Long-term Outcomes of Polytetrafluoroethylene Bicuspid Pulmonary Valve Replacement.

BACKGROUND: In 2016 we reported promising midterm outcomes of bicuspid pulmonary valve replacement using 0.1-mm polytetrafluoroethylene (PTFE) membrane. This follow-up study analyzes long-term outcomes and risk factors for reintervention and structural valve deterioration (SVD). METHODS: We performed a retrospective review of the original 119 patients who underwent PTFE bicuspid pulmonary valve replacement. Median patient age was 16.9 years (range, 0.4-57.1). Reintervention was defined as any surgical or percutaneous catheter procedure on the PTFE valve. SVD was defined as development of a peak pressure gradient ≥ 50 mm Hg or at least a moderate amount of pulmonary regurgitation on follow-up echocardiography. RESULTS: The median follow-up duration was 9.5 years. The survival rate was 96.5% at 5 and 10 years, with 2 early and 2 late mortalities. Freedom from reintervention was 90.0% at 5 years and 63.3% at 10 years. Freedom from SVD was 92.8% at 5 years and 51.1% at 10 years, with regurgitation the predominant mode (64.6%). Freedom from both reintervention and SVD at 5 and 10 years were 89.1% and 49.5%, respectively. Multivariable analysis identified smaller valve diameter (hazard ratio, 0.82; P < .001) and more than trivial pulmonary regurgitation at discharge (hazard ratio, 5.81; P < .001) as risk factors for reintervention or SVD. CONCLUSIONS: Long-term results of the PTFE bicuspid pulmonary valve replacement were acceptable. However, improvements may be needed to reduce technical error and improve durability. Smaller valve diameter and more than trivial pulmonary regurgitation at discharge were risk factors for reintervention or SVD, warranting careful follow-up for timely reintervention.

Characteristics and Treatment Outcomes of Transition among Patients with Inflammatory Bowel Disease.

PURPOSE: This study aimed to assess disease characteristics and outcomes of transition in patient care among adolescent patients with inflammatory bowel disease (IBD). MATERIALS AND METHODS: Data from patients younger than 18 years who were diagnosed with IBD (Crohn's disease, ulcerative colitis, or intestinal Behçet's disease) were investigated. We categorized the patients into two groups: transition IBD group (Group A, diagnosed in pediatric care followed by transfer to/attendance in adult IBD care) and non-transition group (Group B, diagnosed and followed up in pediatric care or adult IBD care without transfer). RESULTS: Data from a total of 242 patients [Group A (n=29, 12.0%), Group B (n=213, 88.0%)] were analyzed. A significantly higher number of patients was diagnosed at an earlier age in Group A than in Group B (p<0.001). Group A patients had more severe disease in terms of number of disease flare ups (p=0.011) and frequency of bowel-related complications (p<0.001). Multiple linear regression analysis showed that Group B patients had more medical non-compliance than Group A patients (ß=2.31, p=0.018). After transition, IBD-related admission frequency, emergency admission frequency, disease flare frequency, and medical non-compliance were significantly improved. CONCLUSION: The transition IBD group had more severe disease. Medical non-compliance was lower in the transition IBD group. Clinical outcomes improved after transition.

Fast and non-destructive Raman spectroscopic determination of multi-walled carbon nanotube (MWCNT) contents in MWCNT/polydimethylsiloxane composites.

A versatile Raman spectroscopic method to determine the contents of carbon nanotubes (CNTs) in CNT/polydimethylsiloxane (PDMS) composites is demonstrated, and important issues directly related to the accuracy of the measurement have been investigated. Initially, Raman microscopic mappings over an area of 6.0 × 6.0 mm2 were carried out on CNT/PDMS composites, which revealed the existence of the partial localization of CNTs on a microscopic scale. Therefore, a laser illumination scheme covering a large sample area of 28.3 mm2 was employed to acquire a sample spectrum representative of the whole CNT concentration. The peak area ratio between the CNT and PDMS peaks clearly varied with the CNT concentration, whereas the reproducibility of measurements was degraded for the composites containing more than 3.0 wt% CNTs because of the decreased Raman sampling volume arising from the absorption of laser radiation by the CNTs. The laser penetration depth was semi-quantitatively investigated by observing the spectra of thin-sliced samples collected by positioning a Teflon disk behind the sample, and Monte Carlo simulations were employed to examine the internal photon propagation as well as explain the experimental observation. In summary, the fundamental issues affecting the Raman measurement of the CNT containing polymer matrix have been clearly addressed, and the finding here will be a beneficial basis for successful Raman spectroscopic analysis of different CNT-containing composites.

Epicardial Fat Thickness and Free Fatty Acid Level are Predictors of Acute Ischemic Stroke with Atrial Fibrillation.

BACKGROUND: Increased epicardial fat is known to be associated with the presence and chronicity of atrial fibrillation (AF). Free fatty acids (FFAs) are major components of epicardial fat; however, their potential association with AF in ischemic stroke has not been investigated. We aimed to assess the performance of echocardiographic epicardial fat thickness (EFT) and plasma FFA level in identifying patients with ischemic stroke and AF. METHODS: We enrolled a total of 214 consecutive patients (mean age, 66.8 ± 12.3 years; 39.7% women) diagnosed with acute ischemic stroke between March 2011 and June 2014. The patients were divided into two groups: ischemic stroke with AF (n = 35, 16.4%) and ischemic stroke without AF (n = 179, 83.6%). RESULTS: The ischemic stroke with AF group showed significantly higher serum FFA level (1379.7 ± 717.5 vs. 757.8 ± 520.5 uEq/L, p < 0.0001) and EFT (6.5 ± 1.2 vs. 5.3 ± 1.2 mm, p < 0.001) than the group without AF. Multivariable logistic regression analysis demonstrated that age (odds ratio [OR], 1.112), serum FFA level (OR, 1.002), and EFT (OR, 1.740) were independently associated with the ischemic stroke group with AF. EFT and FFA significantly improved the goodness-of-fit and discriminability of the simple regression model including age as a covariate (log likelihood difference, 21.35; p < 0.001; c-index difference, 17.9%; p < 0.001). CONCLUSIONS: High EFT and serum FFA level were associated with ischemic stroke in patients with AF. Echocardiographic EFT and serum FFA level can play a significant role in identifying ischemic stroke with AF.

Blunted heart rate recovery is associated with coronary artery spasm in patients with suspected vasospastic angina.

BACKGROUND: Autonomic nervous system activity has been shown to be altered in patients with vasospastic angina (VA). Heart rate recovery (HRR) is a simple, non-invasive measurement of autonomic nervous system dysfunction. We aimed to investigate whether HRR is related to VA, as established by an ergonovine test. METHODS: A total of 976 consecutive patients (47.5% male, mean age 55 years) without significant coronary artery disease who underwent both an ergonovine provocation test and a treadmill exercise test were enrolled. The relationship between VA and HRR was evaluated. RESULTS: A total of 30.7% (300/976) of patients were diagnosed with VA, as documented by the ergonovine provocation test. HRR was significantly reduced in patients with VA compared to patients without VA (24.6 ± 18.0 vs. 30.5 ± 22.2, p < 0.001), and HRR was lowest in patients with multi-vessel spasm (21.9 ± 17.3). The proportion of blunted HRR, which was defined as HRR less than 12 beats, was significantly higher in patients with VA than in those without coronary artery spasm (26.6% vs. 39.3%, p < 0.001). In multivariable regression analyses, age (odds ratio (OR) = 1.03; 95% confidence interval (CI): 1.01-1.04; p = 0.001), blunted HRR (OR = 1.71; 95% CI: 1.26-2.31; p < 0.001), current smoking status (OR = 2.11; 95% CI: 1.50-2.98; p < 0.001), and male gender (OR = 2.00; 95% CI: 1.43-2.78; p < 0.001) were significant independent predictors of VA presence. CONCLUSION: Blunted HRR was an independent predictor of VA presence, which suggests a link between coronary artery spasm and autonomic dysregulation.

The Influence of Epicardial Fat and Nonalcoholic Fatty Liver Disease on Heart Rate Recovery in Metabolic Syndrome.

BACKGROUND: Epicardial adipose tissues reflecting visceral fat accumulations of the heart are associated with metabolic syndrome (MetS) and can be a predictor of other cardiometabolic diseases. It can adversely influence autonomic nervous system (ANS) of heart. Heart rate recovery (HRR) is an easy method for measuring ANS dysfunction. The purpose of this study was to determine whether epicardial fat thickness (EFT) and nonalcoholic fatty liver disease (NAFLD) are related to HRR in patients with MetS. METHODS: We enrolled 772 consecutive patients from a health-screening center who underwent abdominal ultrasonography, treadmill test, and cardiac echocardiography. EFT using echocardiography and HRR by symptom-limited exercise testing was assessed. According to the presence of MetS and NAFLD, patients were classified into the four groups. RESULTS: In NAFLD patients, EFT was higher and HRR was lower, especially in patients with MetS and NAFLD, compared to non-MetS participants without NAFLD (MetS with NAFLD, EFT 7.5 ± 4.4 mm, HRR 31.9 ± 12.7; MetS without NAFLD, EFT 4.9 ± 3.0 mm, HRR 39.5 ± 11.1; non-MetS with NAFLD, EFT 5.9 ± 3.6 mm, HRR 36.6 ± 12.7; and non-MetS without NAFLD, EFT 4.4 ± 3.5 mm, HRR 43.4 ± 14.5, p < 0.001). Patients with severe liver steatosis (LS) showed significantly higher EFT than those with moderate LS (14.2 ± 2.0 vs. 7.5 ± 3.1 mm, P < 0.001), and EFT was positively correlated with severity of LS (r = 0.431, P < 0.001). HRR was significantly correlated with EFT (r = -0.386, P < 0.001) and severity of LS (r = -0.324, P < 0.001). CONCLUSIONS: EFT and NAFLD were significantly correlated with HRR in patients with MetS and they may be highly related to increased cardiovascular risk. These results suggest a cross-link among EFT, NAFLD, and cardiac autonomic dysfunction in patients with MetS.

Prognostic Utility of Neutrophil-to-Lymphocyte Ratio on Adverse Clinical Outcomes in Patients with Severe Calcific Aortic Stenosis.

BACKGROUND: Inflammation is an important factor in the pathogenesis of calcific aortic stenosis (AS). We aimed to evaluate the association between an inflammatory marker, neutrophil-to-lymphocyte ratio (NLR) and major adverse cardiovascular events (MACE) in patients with severe calcific AS. METHODS: A total of 336 patients with isolated severe calcific AS newly diagnosed between 2010 and 2015 were enrolled in this study. Using Cox proportional hazards (PH) regression models, we investigated the prognostic value of NLR adjusted for baseline covariates including logistic European System for Cardiac Operative Risk Evaluation score (EuroSCORE-I) and undergoing aortic valve replacement (AVR). We also evaluated the clinical relevance of NLR risk groups (divided into low, intermediate, high risk) as categorized by NLR cutoff values. MACE was defined as a composite of all-cause mortality, cardiac death and non-fatal myocardial infarction during the follow-up period. RESULTS: The inflammatory marker NLR was an independent prognostic factor most significantly associated with MACE [hazard ratio (HR), 1.06; 95% confidence interval (CI), 1.04-1.09; p-value <0.001]. The goodness-of-fit and discriminability of the model including EuroSCORE-I and AVR (loglikelihood difference, 15.49; p-value <0.001; c-index difference, 0.035; p-value = 0.03) were significantly improved when NLR was incorporated into the model. The estimated Kaplan-Meier survival rates at 5 years for the NLR risk groups were 84.6% for the low risk group (NLR ≤ 2), 67.7% for the intermediate risk group (2 < NLR ≤ 9), and 42.6% for the high risk group (NLR > 9), respectively. CONCLUSION: The findings of the present study demonstrate the potential utility of NLR in risk stratification of patients with severe calcific AS.

The Combined Impact of Neutrophil-to-Lymphocyte Ratio and Type 2 Diabetic Mellitus on Significant Coronary Artery Disease and Carotid Artery Atherosclerosis.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) has recently emerged as a new important inflammatory marker for predicting cardiovascular events. This study aimed to evaluate the combined impact of NLR and type 2 diabetes mellitus (T2DM) on significant coronary artery disease (CAD) and carotid artery atherosclerosis. METHODS: This study includes a total of 828 patients evaluated by coronary angiography and carotid ultrasonography. Significant CAD was defined as at least one vessel with stenosis greater than 50%. We employed logistic regression models to investigate the association of NLR and T2DM with significant CAD. The goodness-of-fit and discriminability of the models were assessed by the loglikelihood ratio test and C-index, respectively. Also, we investigated the clinical relevance of the categorized NLR that classifies patients into three risk groups (low, intermediate, high). RESULTS: According to logistic regression analysis, both NLR {adjusted odds ratio (OR) 1.31, p < 0.001} and T2DM (adjusted OR 2.46, p = 0.006) were independent risk factors of significant CAD. The addition of NLR and T2DM into a logistic regression model including conventional cardiovascular risk factors significantly improved the goodness-of-fit (p < 0.001) and the discriminability of the model (p = 0.004). Also, T2DM patients assigned into the high risk group (NLR > 2) showed the greater prevalence of significant CAD and carotid artery atherosclerosis compared with patients without T2DM or type 2 diabetic patients assigned into the low risk group (NLR ≤ 1). CONCLUSION: Our results suggest that type 2 diabetic patients with high inflammatory state would be more vulnerable to significant CAD and carotid artery atherosclerosis.

Prognostic factors for patients with bone-only metastasis in breast cancer.

PURPOSE: Bone is the most frequent site of metastasis among breast cancer patients. We investigated prognostic factors affecting survival following bone-only metastasis in breast cancer patients. MATERIALS AND METHODS: The medical records of breast cancer patients who were treated and followed at Gangnam Severance Hospital retrospectively reviewed to identify patients with bone-only metastasis. RESULTS: The median time from the diagnosis of bone-only metastasis to the last follow-up or death was 55.2 [95% confidence interval (CI), 38.6-71.9] months. The Kaplan-Meier overall survival estimate at 10 years for all patients was 34.9%. In the multivariate Cox regression model, bisphosphonate treatment [hazard ratio=0.18; 95% CI, 0.07-0.43], estrogen receptor positivity (hazard ratio=0.51; 95% CI, 0.28-0.94), and solitary bone metastasis (hazard ratio=0.32; 95% CI, 0.14-0.72) were significantly associated with longer overall survival in the bone-only recurrence group. Among the treatment modalities, only bisphosphonate treatment was identified as a significant prognostic factor. CONCLUSION: Identifying the factors influencing breast cancer mortality after bone-only metastasis will help clarify the clinical course and improve the treatment outcome for patients with breast cancer and bone-only metastasis. Bisphosphonates, as a significant prognostic factor, warrant further investigation.

The difference in prognostic factors between early recurrence and late recurrence in estrogen receptor-positive breast cancer: nodal stage differently impacts early and late recurrence.

BACKGROUND: Probability of recurrence in patients with estrogen receptor (ER)-positive breast cancer remains constant for long periods. We compared tumor burden impact on late versus early recurrence in our cohort with long-term follow-up. METHODS: Five hundred and ninety five patients diagnosed with ER-positive breast cancer between 1989 and 2001 were classified into three groups: early recurrence within 5 years, late recurrence after 5 years, and no recurrence. We identified prognostic factors among the groups using logistic regression analysis. RESULTS: At median follow-up of 11.7 years, among 595 ER-positive women, 98 (16.4%) had early recurrence and 58 (9.7%) had late recurrence. On multivariate analysis, higher nodal stage (N0 vs. N2, odds ratio [OR] 3.189; N0 vs. N3, OR 9.948), higher histologic grade (grade 1 vs. grade 2, OR 3.896; grade 1 vs. grade 3, OR 5.945), age >35 years (OR 0.295), and receiving endocrine therapy (OR 0.293) affected early recurrence. Compared to no recurrence, receiving endocrine therapy (OR 0.285) was solely related to decreased risk of late recurrence. Increased risk of early recurrence was noted with the higher nodal stage when early and no recurrences were compared. This phenomenon was not found in late recurrence. In the last comparison between the early and late recurrence, higher nodal stage (N0 vs. N3, OR 16.779) and higher histologic grade (grade 1 vs. grade 3, OR 18.111) repeatedly weighted for early recurrence. CONCLUSIONS: Nodal burden had an attenuated influence on late recurrence, which suggests that, unlike early recurrence, tumor biology might have a more important role than tumor load for late recurrence in ER-positive disease.

Personalized medicine in breast cancer: a systematic review.

The recent advent of "-omics" technologies have heralded a new era of personalized medicine. Personalized medicine is referred to as the ability to segment heterogeneous subsets of patients whose response to a therapeutic intervention within each subset is homogeneous. This new paradigm in healthcare is beginning to affect both research and clinical practice. The key to success in personalized medicine is to uncover molecular biomarkers that drive individual variability in clinical outcomes or drug responses. In this review, we begin with an overview of personalized medicine in breast cancer and illustrate the most encountered statistical approaches in the recent literature tailored for uncovering gene signatures.

Multigene expression-based predictors for sensitivity to Vorinostat and Velcade in non-small cell lung cancer.

The ability to predict the efficacy of molecularly targeted therapies for non-small cell lung cancer (NSCLC) for an individual patient remains problematic. The purpose of this study was to identify, using a refined "coexpression extrapolation (COXEN)" algorithm with a continuous spectrum of drug activity, tumor biomarkers that predict drug sensitivity and therapeutic efficacy in NSCLC to Vorinostat, a histone deacetylase inhibitor, and Velcade, a proteasome inhibitor. Using our refined COXEN algorithm, biomarker prediction models were discovered and trained for Vorinostat and Velcade based on the in vitro drug activity profiles of nine NSCLC cell lines (NCI-9). Independently, a panel of 40 NSCLC cell lines (UVA-40) were treated with Vorinostat or Velcade to obtain 50% growth inhibition values. Genome-wide expression profiles for both the NCI-9 and UVA-40 cell lines were determined using the Affymetrix HG-U133A platform. Modeling generated multigene expression signatures for Vorinostat (45-gene; P = 0.002) and Velcade (15-gene; P = 0.0002), with one overlapping gene (CFLAR). Examination of Vorinostat gene ontogeny revealed a predilection for cellular replication and death, whereas that of Velcade suggested involvement in cellular development and carcinogenesis. Multivariate regression modeling of the refined COXEN scores significantly predicted the activity of combination therapy in NSCLC cells (P = 0.007). Through the refinement of the COXEN algorithm, we provide an in silico method to generate biomarkers that predict tumor sensitivity to molecularly targeted therapies. Use of this refined COXEN method has significant implications for the a priori examination of targeted therapies to more effectively streamline subsequent clinical trial design and cost.

Multi-gene expression-based statistical approaches to predicting patients' clinical outcomes and responses.

Gene expression profiling technique now enables scientists to obtain a genome-wide picture of cellular functions on various human disease mechanisms which has also proven to be extremely valuable in forecasting patients' prognosis and therapeutic responses. A wide range of multivariate techniques have been employed in biomedical applications on such expression profiling data in order to identify expression biomarkers that are highly associated with patients' clinical outcome and to train multi-gene prediction models that can forecast various human disease outcome and drug toxicities. We provide here a brief overview on some of these approaches, succinctly summarizing relevant basic concepts, statistical algorithms, and several practical applications. We also introduce our recent in vitro molecular expression-based algorithm, the so-called COXEN technique, which uses specialized gene profile signatures as a Rosetta Stone for translating the information between two different biological systems or populations.