Cheville, John C.

500 Background: The Memorial Sloan Kettering Cancer Center (MSKCC) prognostic score is based on clinical parameters and has several limitations. We analyzed whole blood mRNA expression in mCCRCC patients (pts) and compared it to MSKCC for predicting overall survival (OS). Methods: A prospective collection of whole blood in PAXgene RNA tubes from mCCRCC pts was performed between 2011 and 2015 with uniform processing. A discovery set (DS) of 19 randomly selected pt samples was used to generate whole transcriptome RNA sequencing and signatures describing differential gene expression patterns associated with OS. We calculated the fragment per kilobase of transcript per million (FPKM) of each transcript and gene to identify correlations between the differentially expressed genes and MSKCC score. Candidate genes were selected based on statistical significance (p<0.05) and associations with OS. In an independent validation set (VS) of 47 pts with mCCRCC, we used the nCounter Analysis System (NanoString Technologies, Seattle, WA, USA) to quantify gene transcript expression selected from the DS. Cox regression and Kaplan-Meier analysis were used for association of candidate mRNAs in the VS with OS (time of metastatic recurrence to death or last follow-up). We compared our gene signature to the MSKCC prognostic score for poor versus good survival. Results: In the DS, at a median follow-up of 4.13 years (yrs) (range: 1.3-4.5), 11 patients had died. We identified eighteen genes in the DS with statistically significant differential gene expression patterns and ability to discriminate patient OS. In the VS at a median follow-up of 4.9 yrs (range: 0.1-11.3), twenty-five patients had died. We confirmed two of the eighteen selected genes that had strong prognostic significance: BAG1 [hazard ratio (HR) 0.31, p=0.007] and NOP56 [HR 0.28, p=0.004]. Comparing OS between good and poor outcome groups for these 2 scores, our two-gene panel had higher prognostic ability (HR 20.07, p <0.0001) than the MSKCC prognostic score (HR 3.19, p 0.04). Conclusions: Prognostic value of using whole blood mRNA gene profiling in mCCRCC is feasible and should be prospectively confirmed in larger studies.

433 Background: Current guidelines suggest that percutaneous thermal ablation (PTA) can be utilized in those with significant comorbidity who are unable to tolerate surgery (radical or partial nephrectomy). However, the use of PTA in healthy patients, who are otherwise candidates for surgery, has been limited. Here, we reviewed our institutional experience in healthy patients electing to undergo PTA, specifically cryoablation. Methods: We identified patients ≤65 years undergoing percutaneous cryoablation for solitary, non-metastatic renal masses <7cm (cT1). We further limited our cohort to patients with an ASA score of 1 or 2, and in whom pre-operative eGFR was >60. Clincopathologic characteristics and recurrence patterns (local recurrence within the kidney versus metastatic disease) were evaluated. Results: Between March 2003 and December 2015, 705 patients underwent cryoablation, of whom 43 (6.1%) were deemed to be “healthy”. Median age of this cohort was 57 years (IQR 52−62), with pre-ablation eGFR of 75.6 (IQR 69.0-86.3). Seven patients (16.3%) had a prior partial nephrectomy, and 5 (11.6%) had a solitary kidney. The majority (40, 93.0%) of ablated masses were cT1a, with 3 (7.0%) being cT1b. Median tumor size was 2.0 cm. 27 masses (63.7%) were biopsy-proven renal cell carcinoma (RCC) and 6 (13.6%) were benign; histology was unknown in 10 (22.7%). Follow-up imaging was available for 37 patients. Median radiological follow-up was 22 months (IQR 9-42), during which time 2 patients developed metastatic disease and 1 developed local recurrence; all events were in patients with biopsy-proven RCC. No patients died from RCC during this time period. Conclusions: In this single institution cohort of “healthier” patients with cT1 solitary renal masses, cryoablation offered reasonable short term oncologic control. While longer follow-up data are needed to evaluate for durability, cryoablation in healthy patients, particularly those with challenging surgical anatomy, warrants further study.

364 Background: Venous thromboembolism (VTE) has been reported to occur in 2-5% of patients undergoing radical cystectomy (RC). While VTE is an important cause of perioperative morbidity, the association of these events with long-term cancer prognosis has not been established. Herein, we evaluated the association of perioperative VTE with patients’ risk of subsequent disease recurrence and mortality. Methods: We reviewed 2889 patients undergoing RC between 1980−2009 at the Mayo Clinic to identify patients diagnosed with a VTE within 90 days of RC. These cases were then matched in a 1:2 fashion to control patients undergoing RC who did not develop VTE. Matching was performed on the basis of age, BMI, receipt of neoadjuvant chemotherapy, and pathologic T and N stages. Recurrence-free (RFS), cancer-specific (CSS), and overall survival (OS) were estimated utilizing the Kaplan-Meier method and compared with the log-rank test. Results: A total of 132 patients with a VTE within 90 days of RC were identified, accounting for 4.6% of all patients analyzed. These cases were matched to 257 controls per criteria noted above, and were overall well-matched. Of the 389 patients in this study, median follow-up after RC was 9.2 years, during which time 152 (39%) patients experienced recurrence and 306 (78%) died, including 157 (40%) who died of bladder cancer. We found no significant difference in 5-year RFS (59% versus 61%; p = 0.75); CSS (57% versus 64%; p = 0.13); or OS (45% versus 50%; p = 0.15) between patients with versus without perioperative VTE, respectively. Conclusions: We found that VTE within 90 days of RC did not significantly impact long-term cancer outcomes. While these events represent an important cause of perioperative morbidity, no interaction with oncologic control was noted, and patients may be counseled accordingly.

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.

308 Background: Receipt of pelvic radiotherapy (PRT) prior to radical cystectomy (RC) has unclear association on oncologic outcomes. Methods: The Mayo Clinic Cystectomy Registry was queried to review 2139 patients undergoing RC for M0 bladder cancer between 1990 and 2010. We then identified patients receiving PRT prior to RC, and matched these cases to non-radiated controls (~1:2) on the basis of age, sex, receipt of neoadjuvant chemotherapy, and pathologic T and N stages. Cancer-specific survival (CSS), and progression-free survival (PFS) were estimated using the Kaplan-Meier method and compared with the log-rank test. Results: Of 2139 patients undergoing RC, 104 (4.9%) had received PRT prior to surgery. These patients were matched to 191 non-radiated control patients (no PRT). Overall, patients were well-matched on disease and patient characteristics. Median follow-up was 9.6 years (IQR 6.0, 14.8). During this time, 108 patients experienced disease recurrence and 218 died, including 122 who died from bladder cancer. Five-year CSS among patients who did versus did not receive PRT was 55% versus 63% (p=0.10), while the 5-year PFS was 55% versus 61% (p=0.32). Furthermore, the pattern of disease recurrence (abdominal/visceral, urothelial, local/pelvic, thoracic, soft tissue/other) did not differ between the no PRT and PRT groups (all p>0.05). Conclusions: Receipt of PRT prior to RC is not associated with worse oncologic outcomes. While prior PRT may increase surgical complexity, CSS, PFS, and patterns of recurrence are similar to patients who have not received PRT.

516 Background: The impact of diabetes mellitus (DM) on outcomes in patients with renal cell carcinoma (RCC) is controversial. Herein, we evaluated the association of DM with survival among patients with RCC. Methods: We reviewed 2,589 patients treated with nephrectomy for sporadic, unilateral, M0 RCC between 1990 and 2008 and compared demographic and tumor characteristics in patients with and without DM (nonDM). Patients with DM (n=313) were matched 1:2 to nonDM patients according to date of surgery, age, smoking status, obesity, ECOG performance status (PS), CKD stage, histological subtype, and nuclear grade. Cancer-specific (CSS) and overall survival (OS) were compared by Kaplan-Meier analysis. The association of DM with outcomes was evaluated with Cox proportional hazards regression models. Results: A total of 313 (12%) patients had DM. DM patients were significantly older at RCC diagnosis, more likely to be obese, and had higher Charlson scores, CKD class, rates of smoking, and worse PS at surgery (p<0.001). Patients with DM were also more likely to have ccRCC (83% vs. 76%, p=0.02) and to undergo nephron-sparing surgery (42% vs. 35%, p=0.01), while other pathologic features were similar in DM and nonDM. Among the 939 matched cases and controls, 463 patients died within a median of 5.5 years after nephrectomy. Median follow-up for survivors was 8.6 years. Five-year CSS was not significantly different among DM patients 84% vs. nonDM patients 87% (p=0.11), although 5-year OS was significantly worse among DM patients (66% vs. 75%; p<0.001). Indeed, even after adjusting for Charlson score, DM patients were noted to have a significantly increased risk of all-cause mortality (HR 1.33; p=0.004). In a subanalysis of patients with clear cell RCC, DM patients were more likely to die from RCC compared with nonDM patients after adjusting for the SSIGN (Stage, Size, Grade, Necrosis) score (HR 1.44; p=0.034). Conclusions: In this surgical cohort, DM was independently associated with decreased CSS among patients with ccRCC and with decreased OS in all RCC subtypes. Further studies to determine the potential biologic mechanism for this interaction are warranted.

402 Background: The American Urological Association (AUA) and the National Comprehensive Cancer Network (NCCN) are highly utilized sources for surveillance strategies following surgical treatment for renal cell carcinoma (RCC). However, the duration of follow-up may be inadequate to capture the majority of recurrences. Herein, we assess the ability of these guidelines to effectively capture recurrences of RCC following primary surgical resection. Methods: We reviewed our institutional database of 3,725 patients treated with radical or partial nephrectomy for M0 sporadic RCC between 1970-2008. For comparison to the AUA guidelines, patients were stratified into low risk following partial nephrectomy (LRp) or radical nephrectomy (LRr) = pT1N0, and moderate/high risk (M/HR) = pT2-4 N0-1. Guideline effectiveness was assessed by calculating the percentage of recurrences detected within the prescribed follow-up periods given for site-specific recurrence: AUA—LRp: 3yrs for all sites; LRr: 1yr for abdominal and 3yrs for chest/bone/other sites; M/HR: 5yrs for all sites; NCCN—6 months for abdominal/chest sites and 5yrs for bone/other sites. Results: Of the 3,725 patients, 2721 (73.1%) underwent radical nephrectomy, 2,210 (59.3%) were classified as pT1 NX-0 and 2,910 (78.1%) as clear cell RCC. Median postoperative follow-up was 8.9yrs (IQR 5.5-14.2) during which 1,114 (29.9%) patients developed recurrence. Of these recurrences, 760 (68.2%) would have been detected using the AUA guidelines and 432 (38.8%) by NCCN recommendations. Within AUA risk groups, 37.2% recurrences were captured in LRp, 31.4% in LRr and 80.2% in M/HR. Capture of 90% of recurrences in the abdomen and chest would require surveillance for 9yrs and 8 yrs, respectively in LRp, 15yrs and 12yrs in LRr and 11yrs and 10yrs in M/HR. Conclusions: Duration of follow-up recommended by current surveillance algorithms by the AUA and NCCN do not adequately capture many recurrences in RCC following radical or partial nephrectomy. Guidelines using risk stratification and site-specific recurrence parameters to assign length of surveillance may allow providers to better individualize surveillance regimens.

310 Background: The European Association of Urology (EAU) and the National Comprehensive Cancer Network (NCCN) provide general guidelines for bladder cancer (BC) surveillance following radical cystectomy (RC). However, it is unclear how well these guidelines capture recurrences after surgery. Herein, we assess the ability of current guidelines to effectively capture BC recurrence following RC and propose a risk stratified and recurrence site-specific surveillance strategy. Methods: We reviewed our institutional database of 1,800 patients who underwent primary RC between 1980-2007. Guideline effectiveness was assessed by calculating the percentage of recurrences detected within the prescribed follow-up periods: EAU—5yrs; NCCN—2yrs. Patients were then stratified according to stage: < = pT1Nx-0, > = pT2Nx-0, pN+, and recurrence site: urothelium, abdomen, chest, other. Recurrence free survival estimates for stage groups and recurrence site were assessed with Kaplan Meier models. Results: Of the 1,800 patients, 634 (35.2%) were classified as > pT2Nx-0 and 234 (13%) as pN+ and overall 228 (12.7%) received perioperative chemotherapy. Median postoperative follow-up was 10.6yrs (IQR 6.8-15.2), during which 716 (39.8%) patients developed recurrence. Of these recurrences, 492 (68.7%) would have been detected using the NCCN guidelines and 644 (89.8%) by EAU recommendations. However, ending oncologic surveillance at 5 years would only capture 81.7% of all recurrences for < = pT1Nx-0 patients and 83% of urothelial specific recurrences across all stage groups. Capture of 90% of recurrences, by stage group, in the urothelium, abdomen and chest would require surveillance for 8yrs, 8yrs and 4yrs, respectively in < = pT1Nx-0, 6yrs, 4yrs and 3yrs in > = pT2Nx-0 and 3yrs, 3yrs and 2yrs for pN+ patients. Conclusions: Duration of surveillance recommended for BC following RC by the EAU and NCCN do not comprehensively capture recurrences seen, specifically, in low risk patients and in cases of urothelial recurrence. Guidelines using risk stratification and site-specific recurrence patterns to assign length of surveillance may allow providers to better individualize surveillance regimens.