Progesterone Receptor Status and Ki-67 Index May Predict Early Relapse in Luminal B/HER2 Negative Breast Cancer Patients: A Retrospective Study

Purpose

Few studies has documented early relapse in luminal B/HER2-negative breast cancer. We examined prognostic factors for early relapse among these patients to improve treatment decision-making.

Patients and Methods

A total 398 patients with luminal B/HER2-negative breast cancer were included. Kaplan-Meier curves were applied to estimate disease-free survival and Cox regression to identify prognostic factors.

Results

Progesterone receptor (PR) negative expression was associated with higher tumor grade (p<.001) and higher Ki-67 index (p = .010). PR-negative patients received more chemotherapy than the PR-positive group (p = .009). After a median follow-up of 28 months, 17 patients (4.3%) had early relapses and 8 patients (2.0%) died of breast cancer. The 2-year disease-free survival was 97.7% in the PR-positive and 90.4% in the PR-negative groups (Log-rank p = .002). Also, patients with a high Ki-67 index (defined as >30%) had a reduced disease-free survival (DFS) when compared with low Ki-67 index group (≤30%) (98.0% vs 92.4%, respectively, Log-rank p = .013). In multivariate analysis, PR negativity was significantly associated with a reduced DFS (HR = 3.91, 95% CI 1.29–11.88, p = .016).

Conclusion

In this study, PR negativity was a prognostic factor for early relapse in luminal B/HER2-negative breast cancer, while a high Ki-67 index suggested a higher risk of early relapse.     

A Comprehensive Expression Analysis of Mucins in Appendiceal Carcinoma in a Multicenter Study: MUC3 Is a Novel Prognostic Factor

Background

Mucins are implicated in survival in various cancers, but there have been no report addressed on survival in appendiceal carcinoma, an uncommon disease with different clinical and pathological features from those of other colon cancers. We aimed to investigate the clinical implications of expression of mucins in appendiceal carcinoma.

Methods

Expression profiles of MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC6, MUC16 and MUC17 in cancer tissue were examined by immunohistochemistry in 108 cases of surgically resected appendiceal carcinoma.

Results

The following relationships of mucins with clinicopathologic factors were identified: MUC1 with positive lymphatic invasion (p = 0.036); MUC2 with histological type (mucinous carcinoma, p<0.001), superficial invasion depth (p = 0.007), negative venous invasion (p = 0.003), and curative resection (p = 0.019); MUC3 with non-curative resection (p = 0.017); MUC5AC with histological type (mucinous carcinoma, p = 0.002), negative lymphatic invasion (p = 0.021), and negative venous invasion (p = 0.022); and MUC16 with positive lymph node metastasis (p = 0.035), positive venous invasion (p<0.05), and non-curative resection (p = 0.035). A poor prognosis was related to positive lymph node metastasis (p = 0.04), positive lymphatic invasion (p = 0.02), positive venous invasion (p<0.001), non-curative resection (p<0.001), and positive expression of MUC3 (p = 0.004). In multivariate analysis, positive venous invasion (HR: 6.93, 95% CI: 1.93–24.96, p = 0.003), non-curative resection (HR: 10.19, 95% CI: 3.05–34.07, p<0.001) and positive MUC3 expression (HR: 3.37, 95% CI: 1.13–10.03, p = 0.03) were identified as significant independent prognostic factors in patients with appendiceal carcinoma.

Conclusions

Expression of MUC3 in appendiceal carcinoma is an independent factor for poor prognosis and a useful predictor of outcome in patients with appendiceal carcinoma after surgery.     

Low CD10 mRNA Expression Identifies High-Risk Ductal Carcinoma In Situ (DCIS)

Purpose

Optimal management of breast ductal carcinoma in situ (DCIS) is controversial, and many patients are still overtreated. The local death of myoepithelial cells (MECs) is believed to be a pre-requisite to tumor invasion. We thus hypothesized that loss of CD10 expression, a MEC surface peptidase, would signify basement membrane disruption and confer increased risk of relapse in DCIS. The aim of our study was to retrospectively evaluate the prognostic value of CD10 in DCIS.

Experimental Design

CD10 expression was evaluated by quantitative RT-PCR and immunohistochemistry using paraffin-embedded samples of normal breast tissue (n = 11); of morphologically normal ducts associated with DCIS (n = 10); and of DCIS without an invasive component (n = 154).

Results

CD10 immunostaining was only observed in MECs in normal tissue and in DCIS. Normal tissue showed high mRNA expression levels of CD10, whereas DCIS showed a variable range. After a median follow-up of 6 years, DCIS with CD10 expression below the levels observed in normal tissue (71%) demonstrated a higher risk of local relapse (HR = 1.88; [95CI:1.30–2.70], p = 0.001) in univariate analysis. No relapse was observed in patients expressing high CD10 mRNA levels (29%) similar to the ones observed in normal tissue. In multivariate analysis including known prognostic factors, low CD10 mRNA expression remained significant (HR = 2.25; [95%CI:1.24–4.09], p = 0.008), as did the recently revised Van Nuys Prognostic Index (VNPI) score (HR = 2.03; [95%CI:1.23–3.35], p = 0.006).

Conclusion

The decrease of CD10 expression in MECs is associated with a higher risk of relapse in DCIS; this knowledge has the potential to improve DCIS management.     

Increased Expression of Pregnancy Up-Regulated Non-Ubiquitous Calmodulin Kinase Is Associated with Poor Prognosis in Clear Cell Renal Cell Carcinoma

Purpose

The aims of this study were to evaluate the clinical significance and potential prognostic value of pregnancy up-regulated non-ubiquitous calmodulin kinase (PNCK) in clear cell renal cell carcinoma (ccRCC) patients.

Materials and Methods

The expression of PNCK mRNA was determined in 24 paired samples of ccRCCs and adjacent normal tissues using real-time RT-PCR. The expression of PNCK was determined in 248 samples of ccRCCs and 92 paired samples of adjacent normal tissues by immunohistochemical analysis. Statistical analysis was performed to define the relationship between PNCK expression and the clinical features of ccRCC.

Results

The mRNA level of PNCK was significantly higher in tumorous tissues than in the adjacent non-tumorous tissues (p<0.001). An immunohistochemical analysis of 92 paired tissue specimens showed that PNCK expression was higher in tumorous tissues than in the adjacent non-tumorous tissues (p<0.001). Moreover, there was a significant correlation between the PNCK expression and various clinicopathological parameters such as Fuhrman grade (p = 0.011), tumor size (p<0.001), T stage (p<0.001) and N stage (p = 0.015). Patients with higher PNCK expression had shorter overall survival time than those with lower PNCK expression (p<0.001). Multivariate analysis indicated that PNCK expression was an independent predictor for poor survival of ccRCC patients.

Conclusions

To our knowledge, this is the first study that determines the relationship between PNCK and prognosis in ccRCC. We found that increased PNCK expression is associated with poor prognosis in ccRCC. PNCK may represent a novel prognostic marker for ccRCC.     

Concomitant Tumor Expression of EGFR and TATI/SPINK1 Associates with Better Prognosis in Colorectal Cancer

Background

Epidermal growth factor receptor (EGFR) activation plays a role in colorectal cancer (CRC) carcinogenesis, and anti-EGFR drugs are used in treatment of advanced CRC. One of the EGFR ligands is tumor-associated trypsinogen inhibitor TATI, also called serine protease inhibitor Kazal type1 (SPINK 1), which we recently showed to be an independent prognostic marker in CRC.

Methods

We studied the prognostic value of immunohistochemical expression of EGFR and concomitant expression of EGFR and TATI/SPINK1 in a series of 619 colorectal cancer patients.

Results

Of the samples, 92% were positive for EGFR. EGFR+/TATI+ was seen in 62.8%, EGFR+/TATI− in 29.5%, EGFR−/TATI+ in 4.9%, and EGFR−/TATI− in 2.7% of patients. EGFR expression correlated with WHO grade (p = 0.040). In univariate analysis, EGFR expression correlated with favourable survival (p = 0.006). EGFR+/TATI+ patients showed better survival than did those with other combinations (p<0.001). In multivariate analysis, EGFR+/TATI+ was an independent prognostic factor of favourable prognosis (p<0.001).

Conclusion

Concomitant positivity of EGFR and TATI/SPINK1 predicts favourable prognosis in CRC.     

Disparities in Outcomes following Admission for Cholangitis

Introduction

Few have examined determinants of adverse outcomes in patients presenting with ascending cholangitis. The objective of this study was to examine factors associated with in-hospital mortality, prolonged length of stay (LOS) and increased hospital charges (HC) in patients presenting with acute cholangitis.

Methods

Within the Health Care Utilization Project Nationwide Inpatient Sample (NIS), we focused on patients, 18 years and older, admitted to the emergency department with cholangitis as primary diagnosis (1998–2009). Models were fitted to predict likelihood of in-hospital mortality, prolonged LOS and increased HC. Covariates included race, day of admission, insurance status, socio-economical status and other patient and hospital characteristics.

Results

Overall, weighted estimates of 248,942 patients were admitted with acute cholangitis between 1998 and 2009, of which 13,534 (5.4%) died during the admission. Multivariable analyses revealed that relative to Caucasian patients, African American, Hispanic and Asian and Pacific Islander patients were more likely to die (OR = 1.61, p<0.001, OR = 1.20, p = 0.01 and OR = 1.26, p = 0.008), to experience a prolonged LOS (OR = 1.77, p<0.001, OR = 1.30, p<0.001, 1.34, p<0.001), and to incur high HC (OR = 1.83, p<0.001, OR = 1.51, p<0.001, OR = 1.56, p<0.001). Moreover, Medicaid and Medicare patients were more likely to die (OR = 1.64, p<0.001, OR = 1.24, p<0.001), to experience a prolonged LOS (1.74, p<0.001, OR = 1.25, p<0.001) and to incur high HC (OR = 1.23, p = 0.002, OR = 1.12, p = 0.002) compared to privately insured patients. In subgroup analysis, there were no differences for Medicare patients age 65 years and over. However, those under 65, most of whom have disability or end stage renal disease, were more likely to experience the negative outcomes.

Conclusion

Race and insurance status represent independent predictors of in-hospital mortality and adverse outcomes in patients presenting with cholangitis. Whether these disparities are due to biological predisposition or unequal quality of care requires further investigation. Regardless, efforts should be made to reduce these outcome disparities.     

Impact of Squamous and Glandular Differentiation on Oncologic Outcomes in Upper and Lower Tract Urothelial Carcinoma

Purpose

To investigate the prognostic significance of squamous and/or glandular differentiation in urothelial carcinoma (UC).

Materials and Methods

Among 800 consecutive patients who underwent radical cystectomy or nephroureterectomy at our institution from January 1990 to December 2010, 696 patients were included for the analysis. Clinicopathologic variables were compared according to the presence of squamous and/or glandular differentiation and the tumor location.

Results

A total of 51 (7.3%) patients had squamous and/or glandular differentiation. Patients with squamous and/or glandular differentiation had higher pathological T stage (p<0.001) and grade (p<0.001) than those with pure form of UC. After the median follow-up of 55.2 months, 84 (24.6%) and 82 (23.1%) died of upper urinary tract UC and UC of bladder, respectively. Patients with squamous and/or glandular differentiation in upper urinary tract UC showed poorer cancer-specific survival (CSS) (p<0.001) and overall survival (OS) (p<0.001) than those with pure form in upper urinary tract UC (p<0.001), but not in UC of bladder (p = 0.178 for CSS and p = 0.172 for OS). On multivariate Cox regression analysis, squamous and/or glandular differentiation was an independent predictor of CSS (hazard ratio [HR] 1.76; 95% confidence interval [CI] 1.08–2.85, p = 0.023), but it was not associated with OS (HR 1.52; 95% CI 1.00–2.32, p = 0.051).

Conclusions

The presence of variant histology could be associated with poorer survival outcome in patients with UC. Squamous and/or glandular differentiation is associated with features of biologically aggressive disease and an independent predictor of CSS.     

Plasma Levels of Soluble Urokinase-Type Plasminogen Activator Receptor Associate with the Clinical Severity of Acute Puumala Hantavirus Infection

Objectives

Urokinase-type plasminogen activator receptor is a multifunctional glycoprotein, the expression of which is increased during inflammation. It is known to bind to β₃-integrins, which are elementary for the cellular entry of hantaviruses. Plasma soluble form of the receptor (suPAR) levels were evaluated as a predictor of severe Puumala hantavirus (PUUV) infection and as a possible factor involved in the pathogenesis of the disease.

Design

A single-centre prospective cohort study.

Subjects and Methods

Plasma suPAR levels were measured twice during the acute phase and once during the convalescence in 97 patients with serologically confirmed acute PUUV infection using a commercial enzyme-linked immunosorbent assay (ELISA).

Results

The plasma suPAR levels were significantly higher during the acute phase compared to the control values after the hospitalization (median 8.7 ng/ml, range 4.0–18.2 ng/ml vs. median 4.7 ng/ml, range 2.4–12.2 ng/ml, P<0.001). The maximum suPAR levels correlated with several variables reflecting the severity of the disease. There was a positive correlation with maximum leukocyte count (r = 0.475, p<0.001), maximum plasma creatinine concentration (r = 0.378, p<0.001), change in weight during the hospitalization (r = 0.406, p<0.001) and the length of hospitalization (r = 0.325, p = 0.001), and an inverse correlation with minimum platelet count (r = −0.325, p = 0.001) and minimum hematocrit (r = −0.369, p<0.001).

Conclusion

Plasma suPAR values are markedly increased during acute PUUV infection and associate with the severity of the disease. The overexpression of suPAR possibly activates β₃-integrin in PUUV infection, and thus might be involved in the pathogenesis of the disease.     

Longitudinal Strain Is a Marker of Microvascular Obstruction and Infarct Size in Patients with Acute ST-Segment Elevation Myocardial Infarction

Objectives

We assessed the value of speckle tracking imaging performed early after a first ST-segment elevation myocardial infarction (STEMI) in order to predict infarct size and functional recovery at 3-month follow-up.

Methods

44 patients with STEMI who underwent revascularization within 12 h of symptom onset were prospectively enrolled. Echocardiography was performed 3.9±1.2 days after myocardial reperfusion, assessing circumferential (CGS), radial (RGS), and longitudinal global (GLS) strains. Late gadolinium-enhanced cardiac magnetic imaging (CMR), for assessing cardiac function, infarct size, and microvascular obstruction (MVO), was conducted 5.6±2.5 days and 99.4±4.6 days after myocardial reperfusion.

Results

GLS was evaluable in 97% of the patients, while CGS and RGS could be assessed in 85%. Infarct size significantly correlated with GLS (R = 0.601, p<0.001), RGS (R = −0.405, p = 0.010), CGS (R = 0.526, p = 0.001), ejection fraction (R = −0.699, p<0.001), wall motion score index (WMSI) (R = 0.539, p = 0.001), and left atrial volume (R = 0.510, p<0.001). Baseline ejection fraction and GLS were independent predictors of 3-month infarct size. MVO mass significantly correlated with GLS (R = 0.376, p = 0.010), WMSI (R = 0.387, p = 0.011), and ejection fraction (R = −0.389, p = 0.011). In multivariate analysis, GLS was the only independent predictor of MVO mass (p = 0.015). Longitudinal strain >−6.0% within the infarcted area exhibited 96% specificity and 61% sensitivity for predicting the persistence of akinesia (≥3 segments) at 3-month follow-up.

Conclusions

Speckle-tracking strain imaging performed early after a STEMI is easy-to-use as a marker for persistent akinetic territories at 3 months. In addition, GLS correlated significantly with MVO and final infarct size, both parameters being relevant post-MI prognostic factors, usually obtained via CMR.     

The Impact of Stressful Life Events on Excessive Alcohol Consumption in the French Population: Findings from the GAZEL Cohort Study

Background

Major life changes may play a causative role in health through lifestyle factors, such as alcohol. The objective was to examine the impact of stressful life events on heavy alcohol consumption among French adults.

Methods

Trajectories of excessive alcohol consumption in 20,625 employees of the French national gas and electricity company for up to 5 years before and 5 years after an event, with annual measurements from 1992. We used repeated measures analysis of time series data indexed to events, employing generalized estimating equations.

Results

For women, excessive alcohol use increased before important purchase (p = 0.021), children leaving home (p<0.001), and death of loved ones (p = 0.03), and decreased before widowhood (p = 0.015); in the year straddling the event, increased consumption was observed for important purchase (p = 0.018) and retirement (p = 0.002); at the time of the event, consumption decreased for marriage (p = 0.002), divorce, widowhood, and death of loved one (all p<0.001), and increased for retirement (p = 0.035). For men, heavy alcohol consumption increased in the years up to and surrounding the death of loved ones, retirement, and important purchase (all p<0.001), and decreased after (all p<0.001, except death of loved one: p = 0.006); at the time of the event, consumption decreased for all events except for children leaving home and retirement, where we observed an increase (all p<0.001). For women and men, heavy alcohol consumption decreased prior to marriage and divorce and increased after (all p<0.001, except for women and marriage: p = 0.01).

Conclusion

Stressful life events promote healthy and unhealthy alcohol consumption. Certain events impact alcohol intake temporarily while others have longer-term implications. Research should disentangle women''s and men''s distinct perceptions of events over time.     

Influence of the C242T Polymorphism of the p22-phox Gene (CYBA) on the Interaction between Urinary Sodium Excretion and Blood Pressure in an Urban Brazilian Population

Background

Reactive oxygen species are implicated in the physiopathogenesis of salt-induced hypertension and the C242T polymorphism of the p22-phox gene has been associated with higher superoxide production. This study investigated the impact of this polymorphism on the relationship between urinary sodium excretion (USE) and blood pressure levels in an urban Brazilian population.

Methods

We cross-sectionally evaluated 1,298 subjects from the city of Vitoria-ES, located in the Southeast region of Brazil, by clinical history, physical examination, anthropometry, analysis of laboratory parameters, USE measurement and p22-phox C242T polymorphism genotyping.

Results

No significant differences in studied parameters were detected between the studied genotype groups (CC vs. CT+TT). Systolic blood pressure exhibited significant correlation with USE only in T allele carriers (r = 0.166; p<0.001), while diastolic blood pressure and hypertension status correlated with USE in both genotypes albeit more weakly in subjects with CC genotype (r = 0.098; p = 0.021 and r = 0.105; p = 0.013, respectively) than in T carriers (r = 0.236; p<0.001 and r = 0.213; p<0.001, respectively). Regression analyses adjusted for confounding factors showed that USE remained independently associated with systolic (p<0.001) and diastolic blood pressure (p<0.001) and hypertension status (p = 0.004) only in T allele carriers. Finally, higher diastolic and systolic blood pressure levels were detected in T allele carriers than in CC genotype individuals in the highest tertile of USE.

Conclusions

The p22-phox 242T allele is associated with higher blood pressure levels among subjects with higher USE in an urban Brazilian population.     

Association of Severe Thrombocytopenia and Poor Prognosis in Pregnancies with Aplastic Anemia

Purpose

We sought to estimate the risks of adverse obstetric outcomes and disease outcomes associated with severe thrombocytopenia in pregnant women with aplastic anemia (AA).

Methods

In a retrospective study, we compared demographics, clinical characteristics, laboratory results, and outcomes between severe thrombocytopenia (ST) and non-severe thrombocytopenia (non-ST) groups comprising pregnant women with AA.

Results

Of 61 AA patients, 43 (70%) were diagnosed as AA before pregnancy and 18 (30%) were AA during pregnancy. The ST group exhibited lower gestational age at nadir of platelet count (26.0 versus 37.0 weeks, p<0.001) and at delivery (37.3 versus 39.1 weeks, p = 0.008), and a higher rate of bleeding gums (33.8 versus 7.7%, p = 0.015) than the non-ST group. In addition, the ST group exhibited more transfusions during pregnancy (72.7 versus 15.4%, p<0.001) and postpartum period (45.0 versus 2.7%, p<0.001), and more bone marrow transplant after delivery (25.0 versus 0.0%, p<0.001) than the non-ST group. The ST group had a higher odds ratio of composite disease complications (OR, 9.63; 95% CI, 2.82–32.9; p<0.001) and composite obstetric complications (OR, 6.78; 95% CI, 2.11–21.8; p = 0.001) than the non-ST group.

Conclusions

Severe thrombocytopenia is more associated with obstetric and disease complications than is non-severe thrombocytopenia in pregnant women with AA.     

Potential Role of M. tuberculosis Specific IFN-γ and IL-2 ELISPOT Assays in Discriminating Children with Active or Latent Tuberculosis

Background

Although currently available IGRA have been reported to be promising markers for TB infection, they cannot distinguish active tuberculosis (TB) from latent infection (LTBI).

Objective

Children with LTBI, active TB disease or uninfected were prospectively evaluated by an in-house ELISPOT assay in order to investigate possible immunological markers for a differential diagnosis between LTBI and active TB.

Methods

Children at risk for TB infection prospectively enrolled in our infectious disease unit were evaluated by in-house IFN-γ and IL-2 based ELISPOT assays using a panel of Mycobacterium tuberculosis antigens.

Results

Twenty-nine children were classified as uninfected, 21 as LTBI and 25 as active TB cases (including 5 definite and 20 probable cases). Significantly higher IFN-γ ELISPOT responses were observed in infected vs. uninfected children for ESAT-6 (p<0.0001), CFP-10 (p<0.0001), TB 10.3 (p = 0.003), and AlaDH (p = 0.001), while differences were not significant considering Ag85B (p = 0.063), PstS1 (p = 0.512), and HspX (16 kDa) (p = 0.139). IL-2 ELISPOT assay responses were different for ESAT-6 (p<0.0001), CFP-10 (p<0.0001), TB 10.3 (p<0.0001), HspX (16 kDa) (p<0.0001), PstS1 (p<0.0001) and AlaDH (p = 0.001); but not for Ag85B (p = 0.063). Comparing results between children with LTBI and those with TB disease differences were significant for IFN-γ ELISPOT only for AlaDH antigen (p = 0.021) and for IL-2 ELISPOT assay for AlaDH (p<0.0001) and TB 10.3 antigen (p = 0.043). ROC analyses demonstrated sensitivity of 100% and specificity of 81% of AlaDH-IL-2 ELISPOT assay in discriminating between latent and active TB using a cut off of 12.5 SCF per million PBMCs.

Conclusion

Our data suggest that IL-2 based ELISPOT with AlaDH antigen may be of help in discriminating children with active from those with latent TB.     

Effectiveness of Music Education for the Improvement of Reading Skills and Academic Achievement in Young Poor Readers: A Pragmatic Cluster-Randomized,Controlled Clinical Trial

Introduction

Difficulties in word-level reading skills are prevalent in Brazilian schools and may deter children from gaining the knowledge obtained through reading and academic achievement. Music education has emerged as a potential method to improve reading skills because due to a common neurobiological substratum.

Objective

To evaluate the effectiveness of music education for the improvement of reading skills and academic achievement among children (eight to 10 years of age) with reading difficulties.

Method

235 children with reading difficulties in 10 schools participated in a five-month, randomized clinical trial in cluster (RCT) in an impoverished zone within the city of São Paulo to test the effects of music education intervention while assessing reading skills and academic achievement during the school year. Five schools were chosen randomly to incorporate music classes (n = 114), and five served as controls (n = 121). Two different methods of analysis were used to evaluate the effectiveness of the intervention: The standard method was intention-to-treat (ITT), and the other was the Complier Average Causal Effect (CACE) estimation method, which took compliance status into account.

Results

The ITT analyses were not very promising; only one marginal effect existed for the rate of correct real words read per minute. Indeed, considering ITT, improvements were observed in the secondary outcomes (slope of Portuguese = 0.21 [p<0.001] and slope of math = 0.25 [p<0.001]). As for CACE estimation (i.e., complier children versus non-complier children), more promising effects were observed in terms of the rate of correct words read per minute [β = 13.98, p<0.001] and phonological awareness [β = 19.72, p<0.001] as well as secondary outcomes (academic achievement in Portuguese [β = 0.77, p<0.0001] and math [β = 0.49, p<0.001] throughout the school year).

Conclusion

The results may be seen as promising, but they are not, in themselves, enough to make music lessons as public policy.     

Bleeding Risk and Mortality of Edoxaban: A Pooled Meta-Analysis of Randomized Controlled Trials

Objective(s)

Edoxaban, a factor Xa inhibitor, is a new oral anticoagulant that has been developed as an alternative to vitamin K antagonists. However, its safety remains unexplored.

Methods

Medline, Embase and Web of Science were searched to March 8, 2014 for prospective, randomized controlled trials (RCTs) that assessed the safety profile of edoxaban with warfarin. Safety outcomes examined included bleeding risk and mortality.

Results

Five trials including 31,262 patients that met the inclusion criteria were pooled. Overall, edoxaban was associated with a significant decrease in major or clinically relevant nonmajor bleeding events [risk ratio (RR) 0.78, 95% confidence interval (CI) 0.74 to 0.82, p<0.001] and any bleeding events [RR 0.82, 95% CI 0.79 to 0.85, p<0.001]. Edoxaban also showed superiority to warfarin both in all-cause mortality [RR 0.92, 95% CI0.85 to0.99, p = 0.02] and cardiovascular mortality [RR 0.87, 95% CI0.79 to 0.96, p = 0.004]. Subgroup analyses indicated that RRs of edoxaban 30, 60 or 120 mg/d were 0.67 (p<0.001), 0.87 (p<0.001) and 3.3 (p = 0.004) respectively in major or clinically relevant nonmajor bleeding; 0.71 (p<0.001), 0.89 (p<0.001) and 2.29 (p = 0.002) respectively in any bleeding; as well as 0.86 (p = 0.01), 0.87 (p = 0.01) and 0.28 (p = 0.41) respectively in cardiovascular death… Meanwhile, paramount to note that pooled results other than the largest trial showed edoxaban was still associated with a decrease in the rate of major or clinically relevant nonmajor bleeding event (p = 0.02) and any bleeding (p = 0.002), but neither in all-cause death (p = 0.66) nor cardiovascular death (p = 0.70).

Conclusions

Edoxaban, a novel orally available direct factor Xa inhibitor, seems to have a favorable safety profiles with respect to bleeding risk and non-inferior in mortality when compared to warfarin. Further prospective RCTs are urgently needed to confirm the results of this meta-analysis.     

Proximal Tubule Dysfunction Is Associated with Podocyte Damage Biomarkers Nephrin and Vascular Endothelial Growth Factor in Type 2 Diabetes Mellitus Patients: A Cross-Sectional Study

Background

There is an ongoing debate as to whether early diabetic nephropathy in Type 2 diabetes mellitus may be attributed to the glomerulus or to the proximal tubule. Urinary excretion of nephrin and vascular endothelial growth factor may increase even in the normoalbuminuria stage. In the course of diabetic nephropathy, the proximal tubule may be involved in the uptake of urinary nephrin and vascular endothelial growth factor.

Materials and Methods

Two groups of consecutive Type 2 diabetes mellitus outpatients (38 normo-, 32 microalbuminuric) and 21 healthy subjects were enrolled in a cross-sectional study and evaluated concerning the relation of proximal tubule dysfunction with the podocyte biomarkers excretion, assessed by ELISA methods. The impact of advanced glycation end-products on this relation was also queried.

Results

Urinary alpha₁-microglobulin and kidney injury molecule-1 correlated with urinary albumin:creatinine ratio (R² = 0.269; p<0.001; R² = 0.125; p<0.001), nephrinuria (R² = 0.529; p<0.001; R² = 0.203; p<0.001), urinary vascular endothelial growth factor (R² = 0.709; p<0.001; R² = 0.360; p<0.001), urinary advanced glycation end-products (R² = 0.578; p<0.001; R² = 0.405; p<0.001), serum cystatin C (R² = 0.130; p<0.001; R² = 0.128; p<0.001), and glomerular filtration rate (R² = 0.167; p<0.001; R² = 0.166; p<0.001); nephrinuria and urinary vascular endothelial growth factor correlated with urinary albumin:creatinine ratio (R² = 0.498; p<0.001; R² = 0.227; p<0.001), urinary advanced glycation end-products (R² = 0.251; p<0.001; R² = 0.308; p<0.001), serum cystatin C (R² = 0.157; p<0.001; R² = 0.226; p<0.001), and glomerular filtration rate (R² = 0.087; p = 0.007; R² = 0.218; p<0.001).

Conclusions

In Type 2 diabetes mellitus there is an association of proximal tubule dysfunction with podocyte damage biomarkers, even in the normoalbuminuria stage. This observation suggests a potential role of the proximal tubule in urinary nephrin and urinary vascular endothelial growth factor processing in early diabetic nephropathy, a fact which could be related to advanced glycation end-products intervention. Podocyte damage and proximal tubule dysfunction biomarkers could be validated as a practical approach to the diagnosis of early diabetic nephropathy by further studies on larger cohorts.     

miR-141 and miR-200c as Markers of Overall Survival in Early Stage Non-Small Cell Lung Cancer Adenocarcinoma

Background

Several treatments in non-small cell lung cancer (NSCLC) are histology-dependent, and the need for histology-related markers is increasing. MicroRNAs (miRNAs) are promising molecular markers in multiple cancers and show differences in expression depending on histological subtype. The miRNA family miR-200 has been associated with the regulation of epithelial-mesenchymal (EMT)/mesenchymal-epithelial transition (MET). EMT involves profound phenotypic changes that include the loss of cell-cell adhesion, the loss of cell polarity, and the acquisition of migratory and invasive properties that facilitates metastasis. A dual role for the miR-200 family in the prognosis of several tumors has been related to tumor cell origin. However, the prognostic role and function of miR-200 family in early-stage NSCLC adenocarcinoma and squamous cell carcinoma (SCC) have not been well established.

Methods

miRNA expression was determined using TaqMan assays in 155 tumors from resected NSCLC patients. Functional studies were conducted in three NSCLC cell lines: H23, A-549 and HCC-44.

Results

High miR-200c expression was associated with shorter overall survival (OS) in the entire cohort (p = 0.024). High miR-200c (p = 0.0004) and miR-141 (p = 0.009) expression correlated with shorter OS in adenocarcinoma – but not in SCC. In the multivariate analysis, a risk score based on miR-141 and miR-200c expression emerged as an independent prognostic factor for OS in the entire cohort (OR, 2.787; p = 0.033) and in adenocarcinoma patients (OR, 10.649; p = 0.002). Functional analyses showed that miR-200c, was related to mesenchymal-epithelial transition (MET) and affected cell migration and E-cadherin levels, while overexpression of miR-141 reduced KLF6 protein levels and produced an increase of secretion of VEGFA in vitro (H23, p = 0.04; A-549, p = 0.03; HCC-44, p = 0.02) and was associated with higher blood microvessel density in patient tumor samples (p<0.001).

Conclusion

High miR-141 and miR-200c expression are associated with shorter OS in NSCLC patients with adenocarcinoma through MET and angiogenesis.     

Study on Risk Factors for Severe Hand,Foot and Mouth Disease in China

Background

Epidemics of HFMD are elevated every year globally, especially in mainland China. The disease now presents as an increasing threat to public health worldwide.

Methods

Five hundred and seventy-one EV71-infected HFMD patients in Beijing You''an Hospital were grouped by disease severity: Mild (no severe complication) (n = 221), and Severe group (complicated with brainstem encephalitis (BE), and/or pulmonary edema (PE) (n = 350)). Clinical and laboratory findings and levels of 7 serum cytokines were analyzed.

Results

Univariate analysis showed that (RR)>26/min (p<0.001), age<4 yo (p = 0.001), GLU>8.3 mmol/L (p = 0.008), CL<98 mmol/L (p = 0.026), and WBC>1.2×10⁹/L (p = 0.040) were associated with severe cases. Results of multivariate analysis indicated five independent risk factors (RR>26/min (p<0.001), Age<4 yo (p<0.001), GLU>8.3 mmol/L (p = 0.011), LYM>40% (p = 0.010), and ALT>40 U/L (p = 0.045)). In addition to single-factor analysis, we further analyzed the use of different combinations of risk factors. “GLU>8.3 and CL<98 and RR>26” (confidence ration (CR) = 100%) is the top indicator, followed by “ALT>40 and LYM>40% and RR>26 and Age<4 yo” (CR = 92.9%).Serum levels of IL-2, IL-4, IL-10, IFNγ, GM-CSF, and TNFα were higher in severe cases than in mild cases. A new evaluation scoring system by scoring each risk factor 1 and independent risk factor 2 was developed for early identification of severe HFMD cases.

Conclusions

Five independent risk factors, along with indicative combinations of risk factors, for severe cases were identified, and a scoring system was created to facilitate the use of indicators for early medical intervention.     

Liver X Receptor Gene Polymorphisms in Tuberculosis: Effect on Susceptibility

Objectives

The Liver X receptors (LXRs), Liver X receptor A (LXRA) and Liver X receptor B (LXRB), regulate lipid metabolism and antimicrobial response. LXRs have a crucial role in the control of Mycobacterium tuberculosis (M.tb). Lacking LXRs mice is more susceptibility to infection M.tb, developing higher bacterial burdens and an increase in the size and number of granulomatous lesions. We aimed to assess the associations between single nucleotide polymorphisms (SNPs) in LXRs and risk of tuberculosis.

Methods

We sequenced the LXRs genes to detect SNPs and to examine genotypic frequencies in 600 patients and 620 healthy controls to investigate for associations with tuberculosis (TB) in the Chinese Han population. DNA re-sequencing revealed eight common variants in the LXRs genes.

Results

The G allele of rs1449627 and the T allele of rs1405655 demonstrated an increased risk of developing TB (p<0.001, p = 0.002), and the T allele of rs3758673, the T allele of rs2279238, and the C allele of rs1449626 in LXRA and the C allele of rs17373080, the G allele of rs2248949, and the C allele of rs1052677 in LXRB were protective against TB patients compared to healthy controls (p = 0.0002, p = 0.006, p<0.001, p = 0.004, p = 0.008, p = 0.003, respectively). All SNP genotypes were significantly associated with TB. An estimation of the frequencies of haplotypes revealed two potential risk haplotypes,GGCG in LXRB (p = 0.004,) and TTCG in LXRA (p<0.001, p = 0.004). Moreover, three protective haplotypes, TTAT and CCAT in LXRA and CATC in LXRB, were significantly “protective” (p = 0.008, p<0.001, p = 0.031) for TB. Furthermore, we determined that the LXRs SNPs were nominally associated with the clinical pattern of disease.

Conclusions

Our study data supported that LXRs play a fundamental role in the genetic susceptibility to TB and to different clinical patterns of disease. Thus, further investigation is required in larger populations and in additional areas.