Zhenjie Wu

Exosome-Transmitted lncARSR Promotes Sunitinib Resistance in Renal Cancer by Acting as a Competing Endogenous RNA

Sunitinib resistance is a major challenge for advanced renal cell carcinoma (RCC). Understanding the underlying mechanisms and developing effective strategies against sunitinib resistance are highly desired in the clinic. Here we identified an lncRNA, named lncARSR (lncRNA Activated in RCC with Sunitinib Resistance), which correlated with clinically poor sunitinib response. lncARSR promoted sunitinib resistance via competitively binding miR-34/miR-449 to facilitate AXL and c-MET expression in RCC cells. Furthermore, bioactive lncARSR could be incorporated into exosomes and transmitted to sensitive cells, thus disseminating sunitinib resistance. Treatment of sunitinib-resistant RCC with locked nucleic acids targeting lncARSR or an AXL/c-MET inhibitor restored sunitinib response. Therefore, lncARSR may serve as a predictor and a potential therapeutic target for sunitinib resistance.

Robotic versus Open Partial Nephrectomy: A Systematic Review and Meta-Analysis

Objectives To critically review the currently available evidence of studies comparing robotic partial nephrectomy (RPN) and open partial nephrectomy (OPN). Materials and Methods A comprehensive review of the literature from Pubmed, Web of Science and Scopus was performed in October 2013. All relevant studies comparing RPN with OPN were included for further screening. A cumulative meta-analysis of all comparative studies was performed and publication bias was assessed by a funnel plot. Results Eight studies were included for the analysis, including a total of 3418 patients (757 patients in the robotic group and 2661 patients in the open group). Although RPN procedures had a longer operative time (weighted mean difference [WMD]: 40.89; 95% confidence interval [CI], 14.39–67.40; p = 0.002), patients in this group benefited from a lower perioperative complication rate (19.3% for RPN and 29.5% for OPN; odds ratio [OR]: 0.53; 95%CI, 0.42–0.67; p<0.00001), shorter hospital stay (WMD: −2.78; 95%CI, −3.36 to −1.92; p<0.00001), less estimated blood loss(WMD: −106.83; 95%CI, −176.4 to −37.27; p = 0.003). Transfusions, conversion to radical nephrectomy, ischemia time and estimated GFR change, margin status, and overall cost were comparable between the two techniques. The main limitation of the present meta-analysis is the non-randomization of all included studies. Conclusions RPN appears to be an efficient alternative to OPN with the advantages of a lower rate of perioperative complications, shorter length of hospital stay and less blood loss. Nevertheless, high quality prospective randomized studies with longer follow-up period are needed to confirm these findings.

Laparoendoscopic Single-site Partial Nephrectomy: A Multi- institutional Outcome Analysis

BACKGROUND Laparoendoscopic single-site surgery (LESS) has been developed in an attempt to further reduce the surgical trauma associated with conventional laparoscopy. Partial nephrectomy (PN) represents a challenging indication for LESS. OBJECTIVE To report a large multi-institutional series of LESS-PN and to analyze the predictors of outcomes after LESS-PN. DESIGN, SETTING, AND PARTICIPANTS Consecutive cases of LESS-PN done between November 2007 and March 2012 at 11 participating institutions were included in this retrospective analysis. INTERVENTION Each group performed LESS-PN according to its own protocols, entry criteria, and techniques. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Demographic data, main perioperative outcome parameters, and perioperative complications were gathered and analyzed. A multivariable analysis was used to assess the factors predicting a short (≤ 20 min) warm ischemia time (WIT), the occurrence of postoperative complication of any grade, and a favorable outcome, arbitrarily defined as a combination of the following events: short WIT plus no perioperative complications plus negative surgical margins plus no conversion to open surgery or standard laparoscopy. RESULTS AND LIMITATIONS A total of 190 cases were included in this analysis. Mean renal tumor size was 2.6, and PADUA score 7.2. Median operative time was 170 min, with median estimated blood loss (EBL) of 150 ml. A clampless technique was adopted in 70 cases (36.8%), and the median WIT was 16.5 min. PADUA score independently predicted length of WIT (low vs high score: odds ratio [OR]: 5.11 [95% confidence interval (CI), 1.50-17.41]; p=0.009; intermediate vs high score: OR: 5.13 [95% CI, 1.56-16.88]; p=0.007). The overall postoperative complication rate was 14.7%. The adoption of a robotic LESS technique versus conventional LESS (OR: 20.92 [95% CI, 2.66-164.64]; p=0.003) and the occurrence of lower (≤ 250 ml) EBL (OR: 3.60 [95% CI, 1.35-9.56]; p=0.010) were found to be independent predictors of no postoperative complications of any grade. A favorable outcome was obtained in 83 cases (43.68%). On multivariate analysis, the only predictive factor of a favorable outcome was the PADUA score (low vs high score: OR: 4.99 [95% CI, 1.98-12.59]; p<0.001). Limitations of the study were the retrospective design and different selection criteria for the participating centers. CONCLUSIONS LESS-PN can be safely and effectively performed by experienced hands, given a high likelihood of a single additional port. Anatomic tumor characteristics as determined by the PADUA score are independent predictors of a favorable surgical outcome. Thus patients presenting tumors with low PADUA scores represent the best candidates for LESS-PN. The application of a robotic platform is likely to reduce the overall risk of postoperative complications.

High expression of CXCR4, CXCR7 and SDF-1 predicts poor survival in renal cell carcinoma.

BackgroundChemokines and their receptors are known to play important roles in the tumorigenesis of many malignancies. The aim of this study was to evaluate the prognostic impact of the expression of the chemokine SDF-1 and its receptors CXCR4 and CXCR7 in patients with renal cell carcinoma.MethodsThe expression of CXCR4, CXCR7 and SDF-1 in specimens from 97 renal cell carcinoma patients was evaluated by immunohistochemistry on a tissue microarray. These results were correlated with the clinicopathological parameters and survival of the patients.ResultsCXCR4 and CXCR7 were expressed in all patients, whereas SDF-1 was expressed in 61 patients (62.9%). No association was observed between the expression of CXCR4, CXCR7 or SDF-1 and the clinical or pathological data except between SDF-1 expression and Fuhrman’s grade (P = 0.015). Patients with high expression of CXCR4, CXCR7 and SDF-1 had shorter overall survival and recurrence-free survival than those with low expression. In a multivariate analysis, the high expression of CXCR4, CXCR7 and SDF-1 correlated with poor overall survival and recurrence-free survival independent of gender, age, AJCC stage, lymph node status, metastasis, histologic variant and Fuhrman’s grade.ConclusionsHigh levels of CXCR4, CXCR7 and SDF-1 were associated with poor overall survival and recurrence-free survival in renal cell carcinoma patients. CXCR4, CXCR7 and SDF-1 may serve as useful prognostic markers and therapeutic targets for renal cell carcinoma.

Laparoendoscopic single-site adrenalectomy versus conventional laparoscopic surgery: a systematic review and meta-analysis of observational studies.

PURPOSE To assess the surgical efficacy and potential advantages of laparoendoscopic single-site adrenalectomy (LESS-AD) compared with conventional laparoscopic adrenalectomy (CL-AD) based on published literature. METHODS An online systematic search in electronic databasesM including Pubmed, Embase, and the Cochrane Library, as well as manual bibliography searches were performed. All studies that compared LESS-AD with CL-AD were included. The outcome measures were the patient demographics, tumor size, blood loss, operative time, time to resumption of oral intake, hospital stay, postoperative pain, cosmesis satisfaction score, rates of complication, conversion, and transfusion. A meta-analysis of the results was conducted. RESULTS A total of 443 patients were included: 171 patients in the LESS-AD group and 272 patients in the CL-AD group (nine studies). There was no significant difference between the two groups in any of the demographic parameters expect for lesion size (age: P=0.24; sex: P=0.35; body mass index: P=0.79; laterality: P=0.76; size: P=0.002). There was no significant difference in estimated blood loss, time to oral intake resumption, and length of stay between the two groups. The LESS-AD patients had a significantly lower postoperative visual analog pain score compared with the CL-AD group, but a longer operative time was noted. Both groups had a comparable cosmetic satisfaction score. The two groups had a comparable rate of complication, conversion, and transfusion. CONCLUSIONS In early experience, LESS-AD appears to be a safe and feasible alternative to its conventional laparoscopic counterpart with decreased postoperative pain noted, albeit with a longer operative time. As a promising and emerging minimally invasive technique, however, the current evidence has not verified other potential advantages (ie, cosmesis, recovery time, convalescence, port-related complications, etc.) of LESS-AD.

Analysis of oncological outcomes and renal function after laparoendoscopic single-site (LESS) partial nephrectomy: a multi-institutional outcome analysis.

To report on a large multi‐institutional series of laparoendoscopic single‐site (LESS) partial nephrectomy (PN) and analyse renal function and short‐term oncological outcomes.

Propensity-score matched analysis comparing robot-assisted with laparoscopic partial nephrectomy.

To compare the peri‐operative and early renal functional outcomes of robot‐assisted partial nephrectomy (RAPN) and laparoscopic partial nephrectomy (LPN) for kidney tumours.

RCCRT1 is correlated with prognosis and promotes cell migration and invasion in renal cell carcinoma.

OBJECTIVE To investigate the expression pattern of a novel long noncoding ribonucleic acid (RNA), RCCRT1, in renal cell carcinoma (RCC) tissues among the patients with various clinicopathologic features and to detect the role of RCCRT1 in migration and invasion of RCC in vitro. MATERIALS AND METHODS We found out a novel long noncoding RNA, RCCRT1, that expressed differently between high-grade (Fuhrman grade III-IV) and low-grade RCC tissues (Fuhrman grade I-II) by gene chip analysis, then verified it with quantitative polymerase chain reaction. The expression of RCCRT1 was diminished by transfecting with small interfering RNA. RCCRT1 effects were assessed by cell proliferation, cell apoptosis, transwell assay, and wound-healing assay. RESULTS Compared with adjacent noncancerous tissues, RCCRT1 is upregulated remarkably in RCC, particularly in high-grade RCC tissues. After analyzing the relative expression of RCCRT1 in various tissues by quantitative reverse transcription polymerase chain reaction and clinicopathologic characteristics of patients, we drew the conclusion that RCCRT1 is associated with clinicopathologic findings such as tumor size, pathologic T stage, tumor grade, lymph node metastasis, and distant metastasis. Furthermore, small interfering RNA-induced depletion of RCCRT1 expression suppressed migration and invasion in RCC cell lines. CONCLUSION The results of the present study suggest that RCCRT1 promoted migration and invasion of RCC and that RCCRT1 may offer a biomarker to verdict prognosis as well as an attractive new target for prognostic and therapeutic intervention for RCC patients in the future.

T-Cell Immunoglobulin- and Mucin-Domain-Containing Molecule 3 Gene Polymorphisms and Renal Cell Carcinoma

T-cell immunoglobulin- and mucin-domain-containing molecule 3 (TIM-3) is a novel transmembrane protein that is involved in the regulation of T-helper 1 (Th1)-cell-mediated immunity. This study was undertaken to investigate the association of TIM-3 polymorphisms with susceptibility to renal cell carcinoma (RCC) in the Chinese population. Blood was collected from 322 RCC patients and 402 healthy controls. Three polymorphisms in the TIM-3 gene (-1516G/T, -574G/T, and +4259T/G) were genotyped by polymerase chain reaction-restriction fragment length polymorphism. Results showed that the -574G/T and +4259T/G polymorphisms were significantly increased in the RCC cases (odds ratio [OR] = 2.77, 95% confidence interval [CI], 1.42-5.39, p = 0.002 and OR = 3.22, 95% CI, 1.64-6.35, p<0.001). When analyzing the haplotypes of TIM-3 polymorphisms, TTG (-1516, -574, and +4259) revealed a significant correlation with RCC (OR = 3.55, 95% CI, 1.13-11.2, p = 0.033). In addition, the prevalence of +4259T/G polymorphism was higher in RCC cases with metastasis than in those without metastasis (7.4% vs. 3.5%, p = 0.041). These results suggest that polymorphisms in the TIM-3 gene are new risk factors for RCC and that TIM-3 may play important roles in regulating the prognosis of this disease.

Association of CXCL12 and CXCR4 gene polymorphisms with the susceptibility and prognosis of renal cell carcinoma.

CXCL12 and its unique receptor CXCR4, play important roles in inflammation and cancer metastasis. This study was undertaken to investigate the association of CXCL12 and CXCR4 polymorphisms with risk and prognosis of renal cell carcinoma (RCC) in the Chinese population. Blood was collected from 322 RCC patients and 402 healthy controls. The CXCL12 rs1801157G/A polymorphism and CXCR4 rs2228014C/T polymorphism were genotyped by polymerase chain reaction-restriction fragment length polymorphism. Results showed that prevalence of CXCL12 rs1801157AA genotype was significantly increased in RCC cases than in controls [odds ratio (OR) = 3.07, 95% confidence interval (CI), 1.98-5.46, P = 6.1 × 10(-6) ; data were adjusted for age and sex]. Similarly, subjects carrying CXCR4 rs2228014CT or TT genotypes showed significantly high risk of RCC (OR = 1.77, 95% CI, 1.28-2.71, P = 0.0003; OR = 4.01, 95% CI, 1.87-9.12, P = 7.8 × 10(-4) , respectively; data were adjusted for age and sex). When analyzing the survival time of RCC, patients with CXCL12 rs1801157AA genotype revealed significantly shorter survival time compared to cases with CXCL12 rs1801157GG and GA genotypes (P = 0.001), whereas RCC patients carrying CXCR4 rs2228014CT and TT genotypes showed shorter survival time than the wild type (P = 0.002). These data indicated that CXCL12 and CXCR4 may be new risk factors for RCC and could be used as prognostic markers for this malignancy.