A Novel PD-L1 Antibody Promotes Antitumor Function of Peripheral Cytotoxic Lymphocytes after Radical Nephrectomy in Patients with Renal Cell Carcinoma.

The intrinsic and acquired resistance to PD-1/PD-L1 immune checkpoint blockade is an important challenge for patients and clinicians because no reliable tool has been developed to predict individualized response to immunotherapy. In this study, we demonstrate the translational relevance of an ex vivo functional assay that measures the tumor cell killing ability of patient-derived CD8 T and NK cells (referred to as "cytotoxic lymphocytes," or CLs) isolated from the peripheral blood of patients with renal cell carcinoma. Patient-derived PBMCs were isolated before and after nephrectomy from patients with renal cell carcinoma. We compared the efficacy of U.S. Food and Drug Administration (FDA)-approved PD-1/PD-L1 inhibitors (pembrolizumab, nivolumab, atezolizumab) and a newly developed PD-L1 inhibitor (H1A Ab) in eliciting cytotoxic function. CL activity was improved at 3 mo after radical nephrectomy compared with baseline, and it was associated with higher circulating levels of tumor-reactive effector CD8 T cells (CD11ahighCX3CR1+GZMB+). Treatment of PBMCs with FDA-approved PD-1/PD-L1 inhibitors enhanced tumor cell killing activity of CLs, but a differential response was observed at the individual-patient level. H1A demonstrated superior efficacy in promoting CL activity compared with FDA-approved PD-1/PD-L1 inhibitors. PBMC immunophenotyping by mass cytometry revealed enrichment of effector CD8 T and NK cells in H1A-treated PBMCs and immunosuppressive regulatory T cells in atezolizumab-treated samples. Our study lays the ground for future investigation of the therapeutic value of H1A as a next-generation immune checkpoint inhibitor and the potential of measuring CTL activity in PBMCs as a tool to predict individual response to immune checkpoint inhibitors in patients with advanced renal cell carcinoma.

Perioperative nivolumab versus observation in patients with renal cell carcinoma undergoing nephrectomy (PROSPER ECOG-ACRIN EA8143): an open-label, randomised, phase 3 study.

BACKGROUND: The standard of care for patients with intermediate-to-high risk renal cell carcinoma is partial or radical nephrectomy followed by surveillance. We aimed to investigate use of nivolumab before nephrectomy followed by adjuvant nivolumab in patients with high-risk renal cell carcinoma to determine recurrence-free survival compared with surgery only. METHODS: In this open-label, randomised, phase 3 trial (PROSPER EA8143), patients were recruited from 183 community and academic sites across the USA and Canada. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, with previously untreated clinical stage T2 or greater or Tany N+ renal cell carcinoma of clear cell or non-clear cell histology planned for partial or radical nephrectomy. Selected patients with oligometastatic disease, who were disease free at other disease sites within 12 weeks of surgery, were eligible for inclusion. We randomly assigned (1:1) patients using permuted blocks (block size of 4) within stratum (clinical TNM stage) to either nivolumab plus surgery, or surgery only followed by surveillance. In the nivolumab group, nivolumab 480 mg was administered before surgery, followed by nine adjuvant doses. The primary endpoint was investigator-reviewed recurrence-free survival in patients with renal cell carcinoma assessed in all randomly assigned patients regardless of histology. Safety was assessed in all randomly assigned patients who started the assigned protocol treatment. This trial is registered with ClinicalTrials.gov, NCT03055013, and is closed to accrual. FINDINGS: Between Feb 2, 2017, and June 2, 2021, 819 patients were randomly assigned to nivolumab plus surgery (404 [49%]) or surgery only (415 [51%]). 366 (91%) of 404 patients assigned to nivolumab plus surgery and 387 (93%) of 415 patients assigned to surgery only group started treatment. Median age was 61 years (IQR 53-69), 248 (30%) of 819 patients were female, 571 (70%) were male, 672 (88%) were White, and 77 (10%) were Hispanic or Latino. The Data and Safety Monitoring Committee stopped the trial at a planned interim analysis (March 25, 2022) because of futility. Median follow-up was 30·4 months (IQR 21·5-42·4) in the nivolumab group and 30·1 months (21·9-41·8) in the surgery only group. 381 (94%) of 404 patients in the nivolumab plus surgery group and 399 (96%) of 415 in the surgery only group had renal cell carcinoma and were included in the recurrence-free survival analysis. As of data cutoff (May 24, 2023), recurrence-free survival was not significantly different between nivolumab (125 [33%] of 381 had recurrence-free survival events) versus surgery only (133 [33%] of 399; hazard ratio 0·94 [95% CI 0·74-1·21]; one-sided p=0·32). The most common treatment-related grade 3-4 adverse events were elevated lipase (17 [5%] of 366 patients in the nivolumab plus surgery group vs none in the surgery only group), anaemia (seven [2%] vs nine [2%]), increased alanine aminotransferase (ten [3%] vs one [<1%]), abdominal pain (four [1%] vs six [2%]), and increased serum amylase (nine [2%] vs none). 177 (48%) patients in the nivolumab plus surgery group and 93 (24%) in the surgery only group had grade 3-5 adverse events due to any cause, the most common of which were anaemia (23 [6%] vs 19 [5%]), hypertension (27 [7%] vs nine [2%]), and elevated lipase (18 [5%] vs six [2%]). 48 (12%) of 404 patients in the nivolumab group and 40 (10%) of 415 in the surgery only group died, of which eight (2%) and three (1%), respectively, were determined to be treatment-related. INTERPRETATION: Perioperative nivolumab before nephrectomy followed by adjuvant nivolumab did not improve recurrence-free survival versus surgery only followed by surveillance in patients with high-risk renal cell carcinoma. FUNDING: US National Institutes of Health National Cancer Institute and Bristol Myers Squibb.

End-Stage Kidney Disease After Partial and Radical Nephrectomy Among Patients with Severe Chronic Kidney Disease.

PURPOSE: AUA guidelines prioritize nephron sparing in patients with preexisting chronic kidney disease (CKD). However, few studies analyze long-term renal function in patients with preoperative severe CKD who undergo extirpative renal surgery. Herein, we compare the hazard of progression to end-stage kidney disease (ESKD) following partial nephrectomy (PN) and radical nephrectomy (RN) among patients with preoperative severe CKD. MATERIALS AND METHODS: Patients with stage 4 CKD who underwent PN or RN from 1970 to 2018 were identified. A multivariable Fine-Gray subdistribution hazard model was employed to assess associations with progression to ESKD accounting for the competing risk of death. RESULTS: A total of 186 patients with stage 4 CKD underwent PN (n = 71; 38%) or RN (n = 115; 62%) for renal neoplasms with median follow-up of 6.9 years (interquartile range 3.8-14.1). On multivariable analyses adjusting for competing risk of death, the subdistribution hazard ratio (SHR) for older age at surgery (SHR for 5-year increase 0.81; 95% CI 0.73-0.91; P < .001) and higher preoperative estimated glomerular filtration rate (SHR for 5-unit increase 0.63; 95% CI 0.47-0.84; P = .002) was associated with lower hazard of progression to ESKD. There was no significant difference in hazard of ESKD between PN and RN (SHR 0.82; 95% CI 0.50-1.33; P = .4). CONCLUSIONS: Among patients with preoperative severe CKD, higher preoperative estimated glomerular filtration rate was associated with lower hazard of progression to ESKD after extirpative surgery for renal neoplasms. We did not observe a significant difference in overall hazard for developing ESKD between PN and RN.

Mayo Clinic Validation of the AUA Risk Groups for Localized Renal Cell Carcinoma.

PURPOSE: The AUA guidelines introduced a new risk group stratification system based primarily on tumor stage and grade to guide surveillance for patients treated surgically for localized renal cell carcinoma (RCC). We sought to evaluate the predictive ability of these risk groups using progression-free survival (PFS) and cancer-specific survival (CSS), and to compare their performance to that of our published institutional risk models. MATERIALS AND METHODS: We queried our Nephrectomy Registry to identify adults treated with radical or partial nephrectomy for unilateral, M0, clear cell RCC, or papillary RCC from 1980 to 2012. The AUA stratification does not apply to other RCC subtypes as tumor grading for other RCC, such as chromophobe, is not routinely performed. PFS and CSS were estimated using the Kaplan-Meier method. Predictive abilities were evaluated using C indexes from Cox proportional hazards regression models. RESULTS: A total of 3191 patients with clear cell RCC and 633 patients with papillary RCC were included. For patients with clear cell RCC, C indexes for the AUA risk groups and our model were 0.780 and 0.815, respectively (P < .001) for PFS, and 0.811 and 0.857, respectively (P < .001), for CSS. For patients with papillary RCC, C indexes for the AUA risk groups and our model were 0.775 and 0.751, respectively (P = .002) for PFS, and 0.830 and 0.803, respectively (P = .2) for CSS. CONCLUSIONS: The AUA stratification is a parsimonious system for categorizing RCC that provides C indexes of about 0.80 for PFS and CSS following surgery for localized clear cell and papillary RCC.

Age-Based Versus Young-Adult Thresholds for Nephrosclerosis on Kidney Biopsy and Prognostic Implications for CKD.

SIGNIFICANCE STATEMENT: Nephrosclerosis (glomerulosclerosis, interstitial fibrosis, and tubular atrophy) is the defining pathology of both kidney aging and CKD. Optimal thresholds for nephrosclerosis that identify persons with a progressive disease are unknown. This study determined a young-age threshold (18-29 years) and age-based 95th percentile thresholds for nephrosclerosis on the basis of morphometry of kidney biopsy sections from normotensive living kidney donors. These thresholds were 7.1-fold to 36-fold higher in older (70 years or older) versus younger (aged 18-29 years) normotensive donors. Age-based thresholds, but not young-age threshold, were prognostic for determining risk of progressive CKD among patients who underwent a radical nephrectomy or a for-cause native kidney biopsy, suggesting that age-based thresholds are more useful than a single young-age threshold for identifying CKD on biopsy. BACKGROUND: Nephrosclerosis, defined by globally sclerotic glomeruli (GSG) and interstitial fibrosis and tubular atrophy (IFTA), is a pathology of both kidney aging and CKD. A comparison of risk of progressive CKD using aged-based thresholds for nephrosclerosis versus a single young-adult threshold is needed. METHODS: We conducted morphometric analyses of kidney biopsy images for %GSG, %IFTA, and IFTA foci density among 3020 living kidney donors, 1363 patients with kidney tumor, and 314 patients with native kidney disease. Using normotensive donors, we defined young-age thresholds (18-29 years) and age-based (roughly by decade) 95th percentile thresholds. We compared age-adjusted risk of progressive CKD (kidney failure or 40% decline in eGFR) between nephrosclerosis that was "normal compared with young," "normal for age but abnormal compared with young," and "abnormal for age" in patients with tumor and patients with kidney disease. RESULTS: The 95th percentiles in the youngest group (18-29 years) to the oldest group (70 years or older) ranged from 1.7% to 16% for %GSG, 0.18% to 6.5% for %IFTA, and 8.2 to 59.3 per cm 2 for IFTA foci density. Risk of progressive CKD did not differ between persons with nephrosclerosis "normal compared with young" versus "normal for age but abnormal compared with young." Risk of progressive CKD was significantly higher with %GSG, %IFTA, or IFTA foci density that was abnormal versus normal for age in both cohorts. CONCLUSIONS: Given that increased risk of progressive CKD occurs only when nephrosclerosis is abnormal for age, age-based thresholds for nephrosclerosis seem to be better than a single young-age threshold for identifying clinically relevant CKD.

Cost-effectiveness of Adjuvant Pembrolizumab After Nephrectomy for High-risk Renal Cell Carcinoma: Insights for Patient Selection From a Markov Model.

PURPOSE: The KEYNOTE-564 trial demonstrated that adjuvant pembrolizumab after nephrectomy for clear cell renal cell carcinoma decreased the risk of disease progression and potentially overall mortality as well. Herein, we used a Markov model to weigh the costs, toxicities, and efficacy of pembrolizumab to further investigate its utility. MATERIALS AND METHODS: Decision-analytic Markov modeling was used to conduct a cost-utility analysis of adjuvant pembrolizumab versus observation after nephrectomy for high-risk clear cell renal cell carcinoma, using data from KEYNOTE-564 to inform model probabilities. Primary outcomes were quality-adjusted life years, Medicare costs, and incremental cost-effectiveness ratios. The willingness-to-pay threshold utilized was $100,000/quality-adjusted life year. RESULTS: At 5 years, adjuvant treatment with pembrolizumab resulted in 0.3 additional quality-adjusted life years at an additional cost of $99,484 relative to observation. Pembrolizumab was found not to be cost-effective at a 5-year time horizon (incremental cost-effectiveness ratio=$326,534). On sensitivity analysis, pembrolizumab became cost-effective if its per cycle cost was <$5,064 (base=$10,278) or its 5-year progression benefit was >18.8% (base 9%). Upon simulation, pembrolizumab was cost-effective for 29% of patients at 5 years. Specifically, we found that pembrolizumab would be cost-effective at 5 years for patients with at least a 59% 5 year risk of progression, which corresponds to a Mayo Progression-free Survival Score ≥10. CONCLUSIONS: At current prices, adjuvant pembrolizumab was found to be cost-effective only for the highest risk subset of clear cell renal cell carcinoma patients 5 years after treatment, including patients with complete metastasectomy, regional lymph node involvement, or ≥7cm pT3 tumors with sarcomatoid features. Longer-term trial data, including overall survival results, are necessary to confirm these extrapolations.

The Impact of Metastasis Histopathology on Oncologic Outcomes for Patients With Surgically Resected Metastatic Renal Cell Carcinoma.

PURPOSE: Multiple prognostic models exist to assess survival among patients with metastatic clear cell renal cell carcinoma. However, the relative contribution of histopathological features of the metastasis has not been extensively studied. Herein, we compared models using clinical, primary tumor, and metastatic features to predict cancer-specific survival for patients with surgically resected metastatic clear cell renal cell carcinoma. MATERIALS AND METHODS: We studied 266 patients who had undergone nephrectomy between 1970 and 2019, and who had a single site of metastasis completely resected. Two versions of the metastatic clear cell renal cell carcinoma score published by Leibovich et al were calculated, using grade and necrosis from the primary tumor and using grade and necrosis from the metastasis. Predictive abilities of these 2 versions and a third model that included metastatic features only were compared using c-indexes from Cox proportional hazards models. RESULTS: A total of 197 patients died from renal cell carcinoma at a median of 2.3 years (IQR 1.1-4.5); median follow-up among survivors was 13.2 years (IQR 10.0-14.5). The Leibovich score using grade and necrosis from the metastasis (c=0.679) had similar predictive ability compared to the original Leibovich score using grade and necrosis from the primary tumor (c=0.675). A third model (c=0.707) demonstrated that metastasectomy within 2 years after nephrectomy, presence of bone metastasis, high grade, and sarcomatoid differentiation in the metastasis were significantly associated with cancer-specific survival. CONCLUSIONS: Scoring algorithms calculated using histopathological features of the metastasis can be used to predict cancer-specific survival for patients with surgically resected metastatic clear cell renal cell carcinoma. These findings are of particular importance for instances when primary tumor histopathology is not readily available.

Effect of Dataset Size and Medical Image Modality on Convolutional Neural Network Model Performance for Automated Segmentation: A CT and MR Renal Tumor Imaging Study.

The aim of this study is to investigate the use of an exponential-plateau model to determine the required training dataset size that yields the maximum medical image segmentation performance. CT and MR images of patients with renal tumors acquired between 1997 and 2017 were retrospectively collected from our nephrectomy registry. Modality-based datasets of 50, 100, 150, 200, 250, and 300 images were assembled to train models with an 80-20 training-validation split evaluated against 50 randomly held out test set images. A third experiment using the KiTS21 dataset was also used to explore the effects of different model architectures. Exponential-plateau models were used to establish the relationship of dataset size to model generalizability performance. For segmenting non-neoplastic kidney regions on CT and MR imaging, our model yielded test Dice score plateaus of [Formula: see text] and [Formula: see text] with the number of training-validation images needed to reach the plateaus of 54 and 122, respectively. For segmenting CT and MR tumor regions, we modeled a test Dice score plateau of [Formula: see text] and [Formula: see text], with 125 and 389 training-validation images needed to reach the plateaus. For the KiTS21 dataset, the best Dice score plateaus for nn-UNet 2D and 3D architectures were [Formula: see text] and [Formula: see text] with number to reach performance plateau of 177 and 440. Our research validates that differing imaging modalities, target structures, and model architectures all affect the amount of training images required to reach a performance plateau. The modeling approach we developed will help future researchers determine for their experiments when additional training-validation images will likely not further improve model performance.

Unplanned Conversion From Partial to Radical Nephrectomy: An Analysis of Incidence, Etiology, and Risk Factors.

PURPOSE: Conversions from partial to radical nephrectomy are uncommon and reports on this topic are rare. In this study we present a detailed analysis of conversions from partial to radical nephrectomy in a single-institutional contemporary experience and provide an analysis of preoperative risk factors. MATERIALS AND METHODS: Patients who underwent converted (cases) and completed (controls) partial nephrectomy from 2000 to 2015 were matched 1:1 for analysis. Perioperative imaging was reviewed and RENAL (for radius, exophytic/endophytic properties, anterior/posterior descriptor, and location relative to the polar line) nephrometry scores were calculated. Reasons for conversions were abstracted from operative reports. Multivariable conditional logistic regression analyses were used to assess preoperative risk factors for conversion. RESULTS: A total of 168 cases (6.1% of all partial nephrectomies) were identified and matched on tumor size, year of surgery, and surgical approach to 168 controls. Conversion rates decreased from 13% in 2000-2003 to 4% in 2012-2015. Oncologic considerations, such as concern for upstaging and positive margins, were the most cited (56%) reasons for conversion. On multivariable analyses, male sex (odds ratio 2.34; P = .03), Charlson score (odds ratio per 1-unit increase: 1.28; P = .03), posterior and middle (on anteroposterior axis) location (reference: anterior, odds ratio 2.83, P = .02 and odds ratio 6.38, P < .001, respectively) and hilar location (reference: peripheral/central, odds ratio 5.61; P < .001) were associated with increased odds of conversion. CONCLUSIONS: Rates of conversion from partial to radical nephrectomy in our experience were low and decreased over time. Preoperative characteristics such as hilar, posterior, and middle locations were significantly associated with conversions after controlling for tumor size, and offer guidance for operative planning and patient counseling.

Leucine Zipper 4 Autoantibody: A Novel Germ Cell Tumor and Paraneoplastic Biomarker.

OBJECTIVE: This study was undertaken to describe a novel biomarker of germ cell tumor and associated paraneoplastic neurological syndrome (PNS). METHODS: Archival sera from patients with germ cell tumor-associated PNS were evaluated. We identified a common autoantigen in a human testicular cancer cell line (TCam-2) by Western blot and mass spectrometry. Its identity was confirmed by recombinant-protein Western blot, enzyme-linked immunosorbent assay (ELISA), and cell-based assay. Autoantibody specificity was confirmed by analyzing assorted control sera/cerebrospinal fluid. RESULTS: Leucine zipper 4 (LUZP4)-immunoglobulin G (IgG) was detected in 28 patients' sera, 26 of whom (93%) were men. The median age at neurological symptom onset was 45 years (range = 28-84). Median titer (ELISA) was 1:300 (1:50 to >1:6,400, normal value < 1:50). Coexistent kelchlike protein 11-IgG was identified in 18 cases (64%). The most common presenting phenotype was rhombencephalitis (17/28, 61%). Other presentations included limbic encephalitis (n = 5, 18%), seizures and/or encephalitis (n = 2, 7%), and motor neuronopathy/polyradiculopathy (n = 4, 14%). The most common malignancy among cancer-evaluated PNS patients was seminoma (21/27, 78%). Nine of the 21 seminomas detected by whole-body fluorodeoxyglucose positron emission tomography scan (43%) were extratesticular. Both female patients had ovarian teratoma. Regressed testicular germ cell tumors were found in 4 patients. Exposure of T-cell-dendritic-cell cocultures from chronic immunosuppression-naïve LUZP4-IgG-seropositive patients to recombinant LUZP4 protein evoked a marked increase in CD69 expression on both CD4+ and CD8+ T cells when compared to vehicle-exposed and healthy control cultures. INTERPRETATION: LUZP4-IgG represents a novel serological biomarker of PNS and has high predictive value for germ cell tumors. The demonstrated antigen-specific T-cell responses support a CD8+ T-cell-mediated cytotoxic paraneoplastic and antitumor potential. ANN NEUROL 2021;89:1001-1010.

Perioperative Outcomes for Radical Nephrectomy and Level III-IV Inferior Vena Cava Tumor Thrombectomy in Patients with Renal Cell Carcinoma.

OBJECTIVES: This study examined the characteristics, intraoperative, and postoperative course of patients undergoing inferior vena cava tumor thrombectomy for metastatic renal cell carcinoma. DESIGN: A single-center case series that reported demographic data and intraoperative and postoperative outcomes for patients with renal cell carcinoma undergoing inferior vena cava thrombectomy. SETTING: This investigation was performed at a large quaternary referral center. PARTICIPANTS: Adult patients (age ≥18) admitted to the authors' hospital from January 1, 2005, to March 10, 2017, undergoing inferior vena cava thrombectomy for level III and IV renal cell carcinoma. INTERVENTIONS: No interventions were performed. MEASUREMENTS AND MAIN RESULTS: Sixty-five patients who met the inclusion criteria were identified, with 31 patients diagnosed with level III and 34 with level IV renal cell carcinoma. Patients with level IV tumors were significantly more likely to have greater intraoperative blood loss, had longer surgical duration and hospital stays, and had more frequently required blood products, pressors, and cardiopulmonary bypass intraoperatively. Intraoperative transesophageal echo was more frequently used in level IV thrombectomy compared to level III (91.2% v 67.7%). Of patients with level IV thrombus, 41.2% developed postoperative atrial fibrillation compared to only 3.2% with level III thrombus. The 30-day mortality was 4.6% for both groups. CONCLUSIONS: Patients undergoing inferior vena cava tumor thrombectomy for renal cell carcinoma had more complex intraoperative and postoperative courses with level IV compared to level III tumor thrombus.

A Higher Foci Density of Interstitial Fibrosis and Tubular Atrophy Predicts Progressive CKD after a Radical Nephrectomy for Tumor.

BACKGROUND: Chronic tubulointerstitial injury on kidney biopsy is usually quantified by the percentage of cortex with interstitial fibrosis/tubular atrophy (IF/TA). Whether other patterns of IF/TA or inflammation in the tubulointerstitium have prognostic importance beyond percentage IF/TA is unclear. METHODS: We obtained, stained, and digitally scanned full cortical thickness wedge sections of renal parenchyma from patients who underwent a radical nephrectomy for a tumor over 2000-2015, and morphometrically analyzed the tubulointerstitium of the cortex for percentage IF/TA, IF/TA density (foci per mm2 cortex), percentage subcapsular IF/TA, striped IF/TA, percentage inflammation (both within and outside IF/TA regions), and percentage subcapsular inflammation. Patients were followed with visits every 6-12 months. Progressive CKD was defined as dialysis, kidney transplantation, or 40% decline from the postnephrectomy eGFR. Cox models assessed the risk of CKD or noncancer mortality with morphometric measures of tubulointerstitial injury after adjustment for the percentage IF/TA and clinical characteristics. RESULTS: Among 936 patients (mean age, 64 years; postnephrectomy baseline eGFR, 48 ml/min per 1.73m2), 117 progressive CKD events and 183 noncancer deaths occurred over a median 6.4 years. Higher IF/TA density predicted both progressive CKD and noncancer mortality after adjustment for percentage IF/TA and predicted progressive CKD after further adjustment for clinical characteristics. Independent of percentage IF/TA, age, and sex, higher IF/TA density correlated with lower eGFR, smaller nonsclerosed glomeruli, more global glomerulosclerosis, and smaller total cortical volume. CONCLUSIONS: Higher density of IF/TA foci (a more scattered pattern with more and smaller foci) predicts higher risk of progressive CKD after radical nephrectomy compared with the same percentage of IF/TA but with fewer and larger foci.

Hypothermia During Partial Nephrectomy for Patients with Renal Tumors: A Randomized Controlled Trial.

PURPOSE: Surgeons induce renal hypothermia during partial nephrectomy to preserve kidney function, without strong evidence of benefit. This trial examined the effectiveness and safety of renal hypothermia during partial nephrectomy. MATERIALS AND METHODS: We conducted a parallel randomized controlled trial of hypothermia versus no hypothermia (control group) during partial nephrectomy at 6 academic hospitals. Eligible patients had a planned open partial nephrectomy for the treatment of a renal tumor. During surgery, after clamping the renal hilum, patients were randomized to the intervention or control arm in a 1:1 ratio using permuted blocks of variable lengths (2 and 4), stratified by institution, using a computer-based program. Surgeons and study coordinators were masked to treatment allocation until the renal hilum was clamped. Overall glomerular filtration rates were determined before, and 1-year after, surgery. The primary outcome was measured glomerular filtration rate (mGFR) assessed by the plasma clearance of 99mTc-DTPA. The trial (NCT01529658) was designed with 90% power to detect a minimal clinically important difference in mGFR of 10 ml/minute/1.73 m2 at a 5% significance level. RESULTS: Of the 184 patients randomized, hypothermia and control patients had similar baseline mean mGFR (87.1 vs 81.0 ml/minute/1.73 m2). One hundred and sixty-one (79 hypothermia, 82 control) were alive with primary outcome data 1 year after surgery. The change in mGFR 1 year after surgery was -6.6 ml/minute/1.73 m2 in the hypothermia group and -7.8 ml/minute/1.73 m2 in the control group (mean difference 1.2 ml/minute/1.73 m2, 95% CI -3.3 to 5.6). Operated-kidney change in mGFR was similar between groups (-5.8 vs -6.3 ml/minute/1.73 m2; mean difference 0.5 ml/minute/1.73 m2, 95% CI -2.9 to 3.8). No clinically significant difference in the mGFR was observed when patients were stratified by pre-planned subgroups. Renal hypothermia did not impact the secondary outcomes of surgical complications and patient reported quality of life. CONCLUSIONS: Renal hypothermia during partial nephrectomy does not preserve kidney function in patients with normal or mildly impaired renal function.

Larger Nephron Size and Nephrosclerosis Predict Progressive CKD and Mortality after Radical Nephrectomy for Tumor and Independent of Kidney Function.

BACKGROUND: Nephron hypertrophy and nephrosclerosis may be important determinants of CKD and mortality. However, studies of outcomes associated with these microstructural features have been limited to small tissue specimens from patients selected for either good kidney health or known kidney disease. METHODS: To determine whether microstructural features are predictive of progressive CKD and mortality outcomes, we studied patients who underwent a radical nephrectomy for a tumor. Large wedge sections of renal parenchyma distal to the tumor were stained and scanned into high-resolution images; we annotated the cortex and all glomeruli to calculate glomerular volume, cortex volume per glomerulus, and percentage of globally sclerotic glomeruli. Morphometric measurements also included percentages of artery luminal stenosis and interstitial fibrosis/tubular atrophy (IF/TA) of the cortex. At follow-up visits every 6-12 months, we determined which patients experienced progressive CKD (defined as dialysis, kidney transplantation, or a 40% decline from postnephrectomy eGFR). Cox models for these outcomes were adjusted for age, sex, body mass index, hypertension, diabetes, smoking, eGFR, and proteinuria. RESULTS: Among 936 patients (mean age, 64 years; postnephrectomy baseline eGFR, 48 ml/min per 1.73 m2), 117 progressive CKD events, 183 noncancer deaths, and 116 cancer deaths occurred during a median follow-up of 6.4 years. Larger glomerular volume, larger cortex per glomerulus, and higher percentage of globally sclerotic glomeruli or IF/TA predicted progressive CKD. Higher percentage IF/TA also predicted noncancer mortality. Microstructural features did not predict cancer mortality or recurrence. CONCLUSIONS: After a radical nephrectomy, larger nephrons and nephrosclerosis predicted progressive CKD, and IF/TA predicted noncancer mortality. Morphometric analysis of renal parenchyma can predict noncancer clinical events in patients long after their radical nephrectomy.

Partial versus radical nephrectomy in clinical T2 renal masses.

OBJECTIVE: To report perioperative, renal functional and oncologic outcomes for patients undergoing partial or radical nephrectomy for cT2 renal masses. METHODS: Retrospective review of patients who underwent partial (n = 72) or radical nephrectomy (n = 379) for cT2 renal masses from 2000 to 2016. After propensity adjustment using inverse probability weighting, the following were compared by surgery (partial or radical nephrectomy): complications, renal function measured by estimated glomerular filtration rate as continuous and as <60 mL/min/1.73 m2 at 1 and 3 years postoperatively and overall, metastases-free survival and cancer-specific survival in patients with renal cell carcinoma. RESULTS: After propensity adjustment, clinical and radiographic features were well-balanced between groups. Overall and severe complications were more common for partial compared with radical nephrectomy, although not statistically significant (19 vs 13%, P = 0.14 and 4 vs 2%, P = 0.3, respectively). Estimated glomerular filtration rate change at 1 and 3 years was more pronounced in radical compared with partial nephrectomy (median -16 vs -5 and -14 vs -2, respectively, P < 0.001). A greater proportion of radical nephrectomy patients had an estimated glomerular filtration rate <60 at 1 and 3 years (55 vs 17% and 48 vs 17%, respectively, P < 0.01). In renal cell carcinoma patients, overall, metastases-free and cancer-specific survival were not significantly different between groups (median survivor follow up 7.1 years, interquartile range 3.6-11.4). CONCLUSIONS: Partial nephrectomy appears to be a relatively safe and a potentially effective treatment for cT2 renal masses, conferring better renal functional preservation compared with radical nephrectomy. These data support continued use of partial nephrectomy for renal masses >7 cm in appropriately selected patients.

Complete Surgical Metastasectomy of Renal Cell Carcinoma in the Post-Cytokine Era.

PURPOSE: Data supporting complete metastasectomy of metastatic renal cell carcinoma were derived primarily from the era of cytokine therapy. Whether complete metastasectomy remains beneficial in patients who receive more recently approved systemic therapies has not been well studied. The objective of this study was to examine survival outcomes among patients treated with complete metastasectomy in the era of targeted therapy and checkpoint blockade availability. MATERIALS AND METHODS: We queried our institutional nephrectomy registry and identified 586 patients who underwent partial or radical nephrectomy of unilateral, sporadic renal cell carcinoma with a first occurrence of metastasis between 2006 and 2017. Of these patients 158 were treated with complete metastasectomy. Associations of complete metastasectomy with cancer specific and overall survival were assessed using Cox proportional hazards models. RESULTS: Median followup after the diagnosis of metastasis was 3.9 years, during which 403 patients died, including 345 of renal cell carcinoma. Of the patients treated with complete metastasectomy 147 (93%) did not receive any systemic treatment of the index metastatic lesion(s). Two-year cancer specific survival was significantly greater in patients with vs without complete metastasectomy (84% vs 54%, p <0.001). After adjusting for age, gender, and the timing, number and location of metastases complete metastasectomy was associated with a significantly reduced likelihood of death from renal cell carcinoma (HR 0.47, 95% CI 0.34-0.65, p <0.001). CONCLUSIONS: Complete surgical resection of metastases of renal cell carcinoma was associated with improved cancer specific survival in the post-cytokine era. It may be considered in appropriate patients after a process of shared decision making.

Safety and Efficacy of Retrograde Pyeloperfusion for Ureteral Protection during Renal Tumor Cryoablation.

PURPOSE: To determine safety and efficacy of retrograde pyeloperfusion for ureteral protection during cryoablation of adjacent renal tumors. MATERIALS AND METHODS: Retrospective review of 155 patients treated with renal cryoablation, including adjunctive retrograde pyeloperfusion, from 2005 to 2019 was performed. Ice contacted the ureter in 67 of the 155 patients who represented the study cohort. Median patient age was 68 years old (interquartile range [61, 74]), 52 patients (78%) were male, and 37 tumors (55%) were clear cell histology. Mean tumor size was 3.4 ± 1.3 cm, and 42 tumors (63%) were located at the lower pole. Treatment-related complication and oncologic outcomes were recorded based on a review of post-procedural images and chart review. RESULTS: Technical success of cryoablation was attained in 67 cases (100%), and technical success of pyeloperfusion was attained in 66 cases (99%). A total of 13 patients (19.4%) experienced SIR major C or D complications related to the procedure, including hemorrhage (n = 4), urine leak (n = 3), transient urinary obstruction (n = 2), pulmonary embolism (n = 1), hypertensive urgency (n = 1), acute respiratory failure (n = 1), and ureteropelvic junction (UPJ) stricture (n = 1). No complications were attributable to pyeloperfusion. Three of 45 patients with biopsy-proven renal cell carcinoma experienced local recurrence resulting in local recurrence-free survival of 92% (95% confidence interval, 81.5%-100%) 3 years after ablation. CONCLUSIONS: Retrograde pyeloperfusion of the renal collecting system is a relatively safe and efficacious option for ureteral protection during renal tumor cryoablation. This adjunctive procedure should be considered for patients in whom cryoablation of a renal mass could potentially involve the ureter.

8q24 clear cell renal cell carcinoma germline variant is associated with VHL mutation status and clinical aggressiveness.

BACKGROUND: The four most commonly-mutated genes in clear cell renal cell carcinoma (ccRCC) tumors are BAP1, PBRM1, SETD2 and VHL. And, there are currently 14 known RCC germline variants that have been reproducibly shown to be associated with RCC risk. However, the association of germline genetics with tumor genetics and clinical aggressiveness are unknown. METHODS: We analyzed 420 ccRCC patients from The Cancer Genome Atlas. Molecular subtype was determined based on acquired mutations in BAP1, PBRM1, SETD2 and VHL. Aggressive subtype was defined clinically using Mayo SSIGN score and molecularly using the ccA/ccB gene expression subtype. Publically-available Hi-C data were used to link germline risk variants with candidate target genes. RESULTS: The 8q24 variant rs35252396 was significantly associated with VHL mutation status (OR = 1.6, p = 0.0037) and SSIGN score (OR = 1.9, p = 0.00094), after adjusting for multiple comparisons. We observed that, while some germline variants have interactions with nearby genes, some variants demonstrate long-range interactions with target genes. CONCLUSIONS: These data further demonstrate the link between rs35252396, HIF pathway and ccRCC clinical aggressiveness, providing a more comprehensive picture of how germline genetics and tumor genetics interact with respect to tumor development and progression.

Timing and distribution of early renal cell carcinoma recurrences stratified by pathological nodal status in M0 patients at the time of nephrectomy.

OBJECTIVES: To evaluate the timing and distribution of first renal cell carcinoma metastasis after nephrectomy stratified by nodal status. METHODS: We evaluated patients treated with nephrectomy for sporadic, unilateral renal cell carcinoma between 1970 and 2011 who subsequently developed distant metastasis to three or fewer sites. Site-specific metastases-free 2-year survival rates were estimated using the Kaplan-Meier method. Associations of nodal status with time to metastasis were evaluated using multivariable Cox regression models. RESULTS: A total of 1049 patients met the inclusion criteria (135 pN1, 914 pN0/x patients). The median time to identification of first distant metastasis for pN1 patients was 0.4 years (interquartile range 0.2-1.1 years) versus 2.2 years (interquartile range 0.6-6.0 years) in pN0/x patients. The most common site of metastasis was to the lung, but this occurred earlier in pN1 patients (median 0.3 years vs 2.0 years). pN1 was associated with significantly lower site-specific 2-year metastases-free survival when compared with pN0/x for lung (37% vs 70%, P < 0.001), bone (63% vs 87%, P < 0.001), non-regional lymph nodes (60% vs 96%, P < 0.001) and liver metastases (79% vs 91%, P < 0.001). On multivariable analysis, pN1 status remained significantly associated with lung, bone, and non-regional lymph node (all P < 0.001) metastases, but it was no longer associated with liver metastases (P = 0.3). CONCLUSIONS: pN1 nodal status in M0 patients treated with nephrectomy for renal cell carcinoma is associated with more frequent early metastasis to sites conferring poor prognosis when compared with pN0/x. Our findings highlight the importance of rigorous, early surveillance though the multimodal use of a comprehensive history, physical, laboratory and radiological studies, as outlined in societal guidelines.

JAK2/PD-L1/PD-L2 (9p24.1) amplifications in renal cell carcinomas with sarcomatoid transformation: implications for clinical management.

Amplifications of JAK2, PD-L1, and PD-L2 at 9p24.1 lead to constitutive expression of PD-L1. This, coupled with JAK2-activation dependent upregulation of PD-L1 and adaptive/induced expression leads to higher tumor PD-L1 expression and immune evasion. Renal tumors were therefore evaluated for 9p24.1 amplifications. A combination of next generation sequencing-based copy number analysis, fluorescence in situ hybridization for JAK2/INSL6 and PD-L1/PD-L2 and immunohistochemistry for phospho-STAT3 (downstream target of JAK2), PD-L1, PD-L2, and PD-1 was performed. In this study we interrogated a "Discovery" cohort of 593 renal tumors, a "Validation" cohort of 398 high-grade renal tumors, The Cancer Genome Atlas (879 cases) and other public datasets (846 cases). 9p24.1 amplifications were significantly enriched in renal tumors with sarcomatoid transformation (5.95%, 15/252) when compared to all histologic subtypes in the combined "Discovery", "Validation" and public datasets (16/2636, 0.6%, p < 0.00001). Specifically, 9p24.1 amplifications amongst sarcomatoid tumors in public datasets, the "Discovery" and "Validation" cohorts were 7.7% (6/92), 15.1% (5/33), and 3.1% (4/127), respectively. Herein, we describe 13 cases and amplification status for these was characterized using next generation sequencing (n = 9) and/or fluorescence in situ hybridization (n = 10). Correlation with PD-L1 immunohistochemistry (n = 10) revealed constitutive expression (mean H-score: 222/300, n = 10). Analysis of outcomes based on PD-L1 expression in tumor cells performed on 282 cases ("Validation" cohort) did not reveal a significant prognostic effect and was likely reflective of advanced disease. A high incidence of constitutive PD-L1 expression in tumor cells in the "Validation" cohort (H-Score ≥250/300) was noted amongst 83 rhabdoid (6%) and 127 sarcomatoid renal tumors (7.1%). This suggests additional mechanisms of constitutive expression other than amplification events. Importantly, two patients with 9p24.1-amplified sarcomatoid renal tumors showed significant response to immunotherapy. In summary, a subset of renal tumors with sarcomatoid transformation exhibits constitutive PD-L1 overexpression and these patients should be evaluated for enhanced response to immunotherapy.