Association of Elevated C-Reactive Protein with Worsened Outcomes in Different Histologies of Renal Cortical Tumors: Analysis of the INMARC Registry.

BACKGROUND: To evaluate relationship between histological subtypes of renal cell carcinoma (RCC) and preoperative c-reactive protein (CRP). PATIENTS AND METHODS: We queried the International Marker Consortium for Renal Cancer database for patients affected by RCC. Patients were classified according to their histology: benign tumors, clear cell (cc) RCC, chromophobe (ch) RCC, papillary (p) RCC, and variant histology (vh) RCC; and according to CRP (mg/L): low CRP ≤5 and high CRP >5. Primary outcome was all-cause mortality (ACM). Secondary outcomes were cancer-specific mortality (CSM), recurrence and association between CRP and histology. Multivariable analysis (MVA) via Cox regression and multivariable logistic regression were fitted to elucidate predictors of outcomes. RESULTS: Total 3902 patients (high CRP n = 1266) were analyzed; median follow up 51 (IQR 20-91) months. On MVA elevated CRP was an independent risk factor associated with increased risk of ACM in benign tumors (HR 5.98, P < .001), ccRCC (HR 2.69, P < .001), chRCC (HR 3.99, P < .001), pRCC (HR 1.76, P = .009) and vhRCC (HR 2.97, P =.007). MVA for CSM showed CRP as risk factor in ccRCC (HR 2.77, P < .001), chRCC (HR 6.16, P = .003) and pRCC (HR 2.29, P = .011), while in vhRCC was not (P = .27). MVA for recurrence reported CRP as risk factor for ccRCC (HR 1.30, P = .013), while in chRCC (P = .33), pRCC (P = .34) and vhRCC (P = .52) was not. On multivariable logistic regression CRP was a predictor of pRCC (OR 1.003, P = .002), while decreasing CRP was associated with benign tumors (OR 0.994, P = .048). CONCLUSION: Elevated CRP was a robust predictor of worsened ACM in all renal cortical neoplasms. While most frequently observed in pRCC patients, elevated CRP was independently associated with worsened CSM in non-vhRCC. Conversely, elevated CRP was least likely to be noted in benign tumors, and elevation in this subgroup of patients should prompt further consideration for surveillance given increased risk of ACM. Further investigation is requisite.

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.

Preoperative Age and Its Impact on Long-Term Renal Functional Decline after Robotic-Assisted Partial Nephrectomy: Insights from a Tertiary Referral Center.

Background and Objectives: to investigate the impact of age on renal function deterioration after robotic-assisted partial nephrectomy (RAPN) focusing on a decline to moderate and severe forms of chronic kidney disease (CKD). Materials and Methods: This is a single center prospective analysis of patients who underwent RAPN. The outcomes include the development of de novo CKD-S 3a [estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2)] and de novo CKD-S 3b (eGFR < 45 mL/min/1.73/m2). Multivariable analysis (MVA) via Cox regression identified predictors for CKD-S 3a/b. Kaplan -Meier Analyses (KMA) were fitted for survival assessment. Multivariable linear regression was utilized to identify the predictors of last-eGFR. Results: Overall, 258 patients were analyzed [low age (<50) n = 40 (15.5%); intermediate age (50-70) n = 164 (63.5%); high age (>70) n = 54 (20.9%)] with a median follow-up of 31 (IQR 20-42) months. MVA revealed an increasing RENAL score [Hazard Ratio (HR) 1.32, p = 0.009], age 50-70 (HR 6.21, p = 0.01), age ≥ 70 (HR 10.81, p = 0.001), increasing BMI (HR 1.11, p < 0.001) and preoperative CKD 2 (HR 2.43, p = 0.014) are independent risk factors associated with an increased risk of CKD-S 3a; conversely, post-surgical acute kidney injury was not (p = 0.83). MVA for CKD-S 3b revealed an increasing RENAL score (HR 1.51, p = 0.013) and age ≥ 70 (HR 2.73, p = 0.046) are associated with an increased risk of CKD-S 3b. Linear regression analysis revealed increasing age (Coeff. -0.76, p < 0.001), increasing tumor size (Coeff. -0.31, p = 0.03), and increasing BMI (Coeff. -0.64, p = 0.004) are associated with decreasing eGFR at last follow-up. We compare the survival distribution of our cohort stratified by age elderly patients experienced worsened CKD-S 3a/b disease-free survival (p < 0.001; p < 0.001, respectively). Conclusions: Age is independently associated with a greater risk of significant and ongoing decline in kidney function following RAPN. Recognizing the impact of aging on renal function post-surgery can guide better management practices. Further investigations are required.

Robot-assisted laparoscopic nephrectomy: early outcome measures with the implementation of multimodal analgesia and intrathecal morphine via the acute pain service.

PURPOSE: The objective of this study was to perform a retrospective cohort analysis, in which we measured the association of an acute pain service (APS)-driven multimodal analgesia protocol that included preoperative intrathecal morphine (ITM) compared to historic controls (i.e., surgeon-driven analgesia protocol without ITM) with postoperative opioid use. METHODS: This was a retrospective cohort study in which the primary objective was to determine whether there was a decrease in median 24-h opioid consumption (intravenous morphine equivalents [MEQ]) among robotic nephrectomy patients whose pain was managed by the surgical team prior to the APS, versus pain managed by APS. Secondary outcomes included opioid consumption during the 24-48 h and 48-72 h period and hospital length of stay. To create matched cohorts, we performed 1:1 (APS:non-APS) propensity score matching. Due to the cohorts occurring at the different time periods, we performed a segmented regression analysis of an interrupted time series. RESULTS: There were 76 patients in the propensity-matched cohorts, in which 38 (50.0%) were in the APS cohort. The median difference in 24-h opioid consumption in the pre-APS versus APS cohort was 23.0 mg [95% CI 15.0, 31.0] (p < 0.0001), in favor of APS. There were no differences in the secondary outcomes. On segmented regression, there was a statistically significant drop in 24-h opioid consumption in the APS cohort versus pre-APS cohort (p = 0.005). CONCLUSIONS: The implementation of an APS-driven multimodal analgesia protocol with ITM demonstrated a beneficial association with postoperative 24-h opioid consumption following robot-assisted nephrectomy.

NCCN Guidelines® Insights: Kidney Cancer, Version 2.2024.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients with renal cell carcinoma (RCC). These NCCN Guidelines Insights focus on the systemic therapy options for patients with advanced RCC and summarize the new clinical data evaluated by the NCCN panel for the recommended therapies in Version 2.2024 of the NCCN Guidelines for Kidney Cancer.

Unraveling the BMI paradox in different renal cortical tumors: insights from the INMARC registry.

OBJECTIVE: To investigate impact of body mass index (BMI) on survival across different histologies and stages of renal cell carcinoma (RCC). METHODS: We conducted a retrospective multicenter analysis of clear cell (ccRCC) and non-ccRCC. Obesity was defined according to the WHO criteria (non-Asian BMI >30 Kg/m2, Asian BMI >27.5 Kg/m2). Multivariable analysis (MVA) via Cox regression model was conducted for all-cause (ACM), cancer-specific mortality (CSM) and recurrence. RESULTS: A total of 3,880 patients with a median follow-up of 31 (IQR 9-64) months were analyzed. Overall, 1,373 (35.3%) were obese; 2,895 (74.6%) were ccRCC and 985 (25.3%) were non-ccRCC (chRCC 246 [24.9%], pRCC 469 [47.6%] and vhRCC 270 [27.4%]). MVA in ccRCC revealed obesity associated with decreased risk of ACM, CSM and recurrence (hazard ratio [HR] 0.80, P = 0.044; HR 0.71, P = 0.039; HR 0.73, P = 0.012, respectively), while in non-ccRCC was not associated with decreased risk of ACM, CSM, and recurrence (P = 0.84, P = 0.53, P = 0.84, respectively). Subset analysis in stage IV ccRCC demonstrated obesity as associated with a decreased risk of ACM, CSM, and recurrence (HR 0.68, P = 0.04; HR 0.59, P = 0.01; HR 0.59, P = 0.01, respectively), while in stage I-III ccRCC was not (P = 0.21; P = 0.30; P = 0.19, respectively). CONCLUSION: Our findings refute a broad "obesity paradox" for RCC. Obesity was not associated with improved survival in non-ccRCC and in nonmetastatic ccRCC, while metastatic ccRCC patients with obesity had improved survival outcomes.

PADRES: a phase 2 clinical trial of neoadjuvant axitinib for complex partial nephrectomy.

OBJECTIVE: To report the results of PADRES (Prior Axitinib as a Determinant of Outcome of Renal Surgery, NCT03438708), a study investigating neoadjuvant axitinib for tumours of high complexity with imperative indication for partial nephrectomy (PN). METHODS: We conducted a single-arm phase II clinical trial of localized (cT1b-cT3M0) clear-cell renal cell carcinoma (RCC) patients with imperative indications for nephron preservation, where PN is a high-risk procedure due to complexity (RENAL score 10-12). Axitinib 5 mg was administered twice daily for 8 weeks with repeat imaging at completion, followed by surgery. The primary outcome was successful completion of planned PN following axitinib treatment. Secondary objectives included changes in tumour diameter, RENAL nephrometry score, renal function and Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, and surgical complications. RESULTS: Twenty-seven patients were enrolled (median age 69 years). Prior to therapy, twenty patients (74.0%) had ≥ clinical T3a staged tumours. Axitinib resulted in reductions in tumour diameter (7.5 vs 6.2 cm; P < 0.001) and RENAL score (11 vs 10; P < 0.001). Nine patients (33.3%) had partial response based on RECIST and nine (33.3%) were clinically downstaged. PN was performed in twenty patients (74.0%); twenty-five patients (96.2%) had negative margins. Six patients (22.2%) had Clavien III-IV complications. The median change in estimated glomerular filtration rate (preoperative to last follow-up) was 8.5 mL/min/1.73 m2 . CONCLUSION: Neoadjuvant axitnib resulted in reductions in tumour size and complexity, enabling safe and feasible PN and functional preservation in patients with complex renal masses and imperative indication.

A systematic review of robot-assisted partial nephrectomy outcomes for advanced indications: Large tumors (cT2-T3), solitary kidney, completely endophytic, hilar, recurrent, and multiple renal tumors.

Objective: Robot-assisted partial nephrectomy (RAPN) has become widely used for treatment of renal cell carcinoma and it is expanding in the field of complex renal masses. The aim of this systematic review was to analyze outcomes of RAPN for completely endophytic renal masses, large tumors (cT2-T3), renal cell carcinoma in solitary kidney, recurrent tumors, completely endophytic and hilar masses, and simultaneous and multiple tumors. Methods: A comprehensive search in the PubMed, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials databases was performed in December 2022 for English language papers. The primary endpoint was to evaluate the role of RAPN in the setting of each category of complex renal masses considered. The secondary endpoint was to evaluate the surgical and functional outcomes. Results: After screening 1250 records, 43 full-text manuscripts were selected, comprising over 8500 patients. Twelve and thirteen studies reported data for endophytic and hilar renal masses, respectively. Five and three studies reported outcomes for cT2-T3 and solitary kidney patients, respectively. Four studies focused on redo-RAPN for recurrent tumors. Two studies investigated simultaneous bilateral renal masses and five reports focused on multiple tumor excision in ipsilateral kidney. Conclusion: Over the past decade, evidence supporting the use of RAPN for the most challenging nephron-sparing surgery indications has continuously grown. Although limitations remain including study design and lack of detailed long-term functional and oncological outcomes, the adoption of RAPN for the included advanced indications is associated with favorable surgical outcomes with good preservation of renal function without compromising the oncological result. Certainly, a higher likelihood of complication might be expected when facing extremely challenging cases. However, none of these indications should be considered per se an exclusion criterion for performing RAPN. Ultimately, a risk-adapted approach should be employed.

Development of a novel score (RENSAFE) to determine probability of acute kidney injury and renal functional decline post surgery: A multicenter analysis.

OBJECTIVE: To create and validate 2 models called RENSAFE (RENalSAFEty) to predict postoperative acute kidney injury (AKI) and development of chronic kidney disease (CKD) stage 3b in patients undergoing partial (PN) or radical nephrectomy (RN) for kidney cancer. METHODS: Primary objective was to develop a predictive model for AKI (reduction >25% of preoperative eGFR) and de novo CKD≥3b (<45 ml/min/1.73m2), through stepwise logistic regression. Secondary outcomes include elucidation of the relationship between AKI and de novo CKD≥3a (<60 ml/min/1.73m2). Accuracy was tested with receiver operator characteristic area under the curve (AUC). RESULTS: AKI occurred in 452/1,517 patients (29.8%) and CKD≥3b in 116/903 patients (12.8%). Logistic regression demonstrated male sex (OR = 1.3, P = 0.02), ASA score (OR = 1.3, P < 0.01), hypertension (OR = 1.6, P < 0.001), R.E.N.A.L. score (OR = 1.2, P < 0.001), preoperative eGFR<60 (OR = 1.8, P = 0.009), and RN (OR = 10.4, P < 0.0001) as predictors for AKI. Age (OR 1.0, P < 0.001), diabetes mellitus (OR 2.5, P < 0.001), preoperative eGFR <60 (OR 3.6, P < 0.001) and RN (OR 2.2, P < 0.01) were predictors for CKD≥3b. AUC for RENSAFE AKI was 0.80 and 0.76 for CKD≥3b. AKI was predictive for CKD≥3a (OR = 2.2, P < 0.001), but not CKD≥3b (P = 0.1). Using 21% threshold probability for AKI achieved sensitivity: 80.3%, specificity: 61.7% and negative predictive value (NPV): 88.1%. Using 8% cutoff for CKD≥3b achieved sensitivity: 75%, specificity: 65.7%, and NPV: 96%. CONCLUSION: RENSAFE models utilizing perioperative variables that can predict AKI and CKD may help guide shared decision making. Impact of postsurgical AKI was limited to less severe CKD (eGFR<60 ml/min 71.73m2). Confirmatory studies are requisite.

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.

Partial versus radical nephrectomy for complex renal mass: multicenter comparative analysis of functional outcomes (Rosula collaborative group).

BACKGROUND: Utility of partial nephrectomy (PN) for complex renal mass (CRM) is controversial. We determined the impact of surgical modality on postoperative renal functional outcomes for CRM. METHODS: We retrospectively analyzed a multicenter registry (ROSULA). CRM was defined as RENAL Score 10-12. The cohort was divided into PN and radical nephrectomy (RN) for analyses. Primary outcome was development of de-novo estimated glomerular filtration rate (eGFR)<45 mL/min/1.73 m2. Secondary outcomes were de-novo eGFR<60 and ΔeGFR between diagnosis and last follow-up. Cox proportional hazards was used to elucidate predictors for de-novo eGFR<60 and <45. Linear regression was utilized to analyze ΔeGFR. Kaplan-Meier Analysis (KMA) was performed to analyze 5-year freedom from de-novo eGFR<60 and <45. RESULTS: We analyzed 969 patients (RN=429/PN=540; median follow-up 24.0 months). RN patients had lower BMI (P<0.001) and larger tumor size (P<0.001). Overall postoperative complication rate was higher for PN (P<0.001), but there was no difference in major complications (Clavien III-IV; P=0.702). MVA demonstrated age (HR=1.05, P<0.001), tumor-size (HR=1.05, P=0.046), RN (HR=2.57, P<0.001), and BMI (HR=1.04, P=0.001) to be associated with risk for de-novo eGFR<60 mL/min/1.73 m2. Age (HR=1.03, P<0.001), BMI (HR=1.06, P<0.001), baseline eGFR (HR=0.99, P=0.002), tumor size (HR=1.07, P=0.007) and RN (HR=2.39, P<0.001) were risk factors for de-novo eGFR<45 mL/min/1.73 m2. RN (B=-10.89, P<0.001) was associated with greater ΔeGFR. KMA revealed worse 5-year freedom from de-novo eGFR<60 (71% vs. 33%, P<0.001) and de-novo eGFR<45 (79% vs. 65%, P<0.001) for RN. CONCLUSIONS: PN provides functional benefit in selected patients with CRM without significant increase in major complications compared to RN, and should be considered when technically feasible.

Diabetes, Obesity, and Pathological Upstaging in Renal Cell Carcinoma: Results From a Large Multi-institutional Consortium.

PURPOSE: We sought to determine whether clinical risk factors and morphometric features on preoperative imaging can be utilized to identify those patients with cT1 tumors who are at higher risk of upstaging (pT3a). MATERIALS AND METHODS: We performed a retrospective international case-control study of consecutive patients treated surgically with radical or partial nephrectomy for nonmetastatic renal cell carcinoma (cT1 N0) conducted between January 2010 and December 2018. Multivariable logistic regression models were used to study associations of preoperative risk factors on pT3a pathological upstaging among all patients, as well as subsets with those with preoperative tumors ≤4 cm, renal nephrometry scores, tumors ≤4 cm with nephrometry scores, and clear cell histology. We also examined association with pT3a subsets (renal vein, sinus fat, perinephric fat). RESULTS: Among the 4,092 partial nephrectomy and 2,056 radical nephrectomy patients, pathological upstaging occurred in 4.9% and 23.3%, respectively. Among each group independent factors associated with pT3a upstaging were increasing preoperative tumor size, increasing age, and the presence of diabetes. Specifically, among partial nephrectomy subjects diabetes (OR=1.65; 95% CI 1.17, 2.29), male sex (OR=1.62; 95% CI 1.14, 2.33), and increasing BMI (OR=1.03; 95% CI 1.00, 1.05 per 1 unit BMI) were statistically associated with upstaging. Subset analyses identified hilar tumors as more likely to be upstaged (partial nephrectomy OR=1.91; 95% CI 1.12, 3.16; radical nephrectomy OR=2.16; 95% CI 1.44, 3.25). CONCLUSIONS: Diabetes and higher BMI were associated with pathological upstaging, as were preoperative tumor size, increased age, and male sex. Similarly, hilar tumors were frequently upstaged.

Outcomes of Consolidative Nephrectomy following Primary Immunotherapy in Advanced Renal Cell Carcinoma: A Multicenter Analysis.

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.

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.

Recent Advances in the Management of Localized and Locally Advanced Renal Cell Carcinoma: A Narrative Review.

Purpose: To review the current status of surgical and procedural treatments for renal cell carcinoma (RCC), focusing on oncological and functional outcomes, and the use of techniques for advanced disease over the last 10 years. Findings: Partial nephrectomy (PN) has become the reference standard for most T1 and T2 masses. In cT2 RCC, PN exhibits oncological equivalence and improved functional outcomes compared to radical nephrectomy (RN). Additionally, emerging data suggest that PN may be used to treat cT3a RCC. The robot-assisted platform is increasingly used to treat locally advanced RCC. Studies suggest safety and feasibility of robotic RN and robotic inferior vena cava tumor thrombectomy. Additionally, single-port robot-assisted laparoscopic approaches are comparable to multiport approaches in select patients. Long-term data show that cryoablation, radiofrequency ablation, and microwave ablation are equipotent in management of small renal masses. Emerging data suggest that microwave may effectively treat cT1b masses.

Partial or radical nephrectomy for complex renal mass: a comparative analysis of oncological outcomes and complications from the ROSULA (Robotic Surgery for Large Renal Mass) Collaborative Group.

PURPOSE: To compare outcomes of robotic-assisted partial nephrectomy (RAPN) and minimally invasive radical nephrectomy (MIS-RN) for complex renal masses (CRM). METHODS: We conducted a retrospective multicenter analysis of CRM patients who underwent MIS-RN and RAPN. CRM was defined as RENAL score 10-12. Primary outcome was overall survival (OS). Secondary outcomes were cancer-specific survival (CSS), recurrence, and complications. Multivariable analysis (MVA) and Kaplan-Meier Analysis (KMA) were used to analyze functional and survival outcomes for RN vs. PN by pathological stage. RESULTS: 926 patients were analyzed (MIS-RN = 437/RAPN = 489; median follow-up 24.0 months). MVA demonstrated lack of transfusion (HR = 1.63, p = 0.005), low-grade (HR = 1.18, p = 0.018) and smaller tumor size (HR = 1.05, p < 0.001) were associated with OS. Younger age (HR = 1.01, p = 0.017), high-grade (HR = 1.18, p = 0.017), smaller tumor size (HR = 1.05, p < 0.001), and lack of transfusion (HR = 1.39, p = 0.038) were associated with CSS. Increasing tumor size (HR = 1.18, p < 0.001), high-grade (HR = 3.21, p < 0.001), and increasing age (HR = 1.02, p = 0.009) were independent risk factors for recurrence. Type of surgery was not associated with major complications (p = 0.094). For KMA of MIS-RN vs. RAPN for pT1, pT2 and pT3, 5-year OS was 85% vs. 88% (p = 0.078); 82% vs. 80% (p = 0.442) and 84% vs. 83% (p = 0.863), respectively. 5-year CSS was 98% for both procedures (p = 0.473); 94% vs. 92% (p = 0.735) and 91% vs. 90% (p = 0.581). 5-year non-CSS was 87% vs. 93% (p = 0.107); 87% for pT2 (p = 0.485) and 92% for pT3 for both procedures (p = 0.403). CONCLUSION: RAPN in CRM is not associated with increased risk of complications or worsened oncological outcomes when compared to MIS-RN and may be preferred when clinically indicated.

Gender-specific counselling of patients with upper tract urothelial carcinoma and Lynch syndrome.

PURPOSE: Lynch syndrome (LS) is an autosomal dominant genetic syndrome resulting in a wide spectrum of malignancies caused by germline mutations in mismatch repair genes (MMR). Gene mutations have different effects and penetrance between the two genders. The aim of this review is to offer a gender-specific evidence-based clinical guide on diagnosis, screening, surveillance, and counselling of UTUC patients with LS. METHODS: Using MEDLINE, a non-systematic review was performed including articles between 2004 and 2022. English language original articles, reviews, and editorials were selected based on their clinical relevance. RESULTS: Upper tract urothelial carcinoma (UTUC) is the third most common malignancy in Lynch syndrome. Up to 21% of new UTUC cases may have unrecognized LS as the underlying cause. LS-UTUC does not have a clear gender prevalence, even if it seems to slightly prefer the male gender. The MSH6 variant is significantly associated with female gender (p < 0.001) and with gynecological malignancies. Female MSH2 and MLH1 carriers have higher rates for endometrial and ovarian cancer with respect to the general population, while male MSH2 and MLH1 carriers have, respectively, higher rate of prostate cancer and upper GI tract, or biliary or pancreatic cancers. Conflicting evidence remains on the association of testicular cancer with LS. CONCLUSION: LS is a polyhedric disease, having a great impact on patients and their families that requires a multidisciplinary approach. UTUC patients should be systematically screened for LS, and urologists have to be aware that the same MMR mutation may lead to different malignancies according to the patient's gender.

Age-Related Differences in Oncological Outcomes in Renal Cell Carcinoma: Impact of Functional Conservation as Measured by Postoperative eGFR.

INTRODUCTION: We sought to determine whether loss of renal function increases risk of recurrence and metastases in renal cell carcinoma (RCC), and whether this impact was age-related. MATERIALS AND METHODS: We performed a retrospective analysis of the International Marker Consortium for Renal Cancer (INMARC) registry. Patients were separated into younger (<65 years old) and elder (≥65 years old) age groups, and rates of de novo estimated glomerular filtration rate (eGFR<45 mL/min/1.73m2 [eGFR<45]) were calculated. Multivariable analysis (MVA) was conducted for predictors of progression-free survival (PFS) and all-cause mortality (ACM). Kaplan-Meier Analysis (KMA) was conducted for PFS and overall survival (OS) in younger and elder age groups stratified by functional status. RESULTS: We analyzed 1805 patients (1113 age<65, 692 age≥65). On MVA in patients <65, de novo eGFR<45 was independently associated with greater risk for worsened progression (HR=1.61, P=.038) and ACM (HR=1.82, P=.018). For patients ≥65, de novo eGFR<45 was not independently associated with progression (P=.736), or ACM (P=.286). Comparing patients with de novo eGFR<45 vs. eGFR ≥45, KMA demonstrated worsened 5-year PFS and OS in patients <65 (PFS: 68% vs. 86%, P<.001; OS: 73% vs. 90%, P<.001), while in patients ≥65, only 5-year OS was worsened (77% vs. 81%, P<.021). CONCLUSION: Development of de novo eGFR<45 was associated with more profound impact on patients <65 compared to patients ≥65, being an independent risk factor for PFS and ACM. The mechanisms of this phenomenon are unclear but underscore desirability for nephron preservation when safe and feasible in younger patients.