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Segmental ureterectomy (SU) is an alternative to radical nephroureterectomy (RNU) in the treatment of upper-tract urothelial carcinoma (UTUC) of the ureter. SU generally preserves renal function, at the expense of less intensive cancer control. We aim to assess whether SU is associated with inferior survival compared to RNU. Using the National Cancer Database (NCDB), we identified patients diagnosed with localized UTUC of the ureter between 2004–2015. We used a propensity-score-overlap-weighted (PSOW) multivariable survival model to compare survival following SU vs. RNU. PSOW-adjusted Kaplan–Meier curves were generated and we performed a non-inferiority test of overall survival. A population of 13,061 individuals with UTUC of the ureter receiving either SU or RNU was identified; of these, 9016 underwent RNU and 4045 SU. Factors associated with decreased likelihood of receiving SU were female gender (OR, 0.81; 95% CI, 0.75–0.88; p < 0.001), advanced clinical T stage (cT4) (OR, 0.51; 95% CI, 0.30–0.88; p = 0.015), and high-grade tumor (OR, 0.76; 95% CI, 0.67–0.86; p < 0.001). Age greater than 79 years was associated with increased probability of undergoing SU (OR, 1.18; 95% CI, 1.00–1.38; p = 0.047). There was no statistically significant difference in OS between SU and RNU (HR, 0.98; 95% CI, 0.93–1.04; p = 0.538). SU was not inferior to RNU in PSOW-adjusted Cox regression analysis (p < 0.001 for non-inferiority). In weighted cohorts of individuals with UTUC of the ureter, the use of SU was not associated with inferior survival compared to RNU. Urologists should continue to utilize SU in appropriately selected patients.

Utilization of partial nephrectomy (PN) for T2 renal mass is controversial due to concerns regarding burden of morbidity, though most cited data are from open PN (OPN). We compared surgical quality and functional outcomes of RPN and OPN for clinical T2a renal masses (cT2aRM). Retrospective analysis of 150 consecutive patients [RPN 59/OPN 91] who underwent PN from July 2008 to June 2016. Main outcome was achievement of Trifecta [negative surgical margin, no major urologic complications, and ≥90% preservation of estimated glomerular filtration rate (eGFR)]. Multivariable analysis was performed to identify factors of Trifecta attainment. Mean tumor size (RPN 7.9 vs. OPN 8.4 cm, p = 0.139) and median RENAL score (p = 0.361) were similar. No difference was noted for positive margins (RPN 3.4% vs. OPN 1.1%, p = 0.561), ΔeGFR (RPN − 6.2 vs. OPN − 7.8, p = 0.543), and ≥ 90% eGFR recovery (RPN 54.1% vs. OPN 47.2%, p = 0.504). RPN had lower blood loss (p = 0.015), hospital stay (p = 0.013), and Clavien ≥ 3 complications (RPN 5.1% vs. OPN 16.5%, p = 0.041). Trifecta rate was significantly higher in RPN (47.5% vs. 34.0%, p = 0.041). Multivariable analysis demonstrated decreasing RENAL score (OR 1.11, p

INTRODUCTION AND OBJECTIVE:Tobacco use has been shown to be an independent risk factor for postoperative morbidity following a variety of major surgeries. While tobacco use is both a risk factor fo...

The impact of positive surgical margins (PSM) on outcomes in partial nephrectomy (PN) is controversial. We investigated impact of PSM for patients undergoing PN on overall survival (OS) in different stages of renal cell carcinoma (RCC).Retrospective analysis of patients from the US National Cancer Database who underwent PN for cT1a-cT2b N0M0 RCC between 2004-13. Patients were stratified by pathological stage (pT1a, pT1b, pT2a, pT2b, and pT3a [upstaged]) and analyzed by margin status. Cox Regression multivariable analysis (MVA) was performed to investigate associations of PSM and covariates on all-cause mortality (ACM). Kaplan-Meier analysis (KMA) of OS was performed for PSM versus negative margin (NSM) by pathological stage. Sub-analysis of Charlson Comorbidity Index 0 (CCI=0) subgroup was conducted to reduce bias from comorbidities.We analyzed 42,113 PN (pT1a: 33,341 [79.2%]; pT1a, pT1b: 6689 [15.9%]; pT2a: 757 [1.8%]; pT2b: 165 [0.4%]; and pT3a: upstaged 1161 [2.8%]). PSM occurred in 6.7% (2823) (pT1a: 6.5%, pT1b: 6.3%, pT2a: 5.9%, pT2b: 6.1%, pT3a: 14.1%, P0.001). On MVA, PSM was associated with 31% increase in ACM (HR 1.31, P0.001), which persisted in CCI=0 sub-analysis (HR: 1.25, P0.001). KMA revealed negative impact of PSM vs. NSM on 5-year OS: pT1 (87.3% vs. 90.9%, P0.001), pT2 (86.7% vs. 82.5%, P=0.48), and upstaged pT3a (69% vs. 84.2%, P0.001).PSM after PN was independently associated with across-the-board decrement in OS, which worsened in pT3a disease and persisted in sub-analysis of patients with CCI=0. PSM should prompt more aggressive surveillance or definitive resection strategies.

Neoadjuvant Targeted Molecular Therapy in the setting of localized and locally advanced renal cell carcinoma has emerged as a strategy to render primary renal tumors amenable to planned surgical resection in settings where radical resection or nephron-sparing surgery was not thought to be safe or feasible. Presurgical tumor reduction has been demonstrated in a number of studies including a recently published randomized double-blind placebo-controlled study, and an expanding body of literature suggests benefit in select patients. Nonetheless, most reports are small phase II clinical trials or retrospective reports. Thus, large randomized clinical trial data are not present to support this approach, and guidelines for use of presurgical therapy have not been promulgated. The advent of immunomodulation through checkpoint inhibition represents an exciting horizon for neoadjuvant strategies. This article reviews the current status and future prospects of neoadjuvant therapy in nonmetastatic renal cell carcinoma.

The efficacy of partial nephrectomy (PN) in setting of pT3a pathologic-upstaged renal cell carcinoma (RCC) is controversial. We compared oncologic and functional outcomes of radical nephrectomy (RN) and PN in patients with upstaged pT3a RCC.This was a multicenter retrospective analysis of patients with cT1-2N0M0 RCC upstaged to pT3a postoperatively. The primary outcome was recurrence-free survival, with secondary outcomes of overall survival and de novo estimated glomular filtration rate (eGFR) 60. Multivariable analysis was performed to identify predictive factors for oncologic outcomes. Kaplan-Meier analyses (KMA) were obtained to elucidate survival outcomes.A total of 929 patients had pT3a upstaging (686 [72.6%] RN; 243 [25.7%] PN; mean follow-up, 48 months). Tumor size was similar (RN 7.7 cm vs. PN 7.3 cm; P = .083). PN had decreased ΔeGFR (6.1 vs. RN 19.4 mL/min/1.73mIn pathologically upstaged pT3a RCC, PN did not adversely affect risk of recurrence and provided functional benefit. Surgical decision-making in patients at risk for T3a upstaging should be individualized and driven by tumor as well as functional risks.

Aim and Background: To investigate the association of serum uric acid (SUA) levels along with statin use in Renal Cell Carcinoma (RCC), as statins may be associated with improved outcomes in RCC and SUA elevation is associated with increased risk of chronic kidney disease (CKD). Methods: Retrospective study of patients undergoing surgery for RCC with preoperative/postoperative SUA levels between 8/2005&ndash, 8/2018. Analysis was carried out between patients with increased postoperative SUA vs. patients with decreased/stable postoperative SUA. Kaplan-Meier analysis (KMA) calculated overall survival (OS) and recurrence free survival (RFS). Multivariable analysis (MVA) was performed to identify factors associated with increased SUA levels and all-cause mortality. The prognostic significance of variables for OS and RFS was analyzed by cox regression analysis. Results: Decreased/stable SUA levels were noted in 675 (74.6%) and increased SUA levels were noted in 230 (25.4%). A higher proportion of patients with decreased/stable SUA levels took statins (27.9% vs. 18.3%, p = 0.0039). KMA demonstrated improved 5- and 10-year OS (89% vs. 47% and 65% vs. 9%, p &lt, 0.001) and RFS (94% vs. 45% and 93% vs. 34%, p &lt, 0.001), favoring patients with decreased/stable SUA levels. MVA revealed that statin use (Odds ratio (OR) 0.106, p &lt, 0.001), dyslipidemia (OR 2.661, p = 0.004), stage III and IV disease compared to stage I (OR 1.887, p = 0.015 and 10.779, p &lt, 0.001, respectively), and postoperative de novo CKD stage III (OR 5.952, p &lt, 0.001) were predictors for increased postoperative SUA levels. MVA for all-cause mortality showed that increasing BMI (OR 1.085, p = 0.002), increasing ASA score (OR 1.578, p = 0.014), increased SUA levels (OR 4.698, p &lt, 0.001), stage IV disease compared to stage I (OR 7.702, p &lt, 0.001), radical nephrectomy (RN) compared to partial nephrectomy (PN) (OR 1.620, p = 0.019), and de novo CKD stage III (OR 7.068, p &lt, 0.001) were significant factors. Cox proportional hazard analysis for OS revealed that increasing age (HR 1.017, p = 0.004), increasing BMI (Hazard Ratio (HR) 1.099, p &lt, 0.001), increasing SUA (HR 4.708, p &lt, 0.001), stage III and IV compared to stage I (HR 1.537, p = 0.013 and 3.299, p &lt, 0.001), RN vs. PN (HR 1.497, p = 0.029), and de novo CKD stage III (HR 1.684, p &lt, 0.001) were significant factors. Cox proportional hazard analysis for RFS demonstrated that increasing ASA score (HR 1.239, p &lt, 0.001, increasing SUA (HR 9.782, p &lt, 0.001), and stage II, III, and IV disease compared to stage I (HR 2.497, p &lt, 0.001 and 3.195, p &lt, 0.001 and 6.911, p &lt, 0.001) were significant factors. Conclusions: Increasing SUA was associated with poorer outcomes. Decreased SUA levels were associated with statin intake and lower stage disease as well as lack of progression to CKD and anemia. Further investigation is requisite.

INTRODUCTION AND OBJECTIVES:Pathological upstaged pT3a for Renal Cell Carcinoma (RCC) may have a wide variance in outcomes. We sought to redefine and reclassify pT3a RCC. We investigated recurrence and survival outcomes in pT3a disease and aimed to better categorize this cohort for improvement on current TMN staging.METHODS:Multicenter retrospective analysis of patients with cT1-3aN0M0 RCC who underwent radical or partial nephrectomy. After comparison of outcomes between pT1, pT2 and pT3a, patients were substratified within the pT3a category based on presenting clinical stage. Survival outcomes in T3a RCC were compared based on initial presenting clinical T stage. Comparison was drawn between pT1, pT2 and the subdivided pT3a group (cT1→pT3a, cT2→pT3a, and cT3a→pT3a). Primary outcome was recurrence free survival (RFS). Secondary outcome was overall survival (OS). Multivariable (MVA) and Kaplan-Meier (KM) analysis were conducted to elucidate risk factors and outcomes.RESULTS:We analyzed 2573 patients (1223 ...

INTRODUCTION AND OBJECTIVES:Radical Nephrectomy (RN) has been the standard of care for complex and locally advanced renal cell carcinoma (RCC). Partial Nephrectomy (PN) utilization has increased in...

Systemic therapy strategies in the setting of localized and locally advanced renal cell carcinoma have continued to evolve in two directions: (i) as adjuvant therapy (to reduce the risk of recurrence or progression in high-risk localized groups); or (ii) as neoadjuvant therapy as a strategy to render primary renal tumors amenable to planned surgical resection in settings where radical resection or nephron-sparing surgery was not thought to be safe or feasible. In the realm of adjuvant therapy, the results of adjuvant therapy phase III randomized clinical trials have been mixed and contradictory; nevertheless, the findings of the landmark Sunitinib Treatment of Renal Adjuvant Cancer study have led to approval of sunitinib as an adjuvant agent in the USA. In the realm of neoadjuvant therapy, presurgical tumor reduction has been shown in a number of phase II studies utilizing targeted molecular agents and in a recently published small randomized double-blind placebo-controlled study, and an expanding body of literature suggests benefit in select patients. Thus, large randomized clinical trial data are not present to support this approach, and guidelines for use of presurgical therapy have not been promulgated. The advent of immunomodulation through checkpoint inhibition represents an exciting horizon for adjuvant and neoadjuvant strategies. The present article reviews the current status and future prospects of adjuvant and neoadjuvant therapy in localized and locally advanced renal cell carcinoma.

653 Background: We compared surgical quality and functional outcomes of robotic partial nephrectomy (RPN) and open PN (OPN) for cT2a renal masses (cT2aRM). Methods: Retrospective analysis of 150 consecutive patients [RPN 59/OPN 91] from 6/2008 to 6/2016. Main outcome was achievement of Trifecta [negative surgical margin, no major urologic complications, and ≥90% preservation of estimated glomerular filtration rate (eGFR)]. Multivariable analysis was performed to identify factors of Trifecta attainment. Results: Mean tumor size (RPN 7.9 vs. OPN 8.4 cm, p=0.139) and median RENAL score (p=0.361) were similar. No difference was noted for positive margins (RPN 3.4% vs. OPN 1.1%, p=0.561), DeGFR (RPN -6.2 vs. OPN -7.8, p=0.543), and ≥90% eGFR recovery (RPN 54.1% vs. OPN 47.2%, p=0.504). RPN had lower blood loss (p=0.015), hospital stay (p=0.013), and Clavien ≥3 complications (RPN 5.1% vs. OPN 16.5%, p=0.041). Trifecta rate was significantly higher in RPN (47.5% vs. 34.0%, p=0.041). Multivariable analysis demonstrated decreasing RENAL score (OR 1.11, p

758 Background: The identification of venous thrombus in patients with renal cell carcinoma (RCC) is particularly challenging, with a substantial number upstaged to pathologic T3a following intervention. We compared survival outcomes between patients with initial cT3a status versus those upstaged to pT3a. Methods: This is a retrospective, multicenter analysis of patients with cT3a or pT3a RCC who underwent operative management. Primary outcome was recurrence-free survival (RFS). Secondary outcomes were overall survival (OS) and cancer-specific survival (CSS). Cox regression multivariable analysis (MVA) was utilized for primary outcome. Kaplan-Meier analyses (KMA) were conducted to describe RFS, OS, and CSS with log-rank test comparing clinical and upstaged pathologic T3a groups. Results: 770 patients were analyzed (cT3a 184, pT3a 586, median follow-up 28 months). Average pathologic tumor size was smaller in pT3a (7.2 cm vs 8.7 cm, p < 0.01), with no significant differences in clinical variables. A similar proportion underwent radical nephrectomy (vs. partial) (89.7% cT3a and 85.0% pT3a, p = 0.11) with no significant different in positive margin rate (3.8% cT3a, 4.8% pT3a, p = 0.23). However, a higher proportion of patients with cT3a disease were pathologically node positive (19.0% vs. 10.8%, p < 0.01) and demonstrated a higher rate of recurrence (cT3a 51.1% vs. pT3a 34.1%, p < 0.01) despite shorter mean follow-up (cT3a 33.0 vs. pT3a 50.7 mo, p < 0.01). MVA for RFS revealed cT3a staging (pT3a referent, HR 1.72, p < 0.01), positive margins (HR 2.85, p < 0.01), and clear cell histology (HR 1.68, p < 0.01) to be independently associated with higher recurrence rate, while partial nephrectomy (radical referent, HR 0.259, p < 0.01) was associated with a decreased rate. KMA revealed 5-year RFS of 34.4% and 60.6% for cT3a and pT3a respectively (p < 0.01). KMA for secondary outcomes revealed 5-year OS rates of 56.7% and 62.0% (p = 0.02) and 5-year CSS of 74.4% and 67.7% for cT3a and pT3a respectively (p = 0.01). Conclusions: Patients with cT3a RCC have poorer oncologic outcomes than those with upstaged pT3a RCC. Suspected venous involvement on pre-operative imaging may indicate more aggressive or advanced disease than that found during surgery.

Purpose: To compare renal function and survival outcomes in patients with baseline chronic kidney disease (CKD) stage 2 undergoing partial (PN) or radical nephrectomy (RN), as nephron-sparing surgery is considered to be elective in this group. Methods: Retrospective analysis of patients with CKD stage 2 and T1/T2 renal mass undergoing PN or RN from 2001 to 2015. Patients were stratified into substage CKD 2a or CKD 2b and analyzed between types of surgery. Primary outcome was overall survival (OS), eGFR < 45 at last follow-up was the secondary outcome. Multivariable analysis (MVA) was conducted for predictors of eGFR < 45 and OS. Kaplan–Meier analyses were conducted for freedom from eGFR < 45 and OS. Results: 1213 patients analyzed (CKD 2a 609/CKD 2b 604) on MVA, RN (OR 3.68, p = 0.001) and CKD 2b (OR 3.3, p = 0.002) were independently associated with development of eGFR < 45 at last follow-up and RN (OR 3.76, p = 0.005) and eGFR < 45 (OR 2.51, p = 0.029) were associated with decreased OS. Kaplan–Meier analyses revealed that patients with CKD 2a/PN had the highest 5-year freedom from eGFR < 45 (94.3%) compared to CKD 2a/RN patients (91.5%), CKD2b/PN patients (87.6%) and CKD 2b/RN patients 82.0% (p < 0.001). Kaplan–Meier analyses for OS demonstrated that patients with CKD 2a/PN had significantly greater 5-year OS (97.6%) compared to CKD 2a/RN patients (95.2%), CKD 2b/PN patients (93.2%), and CKD 2b/RN patients (92.4%, p = 0.043). Conclusions: Patients with baseline CKD stage 2, particularly CKD 2b and undergoing RN, are at increased risk of GFR < 45, which was associated with decreased OS. In patients with CKD 2b, a nephron-sparing strategy is indicated and should be prioritized when feasible.

Background We analyzed outcomes of neoadjuvant sunitinib in patients with renal-cell carcinoma (RCC) and inferior vena caval (IVC) tumor and compared outcomes to patients who did not undergo neoadjuvant therapy before surgery. Patients and Methods We performed a multicenter retrospective comparison of RCC patients with IVC tumor who underwent neoadjuvant sunitinib before surgery versus those who did not. Response to sunitinib was defined by Response Evaluation Criteria in Solid Tumors (RECIST). Primary outcome was cancer-specific survival. Secondary outcomes included overall survival. Multivariate analysis was performed to identify risk factors associated with primary and secondary outcomes. Kaplan-Meier analysis compared survival in neoadjuvant and primary surgery groups. Results Data of 53 patients were analyzed (19 neoadjuvant sunitinib, 34 primary surgery; median follow-up, 58 months). Eighteen (9 in each group, P = .143) had metastatic RCC. There was no difference in IVC tumor level between the 2 groups (P = .76). After neoadjuvant sunitinib, median primary tumor decreased size from 8.1 to 6.8 cm, and IVC tumor decreased by 1.3 cm. IVC tumor level decreased in 8 (42.1%) of 19 and was stable in 10 (52.6%) of 19; 5 (26.3%) of 19 experienced partial response. Similar proportions of patients underwent robot-assisted or minimally invasive approaches (P = .351), and no differences were noted in complications (P = .194). Multivariate analysis showed neoadjuvant sunitinib was associated with improved cancer-specific survival (odds ratio = 3.28; P = .021). Kaplan-Meier analysis demonstrated significantly longer median cancer-specific survival (72 vs. 38 months, P = .023) for neoadjuvant sunitinib. Conclusion Neoadjuvant sunitinib was associated with a reduction in primary tumor and thrombus size as well as improved survival. Further investigation is needed to determine the utility of neoadjuvant sunitinib in RCC with IVC tumor.

Background: We compared renal functional outcomes of robotic (RPN) and open partial nephrectomy (OPN) in patients with chronic kidney disease (CKD), a definite indication for nephron-sparing surgery. Methods: A multicenter retrospective analysis of OPN and RPN in patients with baseline ≥ CKD Stage III [estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2] was performed. Primary outcome was change in eGFR (ΔeGFR, mL/min/1.73 m2) between preoperative and last follow-up with respect to RENAL nephrometry score group [simple (4–6), intermediate (7–9), complex (10–12)]. Secondary outcomes included eGFR decline > 50%. Results: 728 patients (426 OPN, 302 RPN, mean follow-up 33.3 months) were analyzed. Similar RENAL score distribution (p = 0.148) was noted between groups. RPN had lower median estimated blood loss (p < 0.001), and hospital stay (3 vs. 5 days, p < 0.001). Median ischemia time (OPN 23.7 vs. RPN 21.5 min, p = 0.089), positive margin (p = 0.256), transfusion (p = 0.166), and 30-day complications (p = 0.208) were similar. For OPN vs. RPN, mean ΔeGFR demonstrated no significant difference for simple (0.5 vs. 0.3, p = 0.328), intermediate (2.1 vs. 2.1, p = 0.384), and complex (4.9 vs. 6.1, p = 0.108). Cox regression analysis demonstrated that decreasing preoperative eGFR (OR 1.10, p = 0.001) and complex RENAL score (OR 5.61, p = 0.03) were independent predictors for eGFR decline > 50%. Kaplan–Meier analysis demonstrated 5-year freedom from eGFR decline > 50% of 88.6% for OPN and 88.3% for RPN (p = 0.724). Conclusions: RPN and OPN demonstrated similar renal functional outcomes when stratified by tumor complexity group. Increasing tumor age and tumor complexity were primary drivers associated with functional decline. RPN provides similar renal functional outcomes to OPN in appropriately selected patients.

Heat shock factor 1 (HSF1) initiates a broad transcriptional response to proteotoxic stress while also mediating a cancer-specific transcriptional program. HSF1 is thought to be regulated by molecular chaperones, including Heat Shock Protein 90 (HSP90). HSP90 is proposed to sequester HSF1 in unstressed cells, but visualization of this interaction in vivo requires protein crosslinking. In this report, we show that HSP90 binding to HSF1 depends on HSP90 conformation and is only readily visualized for the ATP-dependent, N-domain dimerized chaperone, a conformation only rarely sampled by mammalian HSP90. We have used this mutationally fixed conformation to map HSP90 binding sites on HSF1. Further, we show that ATP-competitive, N-domain targeted HSP90 inhibitors disrupt this interaction, resulting in the increased duration of HSF1 occupancy of the hsp70 promoter and significant prolongation of both the constitutive and heat-induced HSF1 transcriptional activity. While our data do not support a role for HSP90 in sequestering HSF1 monomers to suppress HSF1 transcriptional activity, our findings do identify a noncanonical role for HSP90 in providing dynamic modulation of HSF1 activity by participating in removal of HSF1 trimers from heat shock elements in DNA, thus terminating the heat shock response.

Background Sunitinib might optimize the feasibility of partial nephrectomy (PN) for complex renal tumors with imperative indications. We compared the renal functional outcomes of patients with complex renal masses who had undergone sunitinib before PN with those of patients who had not required neoadjuvant sunitinib before PN. Patients and Methods We performed a multicenter retrospective analysis of patients with renal cell carcinoma who had undergone PN for a complex renal mass (R.E.N.A.L. nephrometry score, 10-12) and imperative indications from January 2012 to July 2014. Neoadjuvant sunitinib was used in cases for which PN was not considered feasible. The cohort was divided into those patients who had undergone PN without neoadjuvant sunitinib and those who had undergone PN after sunitinib (no-neoadjuvant vs. neoadjuvant). The change in tumor size and R.E.N.A.L. score were assessed. The primary outcome was the change in the estimated glomerular filtration rate (ΔeGFR) from preoperatively to the last postoperative follow-up visit. Results The data from 125 consecutive patients were analyzed (47 neoadjuvant and 78 no-neoadjuvant; median follow-up, 21 months). The neoadjuvant plus PN patients had had a greater median tumor size preoperatively (7.2 vs. 6 cm; P = .045). Sunitinib caused a significant decrease in the median tumor size (from 7.2 to 5.8 cm [19.4%]; P = .012) and R.E.N.A.L. score (from 11 to 9; P = .001). No significant differences were found between the neoadjuvant and no-neoadjuvant groups in the ischemia time ( P = .413) or incidence of complications ( P = .728). The median ΔeGFR was similar (neoadjuvant, 6.4; no-neoadjuvant, 6.1; P = .534). Linear regression analysis for factors associated with an increasing ΔeGFR demonstrated increasing age (estimate, −0.074; P = .009) increasing body mass index (estimate, −0.087; P = .043), and decreasing baseline eGFR (estimate, −0.104; P = .02) as significant factors. Conclusion The use of neoadjuvant sunitinib might facilitate complex PN and result in renal functional outcomes similar to those of patients with a complex renal mass who had not required neoadjuvant sunitinib.

596 Background: C-reactive protein (CRP) is a systemic inflammatory marker which has been associated with overall survival (OS) in Renal Cell Carcinoma (RCC) patients in Asia. Data supporting utility of CRP as a predictive marker in non-Asian populations are sparse and controversial. We analyzed utility of pre-treatment CRP as a predictor of survival and oncological outcomes in a multicenter cohort of RCC patients. Methods: Retrospective international 3 center analysis of patients of patients with RCC with pretreatment CRP values from 2006-2017. CRP > 0.5mg/dl was used as threshold for elevation and the cohort was subdivided into two groups for descriptive analysis (normal-CRP ≤0.5 and elevated-CRP > 0.5). Primary outcome was recurrence-free survival (RFS). Secondary outcome was overall survival (OS). Kaplan-Meier (KMA) and multivariable analyses (MVA) were utilized to delineate survival outcomes and their predictors. Results: Overall 2695 patients were analyzed (1791 Male/904 female, CRP≤0.5 1198/CRP > 0.5 1496; mean follow-up 36 months). Patients with elevated CRP had higher incidence of hypertension (p = 0.001), BMI (p < 0.001), and tumor size (3.91 cm vs. 6.05 cm, p < 0.001). MVA for RFS demonstrated elevated CRP (OR = 0.542, p = 0.005), increasing tumor size (OR = 0.915, p < 0.001), and high tumor grade (OR = 0.322 p < 0.001) to be independent risk factors. MVA for all-cause mortality demonstrated elevated CRP (OR = 12.396, p = 0.005), increasing tumor size (OR = 1.126, p < 0.001), high tumor grade (OR = 2.474, p < 0.001), and receipt of PN (OR = 1.826, p = 0.001) to be independent risk factors. For normal vs. elevated CRP, KMA revealed 5-year RFS of 90% vs. 85% (p = 0.001), 95% vs 85% (p = 0.163), 85% vs 62% (p = 0.001), 50% vs 60% (p = 0.513) for Stages 1, 2, 3, and 4, respectively. KMA revealed 5-year OS of 98% vs 80% (p = 0.001), 95% vs 80% (p = 0.103), 95% vs 65% (p = 0.001), 99% vs 40% (p < 0.001) for Stages 1, 2, 3, and 4, respectively. Conclusions: Pre-treatment CRP was an independent predictor of recurrence free survival and overall survival in a multicenter cohort of RCC patients. While further confirmation is requisite, our findings suggest incorporation of CRP into nomographic and risk stratification protocols.

Because of their importance in maintaining protein homeostasis, molecular chaperones, including heat-shock protein 90 (Hsp90), represent attractive drug targets. Although a number of Hsp90 inhibitors are in preclinical/clinical development, none strongly differentiate between constitutively expressed Hsp90β and stress-induced Hsp90α, the two cytosolic paralogs of this molecular chaperone. Thus, the importance of inhibiting one or the other paralog in different disease states remains unknown. We show that the natural product, gambogic acid (GBA), binds selectively to a site in the middle domain of Hsp90β, identifying GBA as an Hsp90β-specific Hsp90 inhibitor. Furthermore, using computational and medicinal chemistry, we identified a GBA analog, referred to as DAP-19, which binds potently and selectively to Hsp90β. Because of its unprecedented selectivity for Hsp90β among all Hsp90 paralogs, GBA thus provides a new chemical tool to study the unique biological role of this abundantly expressed molecular chaperone in health and disease.

Heat shock factor 1 (HSF1) is an evolutionarily conserved transcription factor that initiates the cytoprotective heat shock response (HSR) and mediates a cancer-specific transcriptional program, which is comprised of over 500 genes and has been associated with poor clinical outcomes. HSF1 is thought to be regulated by molecular chaperones, including Heat Shock Protein 90 (HSP90). The purpose of our study was to describe the interactions between molecular chaperones, such as HSP90 and HSP70, and HSF1 and to determine the mechanism(s) by which HSP90 inhibitors promote the HSR in mammalian cells. Using a combination of techniques including IP-WB, ChIP, and RT-qPCR analysis, we demonstrated that HSP90 binding to HSF1 depends on HSP90 conformation and is only readily visualized for the ATP-dependent, N-domain dimerized chaperone, a conformation rarely sampled by mammalian HSP90. We also showed that ATP-competitive, N-domain targeted HSP90 inhibitors disrupt this interaction and enhance HSF1 phosphorylation, resulting in the increased duration of HSF1 occupancy of the hsp70 promoter and significant prolongation of both the constitutive and heat-induced HSF1 transcriptional activity. While our data do not support a role for HSP90 in sequestering HSF1 monomers to suppress HSF1 transcriptional activity, as has been previously proposed, our findings do identify a noncanonical role for HSP90 in providing dynamic modulation of HSF1 activity by participating in removal of HSF1 trimers from heat shock elements in DNA, thus terminating the heat shock response. Citation Format: Megan L. Tigue, Toshiki Kijima, Thomas L. Prince, Kendrick H. Yim, Harvey Schwartz, Kristin Beebe, Sunmin Lee, Marek A. Budzynski, Heinric Williams, Jane B. Trepel, Lea Sistonen, Stuart Calderwood, Len Neckers. HSP90 inhibitors disrupt a transient HSP90-HSF1 interaction and identify a noncanonical model of HSP90-mediated HSF1 regulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 446.

700 Background: Small renal masses (SRMs, < 4 cm in diameter) are heterogeneous, with significant proportions of benign as well as high-grade malignancy. We developed a scoring system incorporating patient factors, serum markers, and morphometric characteristics to elucidate benign and high grade pathology and guide decision making. Methods: Single institution retrospective analysis of surgically treated SRMs from 2003-2017. Demographic and clinical factors, including RENAL score, were analyzed. Patients were categorized into 3 groups: benign (BNGN), low grade (LG), or high grade (HG) disease and uni- and multivariable logistic regression were used to screen for association between potential parameters and the 3 groups. Each significant variable was analyzed by risk group and broken into quartiles. The 75th percentile of the HG group was assigned a value of 3. Below the 75th percentile of the BNGN group was assigned a value of 1; values that fell between these cutoffs were assigned 2 points. Tumor diameter was weighted twice that of other factors. Receiver-operating-characteristic (ROC) analysis was used to assess for predictive capability. Results: 312 patients were analyzed (65 BNGN, 204 LG, 43 HG). Factors associated with increased risk of HG were male sex (OR 1.868, p = 0.045), higher ALT (OR 1.036, p = 0.022), higher RENAL score (OR 1.318, p = 0.002), and larger tumor diameter (OR 2.415, p < 0.001). Patients with low (5-8), intermediate (9-11) and high (12-14) scores had 32.8%, 5.2%, and 0% frequency of BNGN pathology. Patients with low, intermediate, and high scores had 7.7%, 18.6%, and 34.9% frequency of HG pathology. ROC analysis revealed AUC of 0.767. Conclusions: Preoperative clinical parameters were incorporated into a model that significantly predicts benign and aggressive pathology for SRMs. This risk stratification may provide a non-invasive method to aid in clinical decision making. External validation is requisite.[Table: see text]

642 Background: Incidental pathological upstaging to pT3a disease can occur after surgical treatment of clinical T1 and T2 Renal Cell Carcinoma (RCC), and upstaged pT3a disease is associated with worsened outcomes. Oncologic and survival outcomes within the pT3a category are heterogeneous. We investigated recurrence and survival outcomes in pT3a disease, and aimed to better categorize this cohort for improvement on current TMN staging. Methods: Multi-center retrospective analysis of patients with renal cell carcinoma (cT1-3aN0M0) from 1987-2016. After initial comparison of outcomes between pT1, pT2 and pT3a, patients were substratified within the pT3a category based on presenting clinical stage. Comparison was drawn between pT1, pT2 and the subdivided pT3a group (cT1 → pT3a, cT2 → pT3a, and cT3a → pT3a). Primary outcome was recurrence free survival (RFS). Secondary outcome was overall survival (OS). Kaplan−Meier (KM) analysis was utilized. Results: 2640 patients were analyzed (2125 cT1, 448 cT2, 67 cT3a, mean follow up 67.8 months). Rate of incidental T3a upstaging from cT1-2 was 14.7%. Compared to pT1-2 disease, patients with incidental pT3a upstaging had higher rate of recurrence (7.5% vs. 29.6%, p < 0.001) and all-cause mortality at last follow up (15.9% vs. 25.4%, p < 0.001). With regards to RFS, when pT3a was subdivided based on presenting clinical stage, significant differences in RFS emerged which aligned differently. Compared to 5 year RFS of pT1 (94.4%), cT1 → pT3a aligned with pT2 (76.6% and 81.2%, p = 0.346) while cT2 → pT3a aligned with cT3a → pT3a 47.4% and 44.0%, p = 0.815). With regards to OS, a similar alignment was noted for 5 year OS after subdivision, where pT1 was 89.9%, while cT1 → pT3a correlated with pT2 (79.8% and 83.1%, p = 0.640) and cT2 → pT3a correlated with cT3a → pT3a 67.0% and 64.2%; p = 0.893). Conclusions: Patients with cT1 → pT3a have outcomes more similar to pT2, than patients with cT2 → pT3a which align more closely to cT3a → pT3a. Future refinements of the TNM staging system for RCC should consider re-grouping cT1 → pT3a into the pT2 group. Further confirmation is requisite.

676 Background: AUA guidelines recommend consideration of nephron sparing surgery in patients with comorbidities that are likely to impact renal function, such as diabetes mellitus (DM). We compared the impact of partial nephrectomy (PN) and radical nephrectomy (RN) on overall survival (OS) in patients with pre-existing DM and Stage I Renal Cell Carcinoma (RCC). Methods: Multicenter retrospective analysis of surgically treated Stage I RCC from 2005-16 with or without DM. Primary outcome was OS analyzed by DM+ or DM- and surgical approach (PN or RN) for AJCC Stage I. Logistic (OR) and Cox (HR) regression were utilized for OS. Results: 2173 patients were analyzed (1223 RN, 1819 PN, 555 DM+, 2487 DM-) with mean follow-up of 49.1 months. Increasing Age (OR 1.028, p = .009), RN (OR 2.446, p = .001), and most recent eGFR < 45 (OR 2.306 p = .002) remained significant on multivariate analysis for OS (Table 1). In the PN subgroup, DM+ or DM- was not associated with decreased OS (HR 1.48 p = 0.19). DM+ was associated with decreased OS in the RN subgroup (HR 1.97 p = 0.005). Conclusions: In Stage I RCC, DM and RN negatively impacted OS, while only RN remained significant on MVA. Subgroup analysis of PN showed that OS was similar in DM- and DM+ patients, but diagnosis of DM had a profound impact on OS in the RN group. This supports the guideline statements and offers evidence that urologists should prioritize nephron sparing surgery in patients with DM and Stage I Renal Cell Carcinoma.[Table: see text]

The two cytosolic/nuclear isoforms of the molecular chaperone HSP90, stress-inducible HSP90α and constitutively expressed HSP90β, fold, assemble and maintain the three-dimensional structure of numerous client proteins. Because many HSP90 clients are important in cancer, several HSP90 inhibitors have been evaluated in the clinic. However, little is known concerning possible unique isoform or conformational preferences of either individual HSP90 clients or inhibitors. In this report, we compare the relative interaction strength of both HSP90α and HSP90β with the transcription factors HSF1 and HIF1α, the kinases ERBB2 and MET, the E3-ubiquitin ligases KEAP1 and RHOBTB2, and the HSP90 inhibitors geldanamycin and ganetespib. We observed unexpected differences in relative client and drug preferences for the two HSP90 isoforms, with HSP90α binding each client protein with greater apparent affinity compared to HSP90β, while HSP90β bound each inhibitor with greater relative interaction strength compared to HSP90α. Stable HSP90 interaction was associated with reduced client activity. Using a defined set of HSP90 conformational mutants, we found that some clients interact strongly with a single, ATP-stabilized HSP90 conformation, only transiently populated during the dynamic HSP90 chaperone cycle, while other clients interact equally with multiple HSP90 conformations. These data suggest different functional requirements among HSP90 clientele that, for some clients, are likely to be ATP-independent. Lastly, the two inhibitors examined, although sharing the same binding site, were differentially able to access distinct HSP90 conformational states.