Objective To investigate the impact of squamous and/or glandular differentiation on recurrence and progression in patients with non-muscle-invasive urothelial carcinoma of bladder (NMIUCB) following transurethral resection (TURBT). Methods A total of 869 patients with NMIUCB treated with TURBT at our institution from January 2006 to January 2011 were selected retrospectively for the analysis. Correlations among squamous and/or glandular differentiation with other clinical and pathological features were assessed by chi-square. Recurrence-free survival (RFS) and progression-free survival (PFS) curves were estimated using the Kaplan-Meier method. Univariate and multivariate analyses were performed through a Cox proportional hazards regression model. Results Among 869 consecutive patients, 232 (26.7%) patients had squamous and/or glandular differentiation. High grade tumors were more common in patients with squamous and/or glandular differentiation than those with pure UCB (P<0.001). Correlations between age (P=0.115), gender (P=0.184), tumor size (P=0.223), tumor multiplicity (P=0.108), pathological tumor stage (P=0.909) and squamous and/or glandular differentiation were not statistically significant. There was a statistically prominent tendency towards higher recurrence rate and shorter RFS time in patients with squamous and/or glandular differentiation. However, no statistically significant differences were observed in progression rate and PFS between the two groups. On multivariate Cox regression analysis, squamous and/or glandular differentiation was identified as an independent prognostic predictor of recurrence (HR 1.46, 95% CI, 1.10–1.92, P=0.008). Conclusions The presence of squamous and/or glandular differentiation could be associated with higher recurrence rate and shorter RFS time in patients with NMUCB. It is an independent prognostic predictor of recurrence.

Objective: To investigate the clinicopathological significance of Lymphovascular invasion in the ureteral transitional cell carcinoma after radical nephroureterectomy (RNU).

Renal cell carcinoma (RCC) and urothelial carcinoma (UC) of the renal pelvis are not uncommon urological malignancies. However, simultaneous occurrence of RCC and UC in a patient is extraordinarily rare. We report a case of simultaneous contralateral renal cell carcinoma and urothelial carcinoma of the renal pelvis. The patient, a 72-year-old man, presented to our department with intermittent painless gross hematuria of 3 months duration. Radiologic examination revealed a solid mass in the right kidney and additionally another mass in the pelvis of the contralateral kidney with severe hydronephrosis. For the carcinoma of the pelvis, the patient chose radical nephroureterectomy with bladder cuff removal; for the renal cell carcinoma, the patient chose active surveillance. For follow-up during the surveillance period, we suggested computed tomography (CT) or magnetic resonance imaging every 3 months in the first year, every 6 months in the next 2 years and every year thereafter. After 2 years, the patient is in good health and disease-free under strict surveillance. We discuss this rare occurrence and our management approach.

Bladder cancer is one of the most common malignancies worldwide and the stage pT1nonmuscle invasive bladder cancer (NMIBC) has a high probability of recurrence after initial diagnosis and treatment. However, risk factors predictive of repeated recurrence and progression of pT1 bladder tumors after primary relapse have not been uncovered. Thus, we conducted the retrospective study. A total of 418 patients who suffered initial recurrence after transurethral resection (TUR) of pT1 bladder tumor were selected for the analyses. Clinic information of the patients was retrieved from their medical records. Recurrence-free survival (RFS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Univariate and multivariate analyses were performed using a Cox proportional hazards regression model. The probability of recurrence and progression by multivariate analyses was used as a surrogate marker to construct receiver operating curve (ROC). Results showed that variables including time to prior recurrence time, prior treatment, number of tumor, tumor size, tumor grade, and time of instillation after surgery were associated with the repeated recurrence of pT1 bladder tumor (P < 0.05). The variables including time to prior recurrence time, tumor size, tumor grade, carcinoma in situ (CIS), and time of instillation after surgery were associated with progression of pT1 bladder tumor (P < 0.05). In the present study, the multivariate model showed an area under ROC (AUC) value of 0.754 and 0.798 for tumor recurrence and progression, respectively, which was more effective in prediction than a single risk factor. In conclusion, we have identified several risk factors relevant to RFS and PFS for patients who have had a history of recurrence of pT1 bladder tumor after TUR. These predictive factors may help urologists to stratify patients into distinct risk groups of recurrence and progression, which probably contributes to the individualized treatment for patients.

目的:探讨膀胱癌肉瘤的诊断及治疗方法.方法:回顾性分析我院2005年～2012年收治的3例膀胱癌肉瘤患者的临床资料,3例患者均以全程无痛肉眼血尿为首发症状,伴排尿困难2例,尿频、尿急1例,膀胱镜检示肿瘤发生于膀胱左侧壁2例,膀胱顶底部1例.3例患者中1例行经尿道膀胱肿瘤电切术(TURBT),1例行全膀胱切除术+回肠膀胱术,1例行膀胱全切术+双侧输尿管皮肤造口术.结果:所有患者术后病理均证实为膀胱癌肉瘤,3例均为高级别.患者术后均获随访,随访时间10～36个月,1例术后10个月死亡,1例术后2年死亡.1例术后至今存活3年.结论:膀胱癌肉瘤是一种少见的高度恶性的膀胱肿瘤,根治性膀胱切除术是主要的治疗方式,术后放化疗效果均不理想,预后差.

OBJECTIVE:The objective of this article was to summarize the relationship between some components of metabolic syndrome (MetS) and the histopathologic findings in bladder cancer in a Chinese population.METHODS:We retrospectively analyzed data of 323 patients from the Department of Urology, Second Hospital of Tianjin Medical University between January 2012 and January 2014. All the patients were diagnosed with bladder cancer for the first time. Age, height, weight, histologic stage, grade, the presence of hypertension, diabetes mellitus, and body mass index were evaluated. The 2009 American Joint Committee on Cancer TNM staging system was used, with Ta and T1 tumors accepted as lower stage and T2, T3, and T4 tumors as higher stage bladder cancers. Also, pathologists assigned tumor grade according to the 1973 World Health Organization grading system. Noninvasive papillary urothelial neoplasms of low malignant potential were regarded as low grade. Analyses were completed using chi-square tests and logistic regression analysis.RESULTS:Of the 323 patients, 164 had hypertension, 151 had diabetes mellitus, and 213 had a body mass index ≥25 kg/m(2). MetS was significantly associated with histologic grade (P<0.001) and stage (P=0.006) of bladder cancer. Adjusted for age in binary logistic regression analysis, the presence of MetS predicts the risk of higher T stage (odds ratio =4.029, P<0.001) and grade (odds ratio =3.870, P<0.001) of bladder cancer.CONCLUSION:The patients with MetS in the People's Republic of China were found to have statistically significant higher T stage and grade of bladder cancer.

Background Long noncoding RNAs (lncRNAs) have been implicated playing important roles in human urologic cancers. Up to date, quite a few lncRNAs have been implicated as promising biomarkers for tumor early detection and prognosis monitoring. Methods In the present study, microarray analysis was initially performed to screen the differentially expressed lncRNAs between bladder cancer tissues and paired adjacent non-cancerous tissues (n=3).Subsequent qRT-PCR validation was conducted using tissue samples from 95 patients with bladder cancer. Results Results showed that the expression level of lncRNA-n336928 (noncode database ID: n336928) was significantly higher in bladder cancer tissues compared to that in adjacent noncancerous tissues (P<0.001). Chi-square test showed that expression of lncRNA-n336928 was positively correlated with bladder tumor stage and histological grade (P<0.001). Kaplan-Meier survival analysis revealed that patients with bladder cancer with high expression of lncRNA-n336928 had shorter overall survival time compared to patients with low expression of lncRNA-n336928. Multivariate analysis indicated that lncRNA-n336928 was an independent prognostic factor for overall survival for bladder cancer patients. Conclusions our study shows that high expression of lncRNA-n336928 is associated with the progression of bladder cancer, and that lncRNA-n336928 might serve as a biomarker for prognosis of bladder cancer

Objective: The management of stage 1 and grade 3 (T1G3) bladder cancer continues to be controversial. Although the transurethral resection of bladder tumor (TURBT) followed by intravesical chemotherapy is a conservative strategy for treatment of T1G3 bladder cancer, a relatively high risk of tumor recurrence and progression remains regarding the therapy. This study aimed to compare the efficacy of intravenous chemotherapy combined with intravesical chemotherapy versus intravesical chemotherapy alone for T1G3 bladder cancer after TURBT surgery. Methods: We retrospectively reviewed the cases of 457 patients who were newly diagnosed with T1G3 bladder urothelial carcinoma between January 2009 and March 2014. After TURBT, 281 patients received intravesical chemotherapy alone, whereas 176 patients underwent intravesical chemotherapy in combination with intravenous chemotherapy. Tumor recurrence and progression were monitored periodically by urine cytology and cystoscopy in follow-up. Recurrence-free survival and progression-free survival of the two chemotherapy strategies following TURBT were analyzed. Univariable and multivariable Cox hazards analyses were performed to predict the prognostic factors for tumor recurrence and progression. Results: The tumor recurrence rate was 36.7% for patients who received intravesical chemotherapy alone after TURBT, compared with 19.9% for patients who received intravenous chemotherapy combined with intravesical chemotherapy after TURBT (P<0.001). The progression rate was 10.6% for patients who underwent intravesical chemotherapy alone and 2.3% for patients who underwent the combined chemotherapies (P=0.003). Kaplan-Meier curves showed significant differences in recurrence-free survival and progression-free survival between the two treatment strategies, with a log-rank P-value of <0.001 and 0.003, respectively. Multivariable analyses revealed that intravenous chemotherapy was the independent prognostic factor for tumor recurrence and progression in the cohort. Conclusion: Intravenous chemotherapy combined with intravesical chemotherapy offers a better oncologic outcome than the intravesical chemotherapy alone for patients with T1G3 bladder urothelial carcinoma after TURBT, and it may be considered as a new therapy strategy for T1G3 bladder cancer.

目的:探讨尿路上皮癌伴鳞状分化对初次经尿道膀胱肿瘤电切术(TURBT)术后pT1期患者预后的影响.方法:回顾性分析初次经TURBT手术、术后病理诊断为T1期的531例膀胱尿路上皮癌患者的临床病理资料.根据患者的术后病理诊断将患者分为2组:A组为尿路上皮癌(单纯型)441例,B组为尿路上皮癌伴鳞状分化90例,应用SPSS 20.0统计软件,运用Kaplan-Meier法分析两种临床病理特点对无复发生存期(RFS)和无进展生存期(PFS)的影响,并用Log-rank检验比较生存曲线;运用COX回归模型单因素和多因素分析膀胱尿路上皮癌伴鳞状分化与初次TURBT术后pT1期患者预后之间的关系,评估影响其RFS和PFS的因素.结果:A组单纯尿路上皮癌441例(83.05％),B组尿路上皮癌伴鳞状分化90例(16.95％).B组与A组比较更易具有高级别肿瘤(P＜0.001),同时B组较A组有较高的复发率(P=0.018)、较短的无复发生存期(P＜0.001)以及较高的进展率(P=0.001)、较短的无进展生存期(P＜0.001).B组与A组比较,年龄(P=0.185)、性别(P=0.135)、吸烟(P=0.728)、肿瘤大小(P=0.436)、肿瘤数目(P=0.112)和膀胱灌注(P=0.054)等差异均无统计学意义.COX多因素生存分析显示:吸烟(HR 1.34,95％ CI 1.00-1.79,P=0.048)、鳞状分化的伴发情况(HR 1.43,95％ CI 1.02-2.00,P=0.040)以及病理分级(HR 1.51,95％CI1.13-2.01,P=0.005)等因素显著增加TURBT术后pT1期患者的复发风险;同时,吸烟(HR 1.80,95％ CI 1.17-2.76,P=0.008)、鳞状分化的伴发情况(HR 2.07,95％ CI 1.32-3.24,P=0.001)以及病理分级(HR 1.90,95％ CI 1.24-2.92,P=0.003)等因素显著增加TURBT术后pT1期患者的进展风险.结论:尿路上皮癌伴鳞状分化是TURBT术后pT1期患者的预后独立影响因素,复发率及进展率较高,需密切随访.

This study aimed to determine the expression status of actin-binding protein Girdin in non-muscle invasive bladder cancer (NMIBC) tissues, and to explore the relationships between Girdin expression and the clinicopathological characteristics of bladder carcinoma. The correlations between Girdin expression and the clinicopathological parameters were examined by Chi-square test. Recurrence-free survival (RFS) and progression-free survival (PFS) were analyzed using Kaplan-Meier method. The prognostic significance of Girdin expression was assessed using univariate and multivariate Cox regression analysis models. Results showed that 69 (43.1%) of the 160 NMIBC tissue samples displayed positive expression of Girdin; Girdin positivity was more frequently seen in high-grade tumors than in low-grade tumors (P = 0.019), and in undifferentiated tumors than in differentiated tumors (P = 0.028). In Kaplan-Meier analysis, expression of Girdin was significantly associated with lower RFS (P = 0.007) and PFS (P = 0.024) rates. The univariate analysis revealed that Girdin expression was a risk factor for both recurrence and progression of NMIBC. Further multivariate analysis identified Girdin as an independent predictor of tumor recurrence (hazard ratio [HR]: 2.056, 95% CI: 1.213-3.483, P = 0.007). The present study suggests that Girdin is differentially expressed in bladder tumors and may represent an independent predictor of prognosis for patients with NMIBC.

Chondrosarcoma of the prostate is a rare variant of prostatic cancer. Tumors are most commonly composed of an admixture of both original mesenchymal cells and well-differentiated chondrocytes. It is a kind of highly malignant aggressive tumor, which is rich in blood vessels. A unique case of chondrosarcoma of the prostate detected in a 59-year-old man who underwent transurethral resection of the prostate (TURP) for the treatment of dysuria is presented. Pathology revealed that the resected prostatic mass consisted of malignant mesenchymal and chondrosarcomatous elements. The diagnosis of chondrosarcomatoid carcinoma was finally made. The patient visited the Department of Urology in our hospital in purpose of further evaluation. He received a combination of cutaneous ureterostomy and radiotherapy but the response to the treatment was unsuccessful. Unfortunately, the patient died of MODS two months after the surgery in our hospital.

Objective Utilizing the tandem green fluorescent protein (GFP)-monomeric red fluorescent protein (mRFP) fluorescent reporter tagged lysosome membrane proteins to indicate the change of prostate cancer cell lysosome,constructing an in vitro screening model targeting lysosomal membrane permeabilization(LMP),which would contribute to subsequent drug screeing targeting LMP.Methods (1) Design and build the eukaryotic expression vector of Lysosomal membrane proteins Lamp2C which have been marked by tandem mRFP-GFP fluorescent reporter.(2) Observe the expression of pLamp2C-mRFP-EGFP which is transfected into the PC3 cells by fluorescence microscopy.(3) Incubate PC3 cells with LysoTracker Blue concentration in 55 nmol/L medium after transfection,observing the colocalization of pLamp2C-mRFP-EGFP and lysosomes through confocal microscope.(4) Incubate PC3 cells transfected by pLamp2C-mRFP-EGFP using sphingosine concentration in 40 μmo[/L,assessing the change of green and red fluorescence before(after) sphingosine intervention through confocal microscope.Analyze the colocalization and the change of green and red fluorescence quantitatively by Image J.Results (1) We built pLamp2C-mRFP-EGFP successfully.(2) enhanced green fluorescent protein(EGFP) and RFP expressed normally after transient transfection of pLamp2C-mRFP-EGFP to PC3.(3) The Pearson' s correlation coefficient of colocalization between pLamp2C-mRFP-EGFP and lysosomes was 0.836 2 ±0.051 8.(4) Green fluorescence intensity decreased significantly (t=14.66,P＜ 0.05) from (0.119 0 ± 0.022 3) to (0.063 9 ± 0.015 6),red fluorescence intensity changed from (0.104 9 ±0.010 1) to (0.103 8 ±0.010 9) before and after sphingosine intervention,the difference was not statistically significant (t =1.136,P ＞ 0.05).Conclusion We transfect pLamp2C-mRFP-EGFP on PC3 cells lysosomes successfully.After sphingosine intervention,green fluorescence intensity decreased significantly while red fluorescence intensity didn' t,suggesting PC3 cells lysosomal membrane permeabilization.

目的:探讨非肌层浸润性膀胱癌(non-muscle-invasive bladder cancer,NMIBC)合并糖尿病患者的预后及意义.方法:回顾性分析我院2012年1月～2013年12月经病理检查回报为NMIBC的200例患者临床资料,将患者分为糖尿病组(41例)和非糖尿病组(159例).所有患者均为首发尿路上皮癌.运用Kaplan-Meier 法单因素分析各临床病理特点对患者无复发生存期(recurrence-free survival,RFS)和无进展生存期(progression-free survival,PFS)的影响,并用Log-rank检验比较生存曲线,运用Cox回归模型多因素分析糖尿病与NMIBC之间的关系,并评估影响其RFS和PFS的预后因素.结果:200例NMIBC患者平均随访14.2(4～40)个月,糖尿病组和非糖尿病组肿瘤复发率分别为34.1％(14/41)和28.3％(45/159),中位无复发生存时间分别为12.0个月(4～38个月)和14.7个月(5～40个月),肿瘤进展率分别为9.8％(4/41)和6.9％(11/159),糖尿病组较非糖尿病组肿瘤复发率高(x2=4.875,P=0.027),无复发生存时间短(P＜0.001),而进展率的差异无统计学意义(P=0.770).Cox多因素生存分析显示糖尿病(P＜0.001,HR=2.731)、肿瘤大小(P=0.012,HR=2.344)和NMIBC更高的复发风险相关,而灌注药物(P＜0.001,HR=0.110)会显著降低NMIBC的复发风险.结论:糖尿病是NMIBC患者RFS的独立危险因素,患有糖尿病的NMBIC患者术后复发率更高.

目的:探讨非肌层浸润性膀胱癌(non-muscle-invasive bladder cancer,NMIBC)伴术前脓尿患者的临床特点及脓尿对其预后方面的临床意义.方法:回顾性分析2009年11月～2011年3月我院278例首发非肌层浸润性膀胱癌患者的临床病理资料.定义脓尿为每高倍视野下尿白细胞数量≥5个,根据术前尿白细胞值,将患者分为脓尿-组(尿白细胞＜5)和脓尿+组(尿白细胞≥5),运用卡方检验分析脓尿和各临床病理特点之间的关系,运用Kaplan-Meier法比较两组之间无复发生存期(recurrence-free survival,RFS)和无进展生存期(progression-free survival,PFS)的区别,并用Log-rank检验评估其统计学意义.结果:278例NMIBC患者中,有98例(35.3％)出现术前脓尿,平均随访48.6(3～72)个月.在随访期间内,脓尿的出现与大体积、多发、高TNM分期、高级别肿瘤以及高复发率和高进展率显著相关,且经Kaplan-Meier法分析发现,脓尿+组患者无复发生存率明显低于脓尿-组患者(58.2％ vs.71.7％,P=0.016);同样,脓尿+组患者无进展生存率也明显低于脓尿-组患者(74.5％ vs.85.6％,P=0.018).结论:非肌层浸润性膀胱癌伴术前脓尿患者肿瘤多发且体积大,组织学分级和临床分期高,预后较差,应积极手术治疗并术后密切随访.

Schwannomas are usually benign tumors that arise from well-differentiated Schwann cells. They rarely occur in the retroperitoneum. Here, we present a case of a 60-year-old man with a giant retroperitoneal pelvic mass. Imageological diagnosis suggested a large heterogeneous mass of 16 cm in diameter located in the abdominopelvic retroperitoneum. Complete intralesional enucleation was achieved without any adjacent organs injury except a severe bleeding which was ceased as we applied the bilateral inferior vesical artery embolization. Final histopathological result showed the tumor was a low malignant Schwannoma. The patient's symptoms were greatly improved after operation. Unfortunately, a local recurrence was detected at the six-month follow-up appointment with consequent losing to follow up.

License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php OncoTargets and Therapy 2015:8 3679–3690 OncoTargets and Therapy Dovepress

Objective: Human murine double minute 2 protein (MDM2) is mainly a negative regulator of p53 tumor suppressor pathway. We aimed to investigate the association between MDM2 SNP309 polymorphism and bladder cancer risk. Methods: A total of 535 bladder cancer patients and 649 health controls were recruited for our study. MDM2 SNP309 T>G polymorphism was genotyped by polymerase chain reaction-ligase detection reaction method. Logistic regression was used to analyze the relationship between the genotype and susceptibility of bladder cancer. Kaplan-Meier estimates and log-rank test were obtained to analyze the association between the genotype and risk of recrudesce in nonmuscle-invasive bladder cancer patients. A multivariable Cox proportional hazards model was fitted to identify independent prognostic factors. To further investigate the association, we conducted a meta-analysis including six studies. Results: The frequency of the MDM2 SNP309 T>G polymorphism showed no significant difference between cases and controls (all P>0.05). In the stratification analysis, the results showed that G allele carriers were prone to have a significant decrease in risk of low-grade bladder cancer (adjusted odds ratio: 0.613, 95% confidence interval: 0.427-0.881), and G variant was associated with a significantly reduced risk of recurrence in nonmuscle-invasive bladder cancer patients with or without chemotherapy (P<0.05). The results of the meta-analysis showed that G allele and GG genotype of MDM2 SNP309 polymorphism were significantly associated with increased risk of bladder cancer in Caucasians (both P<0.05), and no association was observed in total populations and Asians (P>0.05). Conclusion: MDM2 SNP309 T>G polymorphism has no influence on bladder cancer risk in Asians, but this single nucleotide polymorphism may be associated with genetic susceptibility of bladder cancer among Caucasians.

Objective To evaluate the clinical significance of lymphovascular invasion (LVI) on recurrence and progression rates in patients with pT1 urothelial carcinoma of bladder after transurethral resection. Methods This retrospective study was performed with 155 patients with newly diagnosed pT1 urothelial carcinoma of bladder who were treated with transurethral resection of bladder tumor at our institution from January 2006 to January 2010. The presence or absence of LVI was examined by pathologists. Chi-square test was performed to identify the correlations between LVI and other clinical and pathological features. Kaplan–Meier method was used to estimate the recurrence-free survival (RFS) and progression-free survival curves and difference was determined by the log-rank test. Univariate and multivariate analyses were performed to determine the predictive factors through a Cox proportional hazards analysis model. Results LVI was detected in a total of 34 patients (21.9%). While LVI was associated with high-grade tumors (P<0.001) and intravesical therapy (P=0.009). Correlations with age (P=0.227), sex (P=0.376), tumor size (P=0.969), tumor multiplicity (P=0.196), carcinoma in situ (P=0.321), and smoking (P=0.438) were not statistically significant. There was a statistically significant tendency toward higher recurrence rate and shorter RFS time in LVI-positive patients. However, no statistically significant differences were observed in progression rate between the two groups. Moreover, multivariate Cox proportional hazards analysis revealed that LVI, tumor size, and smoking were independent prognostic predictors of recurrence. The hazard ratios (95% confidence interval) were 2.042 (1.113–3.746, P=0.021), 1.817 (1.014–3.256, P=0.045), and 2.079 (1.172–3.687, P=0.012), respectively. Conclusion The presence of LVI in transurethral resection of bladder tumor specimens is significantly associated with higher recurrence rate and shorter RFS time in patients with newly diagnosed T1 urothelial carcinoma of the bladder. It is an independent prognostic predictor for disease recurrence. Thus, patients with LVI should be followed up closely.

Long noncoding RNAs (lncRNAs) have been implicated playing important roles in human urologic cancers. In the present study, microarray analysis was initially performed to screen the differentially expressed lncRNAs between bladder cancer tissues and paired adjacent non-cancerous tissues (n = 3). Subsequent qRT-PCR validation was conducted using tissue samples from 95 patients with bladder cancer. Results showed that the expression level of lncRNA-n336928 (noncode database ID: n336928) was significantly higher in bladder cancer tissues compared to that in adjacent noncancerous tissues (P < 0.001). Chi-square test showed that expression of lncRNA-n336928 was positively correlated with bladder tumor stage and histological grade (P < 0.001). Kaplan-Meier survival analysis revealed that patients with bladder cancer with high expression of lncRNA-n336928 had shorter overall survival time compared to the patients with low expression of lncRNA-n336928. Multivariate analysis indicated that lncRNA-n336928 was an independent prognostic factor for overall survival for bladder cancer patients. Collectively, our study shows that high expression of lncRNA-n336928 is associated with the progression of bladder cancer, and that lncRNA-n336928 might serve as a biomarker for prognosis of bladder cancer. (C) 2015 Elsevier Inc. All rights reserved.