Molecular and functional characterization of reversible-sunitinib-tolerance state in human renal cell carcinoma.

Therapy failure with the tyrosine kinase inhibitor (TKI) sunitinib remains a great challenge in metastatic renal cell carcinoma (mRCC). Growing evidence indicates that the tumour subpopulation can enter a transient, non-mutagenic drug-tolerant state to endure the treatment underlying the minimal residual disease and tumour relapse. Drug tolerance to sunitinib remains largely unexplored in RCC. Here, we show that sunitinib-tolerant 786-O/S and Caki-2/S cells are induced by prolonged drug treatment showing reduced drug sensitivity, enhanced clonogenicity, and DNA synthesis. Sunitinib-tolerance developed via dynamic processes, including (i) engagement of c-MET and AXL pathways, (ii) alteration of stress-induced p38 kinase and pro-survival BCL-2 signalling, (iii) extensive actin remodelling, which was correlated with activation of focal adhesion proteins. Remarkably, the acute drug response in both sensitive and sunitinib-tolerant cell lines led to dramatic fine-tuning of the actin-cytoskeleton and boosted cellular migration and invasion, indicating that the drug-response might depend on cell state transition rather than pre-existing mutations. The drug-tolerant state was transiently acquired, as the cells resumed initial drug sensitivity after >10 passages under drug withdrawal, reinforcing the concept of dynamic regulation and phenotypic heterogeneity. Our study described molecular events contributing to the reversible switch into sunitinib-tolerance, providing possible novel therapeutic opportunities in RCC.

Old for young kidney transplantation: a responsible option for our patients to reduce waiting time?

PURPOSE: The Eurotransplant Senior program allocating grafts from donors ≥ 65 years to recipients aged ≥ 65 years has proven good results within the last 20 years. However, "old" grafts are also allocated to younger recipients < 65 years, and this outcome of "old for young" kidney transplantations (KT) still lacks detailed investigations. METHODS: All "old for young" KT performed at four tertiary referral centers were retrospectively compared including a recent follow-up, stratifying for "old for young" (donor ≥ 65 years to recipient < 65 years) vs. "very old for young" KT (donor ≥ 70 years to recipient < 65 years). RESULTS: Overall, 99 patients were included with 56 (56.6%) "old for young" and 43 (43.4%) "very old for young" KT. The median waiting time did not differ (60.7 vs. 45.8 months, respectively) at comparable living donation rates (57.1% vs. 44.2%) as well as intra- and postoperative results. At a median follow-up of 44 months (range 1; 133), the 3-year graft survival of 91% vs. 87% did not significantly vary. In subgroup analyses assessing living donation or donation after brain death (DBD) KT only, the graft survival was significantly longer for "old for young" KT within the living donation subgroup. In multivariate Cox regression analyses, the presence of panel-reactive antibodies was the only significant impact factor on graft survival (HR 8.32, p = 0.001). CONCLUSION: This analysis clearly demonstrates the effectiveness of the "old for young" approach, enabling favorable perioperative results as well as comparable data of graft- and overall survival, while reducing waiting time for eligible patients.

Multicenter evaluation of complex urinary diversion for renal transplantation: outcomes of complex surgical solutions.

PURPOSE: An abnormal lower urinary tract poses significant challenges for transplant surgeons. Besides the ureteral anastomosis to an ileal conduit, there are diverse complex reconstructive solutions. Due to its rarity, standardization and teaching of complex urinary diversion is extremely difficult. METHODS: The indications and outcomes of complex urinary diversions after kidney transplantation (KT) were retrospectively investigated at eight urologic transplant centers including a current follow-up. RESULTS: Of 37 patients with 21 (56%) males, vesicoureteral reflux (24%), spina bifida (22%), and glomerulonephritis (12%) were the most common causes of terminal renal failure. In 30 (81%) patients, urinary diversion was performed before KT, at a median of 107.5 (range, 10; 545) months before. Transplantations were held at a median patient age of 43 (10; 68) years, including six (16%) living donations. Urinary diversion was modified during 12 (32%) transplantations. After KT, the ileal conduit was the most common incontinent urinary diversion in 25 (67%) patients; a Mainz pouch I and bladder augmentation were the most frequent continent diversions (each n = 3). At a median follow-up of 120 months (range 0; 444), 12 (32%) patients had a graft failure with a 5-year graft survival of 79% (95%CI 61; 90). The median overall survival was 227 months (168; 286) and the 5-year overall survival 89% (69.3; 96.4). CONCLUSION: The mid-term kidney transplant function with complex urinary diversion appears to be comparable to transplants with regular urinary diversions. Hence, complex urinary diversion should always be considered as a surgical option, even during transplantation, if necessary.

Radiomics and machine learning for renal tumor subtype assessment using multiphase computed tomography in a multicenter setting.

OBJECTIVES: To distinguish histological subtypes of renal tumors using radiomic features and machine learning (ML) based on multiphase computed tomography (CT). MATERIAL AND METHODS: Patients who underwent surgical treatment for renal tumors at two tertiary centers from 2012 to 2022 were included retrospectively. Preoperative arterial (corticomedullary) and venous (nephrogenic) phase CT scans from these centers, as well as from external imaging facilities, were manually segmented, and standardized radiomic features were extracted. Following preprocessing and addressing the class imbalance, a ML algorithm based on extreme gradient boosting trees (XGB) was employed to predict renal tumor subtypes using 10-fold cross-validation. The evaluation was conducted using the multiclass area under the receiver operating characteristic curve (AUC). Algorithms were trained on data from one center and independently tested on data from the other center. RESULTS: The training cohort comprised n = 297 patients (64.3% clear cell renal cell cancer [RCC], 13.5% papillary renal cell carcinoma (pRCC), 7.4% chromophobe RCC, 9.4% oncocytomas, and 5.4% angiomyolipomas (AML)), and the testing cohort n = 121 patients (56.2%/16.5%/3.3%/21.5%/2.5%). The XGB algorithm demonstrated a diagnostic performance of AUC = 0.81/0.64/0.8 for venous/arterial/combined contrast phase CT in the training cohort, and AUC = 0.75/0.67/0.75 in the independent testing cohort. In pairwise comparisons, the lowest diagnostic accuracy was evident for the identification of oncocytomas (AUC = 0.57-0.69), and the highest for the identification of AMLs (AUC = 0.9-0.94) CONCLUSION: Radiomic feature analyses can distinguish renal tumor subtypes on routinely acquired CTs, with oncocytomas being the hardest subtype to identify. CLINICAL RELEVANCE STATEMENT: Radiomic feature analyses yield robust results for renal tumor assessment on routine CTs. Although radiologists routinely rely on arterial phase CT for renal tumor assessment and operative planning, radiomic features derived from arterial phase did not improve the accuracy of renal tumor subtype identification in our cohort.

Evaluation of Gas 6 as a Prognostic Marker in Papillary Renal Cell Carcinoma.

INTRODUCTION: Growth arrest-specific protein 6 (Gas 6) is a ligand that plays a role in proliferation and migration of cells. For several tumor entities, high levels of Gas 6 are associated with poorer survival. We examined the prognostic role of Gas 6 in renal cell carcinoma (RCC), especially in papillary RCC (pRCC), which is still unclear. METHODS: The patients' sample collection is a joint collaboration of the PANZAR consortium. Patients' medical history and tumor specimens were collected from n = 240 and n = 128 patients with type 1 and 2 pRCC, respectively. Expression of Gas 6 was determined by immunohistochemistry. RESULTS: In total, Gas 6 staining was evaluable in 180 of 240 type 1 and 110 of 128 type 2 pRCC cases. Kaplan-Meier analysis disclosed no significant difference in 5-year overall survival for all pRCC nor either subtype. Also, Gas+ and Gas- groups did not significantly differ in any tumor or patient characteristics. CONCLUSION: Gas 6 was not found to be an independent prognostic marker in pRCC. Future studies are warranted to determine if Gas 6 plays a role as prognostic marker or therapeutic target in pRCC.

An In Vitro Analysis of TKI-Based Sequence Therapy in Renal Cell Carcinoma Cell Lines.

The tyrosine kinase inhibitor (TKI) cabozantinib might impede the growth of the sunitinib-resistant cell lines by targeting MET and AXL overexpression in metastatic renal cell carcinoma (mRCC). We studied the role of MET and AXL in the response to cabozantinib, particularly following long-term administration with sunitinib. Two sunitinib-resistant cell lines, 786-O/S and Caki-2/S, and the matching 786-O/WT and Caki-2/WT cells were exposed to cabozantinib. The drug response was cell-line-specific. The 786-O/S cells were less growth-inhibited by cabozantinib than 786-O/WT cells (p-value = 0.02). In 786-O/S cells, the high level of phosphorylation of MET and AXL was not affected by cabozantinib. Despite cabozantinib hampering the high constitutive phosphorylation of MET, the Caki-2 cells showed low sensitivity to cabozantinib, and this was independent of sunitinib pretreatment. In both sunitinib-resistant cell lines, cabozantinib increased Src-FAK activation and impeded mTOR expression. The modulation of ERK and AKT was cell-line-specific, mirroring the heterogeneity among the patients. Overall, the MET- and AXL-driven status did not affect cell responsiveness to cabozantinib in the second-line treatment. The activation of Src-FAK might counteract cabozantinib activity and contribute to tumor survival and may be considered an early indicator of therapy response.

Over-Expression of LEDGF/p75 in HEp-2 Cells Enhances Autoimmune IgG Response in Patients with Benign Prostatic Hyperplasia-A Novel Diagnostic Approach with Therapeutic Consequence?

Lens epithelium-derived growth factor splice variant of 75 kDa (LEDGF/p75) is an autoantigen over-expressed in solid tumors and acts as a stress-related transcriptional co-activator. Participation of autoimmune responses in the pathophysiology of benign prostatic hyperplasia (PBH) and a corresponding immunosuppressive therapy by TNFalpha antagonists has been recently suggested. Thus, autoAb testing could aid in the diagnosis of BPH patients profiting from such therapy. We generated CRISPR/Cas9 modified HEp-2 LEDGF knock-out (KO) and HEp-2 LEDGF/p75 over-expressing (OE) cells and examined IgG autoantibody reactivity to LEDGF/p75 in patients with prostate cancer (PCa, n = 89), bladder cancer (BCa, n = 116), benign prostatic hyperplasia (BPH, n = 103), and blood donors (BD, n = 60) by indirect immunofluorescence assay (IFA). Surprisingly, we could not detect elevated binding of autoAbs against LEDGF/p75 in cancer patients, but autoAb reactivity to LEDGF/p75 OE cells in about 50% of patients with BPH was unexpectedly significantly increased. Furthermore, a line immunoassay enabling the detection of 18 different autoAbs revealed a significantly increased occurrence of anti-dsDNA autoAbs in 34% of BPH patients in contrast to tumor patients and BD. This finding was confirmed by anti-mitochondrial (mDNA) autoAb detection with the Crithidia luciliae immunofluorescence test, which also showed a significantly higher prevalence (34%) of anti-mDNA autoAbs in BPH. In summary, our study provided further evidence for the occurrence of autoimmune responses in BPH. Furthermore, LEDGF/p75 over-expression renders HEp-2 cells more autoantigenic and an ideal target for autoAb analysis in BPH with a potential therapy consequence.

The Prognostic Impact of PD-L2 in Papillary Renal-Cell Carcinoma.

INTRODUCTION: Programmed death-1 ligand (PD-L1) has been often studied in different types of renal-cell carcinoma (RCC). For example, in clear-cell renal carcinoma it is well established that programmed death-1 receptor and PD-L1 are important prognostic markers. In contrast, the role of programmed death-2 ligand (PD-L2) as prognostic marker remains unclear. The aim of this study was to evaluate if PD-L2 expression could play a role as a prognostic marker for papillary RCC (pRCC). METHODS: The patients' sample collection was a joint collaboration of the PANZAR consortium. Patients' medical history and tumor specimens were collected from n = 240 and n = 128 patients with type 1 and 2 pRCC, respectively. Expression of PD-L2 was determined by immunohistochemistry. In total, PD-L2 staining was evaluable in 185 of 240 type 1 and 99 of 128 type 2 pRCC cases. RESULTS: PD-L2 staining was positive in 67 (36.2%) of type 1 and in 31 (31.3%) of type 2 pRCC specimens. The prevalence of PD-L2+ cells was significantly higher in high-grade type 1 tumors (p = 0.019) and in type 2 patients with metastasis (p = 0.002). Kaplan-Meier analysis disclosed significant differences in 5-year overall survival (OS) for patients with PD-L2- compared to PD-L2+ in pRCC type 1 of 88.4% compared to 73.6% (p = 0.039) and type 2 of 78.8% compared to 39.1% % (p < 0.001). However, multivariate analysis did not identify the presence of PD-L2+ cells neither in type 1 nor type 2 pRCC as an independent predictor of poor OS. DISCUSSION/CONCLUSION: PD-L2 expression did not qualify as an independent prognostic marker in pRCC. Future studies will have to determine whether anti-PD-L2-targeted treatment may play a role in pRCC and expression can potentially serve as a predictive marker for these therapeutic approaches.

Impact of neoadjuvant chemotherapy on survival and recurrence patterns after robot-assisted radical cystectomy for muscle-invasive bladder cancer: Results from the International Robotic Cystectomy Consortium.

OBJECTIVES: To analyze the impact of neoadjuvant chemotherapy on survival and recurrence patterns in muscle-invasive bladder cancer after robot-assisted radical cystectomy. MATERIALS AND METHODS: The International Robotic Cystectomy Consortium database was reviewed to identify patients who underwent robot-assisted radical cystectomy for muscle-invasive bladder cancer between 2002 and 2019. Survival outcomes, response rates, and recurrence patterns were compared between patients who received neoadjuvant chemotherapy and those who did not. Survival distributions were estimated using Kaplan-Meier analyses and compared using the log-rank test. RESULTS: A total of 1370 patients with muscle-invasive bladder cancer were identified, of whom 353 (26%) received neoadjuvant chemotherapy. After a median follow-up of 27 months, neoadjuvant chemotherapy recipients had higher 3-year overall survival (74% vs 57%; log-rank P < 0.01), 3-year cancer-specific survival (83% vs 73%; log-rank P = 0.03), and 3-year relapse-free survival (64% vs 48%; log-rank P < 0.01). Neoadjuvant chemotherapy was a predictor of higher overall survival, cancer-specific survival, and relapse-free survival in univariate but not multivariate analysis. Pathological downstaging (46% vs 23%; P < 0.01), complete responses (24% vs 8%; P < 0.01), and margin negativity (95% vs 91%; P < 0.01) at robot-assisted radical cystectomy were more common in the neoadjuvant chemotherapy group. Neoadjuvant chemotherapy recipients had lower distant (15% vs 22%; P < 0.01) but similar locoregional (12% vs 13%; P = 0.93) recurrence rates. CONCLUSIONS: In this analysis from a large international database, patients with muscle-invasive bladder cancer who received neoadjuvant chemotherapy before robot-assisted radical cystectomy had higher rates of survival, pathological downstaging, and margin-negative resections. They also experienced fewer distant recurrences.

Everolimus after failure of one prior VEGF-targeted therapy in metastatic renal cell carcinoma: Final results of the MARC-2 trial.

MARC-2, a prospective, multicenter phase IV trial, aimed to investigate clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with everolimus after failure of one initial vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy and to identify subgroups benefiting most, based on clinical characteristics and biomarkers. Patients with clear cell mRCC failing one initial VEGFR-TKI received everolimus until progression or unacceptable toxicity. Primary endpoint was 6-month progression-free survival rate (6moPFS). Secondary endpoints were overall response rate (ORR), PFS, overall survival (OS), and safety. Between 2011 and 2015, 63 patients were enrolled. Median age was 65.4 years (range 43.3-81.1). 6moPFS was 39.3% (95% confidence interval [CI], 27.0-51.3) overall, 54.4% (95% CI, 35.2-70.1) vs 23.7% (95% CI, 10.5-39.9) for patients aged ≥65 vs <65 years and 51.4% (95% CI, 34.7-65.7) vs 18.2% (95% CI, 5.7-36.3) for patients with body mass index (BMI) >25 vs ≤25 kg/m2 . A Cox proportional hazards model confirmed a longer PFS for patients aged ≥65 years (hazard ratio [HR] 0.46; 95% CI, 0.26-0.80) and a longer OS for patients with BMI >25 kg/m2 (HR 0.36; 95% CI, 0.18-0.71). Median PFS and median OS were 3.8 months (95% CI, 3.2-6.2) and 16.8 months (95% CI, 14.3-24.3). ORR was 7.9% and disease control rate was 60.3%. No new safety signals emerged. Most common adverse events were stomatitis (31.7%), fatigue (31.7%), and anemia (30.2%). One patient died from treatment-related upper gastrointestinal hemorrhage. Everolimus remains a safe and effective treatment option for mRCC patients after one prior VEGFR-TKI therapy. Patients aged ≥65 years and patients with BMI >25 kg/m2 benefited most.

Robotic Salvage Lymph Node Dissection in Recurrent Prostate Cancer: Lessons Learned from 68 Cases and Implications for Future Clinical Management.

PURPOSE: Salvage lymph node dissection is a rescue treatment for patients with nodal recurrence after radical prostatectomy. Very limited data are available on robotic salvage lymph node dissection. Our purpose was to investigate perioperative and oncological outcomes of robotic salvage lymph node dissection in a large monocentric series. MATERIALS AND METHODS: Perioperative data, complications within 30 days after surgery and oncological outcomes as assessed by histology, prostate specific antigen changes, prostate specific antigen nadir after salvage lymph node dissection, and time to further therapy were analyzed. To identify predictive factors for oncological outcome, Kaplan-Meier and Cox-regression analyses were performed. For cases with a mismatch between preoperative positron emission tomography/computed tomography and the number of histologically positive lymph nodes, prostate specific membrane antigen immunohistochemistry was performed on removed lymph nodes. RESULTS: A total of 68 patients underwent robotic salvage lymph node dissection with a median operation time of 126 minutes, a blood loss of 50 ml, and a length of stay of 4 days. No major complications (>Clavien 3) occurred. Median followup was 12.1 months. Median time to further therapy was 12.4 months, 37% of patients experienced complete biochemical response (prostate specific antigen <0.2 ng/ml) and 11% reached an undetectable prostate specific antigen, which was maintained for >1 year in 3 cases. Lower preoperative prostate specific antigen, longer time between radical prostatectomy and salvage lymph node dissection, preoperative prostate specific membrane antigen positron emission tomography/computed tomography and complete biochemical response after salvage lymph node dissection were significant predictors of longer therapy-free survival (all p <0.005). Prostate specific membrane antigen immunohistochemistry revealed that prostate specific membrane antigen positron emission tomography/computed tomography tends to miss small lymph node metastases <5 mm. CONCLUSIONS: Robotic salvage lymph node dissection is a feasible approach with low perioperative morbidity and delays further systemic therapy in most patients. Prostate specific membrane antigen positron emission tomography/computed tomography detection is mostly limited to tumor foci >5 mm.

Robot-assisted kidney transplantation: update from the European Robotic Urology Section (ERUS) series.

OBJECTIVE: To report the results of the robot-assisted kidney transplantation (RAKT) experience performed in 10 European centres by members of the European Robotic Urology Section (ERUS)-RAKT group. PATIENTS AND METHODS: This is a multicentre prospective observational study of RAKT. Descriptive analysis of recipients and donor characteristics, surgical data, intraoperative outcomes, complications rate and functional results were collected and analysed. RESULTS: Between July 2015 and September 2019, 291 living-donor RAKTs were performed. Recipients were mostly male (189 [65%]), the mean Standard deviation (sd) age was 45.2 (13.35) years, the mean (sd) body mass index was 27.13 (19.28) kg/m2 , and RAKT was pre-emptive in 155 (53.8%) cases. Right and multiple arteries kidneys were used in 15.4%. The mean (sd) total surgical and re-warming time was 244 (70.5) min and 53.16 (15.27) min, respectively. In all, 17 patients presented with postoperative bleeding (5.7%). Five kidneys had delayed graft function; five (2%) were lost due to thrombosis and one due to acute rejection. Two patients had arterial stenosis, three had incisional hernias, six had ureteric stenosis, and nine had lymphoceles. Neither surgical nor re-warming times were correlated with postoperative serum creatinine levels (P > 0.05). Comparison of surgical data between the first 120 cases and the following 171 cases showed a significantly shorter total surgical time in the second group (265 vs 230 min, P = 0.005). CONCLUSIONS: This is the largest European multicentre study of RAKT with good surgical and functional results competitive with open kidney transplant series, with a relatively short learning curve when performed in centres with a wide experience in open kidney transplantation and robotic surgery.

Termination rates and histological reclassification of active surveillance patients with low- and early intermediate-risk prostate cancer: results of the PREFERE trial.

PURPOSE: Active surveillance (AS) strategies for patients with low- and early intermediate-risk prostate cancer are still not consistently defined. Within a controlled randomized trial, active surveillance was compared to other treatment options for patients with prostate cancer. Aim of this analysis was to report on termination rates of patients treated with AS including different grade groups. METHODS: A randomized trial comparing radical prostatectomy, active surveillance, external beam radiotherapy and brachytherapy was performed from 2013 to 2016 and included 345 patients with low- and early intermediate-risk prostate cancer (ISUP grade groups 1 and 2). The trial was prematurely stopped due to slow accrual. A total of 130 patients were treated with active surveillance. Among them, 42 patients were diagnosed with intermediate-risk PCA. Reference pathology and AS quality control were performed throughout. RESULTS: After a median follow-up time of 18.8 months, 73 out of the 130 patients (56%) terminated active surveillance. Of these, 56 (77%) patients were histologically reclassified at the time of rebiopsy, including 35% and 60% of the grade group 1 and 2 patients, respectively. No patients who underwent radical prostatectomy at the time of reclassification had radical prostatectomy specimens ≥ grade group 3. CONCLUSION: In this prospectively analyzed subcohort of patients with AS and conventional staging within a randomized trial, the 2-year histological reclassification rates were higher than those previously reported. Active surveillance may not be based on conventional staging alone, and patients with grade group 2 cancers may be recommended for active surveillance in carefully controlled trials only.

Robotic-assisted kidney transplantation in obese recipients compared to non-obese recipients: the European experience.

PURPOSE: The main objective was to compare minor (Clavien I-II) and major (Clavien ≥ III) intra- and postoperative complications of living donor robotic assisted kidney transplantation (RAKT) in obese (≥ 30 kg/m2 BMI), overweight (< 30/ ≥ 25 kg/m2 BMI) and non-overweight recipients (< 25 kg/m2 BMI). METHODS: For the present retrospective study, we reviewed the multi-institutional ERUS-RAKT database to select consecutive living donor RAKT recipients. Functional outcomes, intra- and postoperative complications were compared between obese, overweight and non-overweight recipients. RESULTS: 169 living donor RAKTs were performed, by 10 surgeons, from July 2015 to September 2018 in the 8 European centers. 32 (18.9%) recipients were obese, 66 (39.1%) were overweight and 71 (42.0%) were non-overweight. Mean follow-up was 1.2 years. There were no major intra-operative complications in either study group. Conversion to open surgery occurred in 1 obese recipient, in 2 overweight recipients and no conversion occurred in non-overweight recipients (p = 0.3). Minor and major postoperative complications rates were similar in the 3 groups. At one-year of follow-up, median eGFR was similar in all groups [54 (45-60) versus 57 (46-70) versus 63 (49-78) ml/min/1.73 m2 in obese, overweight and non-overweight recipient groups, respectively, p = 0.5]. Delayed graft function rate was similar in the 3 groups. Only the number of arteries was an independent predictive factor of suboptimal renal function at post-operative day 30 in the multivariate analysis. CONCLUSION: RAKT in obese recipients is safe, compared to non-overweight recipients and yields very good function, when it performed at high-volume referral centers by highly trained transplant teams.

Does the Side Matter? A Retrospective Cohort Study Comparing Left and Right Pure Laparoscopic Donor Nephrectomies.

OBJECTIVES: Right laparoscopic donor nephrectomy (RLDN) is no longer regarded inferior to left LDN (LLDN). However, this knowledge is based on many studies suffering from inherent learning curves, center-specific imbalances, and different laparoscopic techniques. METHODS: Pure LDNs at a high-volume referral center from 2011 to 2016 were retrospectively analyzed. Patient, graft characteristics, outcomes of LDNs, and corresponding open kidney transplantations were compared between LLDN and RLDN including a follow-up. RESULTS: 160 (78.4%) LLDNs and 44 (21.6%) RLDNs only differed regarding graft characteristics, as more right grafts had multiple veins (34.1 vs. 6.9%, p < 0.001) and worse scintigraphic function (44 vs. 51%, p < 0.001). RLDNs were shorter (201 vs. 220 min, p = 0.032) with longer warm ischemia time (165 vs. 140 s, p < 0.001), but left grafts were transplanted faster (160 vs. 171 min, p = 0.048). Recipients of right kidneys had more postoperative complications (grade 3: 25.6 vs. 11.3%, p = 0.020). At a follow-up of 45 (range 6-79) months, neither the kidney function, nor death-censored graft (5-year: LLDN 89 vs. 92%, p = 0.969) and patient survival (5-year: LLDN 95 vs. 98%, p = 0.747) differed. CONCLUSIONS: Pure LLDN and RLDN can have different outcomes at high-volume centers, especially higher complications for recipients of right grafts. However, long-term function and graft survival are the same irrespective of the chosen side.

Neoadjuvant Chemotherapy is Not Associated with Adverse Perioperative Outcomes after Robot-Assisted Radical Cystectomy: A Case for Increased Use from the IRCC.

PURPOSE: We sought to determine the trend of neoadjuvant chemotherapy use for nonmetastatic muscle invasive urothelial bladder cancer and whether it is associated with adverse perioperative morbidity after robot-assisted radical cystectomy. MATERIALS AND METHODS: We retrospectively reviewed the IRCC (International Robotic Cystectomy Consortium) database between 2006 and 2017. After excluding patients with nonmuscle invasive bladder cancer the patients were divided into 2 groups, including those who did vs did not receive neoadjuvant chemotherapy. Data were reviewed for demographics, preoperative, operative and 90-day perioperative outcomes. We used the Cochran-Armitage trend test to assess trends of neoadjuvant chemotherapy associations with high grade and overall complications with time. Multivariate stepwise regression analyses were done to determine whether neoadjuvant chemotherapy was associated with prolonged operative time, 90-day postoperative complications, readmissions, reoperations and mortality after robot-assisted radical cystectomy. RESULTS: A total of 298 patients (26%) received neoadjuvant chemotherapy. These patients were younger (age 67 vs 69 years, p=0.01) and more frequently had an ASA™ (American Society of Anesthesiologists™) score of 3 or greater (62% vs 55%, p=0.02) and pathological T3 stage or greater disease (28% vs 22%, p=0.04). The use of neoadjuvant chemotherapy increased significantly from 10% in 2006 to 2007 to 42% in 2016 to 2017 (p <0.01). On multivariate analysis neoadjuvant chemotherapy was not significantly associated with prolonged operative time, hospital stay, 90-day postoperative complications, reoperation or mortality. Neoadjuvant chemotherapy was associated with 90-day readmissions after robot-assisted radical cystectomy (OR 5.90, 95% CI 3.30-10.90, p <0.01). CONCLUSIONS: Neoadjuvant chemotherapy utilization has significantly increased in the last decade. It was not associated with perioperative surgical morbidity after robot-assisted radical cystectomy.

A comparative propensity score-matched analysis of perioperative outcomes of intracorporeal vs extracorporeal urinary diversion after robot-assisted radical cystectomy: results from the International Robotic Cystectomy Consortium.

OBJECTIVE: To compare the perioperative outcomes of intracorporeal (ICUD) vs extracorporeal urinary diversion (ECUD) after robot-assisted radical cystectomy (RARC). PATIENTS AND METHODS: We retrospectively reviewed the prospectively maintained International Robotic Cystectomy Consortium (IRCC) database. A total of 972 patients from 28 institutions who underwent RARC were included. Propensity score matching was used to match patients based on age, gender, body mass index (BMI), American Society of Anesthesiologists Score (ASA) score, Charlson Comorbidity Index (CCI) score, prior radiation and abdominal surgery, receipt of neoadjuvant chemotherapy, and clinical staging. Matched cohorts were compared. Multivariate stepwise logistic and linear regression models were fit to evaluate variables associated with receiving ICUD, operating time, 90-day high-grade complications (Clavien-Dindo Classification Grade ≥III), and 90-day readmissions after RARC. RESULTS: Utilisation of ICUD increased from 0% in 2005 to 95% in 2018. The ICUD patients had more overall complications (66% vs 58%, P = 0.01) and readmissions (27% vs 17%, P = 0.01), but not high-grade complications (21% vs 24%, P = 0.22). A more recent RC era and ileal conduit diversion were associated with receiving an ICUD. Higher BMI, ASA score ≥3, and receiving a neobladder were associated with longer operating times. Shorter operating time was associated with male gender, older age, ICUD, and centres with a larger annual average RC volume. Longer intensive care unit stay was associated with 90-day high-grade complications. Higher CCI score, prior radiation therapy, neoadjuvant chemotherapy, and ICUD were associated with a higher risk of 90-day readmissions. CONCLUSIONS: Utilisation of ICUD has increased over the past decade. ICUD was associated with more overall complications and readmissions compared to ECUD, but not high-grade complications.

Minimally invasive robotic versus conventional open living donor kidney transplantation.

PURPOSE: First robotic-assisted kidney transplants (RAKT) were performed in Germany in 2016. To introduce and establish this method as a routine procedure for patients in transplantation medicine, our 2-year experiences are presented. METHODS: Non-randomized open-label cohort study to compare functional and operative results as well as complication rates between RAKT and standard open transplantation. Collected data are part of ERUS RAKT Group Registry. RESULTS: Since initiation of the RAKT program 21/27 transplantations after living kidney donations have been performed as RAKT. This represents the largest series of RAKT in Germany. Patient survival, transplant survival, and primary function rate are 100% (mean follow-up 12.9 ± 8.6 month). Mean incision to closure time was 306.1 ± 45.5, mean handling time 70.8 ± 13.1 min compared to 212.1 ± 40.6 min and 51.7 ± 9.9 min, respectively, in the standard group. Despite extended operating times using the robotic approach, comparable complication rates and graft function with significant reduction in median length of hospital stay (14 vs. 20 days) were observed. CONCLUSIONS: RAKT extends the options for recipients towards minimally invasive techniques. Compared to classic open surgery, RAKT appears to be safe in selected patients without influencing graft outcome or higher complication rates. However, RAKT till today is not suitable for all patients but seems to be one of the upcoming new standard techniques in kidney transplantation.

Metastatic risk stratification of clear cell renal cell carcinoma patients based on genomic aberrations.

Prognostic markers for the definition of the individual metastatic risk in renal cell carcinoma are still missing. The aim of our study was to establish a total number of specific aberrations (TNSA) genetic score as a new prognostic test for metastatic risk evaluation. Fluorescence in situ hybridization (FISH) was performed on isolated cell nuclei of 100 ccRCCs (50 M1/50 M0) and 100 FFPE sections (second cohort, 32 M1/68 M0). For each chromosomal region (1q21.3, 7q36.3, 9p21.3p24.1, 20q11.21q13.32) cut-off values were determined by receiver-operator curve (ROC)-curve analysis. TNSA was calculated based on the dichotomized specific CNVs. The prognostic significance of CNVs was proven by Cox and logistic regression. TNSA was the best predictor of metastasis and recurrence free survival in both cohorts. We derived an algorithm for risk stratification by combining TNSA and T-category, which increased the prognostic accuracy to 87% (specificity = 86%, sensitivity = 88%). This model divides patients into two risk groups with significantly different RFS, CSS, and OS (P = 3.8×10-5 , P = 5×10-6 and P = 3.57×10-8 respectively). The genetic risk model was superior to Leibovich score and was able to identify patients with metachronous metastatic spread which were incorrectly classified as "low" or "intermediate risk." We present a new tool for individual risk stratification by combining genetic alterations with clinico-pathologic parameters. Interphase FISH proves to be a dependable method for prognostic evaluation in primary tumor tissue on isolated cell nuclei as well as on FFPE sections. Especially in organ-confined tumors the genetic score seems to be an important tool to identify patients at high risk for metastatic disease.