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PYCARD is a protein engaged in inflammation, pyroptosis, and apoptosis. However, the function of PYCARD in human cancers remains unclear. The objective of our study was to explore PYCARD expression and prognostic value in human cancers. Public databases were used to assess PYCARD expression and prognostic value. The TISIDB database was used to explore the associations between PYCARD expression and different immune subtypes. The correlations between PYCARD expression and ICP genes, MMR genes, MSI, and TMB were also investigated. The immunotherapy response was assessed using the TIDE database. Single-cell RNA databases evaluated the PYCARD expression of immune cells. External datasets and immunohistochemical staining were conducted to validate PYCARD expression and prognostic value. The results showed that PYCARD expression varied in several cancers and was associated with prognosis, immune-related genes, published biomarkers, and immunotherapy response. Of note, PYCARD expression was upregulated in renal cancers with high diagnostic ability. Upregulation of PYCARD was correlated with worse prognosis in KIRC and external validation cohorts. In conclusion, PYCARD demonstrated strong correlations with prognosis, immune response, and disease progression in pan-cancer analysis. In ccRCC, PYCARD might serve as a biomarker for diagnosis and therapeutic target-boosting immunotherapy response.

Increasing evidence has shown that Rad50, a protein involved in the DNA damage repair process, significantly correlated with tumor prognosis. This study focused on Rad50 expression in tumor samples and its prognostic value for patients with prostate cancer (PCa). In this study, significantly elevated Rad50 expression in PCa tissues compared to normal tissues (P < .01). Five independent Oncomine databases validated significant differential expression of Rad50 (P < .001). Hence, 80 patients with PCa from Fudan University Shanghai Cancer Center (FUSCC) and 351 patients with PCa with available protein expression data from The Cancer Genome Atlas (TCGA) were included to investigate the survival benefit. Univariate and multivariate Cox regression analyses were performed to investigate the significance of clinicopathological factors on disease-free survival (DFS) and overall survival (OS). Kaplan-Meier analysis indicated that elevated Rad50 protein expression levels significantly correlated with unfavorable DFS (P = .005) in the FUSCC cohort and poorer OS (P = .04) in TCGA cohort. Furthermore, coregulation analysis of proteins indicated that 76 coregulated proteins were associated with Rad50, while 11 most highly involved hub proteins, including Rad50, MRE11A, DUT, POLR3A, MCM3AP, RECQL, PNPT1, RANBP3, DDX1, SNRPB, and UGN, were significantly coregulated in the protein-protein interaction network. Functional enrichment analysis consecutively indicated significant functions and signaling pathways including DNA replication, spliceosome, DNA geometric change, homologous recombination, and G2M checkpoint. This study first reveals that elevated Rad50 expression is significantly associated with aggressive progression and poor survival for patients with PCa. Together, these data suggest that Rad50 may act as an oncoprotein, guide the molecular diagnosis, and may shed light on novel individual therapeutic strategies for progressive PCa patients.

Microphthalmia transcription factor (MiT) family translocation renal cell carcinoma (tRCC) is a rare type of kidney cancer, which is not well characterized. Here we show the comprehensive proteogenomic analysis of tRCC tumors and normal adjacent tissues to elucidate the molecular landscape of this disease. Our study reveals that defective DNA repair plays an important role in tRCC carcinogenesis and progression. Metabolic processes are markedly dysregulated at both the mRNA and protein levels. Proteomic and phosphoproteome data identify mTOR signaling pathway as a potential therapeutic target. Moreover, molecular subtyping and immune infiltration analysis characterize the inter-tumoral heterogeneity of tRCC. Multi-omic integration reveals the dysregulation of cellular processes affected by genomic alterations, including oxidative phosphorylation, autophagy, transcription factor activity, and proteasome function. This study represents a comprehensive proteogenomic analysis of tRCC, providing valuable insights into its biological mechanisms, disease diagnosis, and prognostication.

The tumorigenic role and underlying mechanisms of lipid accumulation, commonly observed in many cancers, remain insufficiently understood. In this study, we identified an AMP-activated protein kinase (AMPK)–GATA-binding protein 3 (GATA3)–enoyl-CoA hydratase short-chain 1 (ECHS1) pathway that induces lipid accumulation and promotes cell proliferation in clear cell renal cell carcinoma (ccRCC). Decreased expression of ECHS1, which is responsible for inactivation of fatty acid (FA) oxidation and activation of de novo FA synthesis, positively associated with ccRCC progression and predicted poor patient survival. Mechanistically, ECHS1 downregulation induced FA and branched-chain amino acid (BCAA) accumulation, which inhibited AMPK-promoted expression of GATA3, a transcriptional activator of ECHS1. BCAA accumulation induced activation of mTORC1 and de novo FA synthesis, and promoted cell proliferation. Furthermore, GATA3 expression phenocopied ECHS1 in predicting ccRCC progression and patient survival. The AMPK–GATA3–ECHS1 pathway may offer new therapeutic approaches and prognostic assessment for ccRCC in the clinic. Significance: These findings uncover molecular mechanisms underlying lipid accumulation in ccRCC, suggesting the AMPK–GATA3–ECHS1 pathway as a potential therapeutic target and prognostic biomarker.

Epithelial-to-mesenchymal transition (EMT) is important in tumor invasiveness and metastasis. We aimed to determine prognostic value of six key EMT markers (CDH1, CDH2, SNAI1, SNAI2, VIM, TWIST1) in clear cell renal cell carcinoma (ccRCC). A total of 533 ccRCC patients with RNASeq data from The Cancer Genome Atlas (TCGA) cohort were included for analysis. Gene expression of these EMT markers was compared between tumor and normal tissues based on Oncomine database and TCGA cohort. Their correlations with progression-free survival (PFS) and overall survival (OS) were also examined in both TCGA cohort and FUSCC (Fudan University Shanghai Cancer Center) cohort. Cox proportional hazards regression model and Kaplan-Meier plot were used to assess the relative factors. Functional enrichment analyses were utilized to describe biologic function annotations and significantly involved hallmarks pathways of each gene. We found that Epithelial marker, CDH1 expression was lower, while mesenchymal markers (CDH2, SNAI1, VIM, TWIST1) expression was higher in ccRCC primary tumors. In the TCGA cohort, we found that patients with higher expression of VIM, TWIST1 or lower expression of CDH1 had worse prognosis. Further, in the FUSCC cohort, we confirmed the predictive ability of mesenchymal markers and epithelial marker expression in PFS and OS of ccRCC patients. After generating Cox regression models, EMT markers (CDH1, SNAI1, VIM, and TWIST1) were independent prognostic factors of both PFS and OS in ccRCC patients. Our preliminary EMT prediction model can facilitate further screening of EMT biomarkers and cast a better understanding of EMT gene function in ccRCC.

Telomere length measured in lymphocytes has been evaluated as a potential biomarker for prostate cancer (PCa) risk. Identifying genetic variants that affect telomere length and testing their association with disease could clarify any causal role. We therefore investigated associations between genetic variants in three telomere length-related genes and PCa risk in a case-control study. The influence of these variants on the leukocyte telomere lengths was then appraised by real-time PCR. RTEL1 rs2297441 [odds ratio (OR): 1.23; 95% confidence interval (CI): 1.03-1.46, P = 0.021] and rs3208008 (OR: 1.23; 95% CI: 1.03-1.46) were associated with PCa risk. These two risk single nucleotide polymorphisms (SNPs) (OR: 0.59; 95% CI: 0.39-0.89, P = 0.012 and OR: 0.58; 95% CI: 0.38-0.87, P = 0.009, respectively) and another SNP PARP1 rs1136410 (OR: 1.53; 95% CI: 1.01-2.31, P = 0.043) were also associated with leukocyte telomere length. These findings support that genetic determinants of telomere length may influence PCa risk.

To investigate the role of tumor growth velocity in defining tumor progression in metastatic renal cell carcinoma patients treated with the vascular endothelial growth factor tyrosine kinase inhibitor, sorafenib.A modified calculation for tumor growth velocity was introduced to evaluate the tumor growth velocity, before and after sorafenib withdrawal. Known prognostic factors together with tumor growth velocity before drug withdrawal and tumor growth velocity after drug withdrawal were compared using a χA total of 114 patients who reached progressive disease and withdrew from sorafenib were enrolled after a median follow-up period of 107.8 months. Tumor growth velocity before drug withdrawal was 7.347 ± 4.040, and tumor growth velocity after drug withdrawal was 11.647 ± 5.937 (P 0.001). Higher tumor growth velocity before drug withdrawal was correlated with a higher risk Memorial Sloan Kettering Cancer Center score (P = 0.022), Karnofsky Performance Status 80 (P = 0.028), non-clear cell carcinoma (P = 0.037), higher tumor nucleus grade (P 0.001) and best treatment response (P 0.001). Patients with tumor growth velocity before drug withdrawal 5.0 had shorter overall survival (P 0.001). On multivariate analysis, factors associated with overall survival were high/intermediate Memorial Sloan Kettering Cancer Center risk score (hazard ratio 2.119, P = 0.006), non-clear histological subtype (hazard ratio 1.900, P = 0.031), tumor growth velocity before drug withdrawal ≥5.0 (hazard ratio 2.758, P 0.001) and progressive disease as best response (hazard ratio 2.069, P = 0.001).Significantly faster tumor growth can be observed if sorafenib is discontinued in the case of disease progression. Thus, we suggest not to withdraw targeted agents until tumor growth velocity is 5.0.

BACKGROUND This study aimed to evaluate the factors associated with a survival benefit for patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib, with and without cytoreductive nephrectomy (CN). MATERIAL AND METHODS This retrospective clinical study included 118 patients with mRCC who were treated with CN and sunitinib (CN-sunitinib) (N=70) and with sunitinib-alone (N=48). Categorical clinicopathological variables were compared with hypothesis tests using contingency tables and a chi-squared test. Independent indicators for progression-free survival (PFS) and overall survival (OS) were analyzed with univariate and multivariate Cox regression models. The Kaplan-Meier method and log-rank test were used to evaluate patient survival. RESULTS The median PFS and OS for the 118 patients were 8.38 and 15.48 months, respectively. There were no significant differences between the CN-sunitinib group and the sunitinib-alone group for either PFS (7.2 months vs. 11.6 months; P=0.525) or OS (16.7 months vs. 15.2 months; P=0.839). Stratification of patients based on clinicopathological characteristics showed that CN was significantly associated with reduced PFS and OS for patients with lymph node metastasis (PFS, P

Growing evidence has highlighted the immune response as an important feature of carcinogenesis and therapeutic efficacy in clear cell renal cell carcinoma (ccRCC). This study categorized ccRCC cases into high and low score groups based on their immune/stromal scores generated by the ESTIMATE algorithm, and identified an association between these scores and prognosis. Differentially expressed tumor environment (TME)-related genes extracted from common upregulated components in immune and stromal scores were described using functional annotations and protein-protein interaction (PPI) networks. Most PPIs were selected for further prognostic investigation. Many additional previously neglected signatures, including AGPAT9, AQP7, HMGCS2, KLF15, MLXIPL, PPARGC1A, exhibited significant prognostic potential. In addition, multivariate Cox analysis indicated that MIXIPL and PPARGC1A were the most significant prognostic signatures, and were closely related to immune infiltration in TCGA cohort. External prognostic validation of MIXIPL and PPARGC1A was undertaken in 380 ccRCC cases from a real-world cohort. These findings indicate the relevance of monitoring and manipulation of the microenvironment for ccRCC prognosis and precision immunotherapy.

Background and objectives: Multi-gene signature can be used as prognostic indicator in many types of cancer, but the association with early-relapse in patients with stage I-III clear cell and papillary renal cell cancer (RCC) is unknown. We aim to establish a mRNAs signature for improving prediction of early-relapse in patients with stage I-III clear cell and papillary RCC. Methods: The data of 610 patients with stage I-III RCC from The Cancer Genome Atlas (TCGA) and 270 patients from Fudan University Shanghai Cancer Center (FUSCC) were extracted. Propensity score matching analysis, linear models for microarray data VOOM method, least absolute shrinkage and selection operation Cox regression modeling analysis was conducted in turn for selecting multi-mRNA signature. Survival differences were assessed by Kaplan-Meier estimate and compared using log-rank test. Multivariable Cox regression and time-dependent receiver operating characteristic curves were used to evaluate the association of mRNAs signature with relapse-free survival (RFS). Results: Seventeen mRNAs were identified to constitute the early-relapse signature. Among patients with stage I-III RCC, those with high-risk score calculated from 17 mRNAs signature showed shorter RFS than those with low-risk score, both in TCGA discovery and internal validation sets, and in FUSCC discovery and internal validation sets (all p < 0.05). In multivariable Cox regression analysis, the 17 mRNAs signature remained an independent prognostic factor both in TCGA discovery (HR 2.43, 95%CI 1.98-2.96) and internal validation sets (HR 1.66, 95%CI 1.19-2.30), and FUSCC discovery (HR 1.28, 95%CI 1.13-1.43) and internal validation sets (HR 1.65, 95%CI 1.11-2.48). Additionally, the 17 mRNAs signature achieved a higher accuracy for RFS estimation beyond clinical indicator. Conclusion: The 17 mRNAs signature could classify stage I-III RCC patients into low- or high-risk of early-relapse, and will help to guide interventions to optimize survival outcomes.

Additional file 3: Table S1. Clinicopathological characteristics baseline in relation to AQP9 expression status in TCGA cohort. Table S2. Univariate Cox logistic regression analysis of PFS in TCGA and FUSCC cohort (PFS: progression-free survival; TCGA: the Cancer Genome Atlas; FUSCC: Fudan university shanghai cancer center). Table S3. Univariate Cox logistic regression analysis of OS in TCGA and FUSCC cohort (OS: overall survival; TCGA: the Cancer Genome Atlas; FUSCC: Fudan university shanghai cancer center). Table S4. Correlation analysis between AQP9 and immune cell infiltrations in ccRCC samples using TIMER.

Data on long-term survival and prognostic significance of demographic factors and adverse events (AEs) associated with sorafenib, an orally administered multikinase inhibitor in Chinese population with advanced renal cell carcinoma (RCC) are limited. Outcome data from adult patients (n = 256) with advanced RCC who received sorafenib (400 mg twice daily) either as first-line or second-line therapy between April 2006 and May 2013 were analyzed retrospectively. The primary endpoint was median overall survival (OS), determined to be 22.2 (95% CI: 17.1-27.4) months, and the secondary endpoint was overall median progression-free survival (PFS), determined to be 13.6 (95% CI: 10.7-16.4) months at a median follow-up time of 61.8 (95% CI: 16.2-97.4) months. Analysis of the incidence of AEs revealed the most common side effect as hand-foot skin reactions (60.5%) followed by diarrhea (38.7%), fatigue (35.5%), alopecia (34.0%), rash (24.6%), hypertension (21.5%) and gingival hemorrhage (21.1%). Multivariate regression analysis revealed older age (≥ 58 years), lower Memorial Sloan-Kettering Cancer Center score, time from nephrectomy to sorafenib treatment, number of metastatic tumors and best response as significant and independent demographic predictors for improved PFS and/or OS (p ≤ 0.05). Alopecia was identified as a significant and independent predictor of increased OS, whereas vomiting and weight loss were identified as significant predictors of decreased OS (p ≤ 0.05). Sorafenib significantly improved OS and PFS in Chinese patients with advanced RCC. Considering the identified significant prognostic demographic factors along with the advocated prognostic manageable AEs while identifying treatment strategy may help clinicians select the best treatment modality and better predict survival in these patients.

Surgical excision is essential for management of the rare and aggressive neoplasm adrenal cortical carcinoma (ACC). Five-year overall survival (OS) after surgery for ACC is dependent on disease stage, but for all stages the risk of death declines with time after surgery. We calculated the effect of post-surgical duration on conditional survival (CS) among ACC patients. A total of 641 patients with M0 ACC were selected from the Surveillance, Epidemiology, and End Results (SEER) registry (1988-2012). OS for the entire cohort at 1, 2, 3, 4, 5 and 6 years was 81.4%, 66.8%, 56.3%, 50.3%, 47.2% and 44.3%, respectively. CS for an additional year given prior survival for 0, 1, 2, 3, 4 or 5 years was 81.4%, 81.1%, 83.0%, 87.5%, 93.4% and 93.4%, respectively. Age, tumor stage, tumor grade and marital status affected OS and CS. Increases in 1-year CS over time were more pronounced in patients with poorer prognostic factors. With longer follow-up, tumor stage- and grade-dependent differences in CS decreased or even disappeared. CS may provide more meaningful life expectancy predictions for survivors of ACC than conventional survival analysis.

// Da-Long Cao 1, 2 , Ding-Wei Ye 1, 2 , Bo Dai 1, 2 , Hai-Liang Zhang 1, 2 , Yi-Jun Shen 1, 2 , Yao Zhu 1, 2 , Yi-Ping Zhu 1, 2 , Guo-Hai Shi 1, 2 , Chun-Guang Ma 1, 2 , Wen-Jun Xiao 1, 2 , Xiao-Jian Qin 1, 2 , Guo-Wen Lin 1, 2 1 Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China Correspondence to: Ding-Wei Ye, e-mail: dwyeli@163.com Keywords: prostate cancer, susceptibility, polymorphism, glutathione S-transferases T1, glutathione S-transferases M1 Received: June 21, 2015 Accepted: September 14, 2015 Published: September 24, 2015 ABSTRACT Background: Genetic polymorphism was hypothesized to be reason of variation in prostate cancer incidence among different racial group. Based on that published data on the association of prostate cancer susceptibility with polymorphisms in genes encoding Glutathione S-transferases (GSTs) were inconclusive, the aim of this study was to more precisely address the role of GSTs polymorphisms (especially, GSTT1 and GSTM1 deletions) on prostate cancer risk in Asian descent. Methods: A meta-analysis including 8 articles with 711 cases and 1122 controls for GSTT1 and 1098 cases and 1588 controls for GSTM1 was performed. Results: Significantly increased prostate cancer risk was found among subjects carrying GSTM1 null genotype (odds ratio (OR) = 1.403; 95% confidence interval (CI) = 1.088 – 1.808) but not among subjects carrying GSTT1 deletion genotype (OR = 0.959; 95%CI = 0.709 – 1.297). When stratified by country, the null genotype of GSTT1 neither increased nor decreased prostate cancer risk significantly in China (OR = 1.355; 95%CI = 0.895 – 2.049), Japan (OR = 0.812; 95%CI = 0.545 – 1.211), and Korea (OR = 1.056; 95%CI = 0.727 – 1.534). While significant association of elevated prostate cancer risk with GSTM1 deletion were found in China (OR = 1.665; 95%CI = 1.324 – .094) and Korea (OR = 1.914; 95%CI = 1.311 – 2.793) but not in Japan (OR = 0.980; 95%CI = 0.726 – 1.321). Conclusion: In summary, this meta-analysis suggested that the null genotype of GSTM1 rather than GSTT1 may be involved in the etiology of prostate cancer in Asian population.

The neutrophil-to-lymphocyte ratio (NLR) is associated with clinical outcomes of various cancers. This study aimed to evaluate whether pretreatment NLR can be used as a prognostic factor in patients with metastatic renal cell carcinoma (mRCC) receiving targeted therapy. In this single-center retrospective study, the Kaplan–Meier method was used to estimate progression-free survival (PFS) and overall survival (OS) of 373 mRCC patients receiving targeted therapy. The survival outcomes of patients with high (≥2.2) and low (

This study aimed to evaluate the role of serum lipid profiles as novel biomarkers in predicting pathological characteristics of prostate cancer (PCa). We retrospectively analyzed 322 consecutive patients with clinically localized PCa receiving radical prostatectomy (RP) and extended pelvic lymphadenectomy. Unconditional logistic regression was used to estimate the prostatectomy Gleason score (pGS), pathological stage and lymph node involvement (LNI) in RP specimens. Preoperative prostate-specific antigen (PSA) levels, biopsy GS (bGS), and preoperative tumor, node, metastasis staging were used as basic variables to predict postoperative pathological characteristics. Preoperative serum lipid profiles were introduced as potential predictors. A receiver operating characteristic (ROC) curve was used to determine predictive efficacy. Significant differences in pathological characteristics were observed among patients with normal and abnormal total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL) levels, with the exception of pGS in the TG group. Multivariable regression analysis revealed that the odds ratio for high levels of TC for LNI compared with normal TC levels was 6.386 (95% confidence interval [CI] 1.510-27.010), 3.270 (95% CI: 1.470-7.278) for high levels of TG for pT3-4 disease, and 2.670 (95% CI: 1.134-6.287) for high levels of LDL for pGS. The area under the ROC curve of the models with dyslipidemia was larger than that in models without dyslipidemia, in predicting pathological characteristics. Abnormal TC, TG, and LDL levels are significantly associated with postoperative pathological status in PCa patients. Together with preoperative PSA levels, bGS, and clinical stage, dyslipidemia is more accurate in predicting pathological characteristics.

// Gui-Ming Zhang 1, 2 , Fang-Ning Wan 1, 2 , Xiao-Jian Qin 1 , Da-Long Cao 1 , Hai-Liang Zhang 1 , Yao Zhu 1 , Bo Dai 1 , Guo-Hai Shi 1 , Ding-Wei Ye 1 1 Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China Correspondence to: Guo-Hai Shi, e-mail: guohaishi@126.com Ding-Wei Ye, e-mail: yedingwei1963@126.com Keywords: TREK-1, prostate cancer, biochemical recurrence, cell proliferation, cell cycle Received: March 05, 2015 Accepted: April 13, 2015 Published: April 21, 2015 ABSTRACT Background: TREK-1 channels belong to the two-pore domain potassium channel superfamily and play an important role in central nervous system diseases. However, few studies have examined their role in carcinogenesis. Methods: In this study, we assessed the expression of TREK-1 in 100 prostate cancer (PCa) tissues using immunohistochemistry and further analyzed its clinicopathological significance. Next, cell proliferation and cell cycle analysis were carried out on human PCa PC-3 cell lines where TREK-1 was stably knockdown. Results: We found that compared with normal prostate tissues, PCa tissues showed overexpressed TREK-1 levels and TREK-1 levels were positively associated with Gleason score and T staging. High level of TREK-1 expression was related to shorter castration resistance free survival (CRFS). Furthermore, knockdown of TREK-1 significantly inhibited PCa cell proliferation in vitro and in vivo , and induced a G1/S cell cycle arrest. Conclusion: Our results suggest that TREK-1 might be a biomarker in CRFS judgment of PCa, as well as a potential therapeutic target.

The predictive factors of prognosis and treatment strategies for small-cell carcinoma (SCC) of the urinary tract are controversial. This study was aimed to investigate the clinical experience and management of patients with SCC of the urinary tract. We collected data of patients who were diagnosed with genitourinary SCC (GSCC) between 2002 and 2013 and were treated in the Fudan University Shanghai Cancer Center. A total of 18 patients were diagnosed with GSCC of which 10 originated from the prostate, seven from the bladder and one from the adrenal gland. The mean follow-up time was 15.5 months and progression-free survival (PFS) was 9.3 months. Primary tumor resection was attempted in 13 of 18 patients (72.2%) in whom radical surgery was performed in six of 14 (42.9%) limited disease patients. Most of the patients (13, 72.2%) received cisplatin-based chemotherapy. Patients who had normal lactic dehydrogenase (LDH) levels showed a significantly higher median PFS and overall survival (OS) compared with patients with high LDH levels (P = 0.030, P= 0.010). Patients with limited disease treated with a radical operation experienced a non-significant (P = 0.211) longer PFS compared with patients who were not treated, but this reached statistical significance after analyzing OS (P = 0.211, P= 0.039). Our patients showed a poor prognosis as reported previously. Serum LDH levels beyond the normal range indicate a poor prognosis. For GSCC patients who are diagnosed with limited disease, radical surgery is strongly recommended along with cisplatin-based chemotherapy.

Objective To investigate whether visceral obesity is associated with certain histological subtypes of renal cell carcinoma (RCC) in a multicentre Chinese cohort. Patients and Methods A kidney tumour database was created using three tertiary centres in China; 487 patients were enrolled presenting with localised RCC and complete computer tomography (CT)/magnetic resonance imaging (MRI) information. A single-slice CT image was used to measure the area of visceral and subcutaneous adipose tissues in each patient. Statistical methods were used to analyse clear-cell RCC (ccRCC) and non-clear-cell RCC (non-ccRCC) as they relate to visceral fat area (VFA) and other risk factors, such as age, gender, tumour size, diabetes, hypertension, total fat area (TFA) and body mass index (BMI). Results In all, 418 patients had a ccRCC subtype and 69 had a non-ccRCC subtype. For all the patients with RCC, the mean VFA was 102 cm2, while mean BMI was 24 kg/m2. The mean VFA was greater in ccRCC than non-ccRCC patients by 25 cm2. There were significant differences in the mean VFA and TFA between patients with ccRCC and those with non-ccRCC. Multivariate analysis showed that the presence of VFA was more important than the effects of BMI and Type 2 diabetes on pathology prediction. In patients with a normal BMI, those with a higher quartile of VFA were more likely to develop ccRCC than those with a low VFA. Conclusions Increased visceral fat was found to be associated with ccRCC and the significance of VFA outweighed the effects of BMI and Type 2 diabetes for the prediction of RCC pathology in multivariate analyses. As a result, VFA could constitute a primary explanation for the link between obesity and ccRCC.

Background Vascular endothelial growth factor-targeted therapy has been standard care for metastatic renal cell carcinoma for years. However, little clinical experience on these agents in the treatment of sarcomatoid tumors has been documented. The aim of the present study was to detect the expression of c-KIT in the primary tumor of metastatic renal cell carcinoma with sarcomatoid feature, and to reveal its potential value of predicting the efficacy of sorafenib treatment and survival of the patients. Patients and Methods Seventeen patients were enrolled and treated with sorafenib as a second-line treatment after cytokine therapy. The expressions of c-KIT was tested immunohistochemically in the 17 specimens of primary renal tumors. The correlation between c-KIT status and treatment effect was compared. Univariate and multivariate analysis were employed to determine the survival difference between c-KIT-positive and c-KIT-negative patients. Results Twelve of 17 specimens (70.6%) were detected to be overexpressing c-KIT. c-KIT positive patients had higher disease control rate (75%) compared with c-KIT-negative patients (25%), P = .036. Median overall survival time was 92 weeks for c-KIT positive patients and 44 weeks for c-KIT negative patients, log rank χ2 = 9.566, P = .002. Multivariate Cox regression model analysis only revealed number of metastatic organs and c-KIT as independent prognostic factors. Conclusion Our findings suggest that c-KIT can be a potential predictive factor for metastatic renal cell carcinoma with sarcomatoid feature in treatment using sorafenib, and patients with positive c-KIT expression might have better responses and obtain longer overall survival time.

PBRM1 is a novel tumor suppressor gene that can inhibit cancer cell proliferation and predict the outcome of renal cell carcinoma (RCC), but its biological role needs further elucidation. We examined expression of the PBRM1 gene in RCC cell lines and the effect of PBRM1 on cell proliferation and cell cycle in RCC ACHN cells. Microarray processing and analysis was used to explore novel pathways involved in tumorigenesis related to PBRM1 knockdown. PBRM1 was expressed at high levels in RCC ACHN cells and lentivirus-mediated PBRM1 knockdown in these cells caused an increase in the proportion of cells in S phase of the cell cycle and promoted in vitro proliferation and migration. In vivo experiments showed that downregulation of PBRM1 promoted tumorigenesis in nude mice. In pathway gene chip analysis, the chemokine/chemokine receptor interaction pathway showed the greatest difference in gene expression upon PBRM1 knockdown. Protein levels of IL6ST and CCL2 were increased, whereas levels of interleukin (IL)-8, IL-6, and CXCL2 were decreased, in knockdown cells. Re-expression of IL-8 in PBRM1 knockdown ACHN cells could significantly decrease cell proliferation/migration and induced cell arrest in the G2/M phase. These findings indicate that PBRM1 alters cell cycle progression and inhibits proliferation and migration of ACHN cells through the chemokine/chemokine receptor pathway.

Methylenetetrahydrofolate reductase (MTHFR) c.677C>T and c.1298A>C variants were known to be associated with prostate cancer (PCa) risk with conflicting results, because of MTHFR and nutrient status interaction in the prostate development. In this large-scale, hospital-based, case-control study of 1817 PCa cases and 2026 cancer-free controls, we aimed to clarify the association between these two MTHFR variants and PCa risk in Shanghai and to explore the underlying molecular mechanisms. We found that both the heterozygous CT (adjusted OR = 0.78, 95% CI: 0.67–0.92) and the homozygous TT genotypes (adjusted OR = 0.68, 95% CI: 0.55–0.83) of c.677C>T were associated with a significantly decreased risk of PCa compared with homozygous wild-type CC genotype, respectively, using multivariate logistic regression. Furthermore, we confirmed that MTHFR c.677T allele was related to an increased serum homocysteine level in the Han Chinese population in Shanghai. In the cultured PCa cell lines, we observed that MTHFR c.677T could elevate the cellular homocysteine level and cause DNA damage, thus increasing cell apoptosis and finally inhibiting cell proliferation. In conclusion, MTHFR c.677T was a protective factor of PCa risk in ethnic Han Chinese males by inducing DNA damage and cell apoptosis.

Aberrant DNA methylation has been implicated in prostate carcinogenesis. The one-carbon metabolism pathway and related metabolites determine cellular DNA methylation and thus is thought to play a pivotal role in PCa occurrence. This study aimed to investigate the contribution of genetic variants in one-carbon metabolism genes to prostate cancer (PCa) risk and the underlying biological mechanisms. In this hospital-based case-control study of 1817 PCa cases and 2026 cancer-free controls, we genotyped six polymorphisms in three one-carbon metabolism genes and assessed their association with the risk of PCa. We found two noncoding MTR variants, rs28372871 T > G and rs1131450 G > A, were independently associated with a significantly increased risk of PCa. The rs28372871 GG genotype (adjusted OR = 1.40, P = 0.004) and rs1131450 AA genotype (adjusted OR = 1.64, P = 0.007) exhibited 1.40-fold and 1.64-fold higher risk of PCa, respectively, compared with their respective homozygous wild-type genotypes. Further functional analyses revealed these two variants contribute to reducing MTR expression, elevating homocysteine and SAH levels, reducing methionine and SAM levels, increasing SAH/SAM ratio, and promoting the invasion of PCa cells in vitro. Collectively, our data suggest regulatory variants of the MTR gene significantly increase the PCa risk via decreasing methylation potential. These findings provide a novel molecular mechanism for the prostate carcinogenesis.

Background Laparoscopic partial nephrectomy (LPN) is not a novel but a relatively technically challenging surgical procedure. Off-clamp LPN with zero ischemia can completely eliminate ischemic reperfusion injury to the kidney. The purpose of this study was to evaluate the safety and functional outcome of nephrometry score-guided off-clamp technique in LPN. Methods A total of 44 patients underwent LPN between January 2015 and July 2015 for renal mass with radius, exophytic/endophytic, nearness to sinus, anterior/posterior location (RENAL) score 4 were enrolled. Twenty-two of them underwent off-clamp LPN with zero ischemia, and the other 22 received standard LPN with common renal artery clamp. Estimate blood loss (EBL), total operation time, resection time, renorrhaphy time, preoperative estimated glomerular filtration rate (eGFR), postoperative eGFR, eGFR change, and drainage after surgery were compared between these two groups using t test. Results Patients’ characteristics including gender, age, BMI, tumor size, and RENAL score were balanced between the two groups. Average EBL was more in the off-clamp group than in the on-clamp group (134.32 versus 70.23 ml, p = 0.001). Average eGFR change was less in the off-clamp group than in the on-clamp group (−1.56 versus −6.45, p

To investigate the oncologic influence of transurethral resection of the prostate (TURP) as a cytoreductive surgery in metastatic hormone sensitive prostate cancer (mHSPC), in the setting of continuous complete androgen blockade (CAB).Medical histories of 146 consecutive Chinese males with newly diagnosed mHSPC, registered in our institution in 2006 and 2007, were reviewed. All of these patients received CAB as initial systematic therapy. Demographics and cancer control outcomes from 39 mHSPC patients who underwent TURP for a relief of bladder outlet obstruction were compared with those of the other 107 who received CAB only when they were still hormone-sensitive. Median follow-up was 15 months (3 to 27 months).Age at diagnosis, baseline PSA, and biopsy Gleason score were comparable between the 2 groups. Patients who underwent a TURP had lower PSA nadir (median 0.15 ng/ml vs. 0.82 ng/ml, P = 0.015) and longer time to PSA nadir (11.2 months vs. 6.4 months, P0.001). More patients in the non-TURP group developed hormone refractory prostate cancer (P = 0.007). The TURP group had a tendency towards longer disease-specific survival and overall survival (24.4 months vs. 24.1 months and 24.4 months vs. 22.9 months, respectively), though this did not reach statistical significance.TURP resulted in a better and more prolonged response to hormone therapy in mHSPC, with a trend towards positive influence in disease specific survival and overall survival. To date, our preliminary report is the first study regarding long-term survival of cytoreductive surgery in mHSPC, and further investigations are warranted.

Objectives: Previous prognostic factor models for metastatic renal cell carcinoma (mRCC) have not included erythrocyte sedimentation rate (ESR). We designed the present study to evaluate the prognostic value of ESR for mRCC patients treated with sorafenib. Methods: Sorafenib was given to 83 patients with clear cell mRCC. Serum ESR was tested before treatment and every 4 weeks after first administration of sorafenib. Oncological evaluation was carried out every 8 weeks. Analyzed factors included age, sex, performance status, method of nephrectomy, number of metastatic organs, anemia, lactate dehydrogenase, corrected calcium, albumin, baseline ESR level and ESR kinetics status. Kaplan–Meier and Cox regression analyses on progression-free survival (PFS) were carried out. Results: Baseline ESR levels ranged from 3 to 154 mm/h, and 43 (41.0%) patients had an ESR level higher than 40 mm/h. Median PFS was 10.0 months (95% CI 7.6–12.4 months). Dividing the cohort into three groups according to ESR kinetics status, median PFS was 27 months in the decreased ESR group, 12 months in the stable ESR group and 6 months in the increased ESR group. Performance status, time from diagnoses to sorafenib treatment, number of metastatic organs and ESR kinetics were independent predictors for PFS in multivariable Cox regression model analysis, with an area under the curve of 0.865 in a binary logistic regression model of 12-month PFS probability. Conclusions: ESR kinetics can be useful to monitor the treatment response and to predict PFS for mRCC patients treated with sorafenib as second-line therapy.

BACKGROUND miR-21 has been recognized as an “onco-microRNA” with the activity of negatively modulating the expression of tumor-suppressor genes. However, its role in prostate cancer (CaP) has not been well-documented. We designed this study to assess the potential function of serum miR-21 in the progression of CaP. METHODS Serum samples of 56 patients, including 20 patients with localized CaP, 20 with androgen-dependent prostate cancer (ADPC), 10 with hormone-refractory prostate cancer (HRPC), and 6 with benign prostatic hyperplasia (BPH), were collected for the measurement of miR-21. The 10 HRPC patients were administered docetaxel-based chemotherapy. Quantification of miR-21 was assayed by specific TaqMan qRT-PCR. RESULTS Serum miR-21 level was found to correlate to serum PSA level in patients with ADPC and HRPC, P = 0.012 and 0.049, respectively. There was no significant difference in serum miR-21 level between BPH, localized CaP and ADPC with PSA level 4 ng/ml. Six of the 10 HRPC patients reached partial remission with a decreased PSA level of >50% after chemotherapy. Serum miR-21 levels were higher in patients who were resistant to docetaxel-based chemotherapy when compared to those sensitive to chemotherapy, P = 0.032. CONCLUSIONS Serum miR-21 levels are elevated in HRPC patients, especially in those resistant to docetaxel-based chemotherapy. It may be applicable as a marker to indicate the transformation to hormone refractory disease, and a potential predictor for the efficacy of docetaxel-based chemotherapy. Prostate 71:326–331, 2011. © 2010 Wiley-Liss, Inc.

To investigate whether microRNA-21 was involved in mediating the chemoresistance of prostate cancer cells to docetaxel. A microarray technique was used to determine the miRNA profile in docetaxel-resistant PC3 cells. Real-time PCR was used to confirm the array results. miR-21 mimics and inhibitors were synthesized and introduced to cells using Lipofectamine 2000. Cell proliferation was examined with the CCK-8 assay. Luciferase reporter containing PDCD 3′UTR was constructed and the activity was detected by a dual luciferase assay. PDCD4 protein expression was evaluated using Western blot. A docetaxel-resistant prostate cancer PC3 cell line (PC3R) was established . Using microarrays, miR-21 was found to be up-regulated in PC3R cells. Ectopic expression of miR-21 increased the resistance to docetaxel in PC3 wild type cells. In contrast, silencing of miR-21 in PC3R cells sensitized the cells to docetaxel. The IC50 values for miR-21-silencing cells and control cells were 28.31 and 35.89 nmol/L, respectively. PDCD4, a direct target gene of miR-21, could mediate chemoresistance to docetaxel in PC3 cells. Our findings suggest that miR-21 contributed to the resistance of PC3 cells to docetaxel, and that targeting miR-21 may offer a promising therapeutic approach in sensitizing prostate cancer to docetaxel treatment.

Introduction: We describe our experience with sorafenib and sunitinib in the treatment of chemotherapy-refractory advanced penile squamous cell carcinoma (SCC). Patients and Methods: Between May 2008 and June 2009, 6 advanced penile cancer patients were treated with sorafenib or sunitinib in our center. All of them had previously received at least two chemotherapy regimens. Tumor responses were evaluated by radiologic assessment and serum SCC antigen change. Immunohistochemical staining of CD34 and Ki-67 was performed in 3 paired tumor tissues before and after treatment. Results: In the 6 patients, 1 partial response and 4 stable diseases were observed. Three patients showed pain response and had an improvement in quality of life. After molecular-targeted therapies, reduction in microvessel density and Ki-67 labeling index was observed in paired specimens. Serum SCC antigen levels were decreased in 5 patients after 1 week of medication. The patient who achieved partial response had an SCC antigen reduction of nearly 95% after treatment with sunitinib. Serious adverse events were fatal infection and rupture of the femoral vessel, which were unlikely related to the medication. Conclusions: The feasibility and activity of sorafenib and sunitinib in our series suggest that this approach may be a promising alternative in chemotherapy-refractory advanced penile SCC.

We investigated the potential value of prostate-specific antigen half-life (PSAHL) and decreasing velocity (PSAVd) to predict progression-free survival (PFS) and overall survival (OS) in Chinese patients with prostate cancer. A total of 153 patients treated with hormonal therapy were included in the study. Of these, 78 patients progressed to hormone-refractory prostate cancer (HRPC) and 24 patients died by the end of follow-up. PSAHL was defined as the time during which prostate-specific antigen (PSA) concentration became half of the initial value during the first hormonal therapy. PSAVd reflected the decreasing velocity of PSA during the first hormonal therapy. PFS was defined as the interval from the beginning of hormonal therapy to HRPC. Cox proportional hazards regression analysis was used to evaluate whether PSAHL and PSAVd were significantly associated with PFS and OS. The median PSAHL and PSAVd were 0.50 months and 33.8 ng mL(-1) per month. The median PFS and OS were 22.7 months (95% confidence interval [CI], 22.0-29.6 months) and 43.5 months (95% CI, 37.9-48.4 months), respectively. On univariate and multivariate analysis, long PSAHL (> 0.5 months), metastatic disease, high biopsy Gleason scores (>or= 8) and high nadir PSA (> 0.4 ng mL(-1)) were all found to be significantly associated with short PFS. Long PSAHL, high nadir PSA and short PSA doubling time (PSADT

Electrocautery, harmonic scalpel tissue dissection and other surgical techniques can generate surgical smoke with high proportion of 'fine particles' (PM(2.5))2.5 μm, which is known to have adverse effects on human health. The high-risk zone for PM(2.5) during surgeries by time and by distance has not been well evaluated.The study included open superficial, open abdominal, open pelvic, laparoscopic and transurethral urology surgeries, five of each. A particle counter was placed at three different distances from the incision site, and the real-time PM(2.5) concentration was displayed after each cut. Air Quality Index (AQI) revised by the US Environmental Protection Agency and the calculated inhalation dose were used to evaluate the severity of PM(2.5).In superficial, abdominal and pelvic surgeries, the peak PM(2.5) concentration may reach 245.7, 149.4 and 165.1 μg/m(3) 3-6 s after a single cut 40 cm from the incision site. By the time, AQI usually turns to 'unhealthy' or 'very unhealthy.' In laparoscopic surgeries, 40 cm from the trocar, the air quality reached 'hazardous' in 3 s after opening of the trocar valve with a peak concentration of 517.5 μg/m(3). In transurethral surgeries, the AQI 40 cm away from the resectoscope is generally at moderate level. In each surgery, the chief surgeon may inhale most of the PM(2.5), while the assistant will inhale less than half the dose, and the scrub nurse may inhale nearly none. The use of wall suction may induce a 48-65 % decrease in fine particle inhalation.During surgeries, the concentration of PM(2.5) could reach a very unhealthy status, especially for the chief surgeon who is the nearest to the incision site. Surgical smoke evacuation in the first few seconds of a cut is essential; however, using smoke evacuators such as a wall suction alone may not be enough.

Background The ability of 5α-reductase inhibitors (5ARIs) to decrease blood loss during transurethral resection of the prostate (TURP) for benign prostatic hyperplasia (BPH) remains controversial. We aimed to conduct a meta-analysis of all randomized controlled trials (RCTs) to establish the role of 5ARI use prior to TURP. Methods We searched studies from the electronic databases PubMed, Embase, Scopus, and Cochrane Library from inception to March 25, 2014. Meta-analysis was performed using the statistical software Review Manager version 5.1. Results Seventeen RCTs including 1489 patients were examined. We observed that preoperative treatment with finasteride can decrease total blood loss, blood loss per gram of resected prostate tissue, hemoglobin level alteration, microvessel density (MVD), and vascular endothelial growth factor level. Neither finasteride nor dutasteride reduced operative time, prostate volume, or the weight of gland resected. In contrast, pretreatment with dutasteride before TURP did not decrease the total blood loss or MVD. Conclusions Pretreatment with finasteride does seem to reduce perioperative blood loss related to TURP for BPH patients. However, the effect of preoperative dutasteride was inconclusive. Further studies are required to strengthen future recommendations regarding the use of 5ARI as a standard pre-TURP treatment and its optimal regimen.