Multivariate Cox Hazard Regression Analysis Research Articles

Abnormally expressed circular RNAs as novel non-invasive biomarkers for hepatocellular carcinoma: A meta-analysis.

BACKGROUNDCircular RNAs (circRNAs) are a newly discovered class of endogenous non-coding RNAs that may have roles in cancer genesis and development. In the recent literature, dysregulated circRNAs have been extensively investigated in hepatocellular carcinoma (HCC). Whether or not circRNAs are of clinical value for the management of HCC has not been characterized.AIMTo meta-analyze the diagnostic and prognostic value of abnormally expressed circRNAs in HCC.METHODSEligible studies were sourced from PubMed, EMBASE, and CNKI online databases. Data on patients’ clinical characteristics, including diagnostic efficacy and overall survival, were extracted. The diagnostic and prognostic parameters were respectively synthesized using the bivariate meta-analysis model and multivariate Cox hazard regression analysis based on Stata 12.0. The trim and fill method was adopted to assess the possible effects from publication bias.RESULTSA total of 21 eligible studies were included. The pooled sensitivity, specificity, and area under the curve of abnormally expressed circRNAs in distinguishing HCC from non-cancer controls were 0.78 (95%CI: 0.69–0.85), 0.80 (95%CI: 0.74–0.86), and 0.86, respectively. Survival analyses showed that the down-regulated circRNA expression signature correlated perfectly with HCC survival [hazard ratio (HR) = 0.42, 95%CI: 0.19–0.91, P = 0.028; I2 = 92.7%, P = 0.000], whereas the HCC cases with high circRNA levels had significantly poorer prognoses than those of patients with low circRNA levels (HR = 2.22, 95%CI: 1.50–3.30, P = 0.000; I2 = 91%, P = 0.000). Moreover, abnormally expressed circRNAs were intimately associated with tumor size, differentiation grade, microvascular invasion, metastasis, TNM stage, and serum alpha fetal protein level in patients with HCC. Stratified analysis based on sample type, control source, and expression status also yielded robust results.CONCLUSIONAbnormally expressed circRNA signatures show immense potential as novel non-invasive biomarker(s) for HCC diagnosis and prognosis.

Current trend of worsening prognosis of prostate small cell carcinoma: A population-based study.

ObjectiveTo determine the accurate age‐adjusted incidence of prostate small cell carcinoma (SCC), update the clinical and pathological characteristics, as well as survival data of prostate SCC from Surveillance, Epidemiology, and End Results (SEER) datasets.MethodsA total of 260 patients with prostate SCC were selected from the SEER database of the National Cancer Institute between 2004 and 2015. Age‐adjusted incidence (AAI) rates, the observed and relative survival rates were evaluated over time by the SEER*Stat Software version 8.3.5. Overall survival (OS) rates that stratified by summary stage and treatment effects were evaluated by Kaplan‐Meier method. The significant differences were assessed in a log‐rank test. Univariate and multivariate cox hazard regression analysis were performed to determine independent predictors of OS.ResultsThe incidence of prostate SCC has increased over time. The average age of prostate SCC patients was 70.25 years. More than 90% of tumors were poorly differentiated or undifferentiated. The majority of prostate SCC (77.7%) was at stage IV. 49% of patients had lymph node metastases and 68% of patients presented distant metastases (Compared with 60.5% of patients with distant metastases between 1973‐2003). Interestingly only 23.5% patients had high level PSA (>10 ng/mL). 58.8% of patients underwent chemotherapy, 25.4% of patients were treated by surgery, and 31.9% of patients were treated by radiotherapy. The observed survival rates of 1‐year, 2‐year, and 5‐year were 42.1%, 22.1%, and 12.5%, respectively (Compared with 47.9%, 27.5%, and 14.3%, respectively, between 1973 and 2003). Chemotherapy prolonged the OS of patients with regional (distant) metastases from 3 months (2 months) to 12 months (9 months). Multivariate cox regression analysis showed age, race, and stage were independent prognostic factors for prostate SCC patients.ConclusionProstate SCC is a highly malignant cancer and our analysis of recent data has shown its incidence is increasing. Incidence rate of metastatic prostate SCC has increased and the survival rates have worsened in recent years. However, chemotherapy shows some survival benefit for prostate SCC patients with regional and distant metastasis over other treatment methods. Further work is needed to understand the reason prognosis of this type prostate cancer is worsening.

Total arch replacement in octogenarians and nonagenarians: A single-center 18-year experience

BackgroundThis study evaluates our 18-year experience of total arch replacement in the octogenarian and nonagenarian population. MethodsBetween October 1999 and March 2018, a total of 740 patients underwent total arch replacement at our institution. A total of 139 patients were aged 80 years or more (83.1 ± 2.8 years), and 601 patients were aged less than 80 years (66.9 ± 11.3 years). Early and late outcomes were compared between the groups. ResultsIn the group aged 80 years or more, operative mortality occurred in 12 patients (8.6%) and significantly improved over time (P = .010). Operative mortality was significantly higher in the group aged 80 years or more (P = .033) when compared with the group aged less than 80 years (4.0%). Regarding postoperative complications, deep sternal wound infection, pneumonia, and tracheostomy occurred in significantly more patients in the group aged 80 years or more. In the group aged 80 years or more, there were 52 late deaths, with 4 aortic-related deaths. Overall survival was 55.4% ± 5.0% at 5 years and 32.2% ± 6.1% at 8 years. Multivariable Cox-hazard regression analysis demonstrated that chronic kidney disease, nonelective surgery, and concurrent procedures were significant risk factors for overall survival in the group aged 80 years or more. Cumulative incidence for reoperation was significantly lower in the group aged 80 years or more (8.7% at 5 years) compared with the group aged less than 80 years (14.2% at 5 years). ConclusionsTotal arch replacement was performed with an acceptable overall survival in octogenarians and nonagenarians, although operative mortality was higher than in younger patients. However, older patients had a lesser burden of reoperation compared with younger patients.

Association between advanced fibrosis in fatty liver disease and overall mortality based on body fat distribution.

Studies on association between fatty liver disease and overall mortality have yielded conflicting results. We evaluated the impact of fatty liver disease and advanced fibrosis on overall morality with a focus on body size and abdominal fat distribution measured by computed tomography. We performed a prospective cohort study including 34080 subjects (mean age, 51.4years; 58.6% men) who underwent abdominal ultrasonography and fat computed tomography, from 2007 to 2015. Fatty liver was diagnosed by ultrasonography, and advanced fibrosis was defined as high probability of advanced fibrosis based on three noninvasive methods, aspartate aminotransferase-to-platelet ratio index, non-alcoholic fatty liver disease fibrosis score, and fibrosis-4 score. Body size was categorized by body mass index into obese (≥25kg/m2 ) or nonobese (<25kg/m2 ). Multivariate proportional Cox hazard regression analyses were performed. The prevalence of fatty liver disease was 37.5%, while the prevalence of advanced fibrosis in fatty liver disease was 1.8%. During a median follow-up of 87months (interquartile range, 62-110), 296 deaths occurred. Fatty liver disease was not associated with higher overall mortality (multivariate-adjusted hazard ratio [HR] 1.02, 95% confidence interval [CI] 0.77-1.34), while increased subcutaneous adiposity was associated with decreased mortality (HR 0.72, 95% CI 0.60-0.88). Advanced fibrosis resulted in a 3.5-fold increase in overall mortality (adjusted HR 3.52, 95% CI 1.86-6.65), which was more pronounced in the nonobese. While fatty liver disease did not impact overall mortality, subcutaneous adiposity was associated with reduced overall mortality. Advanced fibrosis was an independent predictor of increase in overall mortality.

Comprehensive analysis of five long noncoding RNAs expression as competing endogenous RNAs in regulating hepatoma carcinoma.

Liver cancer is the most common cancer and is the epitome of a recalcitrant cancer. Increasing evidence shown that long noncoding RNAs (lncRNA) were associated with cancer‐related death and could function as a competing endogenous RNA (ceRNA). To explore regulatory roles and potential prognostic biomarkers of lncRNA for liver cancer, RNA‐sequencing expression data were downloaded from the TCGA database and GEO database. A total of 357 patients were randomly divided into a discovery group and a validation group, of which 313 patients can obtain clinical data. In discovery phrase, 58 lncRNAs, 16 miRNAs, and 34 mRNAs were screened to construct the ceRNA network based on 252 patients employed from discovery group. Univariate and multivariate Cox hazard regression analysis model revealed that five lncRNAs (AATK‐AS1, C10orf91, LINC00162, LINC00200, and LINC00501) from 58 lncRNAs were formulated to predict the overall survival (OS). We used the value of gene expression and regression coefficients to construct a risk score based on the five lncRNAs. Next, we validated our model in the GSE116174 dataset (n = 64) and the validation group (n = 94) from TCGA database. Subgroup analysis suggest that the five lncRNAs played critical parts in early stage in cancer from both discovery and validation groups. The five lncRNAs were also found to be associated with immune cells infiltration including CD4+ memory activated, NK cells activated and mast cells activated, then the results were also validated according to the validation group. Furthermore, KEGG pathway enrichment analysis showed that these nine coexpressed modules using the method of WGCNA, and many of these pathways are associated with the development and progression of disease. At last, the transcription factor binding sites (TFBS) of the five lncRNAs were predicted, which help us to understand the potential mechanism that the TFBS adjusted the ceRNA network. In summary, the ceRNA regulatory network may contribute to a better understanding of liver cancer mechanism and provide potential prognostic biomarkers and therapeutic targets.

Abstract 1426: Expansion of CD8+PD-1+ T cells restored TCR repertoire as a prognostic marker to adoptive T cell immunotherapy of advanced pancreatic cancer

Abstract Purpose: We have previously reported the clinical benefits of autologous adoptive T cell immunotherapy in advanced pancreatic cancer (APC). We therefore aimed to further identify the core functional population of CD8+ T cells which exerted on the aberrant TCR repertoire and subsequently contribute to favorable prognosis after adoptive T cell therapy(ACT). Experimental Design: PBMC from APC patients (n=25) treated on a protocol of S-1 plus adoptive T cell immunotherapy were expanded ex vivo with a cytokine cocktail. The different fractions of CD8+PD-1+, CD8+LAG-3+, CD8+TIM-3+ and CD8+4-1BB+ T cells from time dependent segment were quantitated and expression of co-inhibitory molecules and biological functions on tumor killing and comparative analysis TCR repertoire from each patient were measured. The multivariate Cox hazards regression analysis was performed to identify the key T cell subset that affected the TCR repertoire recovery and subsequently associated with clinical outcome. Results: The CD3+, CD3+CD4+, and CD3+CD8+ T cells within the expanded cell product reached peak levels by day 15. CD8+ T cells exhibited enhanced expression of PD-1, LAG-3, and TIM-3, but not 4-1BB, after ex vivo expansion. Survival analysis showed that patients with a ratio of post/pre CD8+PD-1+ T cells &amp;gt; 2 had significantly favorable progressive-free survival (PFS) (median PFS time 180 days vs 85 days, P=0.002) and overall survival (OS) (median OS time 238 days versus 142 days, P=0.024). The sorted CD8+PD-1+ T cells displayed enhanced anti-tumor activity, and increased IFN-γ secretion after co-culture with autologous tumor cell lines. TCR repertoire diversity simultaneously rose during the ex vivo expansion and was associated with an increase in CD8+ T cells and decline in CD8+/CD28- T cells. Moreover, an increased TCR diversity was associated with significantly favorable PFS (median PFS time 166 days vs 79 days, P=0.043) and OS (median OS time 216 days versus 112 days, P=0.031) and was associated with the extent of expansion of the CD8+PD-1+ T cells (r2=0.464, P=0.001). Cox proportional hazards analysis showed that post/pre CD8+PD-1+ T cells after expansion ex vivo was an independent prognostic marker associated with both OS(P=0.009) and PFS(P=0.012). Conclusion: CD8+PD-1+ T cells, after ex vivo expansion over 15 days, are tumor-reactive. The extent of CD8+PD-1+ T cell expansion could restore TCR repertoire and was an independent prognostic factor associated with clinical outcomes in APC patients treated with ACT. Citation Format: Guoliang Qiao. Expansion of CD8+PD-1+ T cells restored TCR repertoire as a prognostic marker to adoptive T cell immunotherapy of advanced pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1426.

Peri-strut low-intensity area assessed by midterm follow-up optical coherence tomography may predict target lesion revascularisation after everolimus-eluting stent implantation

Peri-strut low-intensity area (PLIA) assessed by optical coherence tomography (OCT) has been reported as a potential marker of abnormal neointimal healing. We aimed to evaluate the impact of PLIA on clinical events and its risk factors. We enrolled 264 consecutive patients treated with an everolimus-eluting stent (EES) who underwent follow-up OCT six to 12 months after stenting. Target lesion revascularisation (TLR) was evaluated at a mean 42.6 months after stenting. PLIA was identified in 102 patients; 162 patients did not exhibit PLIA. Multivariate Cox hazard regression analysis indicated that the presence of PLIA (PLIA+) was an independent risk factor for an increased incidence of TLR (hazard ratio [HR]: 4.608, p=0.003). In both the early (<1 year) and late (>1 year) phases, the incidence of TLR was significantly higher in the PLIA+ group (p<0.001 and p<0.001, respectively). In the Cox hazard regression analysis, current smoking and increased C-reactive protein level were independently associated with PLIA+ (HR: 1.737, p=0.009; HR: 2.435, p=0.008, respectively). The presence of PLIA on midterm OCT was associated with TLR after EES implantation. Detailed stent assessment by midterm OCT may help to predict stent failure in patients treated with EES.

The Relationship Between ZEB1-AS1 Expression and the Prognosis of Patients With Advanced Gastric Cancer Receiving Chemotherapy.

Long noncoding RNA ZEB1 antisense RNA 1 plays a vital role in tumorigenesis and metastasis. However, the role of ZEB1 antisense RNA 1 in gastric cancer remains unclear. This study aimed to investigate the expression level of ZEB1 antisense RNA 1 in gastric cancer tissues and evaluate its association with clinicopathological features and prognosis of patients with advanced gastric cancer receiving chemotherapy. The expression levels of ZEB1 antisense RNA 1 were examined in 224 pairs of gastric cancer and adjacent noncancerous tissues by quantitative real-time polymerase chain reaction. The associations between ZEB1 antisense RNA 1 expression and clinicopathological features or survival of patients with advanced gastric cancer were assessed. The results showed that the expression levels of ZEB1 antisense RNA 1 in gastric cancer tissues were significantly higher than those in the paracancerous tissues (P < .001). Moreover, the high ZEB1 antisense RNA 1 expression was associated with tumor, nodes, and metastases stage IV (P = .018) and loss of E-cadherin expression (P = .033). Multivariate Cox hazards regression analysis revealed that high ZEB1 antisense RNA 1 expression was an independent risk factor for predicting poor prognosis in patients with advanced gastric cancer (hazard ratio = 1.530, 95% confidence interval, 1.052-2.224, P = .026). In conclusion, the present findings suggest that ZEB1 antisense RNA 1 is an independent prognostic factor for patients with advanced gastric cancer receiving chemotherapy.

Association of self-reported and cotinine-verified smoking status with incidence of metabolic syndrome in 47 379 Korean adults.

The relationship of cotinine-verified vs self-reported smoking status with the incidence of metabolic syndrome (MetS) is not known. This study investigated the effect of urinary cotinine-verified vs self-reported smoking status on incident MetS. In all, 47 379 participants without MetS enrolled in the Kangbuk Samsung Health Study and Kangbuk Samsung Cohort Study between 2011 and 2012 (baseline) were included in this study and followed-up in 2014; median follow-up duration was 25 months. Cotinine-verified current smoking was defined as urinary cotinine concentrations >50 ng/mL. According to cotinine-verified smoking status at baseline and follow-up, individuals were divided into four groups: never, new, former, and sustained smokers. The incidence of MetS in the never, former, new, and sustained smoking groups was 9.9%, 19.4%, 21.4%, and 18.7%, respectively. Multivariate Cox hazard regression analyses revealed that the relative risk (RR) for incident MetS in cotinine-verified former smokers was significantly increased compared with that in cotinine-verified never smokers (RR 1.27; 95% confidence interval [CI] 1.16-1.37), especially in individuals exhibiting weight gain (≥2 kg). These results were consistent with those of self-reported smoking status. Baseline cotinine-verified current smoking (RR 1.09; 95% CI 1.03-1.15) and self-reported former (RR 1.10; 95% CI 1.02-1.18) and current (RR 1.15; 95% CI 1.07-1.23) smoking were also significantly associated with incident MetS. This large observational study showed that cotinine-verified and self-reported former smoking during follow-up increased the risk for incident MetS, especially in individuals exhibiting weight gain (≥2 kg). This suggests that weight control in former smokers would be very important to reduce the development of MetS.

Primary anatomical site, adjuvant therapy, and other prognostic variables for dedifferentiated liposarcoma.

Dedifferentiated liposarcoma (DDLPS) is a high-grade, clinically aggressive tumor associated with low survival probabilities. Prognostic variables for DDLPS have not been previouslyreported in a large patient population. A total of3573 patients with primary DDLPS were analyzed from the National Cancer Data Base (NCDB). The 5- and 10-year survival probabilities were calculated, and the groups were compared using log-rank comparisons and multivariable Coxhazard regression analysis. Median survival was also calculated. Males comprised 65% of the cohort, the median age at diagnosis was 64years of age, and 65.4% of the patients were between 51 and 75years of age. The most common site for primary tumors is the retroperitoneum or abdomen (59.5%). Head or neck tumors had the best 5-year outcomes (86.4%) followed by extremities (67.1%), pelvis (65.8%), thorax or trunk (58.9%), and finally retroperitoneum or abdomen (42.6%). Best outcomes were noted in the 26- to 50-year-old age group (5-year survival:66.8%), < 10cm size (5-year survival:66.1%), FNCLCC grade 1 (5-year survival:69.2%), and stage II disease (5-year survival:66.7%). Radiation therapy yielded the best 5-year and 10-year survival probabilities of 59% and 39.3%, respectively. Out of all the adjuvant therapies, the use of radiation resulted in the best 5-year survival of 63.4%. In the largest and most comprehensive study to date on DDLPS, major findings include primary site as a significant prognostic variable with age at presentation, sex, tumor stage, and type of adjuvant therapy significantly impacting overall survival.

Long-term outcomes of total arch replacement using a 4-branched graft

ObjectiveOur study evaluated the long-term outcomes of total arch replacement using a 4-branched graft. MethodsFrom October 1999 to December 2016, 655 patients underwent total arch replacement using a 4-branched graft (pathology in the 655 patients was distributed as 399 no dissection, 149 acute dissection, and 107 chronic dissection). Two hundred nine patients (31.9%) underwent nonelective surgery. Mean follow-up term was 5.0 ± 4.1 years and follow-up rate was 97.1%. ResultsOf 655 patients who underwent total arch replacement using a 4-branched graft, operative mortality occurred in 34 patients (5.2%) and permanent neurologic deficit occurred in 24 patients (3.7%). One hundred ninety late deaths occurred, with 20 aortic event-related deaths. Overall survival was 73.1% ± 1.9% at 5 years and 54.8% ± 2.7% at 10 years. Multivariate Cox-hazard regression analysis demonstrated that older age, lower estimated glomerular filtration rate, concurrent procedures, permanent neurologic deficit, tracheostomy, and renal failure were significant risk factors for late death. Freedom from repeat operation on the aorta was 98.0% ± 0.7% at 5 years and 93.9% ± 1.8% at 10 years and freedom from additional aortic operation was 87.2% ± 1.5% at 5 years and 77.3% ± 2.7% at 10 years. The incidence of pseudoaneursym was 2.2%. ConclusionsThe long-term outcomes for patients undergoing total arch replacement using 4-branched graft are favorable. However, even in the late phase, periodic follow-up is necessary to address subsequent aorta-related events.

Time- and frequency-domain measures of heart rate variability predict cardiovascular outcome in patients with type 2 diabetes

AimsTo evaluate the association between impaired heart rate variability (HRV) and cardiovascular disease (CVD) in patients with type 2 diabetes (T2DM). MethodsA total of 655 patients with T2DM who underwent cardiovascular autonomic function testing were consecutively recruited and followed up prospectively. Time- and frequency-domain HRV were assessed for 5 min by beat-to-beat heart rate recording. We estimated the development of CVD events during a follow-up period. ResultsDuring a median follow-up of 7.8 years, 9.6% (n = 49) of patients developed CVD (10.6 per 1000 patient-years). The mean age and diabetes duration were 54.9 ± 8.6 years and 9.4 ± 7.3 years, respectively. Patients who had cardiovascular autonomic neuropathy (CAN) had decreased HRV compared with those with normal autonomic function. Multivariable cox hazard regression analysis revealed the lowest 10th percentile of the SD of the normal-to-normal interval (HR 2.62; 95% CI 1.30–5.31), total power (HR 2.81; 95% CI 1.37–5.79), low-frequency power (HR 2.68; 95% CI 1.28–5.59), and high-frequency power (HR 2.24; 95% CI 1.09–4.59) were significant predictors for developing CVD in patients with T2DM. ConclusionsTime- and frequency-domain measures of HRV independently predicted cardiovascular outcome in patients with T2DM.

Relationship Between Cotinine-Verified Smoking Status and Incidence of Hypertension in 74,743 Korean Adults.

The relationship between chronic smoking and hypertension (HTN) is inconclusive in previous studies, which were mainly based on self-reported smoking status. The aim of this study was to evaluate the association of cotinine-verified smoking status with incident HTN.Methods and Results:A total of 74,743 participants (43,104 men; age 38±5.4 years) were included in the study, with a mean follow-up period of 29 months. Individuals were divided into 4 groups on the basis of their cotinine-verified smoking status at baseline and at follow-up (never-smoking, new-smoking, former-smoking, and sustained-smoking). The incidence rate of HTN in the never-smoking, new-smoking, former-smoking, and sustained-smoking groups was 8.2%, 7.6%, 10.1%, and 8.7% for men and 1.8%, 2.5%, 1.5%, and 2.2% for women, respectively. In a multivariate Cox-hazard regression analysis adjusted for the variables with a univariate relationship, new-smoking and sustained-smoking had decreased relative risks (RRs) for incident HTN compared with never-smoking (RR [95% CI], 0.75 [0.58, 0.96] for new-smoking and 0.82 [0.74, 0.90] for sustained-smoking). Cotinine-verified current smoking at baseline was also inversely associated with incident HTN compared with cotinine-verified never-smoking at baseline (0.91 [0.84, 0.98]). These results remained significant only in men, although there was no sex interaction. This longitudinal study showed that cotinine-verified new-smoking and sustained-smoking decreased the risk for incident HTN, especially in men, compared with never-smoking.

Total iron-binding capacity is a novel prognostic marker after curative gastrectomy for gastric cancer.

Patients with gastric cancer (GC) are affected by changes in iron status. Before surgery, GC patients are likely to have iron-deficiency anemia; and after gastrectomy, patients suffer from low nutritional status and low iron. This study investigated preoperative iron status associated with prognosis after curative gastrectomy for gastric cancer. We evaluated preoperative serum hemoglobin (Hgb), Fe and total iron-binding capacity (TIBC) in 298 patients who underwent curative gastrectomy for GC without preoperative chemotherapy, and analyzed these factors' associations with prognosis after surgery. Of the 298 patients, 129 (43.2%) had low Hgb levels, and 33 (11.1%) had low TIBC (< 260µg/dl) that was not associated with Hgb or Fe level. Patients with low TIBC were significantly associated with older age (≥ 65years old; P = 0.0085), low albumin (< 3.9g/dl; P = 0.0388) and high CRP (≥ 0.15mg/dl; P = 0.0018) in multivariate analysis. Low Fe (< 60µg/dl) was not associated with disease-free survival (DFS) or overall survival (OS); however, low Fe was associated with longer cancer-specific survival in Stage III GC patients (P = 0.0333). Both low Hgb and low TIBC were significantly associated with shorter DFS (Hgb: P = 0.0433; TIBC: P < 0.0001) and shorter OS (Hgb: P = 0.0352; TIBC: P < 0.0001). Low TIBC were significantly associated with shorter DFS (HR 2.167, 95% CI 1.231-3.639, P = 0.0086) and shorter OS (HR 2.065, 95% CI 1.144-3.570, P = 0.0173) in multivariate Cox hazard regression analysis. Preoperative serum TIBC level of GC patients who undergo curative gastrectomy is a novel prognostic marker in univariate and multivariate analyses.

Dietary Salt Intake is a Significant Determinant of Impaired Kidney Function in the General Population

Background/Aims: Kidney dysfunction is an important risk factor for cardiovascular disease and end-stage renal disease. This study investigated whether dietary salt intake predicts deterioration of kidney function in the general population. Methods: In all, 12 126 subjects with a normal estimated glomerular filtration rate (eGFR ≥60 mL/min per 1.73m2) attending an annual check-up were enrolled in the study and were followed-up for a median of 1754 days; the endpoint was the development of impaired kidney function (eGFR < 60 mL/min per 1.73m2). Individual salt intake was estimated using spot urine analysis. Results: At baseline, mean (± SD) salt intake and eGFR were 10.6 ± 3.4 g/day and 80.8 ± 12.9 mL/min per 1.73m2, respectively. During the follow-up period, 1384 subjects (25.2 per 1000 person-years) developed impaired kidney function. Multivariate Cox hazard regression analysis revealed salt intake as a significant predictor of the new onset of kidney impairment (hazard ratio 1.045; 95% confidence interval 1.025–1.065). Subjects were divided into two groups based on salt intake; the incidence of impaired kidney function was higher in the group with high than low salt intake (P < 0.001, log-rank test). Multivariate Cox hazard regression analysis indicated a 29% increased risk of developing impaired kidney function in the high-salt group. Multivariate linear regression analysis showed a significant correlation between salt intake and yearly decline in eGFR (β = 0.060, P < 0.001). Conclusion: Salt intake is associated with the development of impaired kidney function in the general population, independent of its effects on blood pressure. Salt restriction may help prevent the development of impaired kidney function.

Circadian Rhythm Sleep-Wake Disorders Predict Shorter Time to Relapse of Mood Episodes in Euthymic Patients With Bipolar Disorder: A Prospective 48-Week Study.

Circadian rhythm dysfunction has been considered to be common in bipolar disorder (BD) and plays an important role in mood dysregulation in this disorder. However, no study has investigated whether circadian rhythm dysfunction would affect the clinical course of BD. The aim of this study was to test the hypothesis that circadian rhythm dysfunction could be a predictor of relapse in euthymic BD patients. One hundred four euthymic outpatients with BD diagnosed according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), participated in this prospective follow-up study from August 2014 to April 2015. At baseline, data on demographic variables and clinical descriptive variables of bipolar disorder were ascertained via clinical interviews. The diagnoses of circadian rhythm sleep-wake disorders (CRSWDs) were made based on participants' sleep logs for 4 weeks and according to the International Classification of Sleep Disorders, Third Edition (ICSD-3). The BD symptoms of the subjects were evaluated using the Montgomery-Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) scores every 4 weeks throughout the 48-week study period. Relapse of BD was defined as scores higher than the cutoff points (MADRS score ≥ 13 and YMRS score ≥ 7). The primary outcome was time to relapse of mood episodes. Thirty-four subjects met criteria for CRSWD at baseline, most frequently delayed sleep-wake phase disorder (n = 27). Of the total 104 subjects, 51 (49.0%) experienced relapse during the 48-week follow-up period. Multivariate Cox hazard regression analyses revealed that 2 or more previous mood episodes within the past year and comorbidity of CRSWD were significantly associated with the time to relapse of mood episodes (P < .001). Comorbid CRSWD, mainly delayed sleep-wake phase disorder, could be a significant predictor of relapse in BD patients.

Circadian rhythm sleep-wake disorders predict shorter time to relapse of mood episodes in euthymic patients with bipolar disorder: a prospective 48-week study

OBJECTIVE Circadian rhythm dysfunction has been considered to be common in bipolar disorder (BD) and plays an important role in mood dysregulation in this disorder. However, no study has investigated whether circadian rhythm dysfunction would affect the clinical course of BD. The aim of this study was to test the hypothesis that circadian rhythm dysfunction could be a predictor of relapse in euthymic BD patients. METHODS One hundred four euthymic outpatients with BD diagnosed according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), participated in this prospective follow-up study from August 2014 to April 2015. At baseline, data on demographic variables and clinical descriptive variables of bipolar disorder were ascertained via clinical interviews. The diagnoses of circadian rhythm sleep-wake disorders (CRSWDs) were made based on participants' sleep logs for 4 weeks and according to the International Classification of Sleep Disorders, Third Edition (ICSD-3). The BD symptoms of the subjects were evaluated using the Montgomery-Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) scores every 4 weeks throughout the 48-week study period. Relapse of BD was defined as scores higher than the cutoff points (MADRS score ≥ 13 and YMRS score ≥ 7). The primary outcome was time to relapse of mood episodes. RESULTS Thirty-four subjects met criteria for CRSWD at baseline, most frequently delayed sleep-wake phase disorder (n = 27). Of the total 104 subjects, 51 (49.0%) experienced relapse during the 48-week follow-up period. Multivariate Cox hazard regression analyses revealed that 2 or more previous mood episodes within the past year and comorbidity of CRSWD were significantly associated with the time to relapse of mood episodes (P < .001). CONCLUSIONS Comorbid CRSWD, mainly delayed sleep-wake phase disorder, could be a significant predictor of relapse in BD patients.

Independent Risk Factors and 2-Year Outcomes of Acute Kidney Injury after Surgery for Congenital Heart Disease

Background: Data are limited regarding risk factors for acute kidney injury (AKI) following cardiac surgery in children with congenital heart disease (CHD). This observational study was performed to examine temporal trends in AKI incidence according to the Pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease (pRIFLE) criteria, identify independent risk factors for AKI after cardiac surgery, and examine associations between AKI and long-term mortality. Methods: We retrospectively evaluated 418 patients (259 males, 159 females; median age, 5 months) who underwent cardiac surgery for CHD between April 2007 and August 2013. Patients were followed up for 2 years. AKI was defined according to the pRIFLE criteria as ≥25% decrease in estimated creatinine clearance. Results: AKI developed postoperatively in 104 cases (24.9%). Approximately 80% belonged to the “Risk” category according to the pRIFLE criteria, and only 21 cases (5%) required renal replacement therapy (peritoneal dialysis in all cases). Multivariate analysis revealed 3 independent risk factors for onset of AKI: young age (<1 year), surgery in Risk Adjustment in Congenital Heart Surgery (RACHS-1) category ≥4, and long cardiopulmonary bypass (CPB) time (≥90 min). Twenty-three patients (22%) with AKI died during the 2-year follow-up. In multivariate cox hazard regression analysis, the most significant contributor to risk of mortality was AKI. Conclusions: Postoperative AKI was strongly associated with young age, high RACHS-1 category, and prolonged CPB time. In addition, mortality rate was higher in patients who survived after recovery from AKI than in those without AKI, even among the lower pRIFLE categories.

Expression of ALCAM (CD166) and PD-L1 (CD274) independently predicts shorter survival in malignant pleural mesothelioma

Diffuse malignant mesothelioma of the pleura is a highly aggressive tumor typically associated with short survival. ALCAM (CD166), a type I transmembrane protein, is a member of the immunoglobulin superfamily. In normal cells, ALCAM regulates physiological processes such as angiogenesis and immune response. In cancer, it is associated with neoplastic progression, including invasion, migration, and metastasis. Furthermore, ALCAM is considered one of the cancer stem cell markers such as ALDH1 (ALDH1A1) and SALL4. The PD-L1 (CD274)/PD-1 (PDCD1, CD279) pathway is crucial for the modulation of immune responses in normal cells. Nevertheless, pathologic activation of the PD-L1/PD-1 pathway participates in immune evasion by tumor cells. Many PD-L1-expressing tumor cells have been identified in different types of cancer, including malignant mesothelioma. In this study, 175 well-characterized primary diffuse pleural mesotheliomas, including the epithelioid (n = 148), biphasic (n = 15), and sarcomatoid (n = 12) histotypes, were evaluated immunohistochemically for cancer stem cell markers (ALCAM, ALDH1, and SALL4) and PD-L1 expression. Twenty-five percent of the mesotheliomas (43/175) expressed ALCAM, whereas ALDH1 and SALL4 positivity was seen in 1% to 2% of cases. Thirty-three percent of the analyzed tumors (57/175) contained PD-L1-positive cells. Overall survival was significantly decreased in the cohort of patients with ALCAM- or PD-L1-positive tumors (both P < .01). Furthermore, the multivariate Cox hazards regression analysis identified ALCAM and PD-L1 (both P < 0.01) as potential independent risk factors. Thus, a combination of these 2 markers might be useful for prognostication and planning the treatment of patients with malignant pleural mesothelioma.

Incidence of incisional hernia after minimally invasive and open radical prostatectomy: a population-based nationwide study

Objective: Minimally invasive techniques (laparoscopic or robot-assisted laparoscopic) are gradually becoming the methods of choice for surgical treatment of prostate cancer. However, the impact of these techniques on the risk of developing incisional hernia has yet to be fully evaluated. The aim of this study was to compare the risk of incisional hernia after open radical prostatectomy (ORP) and minimally invasive radical prostatectomy (MIRP).Materials and methods: From the National Prostate Cancer Register of Sweden, all men who underwent radical prostatectomy for prostate cancer between 2004 and 2013 were identified. These data were linked with the National Patient Register to determine comorbidity and subsequent diagnosis of incisional hernia or surgery for incisional hernia. The endpoint was diagnosis of or surgery for incisional hernia. Multivariate proportional Cox hazard regression analyses were performed to analyze risk factors.Results: In total, 19,743 men underwent radical prostatectomy during the study period. The cumulative incidence of incisional hernia was 1.4% [95% confidence interval (CI) 1.2–1.7%] and 2.3% (CI 1.9–2.7%) 5 years after ORP and MIRP, respectively (p < .05). For men undergoing ORP, age above the median was associated with increased risk of incisional hernia (p < .001). For men undergoing MIRP, age above the median, prostate volume above the median and lymph-node dissection were associated with increased risk of incisional hernia (p < .05).Conclusion: MIRP is associated with a significantly higher risk of developing an incisional hernia compared to ORP. Awareness of appropriate surgical technique may reduce this risk.