Mason, Ross

BACKGROUND: Bim (BCL-2-interacting mediator of cell death) is a downstream pro-apoptotic signaling molecule activated by the PD-1 pathway. OBJECTIVE: We sought to determine if Bim expression in peritumoral T-lymphocytes (PTLs) is associated with survival in patients with metastatic clear cell renal cell carcinoma (ccRCC). METHODS: Immunohistochemistry staining for Bim was performed on paraffin-embedded tumor tissue blocks from patients with metastatic ccRCC who underwent nephrectomy between 1990-2004. Associations of Bim expression with cancer-specific survival (CSS) and overall survival (OS) from date of metastasis were evaluated using multivariable Cox regression models, adjusting for age, sex, and metastases-score. RESULTS: 525 patients with metastatic ccRCC, of whom 169 (32%) had metastases at time of nephrectomy were studied. After multivariable adjustment, high Bim expression remained associated with worse CSS (HR = 1.31; 95% CI 1.07–1.59; p = 0.008) and OS (HR = 1.28; 95% CI 1.06–1.55; p = 0.01). The interaction between Bim and PD-L1 was not statistically significant for CSS ( p = 0.68) or OS ( p = 0.57), suggesting that the associations between Bim and survival outcomes were not significantly different based on tumor PD-L1 expression. CONCLUSION: High Bim expression in PTLs at nephrectomy is prognostic of worse CSS and OS in patients with metastatic ccRCC, irrespective of tumor PD-L1 expression. The role of earlier PD-1/PD-L1-directed therapy warrants evaluation in these patients.

Objectives To evaluate the peri‐operative and renal functional outcomes of patients undergoing synchronous bilateral partial nephrectomy (PN) or percutaneous cryoablation (PCA). Patients and Methods We retrospectively reviewed our institutional nephrectomy and renal mass ablation registries to identify all patients with synchronous bilateral renal masses who underwent simultaneous bilateral PN ( n = 76) or PCA ( n = 13) between 1974 and 2013. Changes in estimated glomerular filtration rate (eGFR) as well as peri‐operative complications are descriptively reported for each procedure. Results The number of treated renal masses in the 76 patients in the PN group and the 13 patients in the PCA group was 249 and 28, respectively. The median (interquartile range [IQR]) age at treatment was 62 (50, 71) years for the PN group and 67 (56, 72) for the PCA group. The median (IQR) maximum tumour sizes were 4.6 (3.4, 6.5) cm and 2.6 (2.4, 3.2) cm for the PN and PCA groups, respectively. The median (IQR) length of hospital stay was 7 (5, 8) days for the PN group and 1 (1, 10) days for the PCA group. The median (IQR) change in eGFR from baseline to discharge was −32 (−46, −15)% for the PN group and −17% (−33, −3) for the PCA group. By 3 months, median (IQR) renal function improved, with changes of −9 (−19, 0)% and −8 (−11, 15)%, respectively, compared with baseline. No patient in either group required renal replacement therapy in the peri‐operative period. Early postoperative complications (within 30 days) occurred in 16 patients (21.6%) in the PN and four patients in the PCA group. In particular, angioembolization for bleeding was required in the postoperative period in two patients (2.7%) in the PN and one patient in the PCA group. Conclusions Our experience suggests that synchronous bilateral PN or PCA are feasible treatment options for select patients presenting with bilateral renal masses. In select cases, both approaches appear to have reasonable rates of peri‐operative complications and effects on renal function.

704 Background: While the probability of benign versus malignant histology based on renal tumor size has been described, this alone does not sufficiently inform decision-making in the modern era since indolent malignant tumors can be surveilled. Thus, we sought to characterize the probability of indolent versus aggressive histology based on radiographic tumor size. Methods: We evaluated patients who underwent radical or partial nephrectomy at Mayo Clinic for a pT1-2, pNx/0, M0 solid renal tumor between 1990-2010. Pathology was reviewed by one genitourinary pathologist. Benign tumors, low grade (1-2) clear cell and papillary renal cell carcinoma (RCC), and any chromophobe, clear cell papillary, mucinous tubular and spindle cell, SDH-B deficient, and tubulocystic RCC were considered indolent. All other histologies were considered aggressive, as were any malignancies with necrosis or sarcomatoid differentiation. Cancer-specific survival (CSS) was estimated using the Kaplan Meier method. Logistic regression models were used to estimate the probability of malignant and aggressive histology based on tumor size. Sex-stratified analyses were also performed. Results: Of the 2650 patients included, there were 1773 patients with indolent tumors (303 benign; 1470 malignant) and 877 with aggressive tumors. Ten-year CSS was 96% for indolent malignant tumors and 82% for aggressive tumors. The predicted probabilities of any malignant histology and aggressive malignant histology increased with tumor size (Table; 1-7cm point estimates shown). For example, a 3 cm tumor had an 87% probability of malignancy and a 27% probability of being aggressive. For any given tumor size, men had a greater probability of aggressive histology than women. Conclusions: We present tumor size-based estimates of the probability of aggressive histology for renal masses. This information should be useful for patient counseling and treatment decision-making. [Table: see text]

703 Background: Clinical and pathologic factors alone have limited prognostic ability in patients with metastatic clear cell renal cell carcinoma (ccRCC). We sought to determine if tissue biomarkers, along with our previously reported clinical metastases score, can be used to predict cancer specific survival (CSS) in patients with metastatic ccRCC. Methods: Patients with metastatic ccRCC who underwent nephrectomy between 1990-2004 were identified using the Mayo Clinic Nephrectomy Registry. Sections from paraffin-embedded primary tumor tissue blocks were used for immunohistochemistry staining for PD-1, B7-H1 (PD-L1), B7-H3, Bim (downstream pro-apoptotic signaling molecule in PD-1 pathway), CA-IX, IMP3, Ki67, and survivin. CSS was the primary outcome. Biomarkers that were significantly associated with CSS after adjusting for the metastases score were used to develop a biomarker-specific multivariable model using a bootstrap resampling approach and forward selection. Predictive ability was summarized using a bootstrap-corrected c-index. Results: The cohort included 602 patients, 192 (32%) with metastases at diagnosis and 410 (68%) who developed metastases after nephrectomy. Median follow-up among survivors was 9.6 years (IQR 4.2,12.8) and 504 patients died of RCC. Bim, IMP3, Ki67, and survivin expression were significantly associated with CSS after adjusting for the metastases score and were used to develop a biomarker-specific model. High Bim (HR 1.44; 95%CI 1.16-1.78; p < 0.001), high survivin (HR 1.35; 95%CI 1.08-1.68; p = 0.008), and the metastases score (HR 1.13 per one point; 95%CI 1.10-1.16; p < 0.001) were retained as independent predictors in the final multivariable model (c-index 0.69). Conclusions: We created a prognostic model combining the clinical metastases score and two primary tissue expression biomarkers, Bim and survivin, for patients with metastatic RCC who underwent nephrectomy. External validation will be required prior to clinical use.

672 Background: The optimal sequence of cytoreductive nephrectomy (CN) and targeted therapy (TT) for patients with metastatic renal cell carcinoma (mRCC) remains to be established. Herein, we compared overall survival (OS) between patients with mRCC receiving initial CN with or without subsequent TT versus initial TT with or without subsequent CN. Methods: The National Cancer Database (NCDB) was used to identify patients diagnosed between 2006-2013 with RCC that was metastatic at diagnosis who received CN, TT, or both. Those with other prior cancer history were excluded. The cumulative incidence of receiving TT after CN and CN after TT were evaluated, with death prior to second treatment as a competing risk. To account for treatment selection bias, inverse probability of treatment weighting (IPTW) was performed based on the propensity to receive initial CN or TT. OS from diagnosis was compared using Cox regression. Sensitivity analyses were performed. Results: The cohort included 15,068 patients, of whom 6,731 underwent initial CN and 8,337 underwent initial TT. At 6 months from diagnosis, the probability of receiving TT after CN was 46.2%, with 13.6% of patients having died after initial CN prior to receiving TT. Meanwhile, the probability at 6 months of undergoing CN after initial TT was 4.4%, with 38.3% of this group having died prior to undergoing CN. In the IPTW analysis, baseline characteristics were balanced (standardized difference < 0.1). Initial CN was associated with improved OS compared to initial TT (median 16.5 vs 9.2 months; HR 0.62; 95%CI 0.61-0.64; p < 0.001). Findings were similar in all sensitivity analyses (propensity score matching and adjustment; regression adjustment; 6-month landmark analysis; clear cell mRCC subset; exclusion of patients who had metastasectomy). Conclusions: Although initial CN was associated improved OS versus initial TT in this national dataset, initial CN was associated with delays in, and even death prior to, receipt of TT. As such, while the survival data here support initial CN in appropriate surgical candidates, continued efforts to develop the optimal multimodal approach to these patients are warranted.

Objectives To compare renal functional changes after percutaneous cryoablation ( PCA ) or partial nephrectomy ( PN ). Patients and Methods Patients who underwent PCA or PN for a solitary renal mass at a single institution were identified (2003–2013). Estimated glomerular filtration rates ( eGFR s) were calculated at baseline, discharge, and at the 3‐month follow‐up using the Chronic Kidney Disease Epidemiology Collaboration equation. Changes in renal function were compared between groups using 1:1 propensity score ( PS ) matching, adjustment for PS quintile, and inverse probability weighting ( IPW ). Results There were 2 040 procedures available for the PS analyses, including 448 PCA and 1 592 PN . After PS adjustments, there were no significant differences in baseline clinical features between PCA and PN patients. In the PS ‐matched analysis, the change in eGFR from baseline to discharge for PCA and PN patients was −3.1 and −1.1 mL /min/1.73 m 2 , respectively ( P = 0.038), with percentage changes of −4.5% and 0% respectively ( P = 0.006). From baseline to the 3‐month follow‐up, the absolute change in eGFR for PCA and PN patients was −4.3 and −2.1 mL /min/1.73 m 2 , respectively ( P = 0.008), and the percentage change was −6.1% and −2.4% respectively ( P = 0.005). Similar results were obtained after adjusting for PS quintiles and in the IPW analysis. Importantly, the rate of chronic kidney disease stage progression at the 3‐month follow‐up was similar between the groups (21% vs 18%). Conclusions Our results confirm that both PCA and PN have a minor impact on renal function. While we observed a statistically greater decline in eGFR after PCA compared with PN , both approaches result in excellent preservation of renal function.

355 Background: While neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) improves survival compared to RC alone for urothelial carcinoma of the bladder (UCB), the bulk of this survival benefit has been attributed to patients who achieve ypT0 status at RC. The implications of having residual UCB (rUCB) at RC after NAC are less clear. As such, we evaluated whether the outcomes for patients with rUCB after NAC differ from stage-matched RC patients who did not receive NAC. Methods: Patients undergoing RC for UCB between 1981-2010 at Mayo Clinic were identified. All RC pathology was re-reviewed by a single genitourinary pathologist. Patients who received NAC were matched 1:2 to patients not exposed to NAC based on pT and pN-stage, margin status, and year of RC. Kaplan Meier and Cox regression analyses were used to evaluate the associations between NAC and cancer-specific (CSS) and overall survival (OS), stratified by presence of rUCB (i.e. (y)pT0N0 and non-(y)pT0N0). Results: We matched 111 patients who underwent NAC + RC to 222 RC-alone patients. Median age was 68 years (IQR 60,74); 59 (18%) were female. Median follow-up among survivors was 7.2 years (IQR 6,16). A total of 248 patients died; 148 died from UCB. In patients without rUCB at RC, there were no differences in 5-yr CSS (86% vs. 90%, p=0.85) or OS (82% vs. 84%, p=0.46) between patients who did and did not receive NAC. Moreover, on multivariable analysis, NAC exposure was not associated with CSS (HR=1.0; 95%CI 0.3-3.1; p=0.9) or OS (HR=0.9; 95%CI 0.4-1.9; p=0.8) in this subgroup. Among patients with rUCB, receipt of NAC was associated with significantly worse 5-yr CSS (32% vs. 56%, p<0.001) and OS (25% vs. 48%, p<0.001). NAC exposure remained independently associated with worse CSS (HR=2.2; 95%CI 1.6-3.1; p<0.001) and OS (HR=2.0; 95%CI 1.5-2.7; p<0.001) among these patients. Conclusions: While patients who achieve a complete response to NAC have excellent survival outcomes, patients with residual UCB at RC after NAC have a worse prognosis compared to stage-matched RC patients not exposed to NAC. Such patients should be considered for enrolment in novel adjuvant therapy trials.

Objective To evaluate the association between renal tumour complexity and outcomes in a large cohort of patients undergoing percutaneous cryoablation ( PCA ). Patients and Methods Patients with renal tumours treated with PCA were identified using our prospectively maintained ablation registry (2003–2015). Salvage procedures and inherited tumour syndromes were excluded. The associations between R.E.N.A.L. nephrometry score ( NS ) and risk of complications, renal function impairment, local failure and cancer‐specific mortality ( CSM ) were evaluated using univariate and multivariable logistic, linear and Cox regression models. Results The cohort included 618 tumours treated during 580 procedures in 565 patients. The median (interquartile range [ IQR ]) follow‐up was 34 (14.66) months. Complications (any grade) during a procedure ( n [total] = 87, 15%) were more frequent with higher NS ( NS 4–6: 10%; NS 7–9: 14%; NS 10–12: 36%; P < 0.001). Higher NS was independently associated with risk of complications (odds ratio [ OR ; per 1 point] = 1.3; 95% confidence interval [ CI ] 1.2–1.5; P < 0.001). Of all the NS components, tumour size was the most strongly associated with complication risk ( OR 3.4; 95% CI 2.2–5.2; P < 0.001). The median ( IQR ) decline in glomerular filtration rate ( GFR ) from baseline was 9% (0, 22) at last follow‐up. Each additional point in NS was associated with a 1.3% (95% CI 0.4–2.1; P = 0.005) greater GFR decline from baseline. NS was not significantly associated with local failure ( n [total] = 14, 2%; NS 4–6: 2%; NS 7–9: 3%; NS 10–12: 5%; P = 0.32) or CSM ( n [total] = 8, 2%; NS 4–6: 2%; NS 7–9: 3%; NS 10–12: 2%; P = 0.88). Conclusion In high‐complexity tumours PCA was associated with a tumour size‐driven increased risk of post‐procedural complications. Higher NS was associated with a small, clinically minor additional decline in renal function. Risks for local failure and CSM were low, regardless of tumour complexity.