A Whole-Genome SNP Association Study of NCI60 Cell Line Panel Indicates a Role of Ca2+ Signaling in Selenium Resistance

Epidemiological studies have suggested an association between selenium intake and protection from a variety of cancer. Considering this clinical importance of selenium, we aimed to identify the genes associated with resistance to selenium treatment. We have applied a previous methodology developed by our group, which is based on the genetic and pharmacological data publicly available for the NCI60 cancer cell line panel. In short, we have categorized the NCI60 cell lines as selenium resistant and sensitive based on their growth inhibition (GI50) data. Then, we have utilized the Affymetrix 125K SNP chip data available and carried out a genome-wide case-control association study for the selenium sensitive and resistant NCI60 cell lines. Our results showed statistically significant association of four SNPs in 5q33–34, 10q11.2, 10q22.3 and 14q13.1 with selenium resistance. These SNPs were located in introns of the genes encoding for a kinase-scaffolding protein (AKAP6), a membrane protein (SGCD), a channel protein (KCNMA1), and a protein kinase (PRKG1). The knock-down of KCNMA1 by siRNA showed increased sensitivity to selenium in both LNCaP and PC3 cell lines. Furthermore, SNP-SNP interaction (epistasis) analysis indicated the interactions of the SNPs in AKAP6 with SGCD as well as SNPs in AKAP6 with KCNMA1 with each other, assuming additive genetic model. These genes were also all involved in the Ca2+ signaling, which has a direct role in induction of apoptosis and induction of apoptosis in tumor cells is consistent with the chemopreventive action of selenium. Once our findings are further validated, this knowledge can be translated into clinics where individuals who can benefit from the chemopreventive characteristics of the selenium supplementation will be easily identified using a simple DNA analysis

The impact of sarcomatoid features on survival outcomes in metastatic renal cell carcinoma patients receiving upfront cytoreductive nephrectomy: a retrospective analysis of a contemporary series

Introduction: Sarcomatoid features (SF) correlate with worst survival outcomes in patients with primary metastatic renal cell carcinoma (mRCC). Some reports suggested a cut-off above 25% sarcomatoid features as a predictor of poorer outcome. We aimed to report survival outcomes on a large dataset of patients with SF treated with cytoreductive nephrectomy (CN). Materials and methods: A purpose built multi-institutional international database (REgistry of MetAstatic RCC- REMARCC project) was used for this retrospective analysis. Patients with diagnosis of mRCC treated with CN with or without metastasectomy were included. The cohort was stratified according to the presence of SF in the primary specimen. Kaplan Meier methods and Cox proportional Hazards Regression Analyses were used to estimate overall mortality rates. The reverse Kaplan Meier method was used to estimate the median (IQR) follow-up. Results: Overall 617 patients who underwent CN were included. Of all, 78 (12.6%) patients received synchronous/metachronous metastasectomy. A total of 118 (19.1%) patients had SF in the final specimen. The median involvement of the sarcomatoid component was 35.0% (IQR 10.0\u201372.5%). Patients with SF were more frequently classified as poor prognosis according to Heng\u2019s criteria (44.9 vs. 33.3%, p = 0.022). Moreover, patients with sarcomatoid features harbored more frequently locally advanced disease [pT3-4 stage tumors (88.1 vs. 73.7%, p = 0.003) and pN1 tumors (28.8 vs. 18.22%, p = 0.025)]. The median follow-up was 55.1 (IQR 25.9\u2013120.6) months. Overall, 395 (64.0%) deaths were recorded in the whole cohort. The median overall survival was shorter for patients with SF (13.1 vs. 27.9 months, p 35% nor those with a SF >50% showed higher overall mortality rates than those with <35% and <50% SF, respectively (p = 0.720 and 0.960, respectively). Patients with SF showed higher overall mortality rates even after accounting for Heng\u2019s risk group, type of surgery and pT and pN stage (HR: 1.35, 95% CI: 1.04\u20131.75, p = 0.024). Conclusions: Patients with mRCC and SF experience higher mortality rates, even when accounting for pathologic status and risk group. Interestingly, the extent of sarcomatoid defined as >50% in the specimen was not predictive of higher mortality rates within patients with SF. These results suggest that all patients with a SF on primary tumor should be carefully followed independently of percentage of sarcomatoid dedifferentiation

Learning Curve in Robot-assisted Kidney Transplantation: Results from the European Robotic Urological Society Working Group

Background: Recently, robot-assisted kidney transplantation (RAKT) was recently introduced as renal replacement mini-invasive surgery. Objective: To report surgical technique, including tips and tricks, and the learning curve for RAKT. Design, setting, and participants: All consecutive RAKTs performed in the five highest-volume centers of the European Robotic Urological Society RAKT group were reviewed, and a step-by-step description of the technique was compiled. Surgical procedure: Surgeries were performed with Da Vinci Si/Xi. The patient was placed in the lithotomy position. The Trendelenburg position was set at 20\u201330\ub0 and the robot was docked between the legs. Measurements: Shewhart control charts and cumulative summation (CUSUM) graphs and trifecta were generated to assess the learning curve according to rewarming time (RWT), intra/postoperative complications, and renal graft function (glomerular filtration rate) on days 7 and 30, and at 1 yr. Linear regressions were performed to compare the learning curves of each surgeon. Results and limitations: Arterial anastomosis time was below the alarm/alert line in 93.3%/88.9% of RAKTs, while venous anastomosis time was below the alarm/alert line in 88.9%/73.9%. The nonanastomotic RWT exceeded +3 standard deviation (SD) in 24.7% of procedures and +2SD in 37.1%. In only 46% cases, the RWT was below the alert line. The ureteroneocystostomy time was below +2SD and +3SD in 87.9% and 90.2% of cases, respectively. CUSUM showed that the learning curve for arterial anastomosis required up to 35 (mean = 16) cases. Complications and delayed graft function rates decreased significantly and reached a plateau after the first 20 cases. Trifecta was achieved in 75% (24/32) of the cases after the first 34 RAKTs in each center. Conclusions: A minimum of 35 cases are necessary to reach reproducibility in terms of RWT, complications, and functional results. Patient summary: Robot-assisted kidney transplantation requires a learning curve of 35 cases to achieve reproducibility in terms of timing, complications, and functional results. Synergy between the surgeon and the assistant is crucial to reduce rewarming time. High-grade complications and delayed graft function are rare after ten surgeries. Hands-on training and proctorship are highly recommended. Robot-assisted kidney transplantation (RAKT) requires a learning curve of 35 cases. Teamwork is crucial to reduce rewarming time. High-grade complications are rare after ten surgeries; functional results are significantly better after 20 cases of RAKT. Hands-on training/proctorship is highly recommended

Impact of metastasectomy on cancer specific and overall survival in metastatic renal cell carcinoma: Analysis of the REMARCC registry

Introduction & Objectives: As treatment paradigms for management of metastatic renal cell carcinoma (mRCC) have shifted, the role of surgical metastasectomy in management of mRCC has been in similar flux. We examined impact on survival of surgical metastatectomy stratified in the setting of different mRCC risk groups. Materials & Methods: Multicenter retrospective analysis of patients from the REMARCC (REgistry of MetAstatic RCC) database. The cohort was subdivided utilizing Motzer RCC criteria (low, intermediate, and high risk), and impact of metastasectomy was analyzed via multivariable analysis (MVA) and Kaplan Meier analysis within each Motzer subgroup (KMA). Primary outcome was overall survival (OS) and secondary outcome was cancer specific mortality (CSM). Results: 431 patients (59 low risk, 274 intermediate risk, 98 high risk) with median follow-up of 19.2 months were analyzed. Metastasectomy was performed in 22 (37%), 66 (24%), and 32 (16%) of low, intermediate and high risk groups (p=0.012). Risk groups differed significantly with respect to ECOG performance status (p<0.001) and number of metastases at diagnosis (low 2, intermediate 3.4, high 5.1, p<0.001). MVA for CSM revealed male sex (OR 1.77, p=0.015), number of metastases at diagnosis (OR 1.18, p<0.001), and higher risk category [low (referent) vs. intermediate OR 2.16, p=0.046, high OR 2.44, p=0.002] to be independent risk factors. MVA for OS demonstrated increasing number of metastases at diagnosis (OR 1.78, p<0.001) and higher risk category [low (referent) vs. intermediate OR 2.37, p=0.03, high OR 2.61, p=0.001] to be independent risk factors. KMA for CSM demonstrated that metastasectomy was associated with longer cancer-specific survival in low (32.78 vs. 76.09 months, p=0.004) but not intermediate (p=0.060) and high risk (p=0.595) groups. KMA for OS demonstrated that metastasectomy was associated with longer median OS in the low (25.8 vs. 92.7 months, p=0.003) and intermediate risk (20.1 vs. 26.3, p=0.038), but not high risk (p=0.911) groups (Figure). Conclusions: Metastasectomy was not associated with benefit in high risk mRCC patients, but was associated with improved CSM in low risk and improved OS in low and intermediate risk mRCC patients. Further investigation is requisite to refine criteria for employment of metastasectomy