Does the Timing of Cytoreductive Nephrectomy Impact Outcomes? Analysis of REMARCC Registry Data for Patients Receiving Tyrosine Kinase Inhibitor Versus Immune Checkpoint Inhibitor Therapy.

Background and objective: The role of cytoreductive nephrectomy (CN) in the treatment of metastatic renal cell carcinoma (mRCC) has been called into question on the basis of clinical trial data from the tyrosine kinase inhibitor (TKI) era. Comparative analyses of CN for patients treated with immuno-oncology (IO) versus TKI agents are sparse. Our objective was to compare CN timing and outcomes among patients who received TKI versus IO therapy. Methods: This was a multicenter retrospective analysis of patients who underwent CN using data from the REMARCC (Registry of Metastatic RCC) database. The cohort was divided into TKI versus IO first-line therapy groups. The primary outcome was all-cause mortality (ACM). Secondary outcomes included cancer-specific mortality (CSM). Multivariable analysis was used to identify factors predictive for ACM and CSM. The Kaplan-Meier method was used to analyze 5-yr overall survival (OS) and cancer-specific survival (CSS) with stratification by primary systemic therapy and timing in relation to CN. Key findings and limitations: We analyzed data for 189 patients (148 TKI + CN, 41 IO +CN; median follow-up 23.2 mo). Multivariable analysis revealed that a greater number of metastases (hazard ratio [HR] 1.06; p = 0.015), greater primary tumor size (HR 1.10; p = 0.043), TKI receipt (HR 2.36; p = 0.015), and initiation of systemic therapy after CN (HR 1.49; p = 0.039) were associated with worse ACM. A greater number of metastases at diagnosis (HR 1.07; p = 0.011), greater primary tumor size (HR 1.12; p = 0.018), TKI receipt (HR 5.43; p = 0.004), and initiation of systemic therapy after CN (HR 2.04; p < 0.001) were associated with worse CSM. Kaplan-Meier analyses revealed greater 5-yr rates for OS (51% vs 27%; p < 0.001) and CSS (83% vs 30%; p < 0.001) for IO +CN versus TKI + CN. This difference persisted in a subgroup analysis for patients with intermediate or poor risk, with 5-yr OS rates of 50% for IO + CN versus 30% for TKI + CN (p < 0.001). A subanalysis stratified by CN timing revealed better 5-yr rates for OS (50% vs 30%; p = 0.042) and CSS (90% vs 30%, p = 0.019) for delayed CN after IO therapy, but not after TKI therapy. Conclusions and clinical implications: For patients who underwent CN, systemic therapy before CN was associated with better outcomes. In addition, IO therapy was associated with better survival outcomes in comparison to TKI therapy. Our findings question the applicability of clinical trial data from the TKI era to CN in the IO era for mRCC. Patient summary: For patients with metastatic kidney cancer treated with surgery, better survival outcomes were observed for those who also received immunotherapy in comparison to therapy targeting specific proteins in the body (tyrosine kinase inhibitors, TKIs). Immunotherapy or TKI treatment resulted in better outcomes if it was received before rather than after surgery.

Prognostic Significance of Grade Discrepancy Between Primary Tumor and Venous Thrombus in Nonmetastatic Clear-cell Renal Cell Carcinoma: Analysis of the REMEMBER Registry and Implications for Adjuvant Therapy.

BACKGROUND: Further stratification of the risk of recurrence of clear-cell renal cell carcinoma (ccRCC) with venous tumor thrombus (VTT) will facilitate selection of candidates for adjuvant therapy. OBJECTIVE: To assess the impact of tumor grade discrepancy (GD) between the primary tumor (PT) and VTT in nonmetastatic ccRCC on disease-free survival (DFS), overall survival (OS), and cancer-specific survival (CSS). DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective analysis of a multi-institutional nationwide data set for patients with pT3N0M0 ccRCC who underwent radical nephrectomy and thrombectomy. OUTCOMES MEASUREMENTS AND STATISTICAL ANALYSIS: Pathology slides were centrally reviewed. GD, a bidirectional variable (upgrading or downgrading), was numerically defined as the VTT grade minus the PT grade. Multivariable models were built to predict DFS, OS, and CSS. RESULTS AND LIMITATIONS: We analyzed data for 604 patients with median follow-up of 42 mo (excluding events). Tumor GD between VTT and PT was observed for 47% (285/604) of the patients and was an independent risk factor with incremental value in predicting the outcomes of interest (all p < 0.05). Incorporation of tumor GD significantly improved the performance of the ECOG-ACRIN 2805 (ASSURE) model. A GD-based model (PT grade, GD, pT stage, PT sarcomatoid features, fat invasion, and VTT consistency) had a c index of 0.72 for DFS. The hazard ratios were 8.0 for GD = +2 (p < 0.001), 1.9 for GD = +1 (p < 0.001), 0.57 for GD = -1 (p = 0.001), and 0.22 for GD = -2 (p = 0.003) versus GD = 0 as the reference. According to model-converted risk scores, DFS, OS, and CSS significantly differed between subgroups with low, intermediate, and high risk (all p < 0.001). CONCLUSIONS: Routine reporting of VTT upgrading or downgrading in relation to the PT and use of our GD-based nomograms can facilitate more informed treatment decisions by tailoring strategies to an individual patient's risk of progression. PATIENT SUMMARY: We developed a tool to improve patient counseling and guide decision-making on other therapies in addition to surgery for patients with the clear-cell type of kidney cancer and tumor invasion of a vein.

The effect of cisplatin-based neoadjuvant chemotherapy on the renal function of patients undergoing radical cystectomy.

INTRODUCTION: Cisplatin-based neoadjuvant chemotherapy (NAC) is the standard of care for patients with muscle-invasive bladder cancer (MIBC) undergoing radical cystectomy (RC). Cisplatin, however, can induce renal toxicity. Furthermore, RC is an independent risk factor for renal injury, with decreases in estimated glomerular filtration rate (eGFR) of up to 6 mL/min/1.73 m2 reported at one year postoperatively. Our objective was to evaluate the effect of cisplatin-based NAC and RC on the renal function of patients undergoing both. METHODS: We analyzed a multicenter database of patients with MIBC, all of whom received cisplatin-based NAC prior to RC. eGFR values were collected at time points T1 (before NAC), T2 (after NAC but before RC), and T3 (one year post-RC). eGFR and proportion of patients with eGFR <60 ml/min/1.73m2 (chronic kidney disease [CKD] stage ≥3) were compared between these time points. As all patients in this dataset had received NAC, we identified a retrospective cohort of patients from one institution who had undergone RC during the same time period without NAC for context. RESULTS: We identified 234 patients with available renal function data. From T1 to T3, there was a mean decline in eGFR of 17% (13 mL/min/1.73 m2) in the NAC cohort and an increase in proportion of patients with stage ≥3 CKD from 27% to 50%. The parallel cohort of patients who did not receive NAC was comprised of 236 patients. The mean baseline eGFR in this cohort was lower than in the NAC cohort (66 vs. 75 mL/min/1.73 m2). The mean eGFR decline in this non-NAC cohort from T1 to T3 was 6% (4 mL/min/1.73 m2), and the proportion of those with stage ≥3 CKD increased from 37% to 51%. CONCLUSIONS: Administration of NAC prior to RC was associated with a 17% decline in eGFR and a nearly doubled incidence of stage ≥3 CKD at one year after RC. Patients who underwent RC without NAC had a higher rate of stage ≥3 CKD at baseline but appeared to have less renal function loss at one year.

Oncologic outcomes following radical nephroureterectomy for upper tract urothelial carcinoma: a literature review.

Background and Objective: Radical nephroureterectomy (RNU) represents the gold standard treatment for non-metastatic upper tract urothelial cancer. We sought to provide a comprehensive review of reported oncologic outcomes of the RNU procedure and of factors that might impact these outcomes. Methods: A non-systematic review of the literature was conducted by performing an electronic literature search using PubMed with "radical nephroureterectomy" and "oncologic outcomes" as free text search terms. Both original articles and systematic reviews were considered. Search was limited to articles in English that were published in the last 20 years. Key Content and Findings: Open and laparoscopic RNU offer comparable oncologic outcomes. In more recent years, the discussion has de facto shifted towards the "oncological safety" of robotic RNU, which also seems to offer comparable oncologic outcomes. Several studies have looked at the impact of different treatment-, patient- and tumor-related factors. Among treatment-related factors, attention has been given to diagnostic ureteroscopy and the risk of intravesical recurrence. Surgical wait time and perioperative blood transfusion have also been studied. Perioperative chemotherapy, specifically adjuvant therapy, was shown to improve survival. Among patient-related factors, baseline chronic kidney disease, diabetes mellitus, body mass index, and systemic inflammation have gained recent attention. Some tumor related factors, such as stage, grade, location, and multifocality may negatively impact survival outcomes. Lymphovascular invasion and histologic variants are clinically significant pathological findings. Conclusions: RNU is a procedure with measured long-term oncologic outcomes. Minimally invasive techniques have gained an established role as they seem to offer comparable oncologic "safety", although special attention is needed in relation to the method of bladder cuff excision. Robotic RNU is gaining popularity, and while evidence remains limited, the current literature supports the oncologic safety of this procedure. Several factors, which can be categorized as treatment-related, patient-related, and tumor-related, might impact the oncologic outcomes of UTUC patients undergoing RNU. These factors can provide crucial information to stratify patients based on their relative risk of disease recurrence and mortality which may guide clinical decision-making.

Proposal for a Two-Tier Re-classification of Stage IV/M1 domain of Renal Cell Carcinoma into M1 ("Oligometastatic") and M2 ("Polymetastatic") subdomains: Analysis of the Registry for Metastatic Renal Cell Carcinoma (REMARCC).

Purpose: We hypothesized that two-tier re-classification of the "M" (metastasis) domain of the Tumor-Node-Metastasis (TNM) staging of Renal Cell Carcinoma (RCC) may improve staging accuracy than the current monolithic classification, as advancements in the understanding of tumor biology have led to increased recognition of the heterogeneous potential of metastatic RCC (mRCC). Methods: Multicenter retrospective analysis of patients from the REMARCC (REgistry of MetAstatic RCC) database. Patients were stratified by number of metastases into two groups, M1 (≤3, "Oligometastatic") and M2 (>3, "Polymetastatic"). Primary outcome was overall survival (OS). Secondary outcomes were cancer-specific survival (CSS). Cox-regression and Kaplan-Meier (KMA) analysis were utilized for outcomes, and receiver operating characteristic analysis (ROC) was utilized to assess diagnostic accuracy compared to current "M" staging. Results: 429 patients were stratified into proposed M1 and M2 groups (M1 = 286/M2 = 143; median follow-up 19.2 months). Cox-regression revealed M2 classification as an independent risk factor for worsened all-cause mortality (HR=1.67, p=0.001) and cancer-specific mortality (HR=1.74, p<0.001). Comparing M1-oligometastatic vs. M2-polymetastatic groups, KMA revealed significantly higher 5-year OS (36% vs. 21%, p<0.001) and 5-year CSS (39% vs. 17%, p<0.001). ROC analyses comparing OS and CSS, for M1/M2 reclassification versus unitary M designation currently in use demonstrated improved c-index for OS (M1/M2 0.635 vs. unitary M 0.500) and CSS (M1/M2 0.627 vs. unitary M 0.500). Conclusion: Subclassification of Stage "M" domain of mRCC into two clinical substage categories based on metastatic burden corresponds to distinctive tumor groups whose oncological potential varies significantly and result in improved predictive capability compared to current staging.

Impact of Maximal Transurethral Resection on Pathological Outcomes at Cystectomy in a Large, Multi-institutional Cohort.

PURPOSE: While the presence of residual disease at the time of radical cystectomy for bladder cancer is an established prognostic indicator, controversy remains regarding the importance of maximal transurethral resection prior to neoadjuvant chemotherapy. We characterized the influence of maximal transurethral resection on pathological and survival outcomes using a large, multi-institutional cohort. MATERIALS AND METHODS: We identified 785 patients from a multi-institutional cohort undergoing radical cystectomy for muscle-invasive bladder cancer after neoadjuvant chemotherapy. We employed bivariate comparisons and stratified multivariable models to quantify the effect of maximal transurethral resection on pathological findings at cystectomy and survival. RESULTS: Of 785 patients, 579 (74%) underwent maximal transurethral resection. Incomplete transurethral resection was more frequent in patients with more advanced clinical tumor (cT) and nodal (cN) stage (P < .001 and P < .01, respectively), with more advanced ypT stage at cystectomy and higher rates of positive surgical margins (P < .01 and P < .05, respectively). In multivariable models, maximal transurethral resection was associated with downstaging at cystectomy (adjusted odds ratio 1.6, 95% CI 1.1-2.5). In Cox proportional hazards analysis, maximal transurethral resection was not associated with overall survival (adjusted HR 0.8, 95% CI 0.6-1.1). CONCLUSIONS: In patients undergoing transurethral resection for muscle-invasive bladder cancer prior to neoadjuvant chemotherapy, maximal resection may improve pathological response at cystectomy. However, the ultimate effects on long-term survival and oncologic outcomes warrant further investigation.

Multicenter evaluation of neoadjuvant and induction gemcitabine-carboplatin versus gemcitabine-cisplatin followed by radical cystectomy for muscle-invasive bladder cancer.

PURPOSE: Cisplatin-based chemotherapy followed by radical cystectomy (RC) is recommended in patients with muscle-invasive bladder cancer (MIBC). However, up to 50% of patients are cisplatin ineligible. The aim of this study was to compare clinical outcomes after ≥ 3 cycles of preoperative gemcitabine-carboplatin (gem-carbo) versus gemcitabine-cisplatin (gem-cis). METHODS: We identified 1865 patients treated at 19 centers between 2000 and 2013. Patients were included if they had received ≥ 3 cycles of neoadjuvant (cT2-4aN0M0) or induction (cTanyN + M0) gem-carbo or gem-cis followed by RC. RESULTS: We included 747 patients treated with gem-carbo (n = 147) or gem-cis (n = 600). Patients treated with gem-carbo had a higher Charlson Comorbidity Index (p = 0.016) and more clinically node-positive disease (32% versus 20%; p = 0.013). The complete pathological response (pCR; ypT0N0) rate did not significantly differ between gem-carbo and gem-cis (20.7% versus 22.1%; p = 0.73). Chemotherapeutic regimen was not significantly associated with pCR (OR 0.99 [95%CI 0.61-1.59]; p = 0.96), overall survival (OS) (HR 1.20 [95%CI 0.85-1.67]; p = 0.31), or cancer-specific survival (CSS) (HR 1.35 [95%CI 0.93-1.96]; p = 0.11). Median OS of patients treated with gem-carbo and gem-cis was 28.6 months (95%CI 18.1-39.1) and 45.1 months (95%CI 32.7-57.6) (p = 0.18), respectively. Median CSS of patients treated with gem-carbo and gem-cis was 28.8 months (95%CI 9.8-47.8) and 71.0 months (95%CI median not reached) (p = 0.02), respectively. Subanalyses of the neoadjuvant and induction setting did not show significant survival differences. CONCLUSION: Our results show that a subset of cisplatin-ineligible patients with MIBC achieve pCR on gem-carbo and that survival outcomes seem comparable to gem-cis provided patients are able to receive ≥ 3 cycles and undergo RC.

Complementary roles of surgery and systemic treatment in clear cell renal cell carcinoma.

Standard-of-care management of renal cell carcinoma (RCC) indisputably relies on surgery for low-risk localized tumours and systemic treatment for poor-prognosis metastatic disease, but a grey area remains, encompassing high-risk localized tumours and patients with metastatic disease with a good-to-intermediate prognosis. Over the past few years, results of major practice-changing trials for the management of metastatic RCC have completely transformed the therapeutic options for this disease. Treatments targeting vascular endothelial growth factor (VEGF) have been the mainstay of therapy for metastatic RCC in the past decade, but the advent of immune checkpoint inhibitors has revolutionized the therapeutic landscape in the metastatic setting. Results from several pivotal trials have shown a substantial benefit from the combination of VEGF-directed therapy and immune checkpoint inhibition, raising new hopes for the treatment of high-risk localized RCC. The potential of these therapeutics to facilitate the surgical extirpation of the tumour in the neoadjuvant setting or to improve disease-free survival in the adjuvant setting has been investigated. The role of surgery for metastatic RCC has been redefined, with results of large trials bringing into question the paradigm of upfront cytoreductive nephrectomy, inherited from the era of cytokine therapy, when initial extirpation of the primary tumour did show clinical benefits. The potential benefits and risks of deferred surgery for residual primary tumours or metastases after partial response to checkpoint inhibitor treatment are also gaining interest, considering the long-lasting effects of these new drugs, which encourages the complete removal of residual masses.

Impact of Metastasectomy on Cancer Specific and Overall Survival in Metastatic Renal Cell Carcinoma: Analysis of the REMARCC Registry.

BACKGROUND: Treatment paradigms for management of metastatic renal cell carcinoma (mRCC) are evolving. We examined impact of surgical metastasectomy on survival across in mRCC stratified by risk-group. METHODS: Multicenter retrospective analysis from the Registry of Metastatic RCC database. The cohort was subdivided utilizing Motzer criteria (favorable-, intermediate-, high-risk). Primary outcome was all-cause mortality (ACM)/overall survival (OS); secondary outcome was cancer-specific mortality (CSM)/cancer-specific survival (CSS). Impact of metastasectomy was analyzed via Cox-Regression analysis adjusting for potential prognostic variables and Kaplan-Meier analysis (KMA) within each risk-group. RESULTS: Four hundred thirty-one patients (59 favorable-risk, 274 intermediate-risk, 98 high-risk; median follow-up 27.2 months) were analyzed. Metastasectomy was performed in 22 (37%), 66 (24%), and 32 (16%) of favorable-, intermediate- and high-risk groups (P = .012). Median number of metastases at diagnosis differed significantly (favorable-risk 2, intermediate-risk 3.4, high-risk 5.1, P < .001). On Cox-regression, high-risk (HR = 1.72, P = .002) was associated with worsened ACM, while metastasectomy was associated with improved ACM (HR = 0.56, P = .005). On KMA, median OS (months) was longer with metastasectomy in favorable- (92.7 vs. 25.8, P = .003) and intermediate-risk (26.3 vs. 20.1, P = .038), but not high-risk (P = .911) groups. Metastasectomy was associated with longer CSS in favorable- (76.1 vs. 32.8, P = .004) but not intermediate- (P = .06) and high-risk (P = .595) groups. CONCLUSIONS: Metastasectomy was independently associated with improved ACM and CSM, as well as improved CSS and OS in favorable- and intermediate-risk mRCC patients. Metastasectomy may be considered as component of multimodal management strategy in favorable and intermediate-risk subgroups. In high-risk patients, metastasectomy should be deferred except in select circumstances.

Neoadjuvant systemic therapy in patients undergoing nephroureterectomy for urothelial cancer: a multidisciplinary systematic review and critical analysis.

INTRODUCTION: The benefit of neoadjuvant systemic therapy (NAST) is not yet supported by randomized controlled trials in upper tract urothelial carcinoma (UTUC), but the evidence is increasing. This narrative systematic review was conducted to evaluate the available evidence on the role of NAST in patients undergoing radical nephroureterectomy (RNU) for UTUC. EVIDENCE ACQUISITION: We searched for all relevant articles or conference abstracts published and indexed in PubMed, Embase, and Scopus on July 19, 2021. The study was reported according to the PRISMA criteria and designed within the PICOS framework. We included studies comparing patients with non-metastatic UTUC who received neoadjuvant chemotherapy (NAC) or immunotherapy (NAI) with patients who underwent definitive surgery alone or surgery plus adjuvant systemic therapy. Prospective uncontrolled studies were also included. EVIDENCE SYNTHESIS: We identified 27 reports (NAC, N.=24 and NAI, N.=3) published between 2010 and 2021. Twenty of the 24 studies on NAC were retrospective comparative analyses, whereas the remaining four were prospective single-arm studies. One of the three NAI studies exclusively enrolled patients with UTUC. NAC was associated with improved survival and better pathological response relative to surgery alone, but there was no clear advantage when compared to surgery plus adjuvant chemotherapy. Overall, the drug-induced toxicity and risk of disease progression were acceptable but the inherent bias across study designs, inadequate reporting and heterogeneous definition of primary outcomes render it difficult to synthesize results, compare centers, and inform practice. CONCLUSIONS: The current level of evidence supporting NAST for UTUC is relatively low and the inability to predict responsiveness and thereby pinpoint the optimal candidates remains a major challenge. There is a need to compare NAST to adjuvant therapies using clearly defined primary endpoints as minimum reporting standards developed by a multidisciplinary team.

Adverse Events of Immune Checkpoint Inhibitors Therapy for Urologic Cancer Patients in Clinical Trials: A Collaborative Systematic Review and Meta-analysis.

CONTEXT: Therapies based on immune checkpoint inhibitors (ICIs) are transforming the treatment landscape of urologic oncology. Nevertheless, an exhaustive overview of the toxicity spectrum of these novel therapies has yet to be provided. OBJECTIVE: To comprehensively investigate the incidence and profile of ICI therapy-related adverse events (AEs) across urologic cancers. EVIDENCE ACQUISITION: We searched for all clinical trials investigating the role of ICI therapy published between January 2010 and September 2021. Studies involving urologic cancers with reported overall incidence or tabulated data of treatment-related AEs (trAEs) or immune-related AEs (irAEs) were included. A systematic review and meta-analysis was performed after protocol registration in PROSPERO (CRD42021276435). EVIDENCE SYNTHESIS: We identified 2638 records, of which 92 studies (including 22942 participants) met the inclusion criteria. The pooled overall incidence was 81.6% (95% confidence interval [CI] 78.0-84.7) for any-grade trAEs and 29.3% (95% CI 24.9-34.1) for grade ≥3 trAEs. The pooled overall incidence was 34.3% (95% CI 28.5-40.7) for any-grade irAEs and 10.2% (95%CI 8.2-12.7) for grade ≥3 irAEs. On a multivariable analysis, cancer type, therapy combination, clinical settings (perioperative vs advanced/metastatic), and drug exposure were independently associated with the occurrence of trAEs or irAEs. The overall rate of treatment-related mortality was 0.94% (140 of 14 899 participants), with pneumonitis (9.3%), pneumonia (7.9%), and respiratory failure (7.1%) being the most common causes. Immune-related mortality occurred in 0.26% (28 of 10 723) patients, with pneumonitis (35.7%), hepatic failure (10.7%), and hepatitis (7.1%) being most common. CONCLUSIONS: Our study provides a comprehensive overview of ICI-associated AEs in urologic cancer patients. The spectrum and incidence of AEs vary across cancer types, ICI types, clinical settings, and therapy combinations. These findings provide important guidance to clinicians in counseling and management of patients with urologic cancers. PATIENT SUMMARY: A high proportion of patients experience immune checkpoint inhibitor-associated toxicity. Physician and patient education is critical for early recognition and proper management.

Impact of frailty on perioperative and oncologic outcomes in patients undergoing surgery or ablation for renal cancer: a systematic review.

INTRODUCTION: Frailty has been recognized as a major risk factor for adverse perioperative and oncological outcomes in patients with genitourinary malignancies. Yet, the evidence supporting such an association in patients with renal cell carcinoma (RCC) is still sparse. Herein we provide an updated comprehensive overview of the impact of frailty on perioperative and oncologic outcomes in patients undergoing surgery or ablation for RCC. EVIDENCE ACQUISITION: A systematic review of the English-language literature was conducted using the MEDLINE (via PubMed), Web of Science and the Cochrane Library databases according to the principles highlighted by the EAU Guidelines Office and the PRISMA statement recommendations. The review protocol was registered on PROSPERO (CRD42021242516). The overall quality of evidence was assessed according to GRADE recommendations. EVIDENCE SYNTHESIS: Overall, 18 studies were included in the qualitative analysis. Most of these were retrospective single-center series including patients undergoing surgery for non-metastatic RCC. The overall quality of evidence was low. A variety of measures were used for frailty assessment, including the Canadian Study of Health and Aging Frailty Index, the five-item frailty index, the Modified Rockwood's Clinical Frailty Scale Score, the Hopkins Frailty score, the Groningen Frailty Index, and the Geriatric nutritional risk index. Sarcopenia was defined based on the Lumbar skeletal muscle mass at cross-sectional imaging, the skeletal muscle index, the total psoas area, or the Psoas Muscle Index. Overall, available studies point to frailty and sarcopenia as potential independent risk factors for worse perioperative and oncological outcomes after surgery or ablation for different RCC stages. Increased patient's frailty was indeed associated with higher risk of perioperative complications, healthcare resources utilization, readmission rates and longer hospitalization periods, as well as potentially lower cancer specific or overall survival. CONCLUSIONS: Frailty has been consistently associated with worse outcomes after surgery for RCC, reinforcing the value of preoperative frailty assessment in carefully selected patients. Given the low quality of the available evidence (especially in the setting of tumor ablation), prospective studies are needed to standardize frailty assessments and to identify patients who are expected to benefit most from preoperative geriatric evaluation, aiming to optimize decision-making and postoperative outcomes in patients with RCC.

Warm ischemia time length during on-clamp partial nephrectomy: does it really matter?

BACKGROUND: The impact of warm ischemia time (WIT) on renal functional recovery remains controversial. We examined the length of WIT>30 min on the long-term renal function following on-clamp partial nephrectomy (PN). METHODS: Data from 23 centers for patients undergoing on-clamp PN between 2000 and 2018 were analyzed. We included patients with two kidneys, single tumor, cT1, minimum 1-year follow-up, and preoperative eGFR≥60 mL/min/1.73m2. Patients were divided into two groups according to WIT length: group I "WIT≤30 min" and group II "WIT>30 min." A propensity-score matched analysis (1:1 match) was performed to eliminate potential confounding factors between groups. We compared eGFR values, eGFR (%) preservation, eGFR decline, events of chronic kidney disease (CKD) upgrading, and CKD-free progression rates between both groups. Cox regression analysis evaluated WIT impact on upgrading of CKD stages. RESULTS: The primary cohort consisted of 3526 patients: group I (N.=2868) and group II (N.=658). After matching the final cohort consisted of 344 patients in each group. At last follow-up, there were no significant differences in median eGFR values at 1, 3, 5, and 10 years (P>0.05) between the matched groups. In addition, the median eGFR (%) preservation and absolute eGFR change were similar (89% in group I vs. 87% in group II, P=0.638) and (-10 in group I vs. -11 in group II, P=0.577), respectively. The 5 years new-onset CKD-free progression rates were comparable in the non-matched groups (79% in group I vs. 81% in group II, log-rank, P=0.763) and the matched groups (78.8% in group I vs. 76.3% in group II, log-rank, P=0.905). Univariable Cox regression analysis showed that WIT>30 min was not a predictor of overall CKD upgrading (HR:0.953, 95%CI 0.829-1.094, P=0.764) nor upgrading into CKD stage ≥III (HR:0.972, 95%CI 0.805-1.173, P=0.764). Retrospective design is a limitation of our study. CONCLUSIONS: Our analysis based on a large multicenter international cohort study suggests that WIT length during PN has no effect on the long-term renal function outcomes in patients having two kidneys and preoperative eGFR≥60 mL/min/1.73m2.

Association of age with response to preoperative chemotherapy in patients with muscle-invasive bladder cancer.

PURPOSE: To assess the association of patient age with response to preoperative chemotherapy in patients with muscle-invasive bladder cancer (MIBC). MATERIALS AND METHODS: We analyzed data from 1105 patients with MIBC. Patients age was evaluated as continuous variable and stratified in quartiles. Pathologic objective response (pOR; ypT0-Ta-Tis-T1N0) and pathologic complete response (pCR; ypT0N0), as well survival outcomes were assessed. We used data of 395 patients from The Cancer Genome Atlas (TCGA) to investigate the prevalence of TCGA molecular subtypes and DNA damage repair (DDR) gene alterations according to patient age. RESULTS: pOR was achieved in 40% of patients. There was no difference in distribution of pOR or pCR between age quartiles. On univariable logistic regression analysis, patient age was not associated with pOR or pCR when evaluated as continuous variables or stratified in quartiles (all p > 0.3). Median follow-up was 18 months (IQR 6-37). On Cox regression and competing risk regression analyses, age was not associated with survival outcomes (all p > 0.05). In the TCGA cohort, patient with age ≤ 60 years has 7% less DDR gene mutations (p = 0.59). We found higher age distribution in patients with luminal (p < 0.001) and luminal infiltrated (p = 0.002) compared to those with luminal papillary subtype. CONCLUSIONS: While younger patients may have less mutational tumor burden, our analysis failed to show an association of age with response to preoperative chemotherapy or survival outcomes. Therefore, the use of preoperative chemotherapy should be considered regardless of patient age.

Surgical Management and Outcomes of Renal Tumors Arising from Horseshoe Kidneys: Results from an International Multicenter Collaboration.

BACKGROUND: Despite being the most frequent renal fusion anomaly, tumors arising from horseshoe kidneys (HSKs) are extremely rare and management guidance is lacking. OBJECTIVE: To evaluate the perioperative, oncological, and functional outcomes of surgically treated HSK tumors. DESIGN, SETTING, AND PARTICIPANTS: A retrospective, multicenter cohort study of 43 HSK tumors in 40 patients was conducted, and technical description of the surgical approach has been provided. SURGICAL PROCEDURE: Surgical resection of renal tumors arising from HSKs was performed either via open surgery or via minimally invasive surgery (MIS). MEASUREMENTS: We analyzed patient and tumor characteristics as well as surgical technique, and functional and oncological outcomes. RESULTS AND LIMITATIONS: Eight patients were treated by MIS and 32 by open surgery. One patient (2.5%) experienced an intraoperative complication and 13 patients (32.5%) experienced postoperative complications, of which three (7.5%) were Clavien-Dindo ≥3 complications. Surgical margins were positive in two tumors (4.7%). The most frequent histology was clear-cell renal cell carcinoma (46.5%). The median follow-up was 51 (interquartile range [IQR] 17-73) mo. The 5-yr overall, cancer-specific, and recurrence-free survival rates were 81.2%, 86.8%, and 83.1%, respectively. The percent decreases in estimated glomerular filtration rate at discharge and the last follow-up were 15% (IQR 4-26%) and 17% (IQR 1-31%), respectively. Limitations include the cohort's retrospective nature, heterogeneity, and small sample size. CONCLUSIONS: Surgical management of tumors in HSKs can be approached via both open surgery and MIS, with maximal preservation of functional renal parenchyma. In this cohort, rates of complications, positive surgical margins, and renal functional decrease were acceptable, considering the anatomical complexity of these kidneys and tumors. These tumors display great variation in histological subtypes. Meticulous presurgical planning, taking advantage of advanced imaging techniques, can aid in achieving good outcomes. PATIENT SUMMARY: We evaluated the surgical management of renal tumors in horseshoe kidneys, which are very rare. Although these procedures are highly complex, outcomes are acceptable. Modern imaging techniques are often required in presurgical planning.

Robot-assisted Radical Nephrectomy: A Systematic Review and Meta-analysis of Comparative Studies.

CONTEXT: Radical nephrectomy (RN) is the gold standard treatment for large and locally advanced renal tumors. Although robot-assisted radical nephrectomy (RRN) is being increasingly adopted, it remains unclear whether it offers benefits over standard laparoscopic radical nephrectomy (LRN) or open radical nephrectomy (ORN). OBJECTIVE: To compare the outcomes of robotic surgery to those of laparoscopic and open surgery in patients undergoing RN for renal cell carcinoma (RCC). EVIDENCE ACQUISITION: A systematic search was performed across MEDLINE, EMBASE, and Web of Science for retrospective and prospective studies comparing RRN to LRN or ORN. A meta-analysis evaluated perioperative safety, effectiveness, survival, and cost-effectiveness outcomes. The weighted mean difference (WMD) and odds ratio (OR) were used to compare continuous and dichotomous variables, respectively. Quality was assessed using the Newcastle-Ottawa scale. Sensitivity analyses were performed to assess the robustness of the estimates. EVIDENCE SYNTHESIS: Twelve studies involving 64 221 patients were identified and included in the analysis. Compared to LRN, RRN was associated with statistically significant longer operative time (WMD 37.44 min; p = 0.03), shorter length of stay (WMD -0.84 days; p = 0.02) and higher total costs (WMD US$4700; p < 0.001). Compared to ORN, RRN was associated with shorter length of stay (WMD -3.06 days; p = 0.002), fewer overall complications (OR 0.56; p < 0.001), lower estimated blood loss (WMD -702 ml; p = 0.01), and higher total hospital costs (WMD US$4520; p = 0.004). There was high heterogeneity across all analyses. CONCLUSIONS: In patients undergoing RN for RCC, RRN seems to offer some key advantages compared to ORN, including shorter hospitalization and fewer complications. Compared to LRN, RRN provides similar surgical outcomes but at higher total costs. These findings should be interpreted within the limitations of this type of analysis, given high heterogeneity between studies and poor robustness for most outcomes. Randomized clinical studies with long-term follow-up are needed to obtain more definitive results. PATIENT SUMMARY: In patients with renal cell carcinoma, robot-assisted radical nephrectomy shows perioperative advantages compared to open radical nephrectomy, but not compared to laparoscopic radical nephrectomy.

Trimodal therapy in muscle invasive bladder cancer management.

INTRODUCTION: Radical cystectomy (RC) is the current mainstay for muscle-invasive bladder cancer (MIBC). Concerns regarding morbidity, mortality and quality of life have favored the introduction of bladder sparing strategies. Trimodal therapy, combining transurethral resection, chemotherapy and radiotherapy is the current standard of care for bladder preservation strategies in selected patients with MIBC. EVIDENCE ACQUISITION: A comprehensive search of the Medline and Embase databases was performed. A total of 19 studies were included in a systematic review of bladder sparing strategies in MIBC management was carried out following the preferred reporting items for systematic reviews and meta-analysis (PRISMA). EVIDENCE SYNTHESIS: The overall median complete response rate after trimodal therapy (TMT) was 77% (55-93). Salvage cystectomy rate with TMT was 17% on average (8-30). For TMT, the 5-year cancer-specific survival and overall survival rates range from 42-82% and 32-74%, respectively. Currently data supporting neoadjuvant or adjuvant chemotherapy in bladder sparing approaches are emerging, but robust definitive conclusions are still lacking. Gastrointestinal toxicity rates are low around 4% (0.5-16), whereas genitourinary toxicity rates reached 8% (1-24). Quality of life outcomes are still underreported. CONCLUSIONS: Published data and clinical experience strongly support trimodal therapy as an acceptable bladder sparing strategy in terms of oncological outcomes and quality of life in selected patients with MIBC. A strong need exists for specialized centers, to increase awareness among urologists, to discuss these options with patients and to stress the increased participation of patients and their families in treatment path decision-making.

Triggers for delayed intervention in patients with small renal masses undergoing active surveillance: a systematic review.

INTRODUCTION: Patients with small renal masses (SRM) can be exposed to overdiagnosis and overtreatment. As such, active surveillance (AS) is recommended by all Guidelines for selected patients. However, it remains underutilized. One key reason is the lack of consensus on the factors prompting delayed intervention (DI). Herein we provide an updated overview of the triggers for DI in patients with SRMs initially undergoing AS. EVIDENCE ACQUISITION: A systematic review of the English-language literature was performed according to the PRISMA statement recommendations using the MEDLINE, Cochrane Central Register of Controlled Trials and Web of Science databases. EVIDENCE SYNTHESIS: Overall, 10 prospective studies including 1870 patients were included. Median patient age ranged between 64 and 75 years, while median tumor size between 1.7 cm to 2.3 cm. The proportion of cystic SRMs ranged from 0% to 30%. Baseline renal tumor biopsy was performed in 7-45.2% of patients. Among these, malignant histology was found in 28.5%-83.3% of cases. Overall, the median growth rate of SRMs ranged between 0.10 and 0.27 cm/year. The proportion of patients undergoing DI ranged between 7% and 44%, after a median AS period of 12-27 months. The most commonly performed type of DI was surgery. Of resected SRMs, 0% to 30% were benign. The actual triggers for DI were either tumor-related (renal mass growth, stage progression, development of local complications/symptoms) or patient-related (patient preference, improved medical conditions, or qualification for other surgical procedures). At a median follow-up of 21.7 - 57-6 months, the proportion of patients experiencing metastatic disease, cancer-specific and other-cause mortality was 0-3.1%, 0-4% and 0-45.6%, respectively. CONCLUSIONS: The available evidence shows that both tumor-related and patient-related factors are ultimate triggers for DI in patients with SRMs undergoing AS. However, the level of evidence is still low and further research is needed to individualize AS strategies according to both tumor biology and patient-related characteristics and values.

Rates and Predictors of Perioperative Complications in Cytoreductive Nephrectomy: Analysis of the Registry for Metastatic Renal Cell Carcinoma.

BACKGROUND: Cytoreductive nephrectomy (CN) plays an important role in the treatment of a subgroup of metastatic renal cell carcinoma (mRCC) patients. OBJECTIVE: We aimed to evaluate morbidity associated with this procedure and identify potential predictors thereof to aid patient selection for this procedure and potentially improve patient outcomes. DESIGN, SETTING, AND PARTICIPANTS: Data from 736 mRCC patients undergoing CN at 14 institutions were retrospectively recorded in the Registry for Metastatic RCC (REMARCC). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Logistic regression analysis was used to identify predictors for intraoperative, any-grade (AGCs), low-grade, and high-grade (HGCs) postoperative complications (according to the Clavien-Dindo classification) as well as 30-d readmission rates. RESULTS AND LIMITATIONS: Intraoperative complications were observed in 69 patients (10.9%). Thrombectomy (odds ratio [OR] 1.38, 95% confidence interval [CI] 1.08-1.75, p = 0.009) and adjacent organ removal (OR 2.7, 95% CI 1.38-5.30) were significant predictors of intraoperative complications at multivariable analysis. Two hundred seventeen patients (29.5%) encountered AGCs, while 45 (6.1%) encountered an HGC, of whom 10 (1.4%) died. Twenty-four (3.3%) patients had multiple postoperative complications. Estimated blood loss (EBL; OR 1.49, 95% CI 1.08-2.05, p = 0.01) was a significant predictor of AGCs at multivariable analysis. CN case load (OR 0.13, 95% CI 0.03-0.59, p = 0.009) and EBL (OR 2.93, 95% CI 1.20-7.15, p = 0.02) were significant predictors solely for HGCs at multivariable analysis. Forty-one patients (11.5%) were readmitted within 30 d of surgery. No significant predictors were identified. Results were confirmed in a subanalysis focusing solely on patients treated in the contemporary targeted therapy era. CONCLUSIONS: Morbidity associated with CN is not negligible. Predictors of high-grade postoperative morbidity are predominantly indicators of complex surgery. EBL is a strong predictor of postoperative complications. CN case load correlates with lower high-grade morbidity and highlights the benefit of centralization of complex surgery. However, risks and benefits should be balanced when considering CN in mRCC patients. PATIENT SUMMARY: We studied patients with metastatic renal cancer to evaluate the outcomes associated with the surgical removal of the primary kidney tumor. We found that this procedure is often complex and adverse events are not uncommon. High intraoperative blood loss and a small number of cases performed at the treating center are associated with a higher rate of postoperative complications.