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Objective: To analyse if exposure to sunitinib in the Immediate Surgery or Surgery After Sunitinib Malate in Treating Patients With Metastatic Kidney Cancer (SURTIME) trial, which investigated opposite sequences of cytoreductive nephrectomy (CN) and systemic therapy, is associated with the overall survival (OS) benefit observed in the deferred CN arm., Patients and Methods: A post hoc analysis of SURTIME trial data. Variables analysed included number of patients receiving sunitinib, time from randomisation to start sunitinib, overall response rate by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1, and duration of drug exposure and dose in the intention-to-treat population of the immediate and deferred arm. Descriptive methods and 95% confidence-intervals (CI) were used., Results: In the deferred arm, 97.7% (95% CI 89.3-99.6%; n = 48) received sunitinib vs 80% (95% CI 66.9-88.7%, n = 40) in the immediate arm. Following immediate CN, 19.6% progressed 4 weeks after CN and the median time to start sunitinib was 39.5 vs 4.5 days in the deferred arm. At week 16, 46.0% had progressed at metastatic sites in the immediate CN arm vs 32.7% in the deferred arm. Sunitinib dose reductions, escalations and interruptions were not statistically significantly different between arms. Among patients who received sunitinib in the immediate or deferred arm the median total sunitinib treatment duration was 172.5 vs 248 days. Reduction of target lesions was more profound in the deferred arm., Conclusions: In comparison to the deferred CN approach, immediate CN impairs administration, onset, and duration of sunitinib. Starting with systemic therapy leads to early and more profound disease control and identification of progression prior to planned CN, which may have contributed to the observed OS benefit., (© 2021 The Authors BJU International © 2021 BJU International.)

Introduction: The "trifecta" is a summary measure of outcome after partial nephrectomy (PN) that encompasses three parameters: negative surgical margin, ≤ 10% decrease in post-operative estimated glomerular filtration rate (eGFR) and absence of urological complications. We assessed trifecta rates in patients undergoing open (OPN), laparoscopic (LPN), and robotic PN (RPN) for a clinical T1 renal mass (≤ 7 cm)., Methods: Clinical and pathologic parameters were extracted from the prospectively maintained Canadian Kidney Cancer Information System for patients treated between January 2011 and October 2018. Comparisons between groups were made using Kruskal-Wallis test for continuous variables and Chi-squared independence test for categorical variables. Multivariable analysis was performed to identify predictors of each component of the trifecta and the trifecta itself., Results: Of 1708 total patients, 746 underwent OPN, 678 LPN, and 284 RPN for a T1 renal mass. A 'trifecta' was achieved in 53% OPN, 52% LPN and 47% RPN (p = 0.194). On multivariable analysis, OPN and LPN were associated with less frequent post-operative decline in eGFR and more frequent trifecta when compared to RPN, but there was no difference between OPN and LPN. OPN also predicted a higher rate of negative margins compared to RPN but not LPN., Conclusion: After correction for confounding variables, OPN and LPN were more likely than RPN to achieve the trifecta, which appeared to be due primarily to loss of renal function. No difference was observed between OPN and LPN. Analyses were limited by the lack of nephrometry score.

Aims: To evaluate the clinical impact of the Canadian criteria for identifying patients and families at risk for hereditary renal cell carcinoma (RCC)., Materials and Methods: The Canadian hereditary RCC risk criteria were applied to patients from 16 centres in the Canadian Kidney Cancer information system (CKCis) prospective database. The primary end point was the proportion of patients who met at least one criterion., Results: Between January 2011 and May 2017, 8388 patients were entered in the database; 291 had inadequate risk data; 2827 (35%) met at least one criterion for genetic testing (at-risk population). Most (83%) met just one criterion. The criterion of non-clear cell histology contributed the largest proportion of at-risk patients (59%), followed by age ≤ 45 years (28%). Sixty-one patients had documentation of genetic testing, with 56 being classified at-risk (2% of at-risk). Twenty patients (35%) of the patients at risk and tested for hereditary RCC were found to harbour a germline mutation., Conclusions: Application of the Canadian hereditary RCC risk criteria to a large prospective database resulted in 35% of patients being identified at risk for hereditary RCC who could qualify for genetic testing. However, the true incidence of hereditary RCC in this population is unknown as most patients did not have documented genetic testing carried out and, thus, the sensitivity and specificity of the criteria cannot be determined. The low proportion of at-risk patients who underwent genetic testing is disappointing and highlights that there may be gaps in reporting, knowledge and/or barriers in access to genetic testing., (Copyright © 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Importance: In clinical practice, patients with primary metastatic renal cell carcinoma (mRCC) have been offered cytoreductive nephrectomy (CN) followed by targeted therapy, but the optimal sequence of surgery and systemic therapy is unknown., Objective: To examine whether a period of sunitinib therapy before CN improves outcome compared with immediate CN followed by sunitinib., Design, Setting, and Participants: This randomized clinical trial began as a phase 3 trial on July 14, 2010, and continued until March 24, 2016, with a median follow-up of 3.3 years and a clinical cutoff date for this report of May 5, 2017. Patients with mRCC of clear cell subtype, resectable primary tumor, and 3 or fewer surgical risk factors were studied., Interventions: Immediate CN followed by sunitinib therapy vs treatment with 3 cycles of sunitinib followed by CN in the absence of progression followed by sunitinib therapy., Main Outcomes and Measures: Progression-free survival was the primary end point, which needed a sample size of 458 patients. Because of poor accrual, the independent data monitoring committee endorsed reporting the intention-to-treat 28-week progression-free rate (PFR) instead. Overall survival (OS), adverse events, and postoperative progression were secondary end points., Results: The study closed after 5.7 years with 99 patients (80 men and 19 women; mean [SD] age, 60 [8.5] years). The 28-week PFR was 42% in the immediate CN arm (n = 50) and 43% in the deferred CN arm (n = 49) (P = .61). The intention-to-treat OS hazard ratio of deferred vs immediate CN was 0.57 (95% CI, 0.34-0.95; P = .03), with a median OS of 32.4 months (95% CI, 14.5-65.3 months) in the deferred CN arm and 15.0 months (95% CI, 9.3-29.5 months) in the immediate CN arm. In the deferred CN arm, 48 of 49 patients (98%; 95% CI, 89%-100%) received sunitinib vs 40 of 50 (80%; 95% CI, 67%-89%) in the immediate arm. Systemic progression before planned CN in the deferred CN arm resulted in a per-protocol recommendation against nephrectomy in 14 patients (29%; 95% CI, 18%-43%)., Conclusions and Relevance: Deferred CN did not improve the 28-week PFR. With the deferred approach, more patients received sunitinib and OS results were higher. Pretreatment with sunitinib may identify patients with inherent resistance to systemic therapy before planned CN. This evidence complements recent data from randomized clinical trials to inform treatment decisions in patients with primary clear cell mRCC requiring sunitinib., Trial Registration: ClinicalTrials.gov identifier: NCT01099423.

Introduction: Partial nephrectomy is a standard of care for non-metastatic renal tumours when technically feasible. Despite the increased use of partial nephrectomy, intraoperative techniques that lead to optimal renal function after surgery have not been rigorously studied. Clamping of the renal hilum to prevent bleeding during resection causes temporary renal ischaemia. The internal temperature of the kidney may be lowered after the renal hilum is clamped (renal hypothermia) in an attempt to mitigate the effects of ischaemia. Our objective is to determine if renal hypothermia during open partial nephrectomy results in improved postoperative renal function at 12 months following surgery as compared with warm ischaemia (no renal hypothermia)., Methods and Analyses: This is a multicentre, randomised, single-blinded controlled trial comparing renal hypothermia versus no hypothermia during open partial nephrectomy. Due to the nature of the intervention, complete blinding of the surgical team is not possible; however, surgeons will be blinded until the time of hilar clamping. Glomerular filtration will be based on plasma clearance of a radionucleotide, and differential renal function will be based on renal scintigraphy. The primary outcome is overall renal function at 12 months measured by the glomerular filtration rate (GFR). Secondary outcomes include change in GFR, GFR of the affected kidney, change in GFR of the affected kidney, serum creatinine, haemoglobin, spot urine albumin to creatinine ratio, quality of life and postoperative complications. Data will be collected at baseline, immediately postoperatively and at 3, 6, 9 and 12 months postoperatively., Ethics and Dissemination: Ethics approval was obtained for all participating study sites. Results of the trial will be submitted for publication in a peer-reviewed journal., Trial Registration Number: NCT01529658; Pre-results., Competing Interests: Competing interests: CM has been an adviser for Abbvie, Astellas, Ferring, Janssen and Sanofi; and has participated in clinical trials supported by Abbvie. LTL has been an adviser for Ferring and Sanofi; and has received a grant from Sanofi. IC has been an adviser for Abbvie and Ferring; and has received speaker honoraria from Abbvie, Acerus and Ferring. The remaining authors report no competing personal or financial interests., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Outside of randomized controlled clinical trials, the understanding of the effectiveness and costs associated with targeted therapies for metastatic renal cell carcinoma (mrcc) is limited in Canada. The purpose of the present study was to use real-world prospective data to assess the effectiveness and cost of targeted therapies for patients with mrcc., Methods: The Canadian Kidney Cancer Information System, a pan-Canadian database, was used to identify prospectively collected data relating to patients with mrcc. First- and subsequent-line time to treatment termination (ttt) was determined from therapy initiation time (sunitinib or pazopanib) to discontinuation of therapy. Kaplan-Meier survival curves were used to estimate the unadjusted and adjusted overall survival (os) by treatment. Unit treatment cost was used to estimate the cost by line of treatment and the total cost of therapy for the management of patients with mrcc., Results: The study included 475 patients receiving sunitinib or pazopanib in the first-line setting. Patients were treated mostly with sunitinib (81%); 19% of patients were treated with pazopanib. The median ttt in the first line was 7.7 months for patients receiving sunitinib and 4.6 months for those receiving pazopanib ( p < 0.001). The adjusted os was 32 months with sunitinib and 21 months with pazopanib (hazard ratio: 1.61; p < 0.01). The total median cost of first- and second-line treatments was $56,476 (interquartile range: $23,738-$130,447) for patients in the sunitinib group and $46,251 (interquartile range: $28,167-$91,394) for those in the pazopanib group., Conclusions: For the two therapies, os differed significantly, with a higher median os being observed in the sunitinib group. The cost of treatment was higher in the sunitinib group, which is to be expected with longer survival., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare the following interests: MJ has received consulting fees from Pfizer and Ipsen; GB has received consulting fees from Pfizer and Novartis and grants from Pfizer; NB has received consulting fees from Pfizer, Novartis, Bristol–Myers Squibb, Ipsen, and Eisai; EL has received speaker fees from Pfizer and funding from Janssen and Astellas for grants; and DH has received consulting fees from Pfizer and Novartis. The remaining authors have no conflicts of interest to disclose.

Background and Objective: The development of new targeted therapies in kidney cancer has shaped disease management in the metastatic phase. Our study aims to conduct a cost-utility analysis of sunitinib versus pazopanib in first-line setting in Canada for metastatic renal cell carcinoma (mRCC) patients using real-world data., Methods: A Markov model with Monte-Carlo microsimulations was developed to estimate the clinical and economic outcomes of patients treated in first-line with sunitinib versus pazopanib. Transition probabilities were estimated using observational data from a Canadian database where real-life clinical practice was captured. The costs of therapies, disease progression, and management of adverse events were included in the model in Canadian dollars ($Can). Utility and disutility values were included for each health state. Incremental cost-utility ratio (ICUR) and incremental cost-effectiveness ratios (ICER) were calculated for a time horizon of 5 years, from the Canadian Healthcare System perspective., Results: The cost difference was $36,303 and the difference in quality-adjusted life year (QALY) was 0.54 in favour of sunitinib with an ICUR of $67,227/QALY for sunitinib versus pazopanib. The major cost component (56%) is related to best supportive care (BSC) where patients tend to stay for a longer period of time compared to other states. The difference in life years gained (LYG) between sunitinib and pazopanib was 1.21 LYG (33.51 vs 19.03 months) and the ICER was $30,002/LYG. Sensitivity analysis demonstrated the robustness of the model with a high probability of sunitinib being a cost-effective option when compared to pazopanib., Conclusion: When using real-world evidence, sunitinib is found to be a cost-effective treatment compared to pazopanib in mRCC patients in Canada.

Introduction: To compare outcomes following laparoscopic renal surgery (LRS) and open renal surgery (ORS) in the treatment of pathologic T3a (pT3a) renal cell carcinoma (RCC) using a propensity matched analysis., Materials and Methods: The Canadian Kidney Cancer Information System is a prospectively maintained database for patients diagnosed with RCC from 15 Canadian institutions. Patients treated for nonmetastatic pT3a RCC between 2008 and 2015 were included. Propensity score matching for age, gender, tumor size, grade, histology, and surgical approach was performed to compare laparoscopic radical and partial nephrectomy (LRN or LPN) with open radical or partial nephrectomy (ORN or OPN). The primary endpoint was recurrence-free survival (RFS)., Results: Two hundred twenty-six (45%) patients underwent LRS (88% LRN and 12% LPN), and 275 (55%) underwent ORS (75% ORN and 25% OPN). After a median follow-up of 21.1 months, 155 (72 LRS and 83 ORS) patients experienced recurrence. The 3-year RFS was 63% and 50% for the LRS and ORS groups, respectively, p = 0.36. On subgroup analysis, there was no significant difference in RFS among patients who underwent radical nephrectomy (3-year RFS 61% in LRN compared with 46% in ORN group, p = 0.32) or partial nephrectomy (77% in LPN compared with 79% in OPN group, p = 0.82)., Conclusions: This study is the largest matched analysis comparing LRS and ORS for pT3a RCC. In matched patients, LRS showed no difference in oncologic outcomes compared with ORS and should be considered when technically feasible.

Introduction and Objective: Patients who undergo surgical management of renal cell carcinoma (RCC) are at risk for chronic kidney disease and its sequelae. This study describes the natural history of renal function after radical and partial nephrectomy and explores factors associated with postoperative decline in renal function., Methods: This is a multi-institutional cohort study of patients in the Canadian Kidney Cancer Information System who underwent partial or radical nephrectomy for RCC. Estimated glomerular filtration rate (eGFR) and stage of chronic kidney disease were determined preoperatively and at 3, 12, and 24 months postoperatively. Linear regression was used to determine the association between postoperative eGFR and type of surgery (radical vs. partial), duration of ischemia, ischemia type (warm vs. cold), and tumor size., Results and Limitations: With a median follow-up of 26 months, 1,379 patients were identified from the Canadian Kidney Cancer Information System database including 665 and 714 who underwent partial and radical nephrectomy, respectively. Patients undergoing radical nephrectomy had a lower eGFR (mean = 19ml/min/1.73m 2 lower) at 3, 12, and 24 months postoperatively (P<0.001). Decline in renal function occurred early and remained stable throughout follow-up. A lower preoperative eGFR and increasing age were also associated with a lower postoperative eGFR (P<0.01). Ischemia type and duration were not predictive of postoperative decline in eGFR (P>0.05). Severe renal failure (eGFR<30ml/min/1.73m 2 ) developed postoperatively in 12.5% and 4.1% of radical and partial nephrectomy patients, respectively (P<0.001)., Conclusions: After the initial postoperative decline, renal function remains stable in patients undergoing surgery for RCC. Patients undergoing radical nephrectomy have a greater long-term reduction in renal function compared with those undergoing partial nephrectomy. Ischemia duration and type are not predictive of postoperative renal function when adhering to generally short ischemia durations., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Renal-cell carcinoma is highly vascular, and proliferates primarily through dysregulation of the vascular endothelial growth factor (VEGF) pathway. We tested sunitinib and sorafenib, two oral anti-angiogenic agents that are effective in advanced renal-cell carcinoma, in patients with resected local disease at high risk for recurrence., Methods: In this double-blind, placebo-controlled, randomised, phase 3 trial, we enrolled patients at 226 study centres in the USA and Canada. Eligible patients had pathological stage high-grade T1b or greater with completely resected non-metastatic renal-cell carcinoma and adequate cardiac, renal, and hepatic function. Patients were stratified by recurrence risk, histology, Eastern Cooperative Oncology Group (ECOG) performance status, and surgical approach, and computerised double-blind randomisation was done centrally with permuted blocks. Patients were randomly assigned (1:1:1) to receive 54 weeks of sunitinib 50 mg per day orally throughout the first 4 weeks of each 6 week cycle, sorafenib 400 mg twice per day orally throughout each cycle, or placebo. Placebo could be sunitinib placebo given continuously for 4 weeks of every 6 week cycle or sorafenib placebo given twice per day throughout the study. The primary objective was to compare disease-free survival between each experimental group and placebo in the intention-to-treat population. All treated patients with at least one follow-up assessment were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT00326898., Findings: Between April 24, 2006, and Sept 1, 2010, 1943 patients from the National Clinical Trials Network were randomly assigned to sunitinib (n=647), sorafenib (n=649), or placebo (n=647). Following high rates of toxicity-related discontinuation after 1323 patients had enrolled (treatment discontinued by 193 [44%] of 438 patients on sunitinib, 199 [45%] of 441 patients on sorafenib), the starting dose of each drug was reduced and then individually titrated up to the original full doses. On Oct 16, 2014, because of low conditional power for the primary endpoint, the ECOG-ACRIN Data Safety Monitoring Committee recommended that blinded follow-up cease and the results be released. The primary analysis showed no significant differences in disease-free survival. Median disease-free survival was 5·8 years (IQR 1·6-8·2) for sunitinib (hazard ratio [HR] 1·02, 97·5% CI 0·85-1·23, p=0·8038), 6·1 years (IQR 1·7-not estimable [NE]) for sorafenib (HR 0·97, 97·5% CI 0·80-1·17, p=0·7184), and 6·6 years (IQR 1·5-NE) for placebo. The most common grade 3 or worse adverse events were hypertension (105 [17%] patients on sunitinib and 102 [16%] patients on sorafenib), hand-foot syndrome (94 [15%] patients on sunitinib and 208 [33%] patients on sorafenib), rash (15 [2%] patients on sunitinib and 95 [15%] patients on sorafenib), and fatigue 110 [18%] patients on sunitinib [corrected]. There were five deaths related to treatment or occurring within 30 days of the end of treatment; one patient receiving sorafenib died from infectious colitis while on treatment and four patients receiving sunitinib died, with one death due to each of neurological sequelae, sequelae of gastric perforation, pulmonary embolus, and disease progression. Revised dosing still resulted in high toxicity., Interpretation: Adjuvant treatment with the VEGF receptor tyrosine kinase inhibitors sorafenib or sunitinib showed no survival benefit relative to placebo in a definitive phase 3 study. Furthermore, substantial treatment discontinuation occurred because of excessive toxicity, despite dose reductions. These results provide a strong rationale against the use of these drugs for high-risk kidney cancer in the adjuvant setting and suggest that the biology of cancer recurrence might be independent of angiogenesis., Funding: US National Cancer Institute and ECOG-ACRIN Cancer Research Group, Pfizer, and Bayer., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Papillary renal cell carcinoma (pRCC) is the second most common RCC subtype and can be further classified as type 1 (pRCC1) or 2 (pRCC2). There is currently minimal understanding of pRCC1 pathogenesis, and treatment decisions are mostly empirical. The aim of this study was to identify biological pathways that are involved in pRCC1 pathogenesis using an integrated genomic approach. By microarray analysis, we identified a number of significantly dysregulated genes and microRNAs (miRNAs) that were unique to pRCC1. Integrated bioinformatics analyses showed enrichment of the focal adhesion and extracellular matrix (ECM) pathways. We experimentally validated that many members of these pathways are dysregulated in pRCC1. We identified and experimentally validated the downregulation of miR-199a-3p in pRCC1. Using cell line models, we showed that miR-199a-3p plays an important role in pRCC1 pathogenesis. Gain of function experiments showed that miR-199a-3p overexpression significantly decreased cell proliferation (p = 0.013). We also provide evidence that miR-199a-3p regulates the expression of genes linked to the focal adhesion and ECM pathways, such as caveolin 2 (CAV2), integrin beta 8 (ITGB8), MET proto-oncogene and mammalian target of rapamycin (MTOR). Using a luciferase reporter assay, we further provide evidence that miR-199a-3p overexpression decreases the expression of MET and MTOR. Using an integrated gene/miRNA approach, we provide evidence linking miRNAs to the focal adhesion and ECM pathways in pRCC1 pathogenesis. This novel information can contribute to the development of effective targeted therapies for pRCC1, for which there is none currently available in the clinic., (Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Purpose: Sunitinib and sorafenib are used widely in the treatment of renal cell carcinoma (RCC). These agents are associated with a significant incidence of cardiovascular (CV) dysfunction and left ventricular ejection fraction (LVEF) declines, observed largely in the metastatic setting. However, in the adjuvant population, the CV effects of these agents remain unknown. We prospectively defined the incidence of cardiotoxicity among resected, high-risk RCC patients treated with these agents., Experimental Design: Sunitinib, sorafenib, or placebo was administered for up to 12 months in patients with high-risk, resected RCC. LVEF was measured by multigated acquisition (MUGA) scans at standard intervals. Additional CV adverse events were reported according to NCI Common Terminology Criteria for Adverse Events (CTCAE)., Results: Among 1,943 patients randomized, 1,599 had at least 1 post-baseline MUGA. Within 6 months, 21 patients (1.3%) experienced a cardiac event, defined as an LVEF decline from baseline that was >15% and below the institutional lower limit of normal. Nine of 513 patients (1.8%) were on sunitinib, 7 of 508 (1.4%) on sorafenib, and 5 of 578 (0.9%) on placebo (P = 0.28 and 0.56 comparing sunitinib and sorafenib to placebo, respectively). With dose interruption or adjustment, 16 of the 21 recovered their LVEF to >50%. The incidence of symptomatic heart failure, arrhythmia, or myocardial ischemia did not differ among groups., Conclusions: In the adjuvant setting, we prospectively define low incidence of cardiotoxicity with sunitinib and sorafenib. These findings may be related to close CV monitoring, or potentially to fewer CV comorbidities in our nonmetastatic population., (©2015 American Association for Cancer Research.)

Purpose: To test the hypothesis that qualitative and quantitative features of contrast material-enhanced ultrasonography (US) can be used to differentiate benign from malignant small renal masses., Materials and Methods: This is an institutional review board approved, HIPAA-compliant prospective study with written informed consent. Patients with histologically characterized solid small renal masses, excluding lipid-rich angiomyolipomas, underwent qualitative contrast-enhanced US with a combination of three different US machines. A subgroup of patients underwent quantitative contrast-enhanced US. Patients received a bolus injection of 0.2 mL of contrast material for qualitative and quantitative evaluations and were followed for 3 minutes. Two radiologists independently reviewed videotaped qualitative contrast-enhanced US examinations and were blinded to the final diagnoses. Features that were evaluated included lesion vascularity relative to the adjacent cortex in the arterial phase, the presence of a capsule, homogeneity, the pattern of vascularity, and washout. One radiologist separately reviewed a subset of contrast-enhanced US examinations that were performed with all three machines. Parameters of a first-pass time intensity curve were calculated for quantitative analysis. The Mann-Whitney test was used for quantitative parameters, the χ(2) or Fisher exact test was used for qualitative parameters, and κ statistics and Fleiss methodology were used to determine interobserver and intermachine agreement., Results: The study population consisted of 91 patients (35 women and 56 men) with 94 lesions. The mean age was 62 years ± 14 (range, 21-91). Three patients had two lesions each, which were evaluated at two different sessions. There were 26 benign small renal masses (including 18 oncocytomas, seven lipid-poor angiomyolipomas, and one hemangioblastoma) and 68 malignant masses (including 41 clear cell, 20 papillary, and seven chromophobe renal cell carcinomas [RCCs[) that were 1.1-4.0 cm in diameter (mean, 2.7 cm ± 0.9). All patients underwent contrast-enhanced US on the same one machine, and 68 patients were imaged on all three machines. Vascularity was present in all lesions (n = 94) at contrast-enhanced US. Lesion hypovascularity relative to the adjacent cortex in the arterial phase was seen in only malignant lesions by both reviewers; reviewer 1 saw hypovascularity in 24 of 94 lesions (P = .0001), and reviewer 2 saw hypovascularity in 21 of 94 lesions (P = .0006), for a specificity of 100% (95% confidence interval [CI]: 84, 100). This feature had κ values of 0.91 (95%CI: 0.82, 1.00) between the two reviewers and 0.85 (95% CI: 0.72, 0.99) between the three machines. Eighteen of 20 papillary RCCs were hypovascular. Quantitative parameters of area under the receiver operating characteristics curve, peak intensity, wash-in slope of 10%-90% and 5%-45%, and washout slope of 100%-10% and 50%-10% were significantly higher in malignant renal masses (P = .018, P = .002, P = .036, P = .016, P = .001, and P = .005, respectively) than in benign lesions., Conclusion: Excluding lipid-rich angiomyolipoma, hypovascularity-which has high interobserver and intermachine agreement-of solid small renal masses relative to the cortex in the arterial phase has 100% specificity (95% CI: 84, 100) for detecting malignancy, most often papillary RCC.

Objective: The purpose of this study was to evaluate the diagnostic performance of chemical-shift MRI in the differentiation of clear cell renal cell carcinoma (RCC) from minimal-fat angiomyolipoma (AML) and non-clear cell RCC., Materials and Methods: In this retrospective study, 97 patients with solid renal tumors without macroscopic fat and with a pathologic diagnosis of clear cell RCC (n = 40), non-clear cell RCC (n = 31), or minimal-fat AML (n = 26) who had undergone renal chemical-shift MRI were included. Size, location, morphology, and signal intensity (SI) of the tumors and the contralateral normal kidneys on T2-weighted and in-phase and opposed-phase images were recorded by readers blinded to the pathology. Percentage tumor-to-renal parenchymal SI drop (percentage SI drop) was calculated and correlated to tumor histology. The statistical analysis was done using Kruskal-Wallis, one-way ANOVA, chi-square, and Fisher exact tests., Results: The percentage SI drop was significantly higher in clear cell RCC compared with non-clear cell RCC and minimal-fat AML (p < 0.001). Percentage SI drop of greater than 20% had 57.5% sensitivity, 96.5% specificity, and 92% positive predictive value (PPV); and percentage SI drop greater than 29% had 40% sensitivity and 100% specificity for diagnosis of clear cell RCC within the cohort of clear cell RCC, minimal-fat AML, and non-clear cell RCC. A significant proportion of minimal-fat AML (46.2%) displayed homogeneous low T2-weighted SI as opposed to clear cell RCC (5%) and non-clear cell RCC (29%) (p < 0.001)., Conclusion: The percentage SI drop on chemical-shift MRI had high specificity and moderate sensitivity in predicting clear cell RCC over non-clear cell RCC and minimal-fat AML. A percentage SI drop greater than 20% in a renal mass without macroscopically visible fat has high PPV for clear cell RCC over minimal-fat AML and non-clear cell RCC. Among morphologic features, homogeneous low T2 SI favors minimal-fat AML over RCC.

Accurate assessment of prognosis of clear cell renal cell carcinoma (ccRCC) is key in optimizing management plans to fit individual patient needs. miRNAs are short noncoding single-stranded RNAs that control the expression of target genes and may act as cancer biomarkers. We analyzed the expression of miR-210 in 276 cases of primary ccRCC and compared its expression in 40 pairs of adjacent normal and cancerous tissues. We assessed its expression in primary and metastatic tumors, in the common RCC subtypes, and the benign oncocytoma. The results were validated with an independent data set from The Cancer Genome Atlas. miR-210 was significantly overexpressed in ccRCC compared with normal kidney. miR-210(+) patients had a statistically higher chance of disease recurrence [hazard ratio (HR), 1.82; P = 0.018] and shorter overall survival (HR, 2.46; P = 0.014). In multivariate analysis, miR-210 lost its statistically significant association with shorter disease-free survival and overall survival after adjusting for tumor size and tumor, node, metastasis stage. Papillary RCC showed comparable miR-210 overexpression, whereas decreased up-regulation was seen in chromophobe RCC and oncocytoma. A number of predicted targets that might be involved in carcinogenesis and aggressive tumor behavior were identified. miR-210 is a potential therapeutic target and independent marker of poor prognosis of ccRCC., (Copyright © 2015 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

MicroRNAs (miRNAs) play a crucial role in tumor progression and metastasis. We, and others, recently identified a number of miRNAs that are dysregulated in metastatic renal cell carcinoma compared with primary renal cell carcinoma. Here, we investigated three miRNAs that are significantly downregulated in metastatic tumors: miR-192, miR-194 and miR-215. Gain-of-function analyses showed that restoration of their expression decreases cell migration and invasion in renal cell carcinoma cell line models, whereas knockdown of these miRNAs resulted in enhancing cellular migration and invasion abilities. We identified three targets of these miRNAs with potential role in tumor aggressiveness: murine double minute 2, thymidylate synthase, and Smad Interacting protein 1/zinc finger E-box binding homeobox 2. We observed a convergent effect (the same molecule can be targeted by all three miRNAs) and a divergent effect (the same miRNA can control multiple targets) for these miRNAs. We experimentally validated these miRNA-target interactions using three independent approaches. First, we observed that miRNA overexpression significantly reduces the mRNA and protein levels of their targets. In the second, we observed significant reduction of the luciferase signal of a vector containing the 3'UTR of the target upon miRNA overexpression. Finally, we show the presence of inverse correlation between miRNA changes and the expression levels of their targets in patient specimens. We also examined the prognostic significance of miR-215 in renal cell carcinoma. Lower expression of miR-215 is associated with significantly reduced disease-free survival time. These findings were validated on an independent data set from The Cancer Genome Atlas. These results can pave the way to the clinical use of miRNAs as prognostic markers and therapeutic targets.

Purpose: Optimal quality of care is needed for ideal outcomes. In renal cell carcinoma (RCC), there is a lack of information defining optimal care. This is particularly important in RCC, with increased complexity of care and a need for coordination among providers. The goal of this study was to identify quality indicators (QIs) and measures of quality care across the RCC disease spectrum., Materials and Methods: A modified Delphi technique was used to select QIs that are relevant and practical to RCC care. This technique involved an expert panel of 13 urologic and medical oncologists who participated in two e-mail questionnaires and an in-person meeting to review and prioritize potential QIs. These potential QIs were identified from a systematic literature review or were suggested by panel members., Results: From 233 literature citations, 34 possible QIs were identified; 24 additional potential QIs were suggested. A final set of 23 QIs was established. These are distributed across the RCC disease spectrum as follows (number of QIs in parentheses): screening (n=1), diagnosis/prognosis (n=3), surgical for localized disease (n=6), surgery for advanced disease (n=3), systemic therapy (n=6), and follow-up (n=2). In addition, two QIs related to survival outcomes (overall and progression-free survival) were selected., Conclusion: A systematic, consensus-based approach was used to determine relevant QIs in RCC care. These 23 QIs will provide a means of evaluating the quality of RCC care in an effort to improve outcomes in patients. The next step will be to establish a means of measuring each QI based on defined or yet-to-be-defined benchmarks.

Objective: The purpose of this study is to evaluate the interval growth, tumor recurrence, and metastatic disease occurrence of cystic renal cell carcinoma (RCC)., Materials and Methods: Pre-and posttreatment imaging of 47 histologically proven cystic RCCs, with at least 6 months of pretreatment imaging monitoring or at least 2 years of posttreatment imaging follow-up, or both, was retrospectively reviewed. Tumor morphologic features, preoperative growth, histologic typing and grading, and the incidence of tumor recurrence or metastasis were evaluated. Growth rate of tumors were compared among various histologic subtypes and Fuhrman grades., Results: Of 47 tumors, 27 (57.5%) were clear cell RCCs, 12 (25.5%) were multilocular RCCs, and eight (17%) were papillary cystic RCCs. Overall, 26 (55.3%) tumors were graded as Fuhrman grade 2, 17 (36.1%) were Fuhrman grade 1, and one tumor was Fuhrman grade 3. Of the 26 tumors with a minimum of 6 months of pretreatment imaging monitoring, 19 (73%) did not show a significant increase in tumor size. The differences in mean growth among the Fuhrman grades and different subtypes were not statistically significant. The average duration of posttreatment follow-up was 51 months. There were no local recurrences among the 43 patients who underwent posttreatment imaging, except for one patient who had metastasis at preoperative clinical presentation., Conclusion: Cystic RCCs exhibit slow indolent growth, if any, and show no significant metastatic or recurrence potential, with excellent clinical outcomes. We raise the need for revisiting current imaging protocols that may involve frequent pre-and posttreatment imaging in cystic RCCs.

Background: Renal cell carcinoma (RCC) is the most common neoplasm of the adult kidney. Metastatic RCC is difficult to treat. The 5-year survival rate for metastatic RCC is ≤10%. Recently, microRNAs (miRNAs) have been shown to have a role in cancer metastasis and potential as prognostic biomarkers in cancer., Method: We performed a miRNA microarray to identify a miRNA signature characteristic of metastatic compared with primary RCCs. We validated our results by quantitative real-time PCR. We performed experimental and bioinformatic analyses to explore the involvement of miR-215 in RCC progression and metastasis., Results: We identified 65 miRNAs that were significantly altered in metastatic compared with primary RCCs. We validated our results by examining the expression of miR-10b, miR-126, miR-196a, miR-204 and miR-215, in two independent cohorts of patients. We showed that overexpression of miR-215 decreased cellular migration and invasion in an RCC cell line model. In addition, through gene expression profiling, we identified direct and indirect targets of miR-215 that can contribute to tumour metastasis., Conclusion: Our analysis showed that miRNAs are altered in metastatic RCCs and can contribute to kidney cancer metastasis through different biological processes. Dysregulated miRNAs represent potential prognostic biomarkers and may have therapeutic applications in kidney cancer.

Purpose: Renal cell carcinoma develops in renal transplant recipients 30 or more times more commonly than in the general population. We assessed the prevalence, histology and outcome of renal cell carcinoma in a large, single center recipient population., Materials and Methods: We examined outcomes in patients who underwent renal transplantation at our center to determine the prevalence, histology and outcome of those in whom renal cell carcinoma developed., Results: A total of 3,568 patients received a renal allograft at our institution between 1966 and 2009. A total of 45 renal cell carcinomas were diagnosed in the native kidney of 39 patients (1.1%) and in 8 (0.2%) renal cell carcinoma developed in the allograft kidney. Mean age at diagnosis was 51.6 and 48.2 years in patients with native kidney and allograft tumors, respectively. The mean interval between transplantation and the native or allograft renal cell carcinoma diagnosis was 10.6 and 12.1 years, respectively. Clear cell renal cell carcinoma was the most common tumor histology in native kidneys, diagnosed in 21 cases, while papillary renal cell carcinoma was diagnosed in 20. Five allograft tumors were papillary renal cell carcinoma and 3 were clear cell renal cell carcinoma. Native kidney tumors were managed by radical nephrectomy in 44 or by observation after biopsy. Allograft tumors were managed by transplant nephrectomy in 3 cases, radio frequency ablation in 3 and partial nephrectomy in 2. At a mean 6.6-year followup 32 patients with native kidney renal cell carcinoma were alive while 7 with allograft tumors were alive at a mean 3.6-year followup., Conclusions: Renal cell carcinoma is more prevalent in patients with renal transplantation than the general population, although the subtype distribution differs. Excellent survival is seen at more than 6 years after treatment., (Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Prolonged surgical wait times have significant effects on a patient's psychological well being and a negative impact on quality of life but the effect on long-term cancer control is controversial. We conducted a systematic review of the renal cancer literature to examine the best available evidence addressing the following key questions: What is the reported time interval for renal cancer patients from the initial surgical consultation until the day of renal cancer surgery? Are there recommendations/guidelines in the urological cancer literature and, if so, how do the Canadian times compare? Is there a known association between duration of wait time beyond the recommended standard and clinical outcome (i.e., recurrence-free survival, overall survival)?, Methods: A structured literature search PubMed, Embase, the Cochrane Database and Google Scholar from January 1965 to October 2005 was conducted for published studies and international guidelines/consensus documents that evaluated surgical wait times for renal cancer. Data extracted from eligible studies included median or mean time to renal cancer surgery from diagnosis or referral, and key patient outcomes, such as survival rate or adjusted hazard ratios (HR)., Results: Only three studies evaluating wait times for renal cancer surgery were identified. Differences in study data availability, method of analysis and wait time definitions precluded statistical pooling of the findings. Wait times from various points of patient contact ranged from a median delay of 26 days (diagnosis to radical surgery, i.e., nephrectomy) to 82 days (general practitioner referral to radical surgery). One study reported a mean of 23.6 days between referral for surgery to hospital admission for nephrectomy. In the Canadian epidemiological study, which focused on all types of urological cancer, median wait time was 64 days from referral to surgery. This was in contrast to national and international guidelines, which recommended a maximum waiting time between 2 and 4 weeks for all cancer surgeries. There were no epidemiological studies evaluating the association between surgical delay and clinical outcomes such as overall survival., Conclusions: In Canada, it appears that current wait times for urological surgeries, such as for renal cancer, are beyond the threshold recommended by national and international expert bodies. Then again, the association between surgical delay and overall survival appears to be unexplored. Research in this area is urgently needed. Notwithstanding, the surgical wait times (SWAT) initiative was developed to provide the necessary guidance and recommendations on these issues to the federal and provincial governments. Through a partnership of the key stakeholders, it is the vision of SWAT to ultimately improve the care and quality of life of bladder cancer patients and their families.

Purpose: Incidentally detected small renal tumors appear to grow slowly and be localized to the kidney. Minimally invasive therapies are being investigated as alternatives to standard surgical techniques. Radiofrequency ablation has been reported for the treatment of small renal cell carcinomas. We developed a radiofrequency technique and established its efficacy and safety in a large animal model., Methods and Methods: A total of 22 lesions were created in normal kidneys of 7 pigs. Radiofrequency energy was administered during open exposure of the kidneys or percutaneously under ultrasound guidance. Lesion development was monitored with gray-scale and power Doppler ultrasound. To avoid heating surrounding tissues new hydro-dissection and gas-dissection techniques were developed. Lesion sizes and characteristics were assessed by ultrasound and pathological examination., Results: No complications were observed due to probe insertion and removal. Perirenal structures were thermally damaged before the development and application of the dissection techniques. Lesion size was accurately predicted by gray-scale ultrasound on day 7. Loss of perfusion in the ablated volume was confirmed by power Doppler ultrasound. Lesions were wedge-shaped, presumably due to the effects of heating on segmental blood flow distribution. Pathological examination revealed changes consistent with thermal injury and ischemic type infarction., Conclusions: Radiofrequency thermal therapy is an effective and efficient method for ablating normal renal tissue in the pig. It may be applied percutaneously under ultrasound guidance with minimal complications provided that vital adjacent structures are protected from thermal damage. Further studies are required in humans before adopting this technique as definitive treatment for small renal cell carcinoma.

Purpose: Ultrasound, computerized tomography and magnetic resonance imaging are widely available. Incidentally discovered small renal masses are reported more frequently. Most of these masses are low stage renal cell carcinomas. To understand better the natural history of these lesions and offer appropriate management, we followed prospectively a series of patients with this type of lesion., Materials and Methods: A total of 13 patients with radiologically detected solitary small renal masses who were unfit for or refused surgery were followed with abdominal imaging for a median of 42 months. Median patient age was 69 years and mean lesion volume at diagnosis was 13.6 cm.3 or 2.95 cm. in diameter. Growth rate was calculated based on tumor volume rather than bi-dimensional diameter. Individual slopes of tumor size in time were calculated., Results: Of the 13 patients 5 underwent surgery following a period of surveillance because of apparent tumor enlargement or new onset of symptoms. Pathological evaluation revealed renal cell carcinoma in all 5. No patient had metastases. Only 2 tumors were fast growing and these were the only 2 cases in which symptoms developed. When these patients were excluded from analysis, average growth rate was 1.32 cm.3 per year (p = 0.5, 95% confidence interval -3.00 to 5.76 cm.3 per year), which was not statistically significantly different from 0 slope or no growth., Conclusions: These results demonstrate that the growth rate of small renal tumors is variable, tumors that are destined to grow and possibly metastasize do so early and most small tumors grow at a low rate or not at all.

We treated 41 patients with transitional cell carcinoma with methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy. Median patient age was 56 years. Of the patients 33 had either distant metastases or locoregional disease that could not be cured by an operation or radiation. Of these patients 30 had measurable disease and 12 responded (4 complete and 8 partial responses, response rate 40 per cent, 95 per cent confidence limits 23 to 59 per cent). Only 2 of these patients remain with an unmaintained complete response at 34 and 52 months. Of 5 patients 3 responded who were treated with neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin for locally advanced bladder cancer before radiation or cystectomy, and only 1 of these patients is free of disease. The remaining 3 patients were treated postoperatively because they were at high risk for recurrence and all are well. Toxicity of the regimen was severe: 41 per cent of the patients experienced neutropenic sepsis and 54 per cent required hospitalization for management of toxic complications. Three patients experienced pulmonary embolism and 1 had deep vein thrombosis. There was 1 drug-related death of sepsis. Although a patient occasionally may have long-term benefit from this chemotherapy our results suggest caution in the widespread application of this protocol.