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Stereotactic magnetic resonance (MR)-guided adaptive radiotherapy (SMART) for renal cell carcinoma may result in more precise treatment delivery through the capabilities for improved image quality, daily adaptive planning, and accounting for respiratory motion during treatment with real-time MR tracking. In this study, we aimed to characterize the safety and feasibility of SMART for localized kidney cancer. Twenty patients with localized kidney cancer (ten treated in a prospective phase 1 trial and ten in the supplemental cohort) were treated to 40 Gy in five fractions on a 0.35 T MR-guided linear accelerator with daily adaptive planning and a cine MR-guided inspiratory breath hold technique. The median follow-up time was 17 mo (interquartile range: 13-20 months). A single patient developed local failure at 30 mo. No grade ≥3 adverse events were reported. The mean decrease in estimated glomerular filtration rate was -1.8 ml/min/1.73 m 2 (95% confidence interval or CI [-6.6 to 3.1 ml/min/1.73 m 2 ]), and the mean decrease in tumor diameter was -0.20 cm (95% CI [-0.6 to 0.2 cm]) at the last follow-up. Anterior location and overlap of the 25 or 28 Gy isodose line with gastrointestinal organs at risk were predictive of the benefit from online adaptive planning. Kidney SMART is feasible and, at the early time point evaluated in this study, was well tolerated with minimal decline in renal function. More studies are warranted to further evaluate the safety and efficacy of this technique. PATIENT SUMMARY: For patients with localized renal cell carcinoma who are not surgical candidates, stereotactic magnetic resonance--guided adaptive radiotherapy is a feasible and safe noninvasive treatment option that results in minimal impact on kidney function., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: To evaluate effect and outcomes of combination primary immunotherapy (IO) and nephrectomy for advanced renal cell carcinoma (RCC)., Methods: We conducted a multicenter, retrospective analysis of patients with advanced/metastatic RCC who received IO followed by nephrectomy. Primary outcome was Bifecta (negative surgical margins and no 30-day surgical complications). Secondary outcomes included progression-free survival (PFS) following surgery, reduction in tumor/thrombus size, RENAL score, and clinical/pathologic downstaging. Cox regression multivariable analysis was conducted for predictors of Bifecta and PFS. Kaplan-Meier analysis assessed PFS, comparing Bifecta and non-Bifecta groups., Results: A total of 56 patients were analyzed (median age 63 years; median follow-up 22.5 months). A total of 40 (71.4%) patients were intermediate IMDC risk. Patients were treated with immunotherapy for median duration of 8.1 months. Immunotherapy resulted in reductions in tumor size (P < .001), thrombus size (P = .02), and RENAL score (P < .001); 38 (67.9%) patients were clinically downstaged on imaging (P < .001) and 25 (44.6%) patients were pathologically downstaged following surgery (P < .001). Bifecta was achieved in 38 (67.9%) patients. Predictors for bifecta achievement included decreasing tumor size (HR 1.08, P = .043) and pathological downstaging (HR 2.13, P = .047). Bifecta (HR 5.65, P = .009), pathologic downstaging (HR 5.15, P = .02), and increasing reduction in tumor size (HR 1.2, P = .007) were associated with improved PFS. Bifecta patients demonstrated improved 2-year PFS (84% vs. 71%, P = .019)., Conclusions: Primary immunotherapy reduced tumor/thrombus size and complexity. Pathologically downstaged patients were more likely to achieve bifecta, and these patients displayed improved 2-year PFS. Our study supports further inquiry in the use of CRN following primary immunotherapy for advanced renal cancer., Competing Interests: Disclosure The authors of this study have no conflicts of interest to disclose., (Copyright © 2023. Published by Elsevier Inc.)

Because metachronous metastatic disease will develop in 20% to 40% of patients with presumed localized renal cell carcinoma (RCC) treated surgically, research is focused on neoadjuvant and adjuvant systemic therapy, to improve disease-free and overall survival. Neoadjuvant therapies trialed include anti-vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) agents, or combination therapies (immunotherapy with TKI), and aim to improve resectability of locoregional RCC. Adjuvant therapies trialed include cytokines, anti-VEGF TKI agents, or immunotherapy. These therapeutics can facilitate the surgical extirpation of the primary kidney tumor in the neoadjuvant setting and improve disease-free survival in the adjuvant setting., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background There is uncertainty in the management of renal masses diagnosed as oncocytomas with image-guided percutaneous biopsy. Purpose To assess the reliability of a diagnosis of oncocytoma based on image-guided percutaneous renal mass biopsy and evaluate patient outcomes following different management strategies. Materials and Methods In this retrospective study, image-guided percutaneous biopsy pathology reports from April 2004 to April 2019 were searched for keywords "oncocytoma" and "oncocytic neoplasm" and compared with surgical pathology or repeat biopsy results. Patients with at least 12 months of clinical follow-up and known cause of death were grouped according to management strategies, and disease-specific survival and metastatic renal cell carcinoma (RCC)-free survival were compared. Mass growth rates were calculated with use of a normal linear mixed model. Results The database yielded 160 biopsy reports of 149 renal masses in 139 patients; 149 masses were categorized as oncocytoma ( n = 107), likely oncocytoma ( n = 12), oncocytic neoplasm ( n = 28), and indeterminate with oncocytoma in differential ( n = 2). Biopsied masses categorized as oncocytoma or likely oncocytoma were oncocytomas in 16 of 17 masses (94%) based on surgical pathology or repeat biopsy; four of eight masses (50%) categorized as oncocytic neoplasms were low-grade RCCs. Outcome analysis included 121 patients (mean age ± SD, 68 years ± 9.1; 82 men); 80 patients initially underwent active surveillance (11 were later treated), 33 underwent ablation, and eight underwent surgery. Disease-specific survival and metastatic-free survival were 100% after each management strategy (median follow-up, 86.6 months; range, 14.2-207.9 months). Mass growth rate (mean, 1.7 mm per year) showed no evidence of a significant difference among biopsy result categories ( P = .37) or initial ( P = .84) or final management strategies ( P = .11). Conclusion Image-guided percutaneous biopsy diagnosis of renal oncocytoma was reliable. Although some masses diagnosed as oncocytic neoplasms were low-grade renal cell carcinomas (RCCs) at final diagnosis, no patients died of RCC, including those managed with active surveillance. © RSNA, 2023 See also the editorial by Lockhart in this issue.

Partial nephrectomy (PN) is recommended for renal cell carcinoma (RCC) of <4 cm. We hypothesized that there is no difference in all-cause mortality (ACM) between cT1a, cT1b, and cT3a <4 cm RCC following PN. The National Cancer Database was interrogated to identify patients aged <60 yr with a Charlson comorbidity index ≤1 diagnosed between 2004 and 2017. Cox proportional-hazard models stratified for cT stage were used to predict 10-yr ACM. A total of 30 195 patients (25 121 cT1a, 4884 cT1b, and 190 cT3a <4 cm) who underwent PN with median follow-up of 64.36 mo (interquartile range 42.91-93.77) were included. Cox analysis revealed no significant difference in 10-yr ACM between cT1a and cT3a <4 cm (hazard ratio [HR] 1.05, 95% confidence interval [CI] 0.58-1.90; p = 0.88). However, the cT1b group had higher ACM (HR 1.31, 95% CI 1.15-1.48; p < 0.01). The positive surgical margin (PSM) rate was higher for cT3a <4 cm than for cT1a tumors (14.2% vs 6.3%; p < 0.01). However, there was no difference in 10-yr ACM rate between cT1a and cT3a <4 cm (10.9% vs 9.7%; p = 0.42). Our results suggest that PN is an option for cT3a RCC <4 cm, particularly in cases in which maximum nephron preservation is essential, such as patients with chronic kidney disease or a solitary kidney, although a higher PSM risk should be appreciated. PATIENT SUMMARY: We found that partial removal of the kidney for localized advanced kidney cancer is safe. The rate of surgical margins positive for the presence of tumor is higher in localized advanced kidney cancer than for less advanced cancers, but there was no difference in 10-year predicted mortality., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Sarcomatoid differentiation in patients diagnosed with renal cell carcinoma (sRCC) imply aggressive behavior and often metastatic disease at the time of diagnosis. We aim to examine the overall survival (OS) in patients with sRCC using the National Cancer Database (NCDB)., Materials and Methods: We identified patients diagnosed with sRCC between 2010-2015. We employed Kaplan-Meier curves and multivariable Cox proportional hazards regression models to examine the impact of several potential risk factors on OS in patients diagnosed with sRCC., Results: In total, 8582 patients with renal cancer were found to have sarcomatoid differentiation, with 4105 patients (47.8%) being diagnosed with AJCC stage IV disease. The median OS was 17.2 months (IQR 5.4, 68.7 months). Compared to patients who did not undergo surgery, OS was significantly longer in patients undergoing partial or total nephrectomy across all stages. This result remained consistent on multivariable Cox proportional hazards regression adjusting for patient and tumor characteristics (Surgery: Hazard ratio 0.54, 95%Confidence interval 0.43 - 0.68, P < .001)., Conclusion: In our cohort sRCC was found to have an unfavorable median OS, which was mainly caused by the high number of cases diagnosed with late-stage disease. Additionally, surgery was associated with favorable OS across all stages. This study supports the notion that surgical therapy, even in the setting of cytoreductive surgery, provides a survival benefit in patients with sRCC., (Copyright © 2022. Published by Elsevier Inc.)

To disentangle the "obesity paradox" in renal cell carcinoma (RCC), we examined associations of body mass index (BMI) and weight change with RCC risk and survival in the Health Professionals Follow-up Study (HPFS) and Nurses' Health Study (NHS) 1 and 2. We estimated cohort-specific and summary covariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for RCC incidence, as well as RCC-specific survival among cases in the pooled HPFS and NHS data. Cumulative average BMI was associated with a higher risk of total RCC (summary HR 2.16, 95% CI 1.77-2.63 for BMI ≥30 vs 18-<25 kg/m 2 ; p trend <0.001) and fatal RCC (HR 2.03, 95% CI 1.37-3.01; p trend <0.001). Prediagnosis BMI was not associated with RCC death. However, first postdiagnosis BMI (HR 0.51, 95% CI 0.29-0.89; p trend 0.006) and prediagnosis to postdiagnosis weight change (HR 0.52, 95% CI 0.29-0.91; p trend 0.001) were significantly inversely associated with RCC death. These results support obesity as a risk factor for total and fatal RCC. They undermine the obesity paradox by suggesting that weight loss around diagnosis, and not low BMI itself, is associated with worse prognosis. PATIENT SUMMARY: We studied obesity in kidney cancer and found that obesity is associated with getting and dying from the disease. Body mass index at diagnosis is not an ideal factor for predicting prognosis, as patients who have lost weight are likely to have more aggressive cancer., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Translocation renal cell carcinoma (tRCC) is a poorly characterized subtype of kidney cancer driven by MiT/TFE gene fusions. Here, we define the landmarks of tRCC through an integrative analysis of 152 patients with tRCC identified across genomic, clinical trial, and retrospective cohorts. Most tRCCs harbor few somatic alterations apart from MiT/TFE fusions and homozygous deletions at chromosome 9p21.3 (19.2% of cases). Transcriptionally, tRCCs display a heightened NRF2-driven antioxidant response that is associated with resistance to targeted therapies. Consistently, we find that outcomes for patients with tRCC treated with vascular endothelial growth factor receptor inhibitors (VEGFR-TKIs) are worse than those treated with immune checkpoint inhibitors (ICI). Using multiparametric immunofluorescence, we find that the tumors are infiltrated with CD8 + T cells, though the T cells harbor an exhaustion immunophenotype distinct from that of clear cell RCC. Our findings comprehensively define the clinical and molecular features of tRCC and may inspire new therapeutic hypotheses., Competing Interests: Declaration of interests Z.B.: research funding from Bristol-Myers Squibb & Genentech/imCORE; honoraria from UpToDate. X.G.: advisory board for Exelixis, Bayer and Guardant Health. D.A.B.: non-financial support from Bristol Myers Squibb, honoraria from LM Education/Exchange Services, advisory board fees from Exelixis and Aveo, and consulting/personal fees from Octane Global, Defined Health, Dedham Group, Adept Field Solutions, Slingshot Insights, Blueprint Partnerships, Charles River Associates, Trinity Group, and Insight Strategy outside of the submitted work. N.I.V.: advisory board to Sanofi/Genzyme, Oncocyte, and Lilly. M.S.H.: consultant, Janssen Pharmaceuticals and UpToDate. R.H.: research funding from Novartis. B.A.M.: consultant for Bayer, Astellas, AstraZeneca, Seattle Genetics, Exelixis, Nektar, Pfizer, Janssen, Genentech, Eisai, Dendreon, Bristol Myers Squibb, Calithera, and EMD Serono; research funding to the institution from Bristol Myers Squibb, Calithera, Exelixis, and Seattle Genetics. A.S.F.: consultant, Olympus America, Inc.; honoraria, Roche, Janssen; advisory board, Vessi Medical. C.J.W.: equity holder of BioNTech, Inc; research funding from Pharmacyclics. D.F.M.: honoraria from BMS, Pfizer, Merck, Alkermes, Inc., EMD Serono, Eli Lilly and Company, Iovance, Eisai, Inc., Werewolf Therapeutics, and Calithera Biosciences; research support from BMS, Merck, Genentech, Pfizer, Exelixis, X4 Pharma, and Alkermes, Inc. D.Y.C.H.: consultancies and research funding from Pfizer, Novartis, BMS, Merck, Eisai, Ipsen, and Exelixis. S.S.: grants from Exelixis, grants from Bristol-Myers Squibb, personal fees from Merck, grants and personal fees from AstraZeneca, personal fees from CRISPR Therapeutics, personal fees from NCI, and personal fees from AACR; a patent for Biogenex with royalties paid. E.M.V.A.: advisory/consulting, Tango Therapeutics, Genome Medical, Invitae, Enara Bio, Janssen, Manifold Bio, Monte Rosa; research support, Novartis, BMS; equity, Tango Therapeutics, Genome Medical, Syapse, Enara Bio, Manifold Bio, Microsoft, Monte Rosa; patents, institutional patents filed on chromatin mutations and immunotherapy response and methods for clinical interpretation. T.K.C.: research (institutional and personal), Alexion, Analysis Group, AstraZeneca, Aveo, Bayer, Bristol Myers-Squibb/ER Squibb and Sons, LLC, Calithera, Cerulean, Corvus, Eisai, Exelixis, F. Hoffmann-La Roche, Foundation Medicine, Inc., Genentech, GlaxoSmithKline, Ipsen, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Roche, Roche Products Limited, Sanofi/Aventis, Takeda, and Tracon; consulting/honoraria or advisory role, Alexion, Analysis Group, AstraZeneca, Aveo, Bayer, Bristol Myers-Squibb/ER Squibb and Sons, LLC, Cerulean, Corvus, Eisai, EMD Serono, Exelixis, Foundation Medicine, Inc., Genentech, GlaxoSmithKline, Heron Therapeutics, Infinity Pharma, Ipsen, Jansen Oncology, IQVIA, Lilly, Merck, NCCN, Novartis, Nuscan, Peloton, Pfizer, Pionyr, Prometheus Labs, Roche, Sanofi/Aventis, Surface Oncology, Tempest, and Up-to-Date; CME-related events (e.g., OncLIve, PVI, MJH Life Sciences); NCI GU Steering Committee; stock ownership, Pionyr and Tempest; patents filed, royalties, or other intellectual properties, related to biomarkers of immune checkpoint blockers and ctDNA; travel, accommodations, expenses, medical writing in relation to consulting, advisory roles, or honoraria; no speaker’s bureau. S.R.V.: consulting, MPM Capital and Vida Ventures; spouse is an employee of and holds equity in Kojin Therapeutics. All other authors report no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Immune checkpoint blockade (ICB) results in durable disease control in a subset of patients with advanced renal cell carcinoma (RCC), but mechanisms driving resistance are poorly understood. We characterize the single-cell transcriptomes of cancer and immune cells from metastatic RCC patients before or after ICB exposure. In responders, subsets of cytotoxic T cells express higher levels of co-inhibitory receptors and effector molecules. Macrophages from treated biopsies shift toward pro-inflammatory states in response to an interferon-rich microenvironment but also upregulate immunosuppressive markers. In cancer cells, we identify bifurcation into two subpopulations differing in angiogenic signaling and upregulation of immunosuppressive programs after ICB. Expression signatures for cancer cell subpopulations and immune evasion are associated with PBRM1 mutation and survival in primary and ICB-treated advanced RCC. Our findings demonstrate that ICB remodels the RCC microenvironment and modifies the interplay between cancer and immune cell populations critical for understanding response and resistance to ICB., Competing Interests: Declaration of interests M.X.H. has consulted for Amplify Medicines and Ikena Oncology. Z.B. reports research support from Bristol-Meyers Squibb (BMS) and Genentech/imCORE unrelated to this study. D.A.B. reports non-financial support from BMS, honoraria from LM Education/Exchange Services, and personal fees from Octane Global, Defined Health, Dedham Group, Adept Field Solutions, Slingshot Insights, Blueprint Partnerships, Charles River Associates, Trinity Group, and Insight Strategy, outside of this work. B.A.M. has consulted for Bayer, Astellas, AstraZeneca, Seattle Genetics, Exelixis, Nektar, Pfizer, Janssen, Genentech, Eisai, and EMD Serono. He received research support to Dana-Farber Cancer Institute from BMS, Calithera, Exelixis, and Seattle Genetics. J.L.G. is a consultant for and/or receives sponsored research support from GlaxoSmithKline (GSK), Array BioPharma, Codagenix, Verseau, Kymera, and Eli Lilly. A. Rotem is an employee of AstraZeneca and an equity holder in NucleAI and Celsius Therapeutics. A. Regev is a founder and equity holder of Celsius Therapeutics, holds equity in Immunitas Therapeutics, and, until August 31, 2020, was an SAB member of Syros Pharmaceuticals, Neogene Therapeutics, Asimov, and Thermo Fisher Scientific; since August 1, 2020, she has been an employee of Genentech. E.M.V.A. reports advisory/consulting with Tango Therapeutics, Genome Medical, Invitae, Monte Rosa, Enara Bio, Manifold Bio, and Janssen; research support from Novartis and BMS; equity in Tango Therapeutics, Genome Medical, Syapse, Manifold Bio, Monte Rosa, and Enara Bio. T.K.C. reports research support/honoraria from, consulting/advisory relationships with, and/or equity stakes in Alexion, Analysis Group, AstraZeneca, Aveo, Bayer, BMS, Calithera, Cerulean, Corvus, Eisai, EMD Serono, Exelixis, F. Hoffmann-La Roche, Foundation Management, Genentech, GSK, Heron Therapeutics, Infinity Pharma, Janssen Oncology, IQVIA, Ipsen, Lilly, Merck, NCCN, Novartis, Peloton, Pfizer, Pionyr, Prometheus Labs, Roche, Roche Products Limited, Sanofi/Aventis, Takeda, Tracon, Surface Oncology, Tempest, Up-to-Date, OncLIve, PVI, and MJH Life Sciences; patents filed, royalties, or other intellectual properties related to biomarkers of immune checkpoint blockers; and support from the Dana-Farber/Harvard Cancer Center Kidney SPORE and Program, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at DFCI., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The tumor immune microenvironment plays a critical role in cancer progression and response to immunotherapy in clear cell renal cell carcinoma (ccRCC), yet the composition and phenotypic states of immune cells in this tumor are incompletely characterized. We performed single-cell RNA and T cell receptor sequencing on 164,722 individual cells from tumor and adjacent non-tumor tissue in patients with ccRCC across disease stages: early, locally advanced, and advanced/metastatic. Terminally exhausted CD8 + T cells were enriched in metastatic disease and were restricted in T cell receptor diversity. Within the myeloid compartment, pro-inflammatory macrophages were decreased, and suppressive M2-like macrophages were increased in advanced disease. Terminally exhausted CD8 + T cells and M2-like macrophages co-occurred in advanced disease and expressed ligands and receptors that support T cell dysfunction and M2-like polarization. This immune dysfunction circuit is associated with a worse prognosis in external cohorts and identifies potentially targetable immune inhibitory pathways in ccRCC., Competing Interests: Declaration of interests D.A.B. reports nonfinancial support from Bristol Myers Squibb, honoraria from LM Education/Exchange Services, and personal fees from Octane Global, Defined Health, Dedham Group, Adept Field Solutions, Slingshot Insights, Blueprint Partnerships, Charles River Associates, Trinity Group, and Insight Strategy, outside of the submitted work. S.H.G. has patents licensed to Novalgen Inc, outside of the submitted work. Z.B. reports nonfinancial support from Bristol Myers Squibb and Genentech/imCore. D.B.K. has acted as an advisor to and has received consulting fees from Neon Therapeutics and owns equity in Agenus, Armata pharmaceuticals, Breakbio, Biomarin Pharmaceutical, Bristol Myers Squibb, Celldex Therapeutics, Chinook Therapeutics, Editas Medicine, Exelixis, Gilead Sciences, IMV, Lexicon Pharmaceuticals, Moderna, and Regeneron Pharmaceuticals. K.M.M. reports research support from Bristol Myers Squibb. B.A.M. reports consulting fees from Bayer, Astellas, Astra Zeneca, Seattle Genetics, Dendreon, Calithera, Exelixis, Nektar, Pfizer, Janssen, Genentech, Eisai, and EMD Serono, and research support to DFCI from Bristol Myers Squibb, Calithera, Exelixis, Seattle Genetics. D.F.M. has received consulting fees from Bristol Myers Squibb, Pfizer, Merck, Alkermes, EMD Serono, Eli Lilly, Iovance, and Eisai, and research support from Bristol Myers Squibb, Merck, Genentech, Pfizer, Exelixis, X4 Pharma, and Alkermes. S.A.S. reports nonfinancial support from Bristol Myers Squibb outside the submitted work. S.A.S. previously advised and has received consulting fees from Neon Therapeutics. S.A.S. reports nonfinancial support from Bristol Myers Squibb, and equity in Agenus Inc., Agios Pharmaceuticals, Breakbio Corp., Bristol Myers Squibb, and Lumos Pharma, outside the submitted work. S.S. reported personal fees from Merck, AstraZeneca, Bristol Myers Squibb, CRISPR Therapeutics AG, AACR, and NCI, grants from Bristol Myers Squibb, AstraZeneca, Novartis, and Exelixis, and royalties from Biogenex. A.H.S. has patents/pending royalties on the PD-1 pathway from Roche and Novartis. A.H.S. is on advisory boards for Bicara, Janssen Immunology, Surface Oncology, Elstar, SQZ Biotechnologies, Elpiscience, Selecta, and Monopteros, and consults for Novartis. A.H.S. has received research funding from AbbVie, Novartis, Roche, UCB, Ipsen, Quark, and Merck. D.F.M. reports personal fees from Bristol Myers Squibb, Pfizer, Merck, Novartis, Exelixis, Array BioPharm, Genentech, Alkermes, Jounce Therapeutics, X4 Pharma, Peloton, EMD Serono, and Eli Lilly, and research support from Bristol Myers Squibb, Prometheus Laboratories, Merck, Genentech, Pfizer, Exelixis, Novartis, X4 Pharma, Alkermes, and Peloton. T.K.C. reports grants and personal fees from Astra Zeneca; personal fees from Bayer; grants and personal fees from Bristol Myers Squibb; personal fees from Cerulean; grants and personal fees from Eisai; personal fees from Foundation Medicine Inc.; grants and personal fees from Exelixis; grants and personal fees from Genentech; personal fees from Roche; grants and personal fees from GlaxoSmithKline; grants and personal fees from Merck, from Novartis, Peloton, and Pfizer; personal fees from Prometheus Labs; grants and personal fees from Corvus; personal fees from Ipsen; grants from Tracon; and grants from Astellas outside the submitted work. The other authors declare no potential conflicts of interest. C.J.W. is an equity holder of BioNTech., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings build on prior work and shed light on the molecular drivers of aggressivity and responsiveness to ICI of S/R RCC.

Background Percutaneous ablation for cT1 renal cell carcinoma (RCC) remains underused, partially because of heterogeneous and limited long-term outcomes data assessing recent cryoablation methods. Purpose To report intermediate- to long-term outcomes of image-guided percutaneous cryoablation of cT1 RCC and to compare outcomes for CT versus MRI guidance. Materials and Methods This HIPAA-compliant retrospective single-institution study assessed patients who underwent percutaneous cryoablation for solitary pathology-proven cT1 RCC between August 2000 and July 2017. Tumors (cT1a, n = 282; cT1b, n = 25; size range, 0.6-6.5 cm; median size, 2.5 cm) underwent cryoablation with CT ( n = 155) or MRI ( n = 152) guidance. Primary end points of overall survival (OS), disease-specific survival (DSS), imaging-confirmed disease-free survival (DFS), and local progression-free survival (LPFS) were calculated by using Kaplan-Meier analysis. Secondary end points of technique efficacy and adverse event rate were also calculated. Primary and secondary end points for CT and MRI guidance were compared by using univariable regression analysis. Results A total of 307 patients (mean age, 68 years ± 11 [standard deviation]; 192 men) were evaluated. Median clinical follow-up lasted 95 months (range, 8-219 months), and median imaging follow-up lasted 41 months (range, 0-189 months). Survival metrics at 3, 5, 10, and 15 years, respectively, included OS of 91% (95% confidence interval [CI]: 88%, 94%), 86% (95% CI: 82%, 90%), 78% (95% CI: 73%, 84%), and 76% (95% CI: 69%, 83%); DSS of 99.6% (95% CI: 99%, 100%), 99% (95% CI: 98%, 100%), 99% (95% CI: 98%, 100%), and 99% (95% CI: 98%, 100%); DFS of 94% (95% CI: 92%, 97%), 91% (95% CI: 88%, 96%), 88% (95% CI: 83%, 93%), and 88% (95% CI: 83%, 93%); and LPFS of 97% (95% CI: 94%, 99%), 95% (95% CI: 93%, 98%), 95% (95% CI: 93%, 98%), and 95% (95% CI: 93%, 98%). Survival did not significantly differ between CT and MRI guidance, with univariable Cox regression analysis hazard ratios of 0.97 (95% CI: 0.57, 1.67; P = .92) for OS, 0.63 (95% CI: 0.26, 1.52; P = .30) for DFS, and 0.83 (95% CI: 0.26, 2.74; P = .77) for LPFS. Primary and secondary technique efficacy were 96% and 99%, respectively. Overall adverse event rate was 14% (43 of 307), including 11 grade 3 events and three grade 4 events according to the Common Terminology Criteria for Adverse Events. Conclusion Percutaneous CT- and MRI-guided cryoablation of cT1 renal cell carcinoma had similar excellent intermediate- and long-term outcomes. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Georgiades in this issue.

Improving early cancer detection has the potential to substantially reduce cancer-related mortality. Cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) is a highly sensitive assay capable of detecting early-stage tumors. We report accurate classification of patients across all stages of renal cell carcinoma (RCC) in plasma (area under the receiver operating characteristic (AUROC) curve of 0.99) and demonstrate the validity of this assay to identify patients with RCC using urine cell-free DNA (cfDNA; AUROC of 0.86).

Objectives: Early surgical resection remains the recommended treatment option for most small renal mass (≤4 cm). We examined the long-term overall survival (OS) of patients managed with delayed and immediate nephrectomy of cT1a renal cancer., Patient and Methods: We utilized the National Cancer Database (2005-2010) to identify 14,677 patients (immediate nephrectomy: 14,050 patients vs. late nephrectomy: 627 patients) aged <70 years with Charlson Comorbidity Index 0 and cT1aN0M0 renal cell carcinoma. Immediate nephrectomy and late nephrectomy were defined as nephrectomy performed <30 days and >180 days from diagnosis, respectively. Inverse probability of treatment weighting-adjusted Kaplan-Meier curves and Cox proportional hazards regression analyses were used to compare OS of patients in the 2 treatment arms. Influence of patient age and Charlson Comorbidity Index on treatment effect was tested by interactions. Sensitivity analysis was performed to explore the outcome of delaying nephrectomy for >12 months., Results: Median patient age was 55 years with a median follow-up of 82.5 months. Inverse probability of treatment weighting-adjusted Kaplan-Meier curves suggest no significant difference between treatment arms (immediate nephrectomy [<30 days] vs. delayed nephrectomy [>180 days]) (Hazard ratio 0.96; 95% confidence interval 0.73-1.26; P = 0.77). This outcome was consistent between all patients regardless of age (P = 0.48). Sensitivity analysis reports no difference in OS even if nephrectomy was delayed by >12 months (P = 0.60)., Conclusions: We report that delayed and immediate nephrectomy for cT1a renal cell carcinoma confers comparable long-term OS. These findings suggest that a period of observation of between 6 and 12 months is safe to allow identification of renal masses, which will benefit from surgical resection., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Upfront cytoreductive nephrectomy (CRN) in renal cell carcinoma (RCC) has come into question in recent prospective clinical trials., Objective: We investigated the effect of systemic therapies on primary tumor response in patients with metastatic RCC., Design, Setting, and Participants: A pooled analysis of 12 phase II/III clinical trials of metastatic RCC patients treated with systemic therapy between 2003 and 2013 was performed. Patients with one target lesion in the kidney and no prior nephrectomy were identified as having their primary tumor in place., Outcome Measurements and Statistical Analysis: The objective response rate (ORR) of the primary tumor was defined as per the Response Evaluation Criteria in Solid Tumors (RECIST). ORR was assessed in the overall population and patient subsets based on prior treatment and International Metastatic RCC Database Consortium (IMDC) risk group. Cox's models adjusting for baseline characteristics, treatment, line of therapy, and site of metastases were used for survival analyses., Results and Limitations: In total, 4736 patients were identified, of whom 565 had their primary tumor in place: 461 (82%) were treatment naïve, 283 (50%) received first-line vascular endothelial growth factor (VEGF)-targeted therapy, and 222 (39%) were IMDC poor risk. The ORRs of the primary tumor were 19% (95% confidence interval 16-23) in patients treated with first-line therapy (any type), 28% (22-33) in those treated with first-line VEGF-targeted therapy, and 23% (19-28) in those treated with VEGF-targeted therapy (any line). The ORRs were 9% (5-13) and 20% (15-27) in IMDC poor- and intermediate-risk patients, respectively., Conclusions: Systemic therapy reduces primary tumor size in patients with metastatic RCC. Responses in primary tumors treated with VEGF-targeted therapy were observed in upward of 28% of patients. Selection of patients for immediate CRN requires careful consideration of patient and disease characteristics., Patient Summary: Antiangiogenic therapy meaningfully decreases the size of primary kidney tumor. Hence, for patients with metastatic disease who are not undergoing upfront cytoreductive nephrectomy, systemic therapy can palliate both primary tumor and metastases., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Cytoreductive nephrectomy (CRN) has long been considered a standard of care in the management of mRCC. This is largely based on randomized trials in the era of interferon (IFN) that demonstrate an improvement in overall survival (OS). With the advent of targeted therapies, the role of CRN has been questioned and multiple retrospective analyses have shown a potential benefit, particularly in intermediate-risk disease. Two long-awaited prospective trials have been published in the past year that explore the role of CRN. The CARMENA trial randomly assigned patients to therapy with sunitinib with or without CRN, showing noninferiority of sunitinib alone versus sunitinib plus CRN with a median OS of 18.4 months versus 13.9 months, respectively (hazard ratio [HR] for mortality, 0.89; 95% CI, 0.71-1.1). The SURTIME trial randomly assigned patients to immediate CRN followed by sunitinib versus a deferred CRN after three cycles of sunitinib. Analysis is limited by early termination as a result of low accrual. Although there was no difference in progression-free survival (PFS), median OS was significantly improved among patients in the deferred CRN arm (HR, 0.57; 95% CI, 0.34-0.95; p = .032). Early systemic therapy is paramount, but there are patients who may derive benefit by incorporating the removal of the primary tumor in their multimodal therapy, perhaps in a deferred setting. As systemic treatment paradigms shift and immunotherapy again moves to the frontline setting with the potential for novel therapeutic approaches, the role of CRN will continue to evolve with the potential to offer surgical interventions with minimal, if any, delay in systemic treatment.

Purpose: Data revealed the benefit of high-volume care in many complex disease processes. Among patients undergoing nephrectomy, those receiving cytoreductive nephrectomy (CN) for metastatic renal cell cancer (mRCC) constitute a unique subset. They often have a greater medical and surgical complexity. Against this backdrop, we sought to investigate the effect of hospital volume on overall survival among patients undergoing CN for mRCC., Material and Methods: We identified 11,089 patients who received CN for mRCC in the National Cancer Database from 1998 to 2012. We ranked hospitals based on annual CN volume. Patients who received surgery in hospitals in the top vs. bottom deciles were compared. Inverse Probability of Treatment Weighting (IPTW)-adjusted Kaplan-Meier and Cox regression analyses were used to compare the primary endpoint of overall survival between balanced cohorts of patients. Secondary endpoints were 30-day mortality, 30-day readmissions, and receipt of subsequent systemic therapy., Results: Median follow-up was 60.39 months (interquartile range [IQR] 35.09-95.95). Median overall survival was 17.61 months (IQR 7.16-44.58). Following propensity score weighting, surgery at a high-volume hospital was associated with a decreased risk of mortality (IPTW-adjusted Cox proportional Hazard Ratio = 0.91; 95% confidence interval: 0.86-0.96). On our IPTW-adjusted Kaplan-Meier analysis, the median survival was 19.94 months (IQR 7.98-50.27) at high-volume hospitals vs. 15.97 months (IQR 6.6-41.56) at low-volume hospitals. With regard to secondary endpoints, the data did not reveal a significant advantage for treatment at a high-volume hospital., Conclusion: We found a significant association between receipt of CN at high-volume hospitals and prolonged overall survival, demonstrated by a nearly 4 month survival benefit., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: Metastasectomy (MSX) is considered a treatment option in patients with metastatic renal cell carcinoma (mRCC) at diagnosis, but its role in the targeted therapy era is unclear. We sought to describe the utilization trends of MSX and survival outcomes in a large US cohort., Materials and Methods: Using the National Cancer Database, we identified patients undergoing MSX for mRCC at diagnosis between 2006 and 2013. Linear regression methods estimated utilization trends, and hierarchical models identified independent predictors of MSX after adjusting for hospital clustering. Kaplan-Meier survival estimates and Cox proportional hazard models were used to evaluate overall survival according to treatment after propensity-score matching., Results: Of 6994 mRCC patients, 1976 underwent MSX (28.3%). Those treated at academic facilities were more likely to undergo a MSX (OR: 1.57, 95% CI 1.20-2.06, p = 0.001). In contrast, older patients (OR: 0.99, 95% CI: 0.98-1.00), black race (OR: 0.65, 95% CI: 0.51-0.82), higher pT stage (OR: 0.76, 95% CI: 0.65-0.89), and who received targeted therapy (OR: 0.72, 95% CI: 0.63-0.82, all p ≤ 0.008) were less likely to undergo MSX. Overall, MSX patients had an improved survival compared to non-MSX patients (HR: 0.83, 95% CI: 0.77-0.90, p < 0.001), as well as among patients treated with targeted therapy (HR: 0.77, 95% CI: 0.77-0.96, p = 0.008)., Conclusions: Our findings indicate that MSX-treated patients may benefit from an improved overall survival compared to non-MSX treated patients. Good patient selection and a proper risk stratification strategy are still very important considerations., (Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Metastasectomy has long been considered a valid treatment option for patients with oligometastatic renal cell carcinoma (oligo-mRCC). However, the literature on complications in this setting is scarce. Our objective was to describe in-hospital complications after metastasectomy in a contemporary cohort of patients with mRCC. Using the National Inpatient Sample database (2000-2011), 45 279 mRCC patients were identified. Of those, 1102 underwent metastasectomies. The metastatic sites were the lungs, bone, liver, lymph nodes, adrenal glands, and brain in, respectively, 52%, 29%, 19%, 14%, 11%, and 3.4% of patients. The overall complication rate was 45.7%. Major complications (Clavien III-V) constituted 27.5%. Resections of hepatic lesions were significantly associated with higher odds of overall complications compared with any other site (odds ratio 2.59, 95% confidence interval 1.84-3.62, p<0.001). While metastasectomy remains a potential treatment option in RCC with oligometastatic disease, the associated complication rates are non-negligible; therefore, careful patient selection is warranted., Patient Summary: We studied outcomes of patients with metastatic kidney cancer treated with metastasectomy. While metastasectomy is a treatment option for metastatic renal cell carcinoma, complications are not insignificant and our results may guide preoperative counseling., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

The incidence of localized renal cell carcinoma (RCC) has been steadily increasing, in large part because of the increased use of imaging. Optimizing the management of localized RCC has become one of the leading priorities and foremost challenges within the urologic-oncologic community. Adequate risk stratification of patients following the diagnosis of localized RCC has become meaningful in deciding whether to treat, how to treat, and how intensively to treat. This article characterizes the existing risk assessment models that can be useful as treatment decision aids for patients with localized RCC., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: The role of cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (mRCC) has become unclear since the introduction of targeted therapies (TT). We sought to evaluate contemporary utilization rates of CN and to examine the survival benefit of CN compared with non-CN patients treated with TT., Methods: We used the National Cancer Data Base to identify patients with clinical mRCC treated with TT between 2006 and 2013. The intervention of interest was CN. Multivariable logistic regression predicting receipt of CN was performed. Overall survival (OS) was examined using Cox regression models and incremental survival analyses were performed. Sensitivity analyses using propensity scores were conducted., Results: Of 15,390 patients treated with TT, 5,374 (35%) underwent CN between 2006 and 2013. Patients who were younger, privately insured, treated at an academic center, and had lower tumor stage and cN0 disease were more likely to undergo CN. The median OS of CN versus non-CN patients was 17.1 (95% CI, 16.3 to 18.0 months) versus 7.7 months (95% CI, 7.4 to 7.9 months; P < .001). In sensitivity analyses using propensity scores adjustment in addition to other available covariates, CN patients had a lower risk of any death (hazard ratio, 0.45; 95% CI, 0.40 to 0.50; P < .001). The survival benefit of CN was +0.7 and +3.6 months in patients who survived ≤ 6 and ≤ 24 months, respectively, versus no CN., Conclusion: CN is performed in three of 10 patients with mRCC who are receiving TT. Several patient and sociodemographic characteristics were associated with receipt of CN. When feasible, CN may offer an OS benefit when combined with TT., Competing Interests: Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article., (© 2016 by American Society of Clinical Oncology.)

Purpose: We evaluate the contemporary incidence and consequences of postoperative rhabdomyolysis after extirpative renal surgery., Materials and Methods: We conducted a population based, retrospective cohort study of patients who underwent extirpative renal surgery with a diagnosis of a renal mass or renal cell carcinoma in the United States between 2004 and 2013. Regression analysis was performed to evaluate 90-day mortality (Clavien grade V), nonfatal major complications (Clavien grade III-IV), hospital readmission rates, direct costs and length of stay., Results: The final weighted cohort included 310,880 open, 174,283 laparoscopic and 69,880 robotic extirpative renal surgery cases during the 10-year study period, with 745 (0.001%) experiencing postoperative rhabdomyolysis. The presence of postoperative rhabdomyolysis led to a significantly higher incidence of 90-day nonfatal major complications (34.7% vs 7.3%, p <0.05) and higher 90-day mortality (4.4% vs 1.02%, p <0.05). Length of stay was twice as long for patients with postoperative rhabdomyolysis (incidence risk ratio 1.83, 95% CI 1.56-2.15, p <0.001). The robotic approach was associated with a higher likelihood of postoperative rhabdomyolysis (vs laparoscopic approach, OR 2.43, p <0.05). Adjusted 90-day median direct hospital costs were USD 7,515 higher for patients with postoperative rhabdomyolysis (p <0.001). Our model revealed that the combination of obesity and prolonged surgery (more than 5 hours) was associated with a higher likelihood of postoperative rhabdomyolysis developing., Conclusions: Our study confirms that postoperative rhabdomyolysis is an uncommon complication among patients undergoing extirpative renal surgery, but has a potentially detrimental impact on surgical morbidity, mortality and costs. Male gender, comorbidities, obesity, prolonged surgery (more than 5 hours) and a robotic approach appear to place patients at higher risk for postoperative rhabdomyolysis., (Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Targeted therapies (TTs) have revolutionized metastatic renal cell carcinoma (mRCC) treatment in the past decade, largely replacing immunotherapy including high-dose interleukin-2 (HD IL-2) therapy. We evaluated trends in HD IL-2 use for mRCC in the TT era., Methods: Our cohort comprised a weighted estimate of all patients undergoing HD IL-2 treatment for mRCC from 2004 to 2012 using the Premier Hospital Database. We assessed temporal trends in HD IL-2 use including patient, disease, and hospital characteristics stratified by era (pre-TT uptake: 2004-2006, uptake: 2007-2009, and post-TT uptake: 2010-2012) and fitted multivariable regression models to identify predictors of treatment toxicity and tolerability., Results: An estimated 2,351 patients received HD IL-2 therapy for mRCC in the United States from 2004 to 2012. The use decreased from 2004 to 2008. HD IL-2 therapy became increasingly centralized in teaching hospitals (24% of treatments in 2004 and 89.5% in 2012). Most patients who received HD IL-2 therapy were men, white, younger than 60 years, had lung metastases, and were otherwise healthy. Vasopressors, intensive care unit admission, and hemodialysis were necessary in 53.4%, 33.0%, and 7.1%, respectively. Factors associated with toxicities in multivariable analyses included being unmarried, male sex, and multiple metastatic sites. African Americans and patients with single-site metastases were less likely to receive multiple treatment cycles., Conclusions: HD IL-2 therapy is used infrequently for mRCC in the United States, and its application has diminished with the uptake of TT. Patients are being increasingly treated in teaching hospitals, suggesting a centralization of care and possible barriers to access. A recent slight increase in HD IL-2 therapy use likely reflects recognition of the inability of TT to effect a complete response., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: Patients with renal cell carcinoma who were treated with radical nephrectomy (RN) or partial nephrectomy (PN) are at risk of postoperative acute kidney injury (AKI), and in consequence, short- and long-term adverse outcomes. We sought to identify independent predictors of 30-day AKI in patients undergoing RN or PN., Materials and Methods: Between 2005 and 2011, patients who underwent RN or PN for renal cell carcinoma within the National Surgical Quality Improvement Program data set were identified. Patients with preexisting severe renal failure, defined as a preoperative estimated glomerular filtration rate<30 ml/min/1.73 m(2), were excluded from the analyses. AKI was defined as an elevation of serum creatinine>2mg/dl above baseline or the need for dialysis within 30 days of surgery. Univariable and multivariable logistic regression analyses were used to examine the association between preoperative factors and the risk of postoperative AKI., Results: Overall, 1,944 (58.6%) and 1,376 (41.4%) patients underwent RN and PN, respectively. Overall, 1.8% of the patients included in the study experienced AKI within an average of 5.4 days after RN or PN. Independent predictors for AKI included obesity (odds ratio [OR] = 2.24, P = 0.04), history of neurovascular disease (OR = 5.29, P<0.001), and a preoperative chronic kidney disease stage II (OR = 10.00, P = 0.03) or stage III (OR = 26.49, P = 0.02). Furthermore, RN (OR = 2.87, P = 0.02) or the open approach (OR = 2.18, P = 0.04) was significantly associated with postoperative AKI. AKI was significantly associated with adverse postoperative outcomes, such as prolonged length of stay, occurrence of any complication, and mortality (all P <0.001)., Conclusions: The assessment of preoperative kidney function and comorbidity status is essential to identify patients at risk of postoperative AKI. In addition to preoperative chronic kidney disease stages II and III, neurovascular disease, obesity, and surgical approach (RN or open) represent predictors of 30-day AKI. Careful patient selection as well as preoperative planning may help reduce this unfavorable postoperative outcome., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: We examined temporal trends in skeletal related events and associated charges in patients with renal cell carcinoma metastatic to bone. We also identified patient and hospital characteristics associated with skeletal related events and related mortality., Materials and Methods: Using the Nationwide Inpatient Sample we abstracted data on patients with renal cell carcinoma who were diagnosed with concomitant bone metastasis between 1998 and 2010. Patients who experienced a skeletal related event were identified and hospital charges were calculated. Multivariate regression models fitted with generalized estimating equations were used to examine predictors of skeletal related events and related in-hospital mortality., Results: Between 1998 and 2010 a weighted estimate of 144,889 renal cell carcinoma hospital visits of patients with bone metastasis was identified in the Nationwide Inpatient Sample, of which 20.8% involved a skeletal related event. In these cases from 1998 to 2010 the inflation adjusted mean yearly costs associated with hospital admission increased by 207% in 2013 United States dollars (estimated annual percent change 8.94%, p<0.001). Conversely, the rates of skeletal related events and skeletal related event associated mortality decreased significantly (estimated annual percent change -1.11% and -2.9%, respectively, each p<0.001)., Conclusions: The prevalence and in-hospital mortality of skeletal related event associated hospitalization for metastatic renal cell carcinoma is decreasing but such charges to health care in the United States are increasing at an alarming rate. These findings highlight the need for cost-effective treatment strategies to prevent or treat these morbid complications., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: A recent increase in the detection of contrast enhancing renal masses 4 cm or smaller suspicious for malignancy has led to the widespread use of nephron sparing options. Limited data exist to help clinicians decide which of these competing nephron sparing therapies is most appropriate. We performed a cost-effectiveness analysis to evaluate the relative clinical and economic merits of commonly available nephron sparing strategies for small renal masses., Materials and Methods: We developed a decision analytic Markov model estimating the costs and health outcomes of treating a healthy 65-year-old patient with an asymptomatic unilateral small renal mass using competing nephron sparing options of immediate intervention (ie open and laparoscopic partial nephrectomy as well as laparoscopic and percutaneous ablation), active surveillance with possible delayed intervention and nonsurgical management with observation. Benefits were measured in quality adjusted life-years. We used a societal perspective, lifetime horizon and willingness to pay threshold of $50,000 per quality adjusted life-year gained. Model results were assessed with sensitivity analyses., Results: In the base case scenario the least costly option was observation and the optimal option was immediate laparoscopic partial nephrectomy, which had an incremental cost-effectiveness ratio of $36,645 per quality adjusted life-year gained compared to surveillance with possible delayed percutaneous ablation. Results were sensitive to age at diagnosis, health status and tumor size., Conclusions: Immediate laparoscopic partial nephrectomy is the preferred nephron sparing option for healthy patients younger than 74 years old with a small renal mass. Surveillance with possible delayed percutaneous ablation is a cost-effective alternative for patients with advanced age or significant comorbidities. Observation maximizes quality adjusted life-years in patients who are poor surgical candidates or with limited life expectancy (less than 3 years)., (Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)