 patients (10 not frail, 24 prefrail, and 53 frail) died (P < .001). Frailty was associated with hospitalization (adjusted hazard ratio, 1.80; 95% confidence interval: 1.38-2.36) and mortality (hazard ratio, 2.37, 95% confidence interval: 1.11-5.02).
The frailty phenotype was common even in, prevalent end-stage renal disease patients on dialysis, and was significantly associated with higher rates of hospitalization and mortality.
Abstract Purpose The objective of this study was to evaluate the efficacy and safety of the lercanidipine/valsartan combination compared with lercanidipine monotherapy in patients with hypertension. ...Methods Part 1 of this study was the randomized, multicenter, double-blind, parallel group, Phase III, 8-week clinical trial to compare superiority of lercanidipine 10 mg/valsartan 80 mg (L10/V80) and lercanidipine 10 mg/valsartan 160 mg (L10/V160) combinations with lercanidipine 10 mg (L10) monotherapy. At screening, hypertensive patients, whose diastolic blood pressure (DBP) was >90 mm Hg after 4 weeks with L10, were randomized to 3 groups of L10, L10/V80, and L10/V160. The primary end point was the change in the mean sitting DBP from baseline (week 0) after 8 weeks of therapy. Patients who were randomly assigned to L10/V160 and whose mean DBP was still ≥ 90 mm Hg in part 1 were enrolled to the up-titration extension study with lercanidipine 20 mg/valsartan 160 mg (L20/V160) (part 2). Findings Of 772 patients screened, 497 were randomized to 3 groups (166 in the L10 group, 168 in the L10/V80 group, and 163 in the L10/V160 group). Mean (SD) age was 55 (9.9) years, and male patients comprised 69%. The mean (SD) baseline systolic blood pressure (SBP)/DBP were 148.4 (15.1)/94.3 (9.5) mm Hg. No significant differences were found between groups in baseline characteristics except the percentages of previous history of antihypertensive medication. The primary end points, the changes of mean (SD) DBP at week 8 from the baseline were −2.0 (8.8) mm Hg in the L10 group, −6.7 (8.5) mm Hg in L10/V80 group, and −8.1 (8.4) mm Hg in L10/V160 group. The adjusted mean difference between the combination groups and the L10 monotherapy group was −4.6 mm Hg (95% CI, −6.5 to −2.6; P < 0.001) in the L10/V80 group and −5.9 mm Hg (95% CI, −7.9 to −4.0, P < 0.001) in the L10/V160 group, which had significantly greater efficacy in BP lowering. A total of 74 patients were enrolled in the part 2 extension study. Changes of mean (SD) DBP and SBP from week 8 to week 12 and week 16 were −5.6 (7.9)/−8.0 (12.0) mm Hg and −5.5 (7.0)/−8.5 (11.3) mm Hg, respectively. For evaluation of the safety profile, the frequencies of adverse events between groups were also not significantly different. The most frequently reported adverse events were headache (6 cases, 20.7%) in the L10 group, dizziness (8 cases, 16.3%) in L10/V80 group, and nasopharyngitis (3 cases, 9.4%) in L10/V160 group, and the incidences of adverse events were not different between groups. Implications Treatment of L10/V80 or L10/V160 combination therapy resulted in significantly greater BP lowering compared with L10 monotherapy. Moreover, the L20/V160 high dose combination had additional BP lowering effect compared with nonresponders with the L10/V160 combination. ClinicalTrials.gov: NCT01928628.
Abstract Objectives The authors aimed to evaluate the role of post-resuscitation electrocardiogram (ECG) in patients showing significant ST-segment changes on the initial ECG and to provide useful ...diagnostic indicators for physicians to determine in which out-of-hospital cardiac arrest (OHCA) patients brain computed tomography (CT) should be performed before emergency coronary angiography. Background The usefulness of immediate brain CT and ECG for all resuscitated patients with nontraumatic OHCA remains controversial. Methods Between January 2010 and December 2014, 1,088 consecutive adult nontraumatic patients with return of spontaneous circulation who visited the emergency department of 3 tertiary care hospitals were enrolled. After excluding 245 patients with obvious extracardiac causes, 200 patients were finally included. Results The patients were categorized into 2 groups: those with ST-segment changes with spontaneous subarachnoid hemorrhage (SAH) (n = 50) and those with OHCA of suspected cardiac origin group (n = 150). The combination of 4 ECG characteristics including narrow QRS (<120 ms), atrial fibrillation, prolonged QTc interval (≥460 ms), and ≥4 ST-segment depressions had a 66.0% sensitivity, 80.0% specificity, 52.4% positive predictive value, and 87.6% negative predictive value for predicting SAH. The area under the receiver-operating characteristic curves in the post-resuscitation ECG findings was 0.816 for SAH. Conclusions SAH was observed in a substantial number of OHCA survivors (25.0%) with significant ST-segment changes on post-resuscitation ECG. Resuscitated patients with narrow QRS complex and any 2 ECG findings of atrial fibrillation, QTc interval prolongation, or ≥4 ST-segment depressions may help identify patients who need brain CT as the next diagnostic work-up.
We retrospectively evaluated outcomes in patients with programmed death-ligand 1 (PD-L1)–positive NSCLC to determine whether baseline (i.e., at study enrollment) brain metastases were associated with ...the efficacy of pembrolizumab versus chemotherapy.
We pooled the data for patients with previously treated or untreated PD-L1‒positive (tumor proportion score TPS, ≥1%) advanced metastatic NSCLC in KEYNOTE-001 (NCT01295827), KEYNOTE-010 (NCT01905657), KEYNOTE-024 (NCT02142738), and KEYNOTE-042 (NCT02220894). Patients received pembrolizumab (2 mg/kg, 10 mg/kg, or 200 mg every 3 wk or 10 mg/kg every 2 wk); chemotherapy was a comparator in all studies except KEYNOTE-001. All studies included patients with previously treated, stable brain metastases.
A total of 3170 patients were included, 293 (9.2%) with and 2877 (90.8%) without baseline brain metastases; median (range) follow-up at data cutoff was 12.9 (0.1‒43.7) months. Pembrolizumab improved overall survival versus chemotherapy in patients with or without baseline brain metastases: benefit was seen in patients with PD-L1 TPS greater than or equal to 50% (0.67 95% confidence intervals (CI): 0.44‒1.02 and 0.66 95% CI: 0.58‒0.76, respectively) and PD-L1 TPS ≥1% (0.83 95% CI: 0.62‒1.10 and 0.78 95% CI: 0.71‒0.85, respectively). Progression-free survival was improved, objective response rates were higher, and the duration of response was longer with pembrolizumab versus chemotherapy regardless of brain metastasis status. The incidence of treatment-related adverse events with pembrolizumab versus chemotherapy was 66.3% versus 84.4% in patients with brain metastases and 67.2% versus 88.3% in those without.
Pembrolizumab monotherapy improved outcomes and was associated with fewer adverse events than chemotherapy in patients with treatment-naive and previously treated PD-L1‒positive advanced/metastatic NSCLC regardless of the presence of baseline treated, stable brain metastases.
Primary small cell carcinoma of the esophagus (SCCE) is characterized as highly aggressive with a poor prognosis. To identify potential prognostic factors and to assess the role of surgical ...procedures, chemotherapy, and radiotherapy for SCCE, we retrospectively analyzed patients with SCCE from three large institutions in China.
All of the SCCE patients between 1998 and 2012 were identified from three clinical databases of the Sun Yat-Sen University Cancer Center, Peking Union Cancer Hospital and Shantou Cancer Hospital. Potential prognostic factors were analyzed with univariate analysis and a Cox regression model. Subgroup analysis based on the 2002 American Joint Committee on Cancer staging system for esophageal cancer was applied to examine the effect of treatment on survival.
In patients with stage I/II SCCE, 85% underwent operations and showed improved survival (median survival time MST 29 vs 17.4 months, p = 0.082). However, chemotherapy did not further improve survival. In patients with stage IIB/III SCCE, chemotherapy, instead of operation, improved survival (MST 13.0 vs 6.1 months, p = 0.003), and radiotherapy resulted in improved survival. In stage IV patients, chemotherapy improved survival (MST 12.5 vs 4.0 months, p < 0.001), and chemotherapy combined with radiotherapy was superior to chemotherapy alone (MST 13.2 vs 8.9 months, p = 0.014).
Surgical procedures alone can be recommended for stage I/IIA patients. In patients with stage IIB disease or above, chemotherapy should be the main treatment approach, and chemotherapy combined with radiotherapy tended to improve survival.
Background Recurrent hepatocellular carcinoma (RHCC) after curative resection is a major challenge for hepatic surgeons. A better understanding of the clonal origin of RHCC will help clinicians ...design personalized therapy and assess postoperative outcomes. The current study was performed to determine the clonal origin of RHCC and its clinical significance. Study Design Fifteen high-frequency of loss of heterozygosity of DNA microsatellites were determined on 100 tumor nodules in 60 matched pairs of RHCC from 40 patients who underwent liver re-resections. The relationships among the origin of clonal patterns of RHCC and the surgicopathologic features and clinical outcomes were analyzed. Results Of 60 pairs of RHCC, there were 2 clonal patterns with 6 subclonal types. Pattern I was multicentric occurrence (MO type) in 14 pairs (23.3%) and pattern II was intrahepatic metastasis (IM type) in 46 pairs (76.7%). The clinicopathologic features, including recurrence time, tumor size, vascular invasion, histological grading, and associated chronic liver diseases in patients with the MO type of RHCC were significantly different from those with the IM type of RHCC (p < 0.05 to 0.001). Compared with patients in the IM group, patients in the MO group had significantly better overall survival (130.8 ± 8.5 months vs 80.8 ± 8.5 months; p < 0.05) and recurrence-free survival (33.8 ± 4.5 months vs 14.2 ± 2.5 months; p < 0.001). Conclusions The MO-type RHCC was closely associated with better postoperative outcomes when compared with the IM-type RHCC. Generally, we recommend liver re-resection for MO-type RHCC, and interventional therapy for IM-type RHCC. Microdissection-based microsatellite loss of heterozygosity protocol has advantages in assessing the clonal origin, modes of personalized treatment, and clinical outcomes of RHCC.
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