UCLA Integrated Staging System Research Articles

Combined Charlson comorbidity/C-Reactive Protein Index Is a Novel Predictor in Renal Cell Carcinoma: Analysis of the International Marker Consortium for Renal Cancer (INMARC) Registry

ObjectiveTo evaluate predictive ability of a novel combined index, Charlson comorbidity index and C-reactive protein (CCI-CRP), for outcomes in renal cell carcinoma (RCC), and compare predictive outcomes with of CCI-CRP to its separate components and to the UCLA integrated staging system (UISS). Patients and MethodsWe retrospectively analyzed INMARC registry of RCC patients. Receiver Operator Characteristics (ROC) analysis was fitted to identify threshold defining low-CRP (LCRP) and high-CRP (HCRP). Patients were stratified according to CCI [low-CCI ≤ 3 (LCCI); intermediate-CCI 4-6 (ICCI); high-CCI > 6 (HCCI)] and CRP level. Kaplan-Meier analysis (KMA) was conducted for overall (OS) and cancer-specific survival (CSS). Based on survival analysis distribution we proposed a new stratification: CCI-CRP. Model performance was assessed with ROC/area under the curve (AUC) analysis and compared to CCI and CRP alone, and UISS. ResultsWe analyzed 2,890 patients (median follow-up 30 months). ROC identified maximum product sensitivity and specificity for CRP at 3.5 mg/L. KMA revealed 5-year OS of 95.6% for LCRP/LCCI, 83% LCRP/ICCI, 73.3% LCRP/HCCI, 62.6% HCRP/LCCI, 51.6% HCRP/ICCI and 40.5% HCRP/HCCI (P < .001). From this distribution, new CCI-CRP is proposed: low CCI-CRP (LCRP/LCCI and LCRP/ICCI), intermediate CCI-CRP (LCRP/HCCI and HCRP/LCCI), and high CCI-CRP (HCRP/ICCI and HCRP/HCCI). AUC for CCI-CRP showed improved performance for predicting OS/CSS vs. CCI alone (0.73 vs. 0.63/0.77 vs. 0.60), CRP alone (0.73 vs. 0.71/0.77 vs. 0.74) and UISS (0.73 vs 0.67/0.77 vs 0.73). ConclusionsCCI-CRP, exhibits increased prognostic performance for survival outcomes in RCC compared to CCI and CRP alone, and UISS. Further investigation is requisite.

Comparison and validation of different risk models for papillary renal cell carcinoma.

Several prognostic algorithms were specifically or nonspecifically used for papillary renal cell carcinoma (PRCC). No consensus was reached upon their efficacy of discrimination. We aim to compare the stratifying ability of current models or systems in predicting the risk of recurrence of PRCC. A PRCC cohort consisting of 308 patients from our institution and 279 patients from The Cancer Genome Atlas (TCGA) was generated. With ISUP grade, TNM classification, UCLA Integrated Staging System (UISS), STAGE, SIZE, GRADE AND NECROSIS (SSIGN), Leibovich model and VENUSS system, recurrence-free survival (RFS), disease-specific survival (DSS) and overall survival (OS) were studied using Kaplan-Meier method and concordance index (c-index) was compared. Differences between risk groups in gene mutation and infiltration of inhibitory immune cells were studied with TCGA database. All the algorithms were able to stratify patients in RFS as well as DSS and OS (all P < 0.001). VENUSS score and risk group generally had the highest and balanced c-index (0.815 and 0.797 for RFS). ISUP grade, TNM stage and Leibovich model had the lowest c-indexes in all analysis. Among the 25 most frequently mutated genes in PRCC, eight had different mutation frequency between VENUSS low- and intermediate-/high-risk patients and mutated KMT2D and PBRM1 resulted in worsened RFS (P = 0.053 and P = 0.007). Increased Treg cells in tumors of intermediate-/high- risk patients were also identified. VENUSS system showed better predictive accuracy in RFS, DSS and OS compared with SSIGN, UISS and Leibovich risk models. VENUSS intermediate-/high-risk patients had increased frequency of mutation in KMT2D and PBRM1 and increased infiltration of Treg cells.

Comparison of patients with renal cell carcinoma in adjuvant therapy trials to a real-world population.

To compare characteristics and outcomes of patients included versus those not in adjuvant therapy trials post complete resection of renal cell carcinoma (RCC). Adult patients following complete resection for clear cell RCC between January 1, 2011, and March 31, 2021, were included. Patients had intermediate high, high risk nonmetastatic disease (modified UCLA Integrated Staging System) or fully resected metastatic (M1) disease as per the inclusion criteria of adjuvant studies. Demographic, clinical, and outcomes between trial and nontrial patients were compared. Of 1,459 eligible patients, 63 (4.3%) participated in an adjuvant trial. Disease characteristics were similar between groups. Trial patients were younger (mean age 58.1 vs. 63.6 years; P < 0.0001) and had lower Charlson Comorbidity Index scores (mean 4.2 vs. 4.9; P = 0.009). Unadjusted disease-free survival (DFS) at 5 years for trial patients was 48.6% and 39.2% for nontrial patients (HR 0.71, 0.48-1.05, P = 0.08). Median DFS was higher for trial patients in comparison to nontrial patients (4.4 years, IQR 1.7- not reached; vs. 3.0 years, IQR 0.8-8.6; P = 0.08). Cancer specific survival (CSS) at 5 years for trial patients was 85.2% in comparison to 78.6% for nontrial patients (HR 0.45, 0.22-0.92, P = 0.03). Unadjusted estimated overall survival (OS) at 5 years was 80.8% for trial patients and 74.8% (HR 0.42, 0.18-0.94; P = 0.04) for nontrial patients. Patients in adjuvant trials were younger and healthier with longer CSS and OS in comparison to those not included in adjuvant trials. These findings may have implications when we generalize trial results to real world patients.

Adjuvant pembrolizumab (pembro) for renal cell carcinoma (RCC) across UCLA Integrated Staging System (UISS) risk groups and disease stage: Subgroup analyses from the KEYNOTE-564 study.

679 Background: Adjuvant pembro prolonged disease-free survival (DFS) for patients (pts) with RCC at increased risk of recurrence after nephrectomy in the phase 3 KEYNOTE-564 study (NCT03142334). This post hoc exploratory analysis evaluated efficacy of adjuvant pembro in pt subgroups based on UISS and disease stage. Methods: Pts with histologically confirmed clear cell RCC (pT2, Grade [G] 4 or sarcomatoid, N0, M0; pT3 or pT4, any G, N0, M0; any pT, any G, N+, M0; or M1 NED) were randomly assigned 1:1 to receive pembro 200 mg IV or placebo (pbo) every 3 weeks for ≤17 cycles (~1 y). DFS was assessed by investigator. UISS risk groups were derived retrospectively from TNM stage, Fuhrman nuclear grade, and ECOG PS. UISS groups were intermediate risk (pT2, G4, N0, M0; pT3, G1, N0, M0; or pT3, G2-4, N0, M0, ECOG 0), high risk (pT3, G2-4, N0, M0, ECOG PS 1; pT4, any G, N0, M0; or N1, M0), or M1 NED. Other subgroups were evaluated based on disease stage. Results: Baseline characteristics were balanced within subgroups. Median follow-up was 30.1 mo (range 20.8-47.5). Of 994 enrolled pts, most had UISS intermediate risk (n = 732, 73.6%; pembro n = 359; pbo n = 373); 195 pts (19.6%; pembro n = 100; pbo n = 95) had UISS high risk, and 58 pts (5.8%; pembro and pbo n = 29 each) had M1 NED. In the UISS intermediate risk group, the hazard ratio (HR) for DFS was 0.65 (95% CI, 0.48-0.88; 24-mo rates, pembro: 81.5%, pbo: 72.4%). In the UISS high-risk group, HR for DFS was 0.77 (95% CI, 0.49-1.20; 24-mo rates, pembro: 65.0%, pbo: 55.9%). In the M1 NED group, HR for DFS was 0.28 (95% CI, 0.12-0.66; 24-mo rates, pembro: 78.4%, pbo: 37.9%). DFS by disease stage is in the Table. Conclusions: Consistent with the results of the intention-to-treat (ITT) population, adjuvant pembro prolonged DFS compared with pbo for all subgroups. Results of this exploratory analysis further support the use of adjuvant pembro after nephrectomy as standard of care for pts with RCC at increased risk of recurrence. Clinical trial information: NCT03142334 . [Table: see text]

Can Pre-Operative Neutrophil-to-Lymphocyte Ratio (NLR) Help Predict Non-Metastatic Renal Carcinoma Recurrence after Nephrectomy? (UroCCR-61 Study).

Recent studies suggested that the neutrophil-to-lymphocyte ratio (NLR) could play a key role in tumor initiation, progression and response to treatments. The main objective was to assess the prognostic value of the pre-operative NLR on recurrence-free survival (RFS) in patients with non-hereditary localized renal cell carcinoma. From the UroCCR database (NCT03293563), factors influencing the disease recurrence of consecutive patients who underwent nephrectomy for cT1-T4 N0M0 were analyzed using multi-variate cox regression and log-rank methods. We included 786 patients, among which 135 (17.2%) experienced a recurrence at a median time of 23.7 [8.5-48.6] months. RFS for patients with a pre-operative NLR of <2.7 was 94% and 88% at 3 and 5 years, respectively, versus 76% and 63% for patients with a NLR of ≥2.7 (p < 0.001, log-rank test). To predict the risk of post-operative recurrence, the NLR was combined with the UCLA integrated staging system (UISS), and we defined four groups of the UroCCR-61 predictive model. The RFS rates at 3 and 5 years were 100% and 97% in the very-low-risk group, 93% and 86% in the low-risk group, 78% and 68% in the intermediate-risk group and 63% and 46% in the high-risk group (p < 0.0001). The pre-operative NLR seems to be an inexpensive and easily accessible prognostic bio-marker for non-metastatic RCCs.

PD18-02 EXTERNAL VALIDATION OF THE ASSURE MODEL TO PREDICT ONCOLOGICAL OUTCOMES AFTER RESECTION OF HIGH-RISK RENAL CELL CARCINOMAS

You have accessJournal of UrologyCME1 May 2022PD18-02 EXTERNAL VALIDATION OF THE ASSURE MODEL TO PREDICT ONCOLOGICAL OUTCOMES AFTER RESECTION OF HIGH-RISK RENAL CELL CARCINOMAS Zine-Eddine Khene, Alessandro Larcher, Jean-Christophe Bernhard, Nicolas Doumerc, Romain Boissier, Idir Ouzaid, Philippe Barthelemy, Morgan Roupret, Francesco Montorsi, Pierre Bigot, and Karim Bensalah Zine-Eddine KheneZine-Eddine Khene More articles by this author , Alessandro LarcherAlessandro Larcher More articles by this author , Jean-Christophe BernhardJean-Christophe Bernhard More articles by this author , Nicolas DoumercNicolas Doumerc More articles by this author , Romain BoissierRomain Boissier More articles by this author , Idir OuzaidIdir Ouzaid More articles by this author , Philippe BarthelemyPhilippe Barthelemy More articles by this author , Morgan RoupretMorgan Roupret More articles by this author , Francesco MontorsiFrancesco Montorsi More articles by this author , Pierre BigotPierre Bigot More articles by this author , and Karim BensalahKarim Bensalah More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002556.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: A prognostic model based on the population of the ASSURE phase III trial has recently been described. The ASSURE model stratifies patients into risk groups to predict survival after surgical resection of intermediate and high-risk localized kidney cancer. Our objective was to validate the ASSURE model in a large independent multi-institutional cohort of patients treated in a “real life” setting outside of a clinical trial. METHODS: Data of patients from ten institutions who underwent radical or partial nephrectomy for a non-metastatic RCC between 2013 and 2019 were analyzed. We exclusively focused on patients with pT1b and ISUP 3-4, pT2, pT3, pT4, and N1 (i.e., those classified as intermediate and high risk according to the ASSURE model). The performance of the ASSURE model was evaluated in terms of discrimination and calibration. In addition, decision curve analysis (DCA) was used to determine whether the clinical value of the new model increased the net benefit over a realistic range of threshold probabilities. Finally, DCA of the ASSURE model was compared with that of older UCLA Integrated Staging System (UISS) and Leibovich 2018 score. RESULTS: 1372 patients were included in the analysis. Median age was 64 years (IQR 55-72). Median tumor size was 6.5 cm (IQR 5-9). The majority of tumors were clear cell RCCs (77%), of high ISUP grade (72% of grade 3 and 4), with 45% exhibiting tumor necrosis and 5% harboring nodal involvement. Median follow up was 54 months (IQR 32-75). Regarding disease-free survival, the ASSURE model showed modest discrimination (65%), miscalibration and poor net benefit compared with UCLA Integrated Staging System (UISS) and Leibovich 2018 models. Similarly, the ability of the ASSURE model to predict overall survival was poor in terms of discrimination (63%), with an overestimation on calibration plots and a modest net benefit for probability threshold between 10-40%. CONCLUSIONS: The ASSURE model is the last reported prognostic model that evaluates survival after surgical resection of a non-metastatic renal cell carcinoma. An improvement of patient classification was not clearly established when compared with available models, and implementation of this model in this setting still needs to be clarified. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e342 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Zine-Eddine Khene More articles by this author Alessandro Larcher More articles by this author Jean-Christophe Bernhard More articles by this author Nicolas Doumerc More articles by this author Romain Boissier More articles by this author Idir Ouzaid More articles by this author Philippe Barthelemy More articles by this author Morgan Roupret More articles by this author Francesco Montorsi More articles by this author Pierre Bigot More articles by this author Karim Bensalah More articles by this author Expand All Advertisement PDF DownloadLoading ...

MP12-01 C-REACTIVE PROTEIN KINETICS TO PREDICT RECURRENCE AFTER RADICAL SURGERY FOR HIGH-RISK RENAL CELL CARCINOMA

You have accessJournal of UrologyCME1 May 2022MP12-01 C-REACTIVE PROTEIN KINETICS TO PREDICT RECURRENCE AFTER RADICAL SURGERY FOR HIGH-RISK RENAL CELL CARCINOMA Yudai Ishiyama, Tsunenori Kondo, Hiroki Ishihara, Kazuhiko Yoshida, Junpei Iizuka, Kazunari Tanabe, and Toshio Takagi Yudai IshiyamaYudai Ishiyama More articles by this author , Tsunenori KondoTsunenori Kondo More articles by this author , Hiroki IshiharaHiroki Ishihara More articles by this author , Kazuhiko YoshidaKazuhiko Yoshida More articles by this author , Junpei IizukaJunpei Iizuka More articles by this author , Kazunari TanabeKazunari Tanabe More articles by this author , and Toshio TakagiToshio Takagi More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002534.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: With new options appearing in adjuvant setting, clinical biomarkers to predict recurrence after radical surgery for high-risk renal cell carcinoma (hrRCC) is in need but scarcely investigated. We aimed to verify the predictive value of perioperative C-reactive protein (CRP) kinetics on RCC recurrence. METHODS: We retrospectively evaluated 154 patients who underwent curative surgery for high-risk (≥pT3 or N0-2 and M0) RCC at two institutions between 2008 and 2020. Serum CRP (mg/dL) within one months before (baseline) and within three months (post) after surgery were obtained. Patients were classified into Normal (<0.5 at baseline) and High (≥0.5 at baseline) according to baseline CRP. The High group were further classified into Normalized (<0.5 at post) or non-normalized (≥0.5 at post), and recurrence-free survival (RFS) was compared between groups. Factors for RFS were further analyzed using multivariable Cox hazards model. C-index for accuracy of predicting RFS was compared with and without addition or CRP kinetics to preexisting models. RESULTS: The RFS was significantly shorter in High (n=72, 46.8) compared to Normal (n=82, 53.2%) group (9.7 vs. 66.7 months, p <0.001). Within High group, non-normalized (n=27, 17.5%) patients showed significantly shorter RFS compared to Normalized (n=45, 29.2%) group (6.2 vs. 10.0, p=0.013). In the multivariable analysis both baseline CRP (HR: 2.05, p=0.003) and kinetics (HR: 2.62, p <0.001) effectively predicted RFS, with HR being higher for kinetics. Higher C-index improvement was observed with CRP kinetics than the baseline CRP levels when added to factors included in Karakiewicz and UCLA Integrated Staging System models. CONCLUSIONS: CRP kinetics effectively predict RCC recurrence after surgery, and may aid in decision-making for adjuvant systemic therapy. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e165 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yudai Ishiyama More articles by this author Tsunenori Kondo More articles by this author Hiroki Ishihara More articles by this author Kazuhiko Yoshida More articles by this author Junpei Iizuka More articles by this author Kazunari Tanabe More articles by this author Toshio Takagi More articles by this author Expand All Advertisement PDF DownloadLoading ...

Comparison of patients with high-risk nonmetastatic clear cell renal carcinoma in adjuvant therapy trials versus nonclinical trial patients.

361 Background: Characteristics of patients with high risk for recurrence non-metastatic renal cell carcinoma (nmRCC) participating in adjuvant therapy clinical trials post-nephrectomy have not been well described. We evaluated high risk nmRCC patients in the CKCis database to explore differences between trial and non-trial patients. Methods: Adult patients undergoing partial or radical nephrectomy for clear cell nmRCC between January 1, 2011 and March 31, 2021 were included. CKCis is a prospective cohort of patients from 14 Canadian academic institutions. Patients with high risk nmRCC (using modified UCLA Integrated Staging System) were included. Demographic, clinical, and survival statistics were analyzed for all patients and comparatively for the trial and non-trial groups. Results: 1459 patients, including 63 in adjuvant trials, were evaluated. 71% were male, 91% had pT3N0M0 disease. Disease characteristics including tumor size, stage, grade, location, necrosis, and margin status were similar between groups. Trial patients were younger (mean age 58.1 vs. 63.6; p &lt; 0.0001) and had lower Charlson Comorbidity Index scores (median 4 [3,6) vs. 5 [4,6] p &lt; 0.001). Estimated overall survival (OS) at 5 years was 80.8% (95% CI, 65,90) for trial patients and 74.8% (95% CI, 71,78.2) for non-trial patients. Recurrence-free survival at 5 years for trial patients was 48.6% (95% CI, 34,61.7) and 39.2% (95% CI, 35.2,43.1) for non-trial patients. Conclusions: Patients in adjuvant trials were younger and healthier at baseline than the average high risk nmRCC CKCis patient. Trial patients appear to have had longer time to recurrence and longer survival compared to non-trial patients, although not reaching statistical significance. Selection bias is common in clinical trials and evaluation of real-world population-based evidence of patients receiving adjuvant therapy will be important to ensure phase 3 trial results have external validity.

Leibovich score is the optimal clinico-pathological system associated with recurrence of non-metastatic clear cell renal cell carcinoma

PurposeTo determine the optimal post-operative risk stratification system associated with survival following surgery for clear cell renal cell carcinoma (ccRCC): tumour grade, tumour stage, Leibovich 2003, Leibovich 2018, Kattan, Stage, size, grade and necrosis (SSIGN) or UCLA Integrated Staging System (UISS) scores. Methods542 patients with non-metastatic ccRCC who underwent nephrectomy 2008−2018 were reviewed. Primary outcome was recurrence-free survival (RFS), with secondary outcomes cancer-specific survival (CSS) and overall survival (OS). ResultsAll systems were significantly associated with RFS, CSS and OS by Kaplan-Meier and unadjusted Cox-regression. ROC analysis identified that Leibovich 2003, Leibovich 2018A or B and SSIGN were optimally association with 5year RFS (AUC (Area under curve) 0.87, 0.86, 0.86 and 0.86), but Leibovich 2003 or 2018A offered additional information on adjusted regression analysis (HR 1.24, P = 0.02; HR 1.17, P = 0.04). ROC analysis identified that Leibovich 2018B, Leibovich 2003, SSIGN and UISS were equally associated with 5 year OS (AUC 0.76, 0.74, 0.73 and 0.72). UISS added additional explanation of the variance in OS on adjusted regression analysis (HR 1.96, P = 0.002). A novel combination of Leibovich 2003 score and Eastern Co-operative Oncology Group (ECOG) performance status improved 5 year OS association compared to the Leibovich 2003 alone (AUC 0.78, P = 0.001), without affecting association with 5year RFS (AUC 0.87, P = 0.75). ConclusionsAll systems were robust tools associated with RFS, CSS and OS in ccRCC. In our cohort, the Leibovich 2003 and Leibovich 2018A scores may be better associated with RFS compared to other strategies. The UISS, Leibovich 2018B or Leibovich 2003 combined with ECOG performance status may stratify OS better than other modalities.

Therapy-relevant gene signatures in the high risk localized renal cell carcinoma setting: Transcriptomic data from patients receiving placebo on a randomized phase III trial (PROTECT).

353 Background: Transcriptomic profiling of the renal cell carcinoma (RCC) tumor microenvironment (TME) has revealed gene signatures predictive of response to therapies in the metastatic setting. High expression of angiogenesis genes correlate with responses to tyrosine kinase inhibitors. Adenosine in the TME exerts immunosuppressive effects that can facilitate tumor growth. Adenosinergic agonism has revealed gene signatures, comprised of inflammatory myeloid mediators, that correlated with response to adenosine pathway inhibition on a previously reported cohort of patients. Given these promising data from the metastatic space, we sought to interrogate prognostic gene expression in the TME from patients with localized disease. Methods: Clinicopathologic and whole-gene microarray data were acquired from 202 patients in the placebo arm of the PROTECT trial (NCT01235962). Transcriptomic scores assessing angiogenesis and adenosine signaling with individual annotations above/below median categorized patients into four groups (angiogenesis high vs. low; adenosine high vs. low). Categorical association with disease free (DFS) and overall survival (OS) was tested with logrank testing and assessed interdependence with the UCLA Integrated Staging System (UISS) in a cox regression model. Results: Overall, 37% of the cohort developed recurrence and 81% were alive at last follow up. Kaplan-Meier analysis showed Adenohi and Angiolo signatures were individually associated with decreased DFS and OS, compared to Adenolo and Angiohi, respectively. Upon integrating these signatures, we found the AdenohiAngiolo group exhibited the worst and the AdenoloAngiohi group had the best DFS and OS. These associations were validated in the TCGA cohort. Multivariate Cox regression models showed AdenohiAngiohi (HR 3.75; 95% CI, 1.72-8.21; p = 0.0009) and AdenohiAngiolo (HR 6.44; 95% CI, 3.06-13.54; p &lt; 0.0001) groups (AdenoloAngiohi as reference group) and pathologic T4 (HR 8.69; 95% CI, 2.66-28.36; p = 0.0003) were significantly associated with worse DFS, but not UISS score (HR 0.56; 95% CI, 0.24-1.31; p = 0.18) and T3 tumors (HR 1.54; 95% CI, 0.8-2.94; p = 0.2; T2 as reference group). Conclusions: RCC TME subgroups stratified into adenosinergic and angiogenic expression profiles carry independent prognostic significance in patients with localized RCC. On multivariate analysis, these gene signatures enhanced conventional clinicopathologic risk stratification variables in predicting DFS after nephrectomy. Given the early data fueling interest in developing the prognostic capacity of these gene signatures in the metastatic space, and their ability to predict outcomes in the post-nephrectomy setting, these biologically relevant subgroups should be explored as a guide for future biomarker-driven adjuvant therapy trials.

Clinical Implications of (Pro)renin Receptor (PRR) Expression in Renal Tumours

(1) Background: Renal cancer is one of the most frequent malignancies in Western countries, with an unpredictable clinical outcome, partly due to its high heterogeneity and the scarcity of reliable biomarkers of tumour progression. (Pro)renin receptor (PRR) is a novel receptor of the renin–angiotensin system (RAS) that has been associated with the development and progression of some solid tumours by RAS-dependent and -independent mechanisms. (2) Methods: In this study, we analysed the immunohistochemical expression of PRR at the centre and border in a series of 83 clear-cell renal cell (CCRCCs), 19 papillary (PRCC) and 7 chromophobe (ChRCC) renal cell carcinomas, and the benign tumour renal oncocytoma (RO, n = 11). (3) Results: PRR is expressed in all the tumour subtypes, with higher mean staining intensity in ChRCCs and ROs. A high expression of PRR at the tumour centre and at the infiltrative front of CCRCC tissues is significantly associated with high grade, tumour diameter, local invasion and stage, and with high mortality risk by UCLA integrated staging system (UISS) scale. (4) Conclusions: These findings indicate that PRR is associated with the development and progression of renal tumours. Its potential as a novel biomarker for RCC diagnosis/prognosis and as a promising therapeutic target should be taken into account in the future.

Immune infiltration and angiogenesis as markers of outcome in the post-nephrectomy setting: Transcriptomic data from patients receiving placebo on a randomized phase III trial (PROTECT).

5082 Background: Defined stromal and immune features of the tumor microenvironment (TME) have proven relevant for outcomes with systemic therapy in advanced clear cell renal cell carcinoma (ccRCC). We hypothesized that these may matter beyond therapeutic applications and could be relevant much earlier in the disease course. We sought to study the TME in high risk ccRCC patients undergoing definitive surgery. Methods: Clinical, pathologic, immunohistochemical, and whole-genome microarray data were acquired on 236 out of 769 patients in the Placebo arm of PROTECT trial (NCT01235962 - pazopanib vs placebo). Transcriptomic scores assessing angiogenesis and myeloid infiltration with individual annotations above/below median were used to categorize patients into four groups (angiogenesis high vs. low; myeloid high vs. low). We tested categorical association with disease free (DFS) and overall survival (OS) using logrank testing and assessed interdependence with relevant clinicopathologic variables, including the UCLA Integrated Staging System (UISS) in a cox regression model. Results: Tumors from236 patients were available for analysis. Overall, 37% developed metastatic recurrence and 81% were alive at last follow up. On univariate analysis increasing tumor stage, higher UISS score, and angiogenesis/myeloid subgroups (high – H and low – L) were associated with worse DFS and OS (all p values &lt;0.05). On multivariate analysis TME subgroups remained significant for worse DFS and OS (Table). Conclusions: Microenvironmental subgroups stratified into angiogenic and myeloid expression profiles carry independent prognostic significance and should be further explored to guide future biomarker-directed adjuvant trials. Clinical trial information: NCT01235962 . [Table: see text]

Prognostic analysis of postoperative clinically nonmetastatic renal cell carcinoma.

ObjectivesTo investigate the survival characteristics of postoperative nonmetastatic renal cell carcinoma (RCC) patients, and the predictive value of a prognostic model.Materials and MethodsWe retrospectively evaluated data from 1202 postoperative nonmetastatic RCC patients who were treated between 1999 and 2012 at West China Hospital, Sichuan University (Chengdu, China). In addition, we also evaluated data relating to 53 205 cases acquired from the Surveillance, Epidemiology, and End Results (SEER) program. Survival analysis was performed on the cases, and subgroups, using the Kaplan‐Meier and Cox regression methods. The concordance index of the Stage Size Grade Necrosis (SSIGN), Leibovich, and the UCLA integrated staging system, scores was determined to evaluate the accuracy of these outcome prediction models.ResultsThe 5‐year overall survival rate for RCC cases in West China Hospital was 87.6%; this was higher than that observed for SEER cases. Survival analysis identified several factors that exerted significant influence over prognosis, including the time of surgery, Eastern Cooperative Oncology Group performance status, tumor stage, size, nuclear differentiation, pathological subtypes, along with necrotic and sarcomatoid differentiation. Moreover tumor stage, size, and nuclear grade were all identified as independent predictors for both our cases and those from the SEER program. Patient groups with advanced RCC, and poorly differentiated RCC subgroups, were both determined to have a poor prognosis. The SSIGN model yielded the best predictive value as a prognostic model, followed by the Leibovich, and UCLA integrated staging system; this was the case for our patients, and for sub‐groups with a poor prognosis.ConclusionThe prognosis of RCC was mostly influenced by tumor stage, size, and nuclear differentiation. SSIGN may represent the most suitable prognostic model for the Chinese population.

Immunologic profile and prognostic significance of tumor-infiltrating lymphocytes in renal cell carcinoma.

673 Background: Renal cell carcinoma (RCC) has been shown to be a genetically and morphologically heterogeneous cancer. As studies show the significance of tumor-infiltrating lymphocytes (TIL) in cancer, it is critical to examine how the phenotype of TILs manifests in RCC. Such analysis may help explain the role of the immune landscape in developing resistance and its contribution to the high treatment failure observed in immunotherapy for RCC. This study compares the immune phenotype of primary tumors, venous tumor thrombi (VTT), and metastases, as well as multiple sites within primary tumors, and investigates whether inter- and intra-tumoral immune heterogeneity is present in RCC. The association of TIL levels and clinical prognosis will also be assessed and compared with current RCC prognostic scores. Methods: Our cohort included 15 VTT and 6 metastases (3 adrenal, 2 bone, 1 liver) with 20 matched primary tumors, as well as 25 non-metastatic primary tumors. The RCC tissue was collected and digested into single cell suspensions. Suspensions were stained for TIL surface markers and processed using flow cytometry. The data was analyzed to capture %CD8+ and %CD4+ in total tumor. The %CD28+ and %PD1+ of CD8+ cells were measured to describe the co-stimulatory and co-inhibitory receptor expression, respectively. Clinical data was obtained to calculate the Mayo Stage, Size, Grade, and Necrosis (SSIGN) and UCLA Integrated Staging System (UISS) scores for each patient and to evaluate recurrence. Results: Immunologic concordance was observed in all measured parameters (%CD8+, %CD4+, %CD28+, and %PD1+) for primary tumors and VTT, for primary tumors and their metastases, and for different sites within 10 primary tumors. In our overall cohort, %CD8+ was found to be inversely associated with recurrence (p = 0.02). Furthermore, %CD8+ was not significantly associated with patient Mayo SSIGN and UISS scores. Conclusions: Despite the genetic and morphologic heterogeneity seen in RCC, immunologic concordance was observed for both inter- and intra-tumoral analysis. The association between %CD8+ and recurrence presents a novel and objective immune-based prognostic factor for RCC, independent of Mayo SSIGN and UISS scores.

Development of a conversation aid tool for patients with localized renal cell carcinoma at high risk of recurrence.

608 Background: Approximately 15% of nephrectomised patients who are diagnosed with loco-regional renal cell carcinoma (RCC) are considered to be at high risk of recurrence according to the postoperative UCLA Integrated Staging System (UISS) and 60% of these patients are expected to recur within five years of diagnosis. This study aimed to develop a conversation aid tool to improve knowledge about RCC for post-nephrectomy RCC patients who are at high-risk of recurrence. Specifically, to enable patients to make an informed decision about whether to proceed/not proceed with adjuvant therapy, should adjuvant therapy become standard-of-care in the future. Methods: A review of existing evidence relating to the development of conversation aid tools and previously developed tools was undertaken. Following the review, a focus group with a steering committee (RCC patients, caregivers and a clinician), and semi-structured interviews were conducted with clinicians to identify information currently provided as standard of care. Additional interviews were conducted with post-nephrectomy patients, to identify information patients would prefer to have been given post-nephrectomy. Results: The evidence review of 10 articles provided a framework for the development of a tool to enable better patient/clinician communication. Clinicians described a typical post-nephrectomy consultation and highlighted key topics of discussion, which included recovery, risk of relapse and ongoing care. The research highlighted that patients are expected to absorb a significant amount of information during consultations in order to take an active role in their care. Findings from the focus group and clinician/patient interviews led to the development of a conversation aid tool providing patients with key questions to ask their clinicians to increase knowledge of RCC post-nephrectomy and also the information they may require when considering adjuvant therapy, including: prognosis, risk of relapse, and the risk/benefit profile of available treatment options. Conclusions: The conversation aid tool may be useful for patients to improve knowledge of RCC and help make informed decisions about their future treatment and care.

Risk Based Surveillance after Surgical Treatment of Renal Cell Carcinoma

We assessed the accuracy of the UISS (UCLA Integrated Staging System) to predict the postoperative recurrence of renal cell carcinoma. We also evaluated whether including patient age and tumor histology would improve clinical decision making. We analyzed the records of 1,630 patients treated with nephrectomy at a single academic center. The accuracy of the UISS model to predict early (12 months or less) and late (more than 60 months) recurrence after surgery was compared with a new model including patient age and disease histology. The new model and the UISS model showed high accuracy to predict early recurrence after surgery (AUC 0.84, 95% CI 0.81-0.88 and 0.83, 95% CI 0.80-0.87, respectively). In patients diagnosed with low risk tumor types (eg papillary type 1 and chromophobe lesions) the average risk of early recurrence significantly decreased in each UISS risk category when tumor histology was added to the predictive model (low risk 1.6% vs 0.6%, intermediate risk 5.5% vs 1.9% and high risk 45% vs 22%). Kaplan-Meier analysis showed no difference in the risk of late recurrence among the UISS risk categories. The UISS model should be applied to tailor the early followup protocol after nephrectomy. Patients with low risk histology deserve less stringent followup regardless of the UISS risk category. Our results do not support a risk stratification model to design a surveillance protocol after 5 years postoperatively.

Expression and activity of angiotensin-regulating enzymes is associated with prognostic outcome in clear cell renal cell carcinoma patients.

The discovery of the intrarenal renin-angiotensin system (iRAS), which regulates angiogenesis, cell differentiation and proliferation, has opened new perspectives in the knowledge of kidney carcinogenesis. In this study we analyzed the immunohistochemical expression and fluorimetric activity of four key peptidases of iRAS in tumor tissue (n = 144) and serum samples (n = 128) from patients with renal neoplasms. Neutral endopeptidase (NEP/CD10), Angiotensin-converting enzyme-2 (ACE2), and aminopeptidase A (APA) were expressed in tumor cells whilst Angiotensin-converting enzyme (ACE) was expressed in the endothelial cells of intratumor blood vessels. The expression of ACE, ACE2 and NEP/CD10 was highest in clear cell renal cell carcinoma (CCRCC) and papillary renal cell carcinoma (PRCC). The expression of these enzymes correlated with CCRCC aggressiveness. In addition, NEP/CD10 correlated with 15-year overall survival. On the other hand, APA expression was decreased in CCRCC with higher grade and stage. The loss of expression of APA independently correlated with a worse 15-year overall survival. Serum activity of ACE2, NEP/CD10 and APA was significantly higher in renal tumor patients than in healthy subjects. Serum ACE activity was lower in high grade and metastatic CCRCC patients, and NEP/CD10 activity was negatively correlated with UISS (UCLA Integrated Staging System) and SSIGN (Mayo Clinic stage, size, grade and necrosis model) scores and with overall survival of CCRCC patients. These results suggest a metabolic imbalance of iRAS in renal tumors. This finding should be taken into account in the search of new diagnostic, prognostic and therapeutic tools for this disease.

A novel preoperative inflammatory marker prognostic score in patients with localized and metastatic renal cell carcinoma

ObjectiveSeveral inflammatory markers have been studied as potential biomarkers in renal cell carcinoma (RCC), however few reports have analyzed their prognostic value in aggregate and in non-clear cell histologies. We hypothesize that a combination of specific inflammatory markers into an RCC Inflammatory Score (RISK) could serve as a rigorous prognostic indicator of overall survival (OS) in patients with clear cell and non-clear cell RCC. MethodsCombination of preoperative C-reactive protein (CRP), albumin, erythrocyte sedimentation rate (ESR), corrected calcium, and aspartate transaminase to alanine transaminase (AST/ALT) ratio was used to develop RISK. RISK was developed using grid-search methodology, receiver-operating-characteristic (ROC) analysis, and sensitivity-specificity trade-off analysis. Prognostic value of RISK was analyzed using the Kaplan–Meier method and Cox proportional regression models. Predictive accuracy was compared with RISK to Size, Size, Grade, and Necrosis (SSIGN) score, University of California-LOS Angeles (UCLA) Integrated Staging System (UISS), and Leibovich Prognosis Score (LPS). ResultsAmong 391 RCC patients treated with nephrectomy, area under the curve (AUC) for RISK was 0.783, which was comparable to SSIGN (AUC 0.776, p = 0.82) and UISS (AUC 0.809, p = 0.317). Among patients with localized disease, AUC for RISK and LPS was 0.742 and 0.706, respectively (p = 0.456). On multivariate analysis, we observed a step-wise statistically significant inverse relationship between increasing RISK group and OS (all p < 0.001). ConclusionRISK is an independent and significant predictor of OS for patients treated with nephrectomy for clear cell and non-clear cell RCC, with accuracy comparable to other histopathological prognostic tools.

Predictive Nomogram for Recurrence following Surgery for Nonmetastatic Renal Cell Cancer with Tumor Thrombus

Following surgery for nonmetastatic renal cell carcinoma with tumor thrombus the risk of recurrence is significant but variable among patients. The purpose of this study was to develop and validate a predictive nomogram for individual estimation of recurrence risk following surgery for renal cell carcinoma with venous tumor thrombus. Comprehensive data were collected on patients with nonmetastatic renal cell carcinoma and thrombus treated at a total of 5 institutions from 2000 to 2013. Independent predictors of recurrent renal cell carcinoma from a competing risks analysis were developed into a nomogram. Predictive accuracy was compared between the development and validation cohorts, and between the nomogram and the UISS (UCLA Integrated Staging System, SSIGN (Stage, Size, Grade and Necrosis) and Sorbellini models. A total of 636 patients were analyzed, including the development cohort of 465 and the validation cohort of 171. Independent predictors, including tumor diameter, body mass index, preoperative hemoglobin less than the lower limit of normal, thrombus level, perinephric fat invasion and nonclear cell histology, were developed into a nomogram. Estimated 5-year recurrence-free survival was 49% overall. Five-year recurrence-free survival in patients with 0, 1, 2 and more than 2 risk factors was 77%, 53%, 47% and 20%, respectively. Predictive accuracy was similar in the development and validation cohorts (AUC 0.726 and 0.724, respectively). Predictive accuracy of the thrombus nomogram was higher than that of the UISS (AUC 0.726 vs 0.595, p = 0.001), SSIGN (AUC 0.713 vs 0.612, p= 0.04) and Sorbellini models (AUC 0.709 vs 0.638, p = 0.02). We present a predictive nomogram for postoperative recurrence in patients with nonmetastatic renal cell carcinoma with venous thrombus. Improving individual postoperative risk assessment may allow for better design and analysis of future adjuvant clinical trials.

MP55-13 COMPARING PREDICTIVE ACCURACY FOR FOUR PROGNOSTIC MODELS OF RECURRENCE FOLLOWING SURGERY IN NON-METASTATIC RENAL CELL CARCINOMA WITH THROMBUS USING CONTEMPORARY DATA FROM SIX INSTITUTIONS

You have accessJournal of UrologyKidney Cancer: Localized: Surgical Therapy III1 Apr 2017MP55-13 COMPARING PREDICTIVE ACCURACY FOR FOUR PROGNOSTIC MODELS OF RECURRENCE FOLLOWING SURGERY IN NON-METASTATIC RENAL CELL CARCINOMA WITH THROMBUS USING CONTEMPORARY DATA FROM SIX INSTITUTIONS Shivashankar Damodaran, Jose A. Karam, Timothy A. Masterson, Viraj A. Master, Vitaly Margulis, Datta Patil, Tyler Bauman, Michael Blute, Jr., Evan Bloom, Haley Robyak, Matthew Kaag, Jay D. Raman, Christopher G. Wood, and E. Jason Abel Shivashankar DamodaranShivashankar Damodaran More articles by this author , Jose A. KaramJose A. Karam More articles by this author , Timothy A. MastersonTimothy A. Masterson More articles by this author , Viraj A. MasterViraj A. Master More articles by this author , Vitaly MargulisVitaly Margulis More articles by this author , Datta PatilDatta Patil More articles by this author , Tyler BaumanTyler Bauman More articles by this author , Michael Blute, Jr.Michael Blute, Jr. More articles by this author , Evan BloomEvan Bloom More articles by this author , Haley RobyakHaley Robyak More articles by this author , Matthew KaagMatthew Kaag More articles by this author , Jay D. RamanJay D. Raman More articles by this author , Christopher G. WoodChristopher G. Wood More articles by this author , and E. Jason AbelE. Jason Abel More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1706AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Predictive models for recurrence in non-metastatic renal cell carcinoma (RCC) have been developed from general populations of RCC patients, including very few high risk patients. According, these models may not be ideal to stratify high risk patients for enrollment in adjuvant clinical trials such as patients with venous tumor thrombus. The purpose of this study was to compare predictive accuracy for a nomogram developed from non-metastatic RCC patients with venous tumor thrombus with 3 existing prognostic models for RCC recurrence following surgery. METHODS A nomogram was developed from independent predictors after multivariable modeling of common clinical and pathologic variables. Receiver operator characteristic (ROC) curves were constructed to compare predictive accuracy of the nomogram with the University of California-Los Angeles Integrated Staging System(UISS), Stage Size Grade Necrosis (SSIGN) and Sorbellini models. RESULTS A total of 669 consecutive non-metastatic RCC patients with tumor thrombus were treated surgically from 2000-2014 at 6 institutions. Variables independently associated with RCC recurrence were increased tumor diameter per centimeter, body mass index per point, preoperative hemoglobin < lower limit of normal, IVC thrombus level above hepatic vein, perinephric fat invasion, and non-clear cell histology. Estimated overall 5-year RFS was 49%. A nomogram was developed using weighted variables in a development cohort (n=465) and validated in a separate cohort (n=204). The AUC for the thrombus nomogram was 0.738, which was significantly higher than AUC for the Sorbellini model (0.623), UISS model (0.615) and SSIGN model (0.584). CONCLUSIONS A nomogram developed specifically for non-metastatic RCC patients with venous tumor thrombus has significantly greater predictive accuracy than general prognostic models in this high risk population. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e735-e736 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Shivashankar Damodaran More articles by this author Jose A. Karam More articles by this author Timothy A. Masterson More articles by this author Viraj A. Master More articles by this author Vitaly Margulis More articles by this author Datta Patil More articles by this author Tyler Bauman More articles by this author Michael Blute, Jr. More articles by this author Evan Bloom More articles by this author Haley Robyak More articles by this author Matthew Kaag More articles by this author Jay D. Raman More articles by this author Christopher G. Wood More articles by this author E. Jason Abel More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...