Integrated Staging System Research Articles

Notch1 Predicts Recurrence and Survival of Patients With Clear-cell Renal Cell Carcinoma After Surgical Resection

To evaluate the prognostic significance of Notch1 activation in patients with clear-cell renal cell carcinoma (ccRCC). We retrospectively enrolled 203 patients with ccRCC undergoing nephrectomy at Zhongshan Hospital of Fudan University between 2003 and 2004. Notch1 activation was assessed by immunohistochemical staining of the intracellular domain of Notch1 (ICN1) in specimens of patients. The Kaplan-Meier method, Cox regression models, and Harrell concordance index (C-index) calculation were used to evaluate the prognostic value of ICN1 expression and its association with clinicopathologic features. Tumor tissues from patients with advanced TNM stage and Fuhrman grade exhibited elevated ICN1 expression, which correlated positively with tumor size, Fuhrman grade, and tumor necrosis. Moreover, high ICN1 expression indicated poor overall survival and recurrence-free survival of patients with ccRCC. After backward elimination, ICN1 expression, as well as Fuhrman grade, Eastern Cooperative Oncology Group performance status, and TNM stage, was identified as an independent adverse prognostic factor for survival and recurrence. The predictive accuracy of well-established TNM, University of California Integrated Staging System, and Mayo Clinic stage, size, grade, and necrosis prognostic models was improved when ICN1 expression was added. Furthermore, a predictive nomogram was generated with identified independent prognosticators to assess patient survival at 5years after surgery. Notch1 activation is a potential independent adverse prognostic biomarker for recurrence and survival of patients with ccRCC after nephrectomy.

Elevated Expression of N-Acetylgalactosaminyltransferase 10 Predicts Poor Survival and Early Recurrence of Patients with Clear-Cell Renal Cell Carcinoma.

The aim of this study was to evaluate the potential prognostic significance of N-acetylgalactosaminyltransferase 10 (GALNT10) in patients with clear-cell renal cell carcinoma (ccRCC) after surgical resection. We retrospectively enrolled 271 patients (202 in the training cohort and 69 in the validation cohort) with ccRCC undergoing nephrectomy at a single institution. Clinicopathologic features, overall survival (OS), and recurrence-free survival (RFS) were recorded. GALNT10 intensities were assessed by immunohistochemistry in the specimens of patients. The Kaplan-Meier method was applied to compare survival curves. Cox regression models were used to analyze the impact of prognostic factors on OS and RFS. Concordance index (C-index) was calculated to assess predictive accuracy. In both cohorts, elevated GALNT10 expression in tumor tissues positively correlated with advanced TNM stage. High GALNT10 expression indicated poor survival and early recurrence of patients with ccRCC, particularly with early-stage disease. After backward elimination, GALNT10 expression was identified as an independent adverse prognostic factor for survival and recurrence. The predictive accuracy of TNM, University of California Los Angeles Integrated Staging System, and stage, size, grade, and necrosis prognostic models was improved when GALNT10 expression was added. GALNT10 expression is a potential independent adverse prognostic biomarker for recurrence and survival of patients with ccRCC after nephrectomy.

Galectin-8 predicts postoperative recurrence of patients with localized T1 clear cell renal cell carcinoma

BackgroundGalectin-8 (Gal-8), belonging to a family of the “tandem repeat”–type galectins that contain 2 carbohydrate recognition domains, serves to retain cell surface residency and signaling of glycoproteins including cytokine and growth factor receptors, and thereby promoting development and progression of various malignancies. This study aims to evaluate the effect of Gal-8 expression on postoperative recurrence of patients with localized pathologic T1 (pT1) clear cell renal cell carcinoma (ccRCC). Patients and methodsIn this retrospective study, we enrolled 244 patients (122 in group A and 122 in group B) with localized pT1 ccRCC undergoing nephrectomy at a single institution. Specimens from patients were collected from January 2003 to December 2008. Median follow-up was 71 months (range: 12–120mo) in group A and 70 months (range: 12–119mo) in group B. Overall, 14 patients experienced recurrence in group A (n = 122) and 22 patients had recurrence in group B (n = 122). Gal-8 expression was assessed by immunohistochemistry in clinical specimens. Kaplan-Meier method with log-rank test was performed to compare survival curves. Cox regression models were used to evaluate the prognostic values of variables on recurrence-free survival. Concordance index was calculated to assess prognostic accuracy. ResultsIn both groups, patients with high expression of Gal-8 were significantly inclined to have high rates of necrosis. High Gal-8 expression indicated early recurrence of patients with localized pT1 ccRCC. Gal-8 expression was determined to be an independent adverse prognostic indicator for recurrence. The accuracy of The Mayo Clinic Stage, Size, Grade, and Necrosis score and University of Los Angeles Integrated Staging System prognostic models was improved when Gal-8 expression was added. ConclusionsGal-8 expression is a potential independent unfavorable prognostic indicator for postoperative recurrence of patients with localized pT1 ccRCC.

Tumor miR-125b predicts recurrence and survival of patients with clear-cell renal cell carcinoma after surgical resection.

The present study aims to evaluate the impact of tumor microRNA-125b (miR-125b) on recurrence and survival of patients with clear-cell renal cell carcinoma (ccRCC) following surgery. We retrospectively enrolled 276 patients (200 in the training cohort and 76 in the validation cohort) with ccRCC undergoing nephrectomy at a single institution. Clinicopathologic features, cancer-specific survival (CSS) and recurrence-free survival (RFS) were recorded. Tumor miR-125b levels were assessed by in situ hybridization (ISH) in specimens of patients. The Kaplan–Meier method was applied to compare survival curves. Cox regression models were used to analyze the impact of prognostic factors on CSS and RFS. A concordance index (C-index) was calculated to assess predictive accuracy. In both cohorts, tumor miR-125b positively correlated with Fuhrman grade. High tumor miR-125b indicated poor survival and early recurrence for patients with ccRCC, especially with advanced stage disease. After multivariable adjustment, tumor miR-125b was identified as an independent adverse prognostic factor for survival and recurrence. The predictive accuracy of traditional TNM and UCLA Integrated Staging System prognostic models was improved when tumor miR-125b was added. The results showed that tumor miR-125b is a potential independent adverse prognostic biomarker for recurrence and survival of patients with ccRCC after nephrectomy.

Snail predicts recurrence and survival of patients with localized clear cell renal cell carcinoma after surgical resection

BackgroundSnail (known as SNAI1), a zinc-finger transcription factor, is best known for the induction of epithelial-to-mesenchymal transition, which has emerged as a recognized mechanism underlying epithelial cancer progression. Herein, the aim is to determine the effect of Snail expression on recurrence and survival of patients with localized clear cell renal cell carcinoma (ccRCC) following surgery. MethodsWe retrospectively enrolled 255 patients (188 in group A and 67 in group B) with localized ccRCC undergoing nephrectomy at a single center. Prognostic value and clinical outcomes were evaluated. ResultsIn both groups, cytoplasmic Snail intensity correlates positively with Fuhrman grade. High nuclear but not cytoplasmic Snail intensity indicates early recurrence and poor survival of patients with localized ccRCC. Moreover, high nuclear Snail intensity predicts unfavorable survival of patients with T2–4 stage cancer and early recurrence of all stage patients. Nuclear Snail intensity was identified as an independent adverse prognostic factor for recurrence and survival. The predictive accuracy of University of Los Angeles Integrated Staging System and the Mayo Clinic Stage, Size, Grade, and Necrosis prognostic models was improved when nuclear Snail expression was added. ConclusionNuclear Snail expression is a potential independent adverse prognostic biomarker for recurrence and survival of patients with localized ccRCC after nephrectomy.

Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Chromosome 9p deletions are an independent predictor of tumor progression following nephrectomy in patients with localized clear cell renal cell carcinoma

ObjectivesChromosome 9p deletions have been observed in 14% to 36% of patients with clear cell renal cell carcinoma (ccRCC) and are associated with advanced-stage tumors. We evaluated whether chromosome 9p deletions are an independent predictor of worse outcomes in patients with localized ccRCC. Materials and methodsIn this retrospective study, tumor samples from 94 patients with ccRCC NX-0 M0 who underwent radical nephrectomy or conservative renal surgery were analyzed using a fluorescence in situ hybridization technique. ResultsThe median follow-up period was 11.7 years, and 9p deletions were identified in 15% of cases. The cancer-specific survival rate estimated at 5 and 10 years was 99% and 96%, respectively, for patients without such chromosomal losses and 71% and 57% in patients with a loss of 9p (P<0.001). Chromosome 9p deletions were an independent prognostic factor in a multivariate analysis, increasing the risk of death due to disease by 28-fold (95% CI: 5–155, P<0.001). In patients with a low risk of progression, i.e., a low Stage, Size, Grade, and Necrosis score (0–2), low risk according to the University of California at Los Angeles Integrated Staging System, and low risk according to the pathological triad used at University of Sao Paulo, tumors with 9p deletions were significantly associated with a poorer cancer-specific survival at 10 years: 70%, 67%, and 67% vs. 98%, 97%, and 98%, respectively, in patients without 9p deletions. ConclusionChromosome 9p deletions independently establish a poorer prognosis for patients with localized ccRCC, providing further relevant clinical information that may improve the predictive ability of the main prognostic systems currently in use.

Prognostic Value of Diametrically Polarized Tumor-Associated Macrophages in Renal Cell Carcinoma

As the most abundant tumor-infiltrating immune cells, tumor-associated macrophages (TAMs) are significant for fostering tumor progression. CD68(+) TAMs display diversely polarized programs comprising CD11c(+) proinflammatory macrophages (M1) and CD206(+) immunosuppressive macrophages (M2). The aim of this study was to determine the survival impact of diametrically polarized TAMs in clear-cell renal cell carcinoma (ccRCC) and their application to stratification of patients according to their prognostic values. The study included 185 consecutive patients with ccRCC who underwent nephrectomy between 1999 and 2001. CD68(+) total and diametrically polarized (CD11c(+) M1 and CD206(+) M2) TAM densities were assessed by immunohistochemistry, and the relationships with clinicopathologic features and prognosis were evaluated. Low CD11c(+) TAM density and high CD206(+) TAM density were associated with reduced cancer-specific survival (P = 0.043 and P = 0.017, respectively), whereas CD68(+) TAM density only had borderline prognostic significance (P = 0.062). Furthermore, combined analysis of CD11c(+) and CD206(+) TAMs (CD11c/CD206 signature) had a better power to predict patients' outcome (P = 0.010). Together with TNM stage, tumor necrosis, and performance status, CD11c/CD206 signature was an independent prognostic factor (P = 0.010). When applied to the University of California Integrated Staging System intermediate-/high-risk group for localized ccRCC, CD11c/CD206 signature could further distinguish patients with dismal prognosis (P = 0.004). Intratumoral balance of diametrically polarized TAMs is a novel independent predictor for survival in patients with ccRCC. Tipping the balance toward an antitumoral phenotype might be a promising target of postoperative adjuvant therapy.

Impact of Recurrent Copy Number Alterations and Cancer Gene Mutations on the Predictive Accuracy of Prognostic Models in Clear Cell Renal Cell Carcinoma

Several recently reported recurrent genomic alterations in clear cell renal cell carcinoma are linked to pathological and clinical outcomes. We determined whether any recurrent cancer gene mutations or copy number alterations identified in the TCGA (The Cancer Genome Atlas) clear cell renal cell carcinoma data set could add to the predictive accuracy of current prognostic models. In 413 patients who underwent nephrectomy/partial nephrectomy we investigated whole exome, copy number array analyses and clinical variables. We identified 65 recurrent genomic alterations based on prevalence and combined them into 35 alterations, including 12 cancer gene mutations. Genomic markers were modeled using the elastic net algorithm with preoperative variables (tumor size plus patient age) and in the postoperative setting using the externally validated Mayo Clinic SSIGN (stage, size, grade and necrosis) prognostic scoring system. These models were subjected to internal validation using bootstrap. Median followup in survivors was 45 months. Several markers correlated with adverse cancer specific survival and time to recurrence on univariate analysis. However, most of them lost significance when controlling for tumor size with or without age in the preoperative models or for SSIGN score in the postoperative setting. Adding multiple genomic markers selected by the elastic net algorithm failed to substantially add to the predictive accuracy of any preoperative or postoperative model for cancer specific survival or time to recurrence. While recurrent copy number alterations and cancer gene mutations are biologically significant, they do not appear to improve the predictive accuracy of existing models of clinical cancer specific survival or time to recurrence for clear cell renal cell carcinoma.

Validation of the CAIX score as a prognostic biomarker for lymphatic spread and cancer-specific survival.

454 Background: We recently developed a novel CAIX density scoring system that was found to be a significant prognostic biomarker in a cohort of patients with high-risk clear cell renal cell carcinoma (ccRCC). We sought to validate the association of CAIX score with lymphatic spread and survival in a cohort of patients with ccRCC. Methods: We reviewed the clinical and pathologic records of 418 patients who underwent radical nephrectomy at UCLA between 1985 and 1999. Clinical features included age, gender, race/ethnicity, and ECOG performance status. Pathologic features included TNM stage, nuclear grade, UCLA Integrated Staging System (UISS), and CAIX staining. CAIX score was stratified into low (0–99), intermediate (100–199), and high (200–300). We examined the association between the CAIX score, disease severity, and survival using logistic and Cox regression analyses, respectively. Results: Mean CAIX score was 237.4 (SD 98.3). Approximately 26% of patients with low CAIX scores had lymphatic involvement, compared with 28% of those with intermediate scores, and 8% with high scores, p&lt;0.01. On multivariate analysis, patients with high CAIX scores had a significantly lower risk of lymphatic involvement (OR 0.19, p&lt;0.01). When compared with those with low CAIX scores, patients with high CAIX scores were significantly less likely to recur (HR 0.53, p=0.02) or die (HR 0.41, p&lt;0.01). Patients with intermediate scores were no less likely to recur HR 0.93, p=0.85) or die of their disease (HR 0.69, p=0.34). Lastly, patients with high-risk non-metastatic ccRCC were less likely to recur (HR 0.04, p&lt;0.01). Conclusions: The CAIX score can help identify the majority of patients presenting with lymphatic spread and serves as a statistically significant prognostic biomarker for recurrence-free and disease-free survival after nephrectomy. We recommend that utility CAIX score be quantified for all patients with high-risk disease.

Loss of BAP1 protein expression is an independent marker of poor prognosis in patients with low-risk clear cell renal cell carcinoma.

The majority of patients diagnosed with clear cell renal cell carcinoma (ccRCC) have low-risk disease with a < 10% chance of ccRCC-specific death. DNA sequencing revealed that mutations in BAP1 (BRCA1 associated protein-1) occur in 5% to 15% of ccRCC cases and are associated with poor outcomes. The vast majority of BAP1 mutations abolish protein expression. In this study, we used a highly sensitive and specific immunohistochemistry (IHC) assay to test whether BAP1 expression is an independent marker of ccRCC-specific survival, particularly in patients with low-risk disease. BAP1 expression was assessed, using IHC, in 1479 patients who underwent nephrectomy to treat clinically localized ccRCC. A centralized pathologist dichotomized patients as either BAP1-positive or BAP1-negative. The authors employed Kaplan-Meier and Cox regression models to associate BAP1 expression with cancer-specific survival. A total of 10.5% of tumors were BAP1-negative, 84.8% of tumors were BAP1-positive, and 4.6% of tumors had ambiguous staining for BAP1. Patients with BAP1-negative tumors have an increased risk of ccRCC-related death (hazard ratio [HR] = 3.06; 95% confidence interval [CI] = 2.28-4.10; P = 6.77 × 10(-14) ). BAP1 expression remained an independent marker of prognosis after adjusting for the UCLA integrated staging system (UISS) (HR = 1.67; 95% CI = 1.24-2.25; P < .001). Finally, BAP1 was an independent prognostic marker in low-risk patients with a Mayo Clinic stage, size, grade, and necrosis (SSIGN) score of ≤ 3 (HR = 3.24; 95% CI = 1.26-8.33; P = .015). This study used a large patient cohort to demonstrate that BAP1 expression is an independent marker of prognosis in patients with low-risk (SSIGN≤ 3) ccRCC.

Non–clear cell histology in patients with metastatic RCC as a prognostic indicator in the targeted therapy era.

454 Background: The role of targeted therapy (TT) in metastatic renal cell carcinoma (mRCC) having non-clear cell histology (non-ccRCC) is still being defined. We sought to examine the factors associated with survival outcomes in patients presenting with various histological subtypes in the TT era. Methods: The UCLA Kidney Cancer Program database containing records of over 2000 patients was queried. The clinicopathologic factors between patients with clear cell subtype (ccRCC) and those with non-clear cell histology were compared using the Student’s T-test and the chi-square test for continuous and categorical variables, where appropriate. Survival outcomes were estimated using Kaplan-Meier (log rank). Univariate and multivariate Cox regression models were used to identify independent associations with survival. Results: Of 157 patients treated with FDA-approved TT, 132 (84%) had ccRCC while 25 (16%) had non-ccRCC. The two groups were balanced for baseline demographic variables, including gender, race, BMI, pack-years of smoking, T-stage, Fuhrman grade, performance status and UCLA Integrated Staging System (UISS) risk category. Median survival of patients with ccRCC and non-ccRCC was 41.6 and 18.1 months (p&lt;0.001). In univariate analysis, non-ccRCC was associated with a 2.7-fold risk of cancer specific death compared to ccRCC patients. Among patients receiving TT-only, median survival of patients with ccRCC and non-ccRCC was 35 and 15.4 months (p=0.007). A subset of ccRCC patients treated sequentially with IMT followed by TT had a median survival of 73 months. Worsening UISS risk class and non-ccRCC histology, but not age, gender, race, tobacco exposure history, or tumor size, were independently associated with the risk of cancer death. Conclusions: Non-clear cell histology remains a significant and independent risk factor for cancer specific death for mRCC patients treated by TT even after controlling for UISS risk category. [Table: see text]

1025 Ten years after the development of the University of California Los Angeles Integrated Staging System: What have we learned from external validation studies?

1025 Ten years after the development of the University of California Los Angeles Integrated Staging System: What have we learned from external validation studies?

Clinical utility of the Glasgow Prognostic Score in patients undergoing curative nephrectomy for renal clear cell cancer: basis of new prognostic scoring systems

Background:Measurement of the systemic inflammatory response in malignancy has been recently refined using a selective combination of C-reactive protein and albumin (modified Glasgow Prognostic Score, mGPS). This has prognostic value in patients with metastatic kidney cancer. This study examines the prognostic value of the mGPS in patients undergoing curative nephrectomy for clear cell cancer.Methods:Patients with localised renal cell carcinoma undergoing potentially curative resection between March 1997 and July 2007 in a single institution were prospectively studied. The mGPS, University of California Los Angeles Integrated Staging System (UISS), ‘Stage Size Grade Necrosis’ (SSIGN), Kattan and Leibovich scores were constructed.Results:A total of 169 patients were studied. The minimum follow-up was 49 months; the median follow-up of the survivors was 98 months. During this period, 35 patients died of their cancer; a further 24 patients died of intercurrent disease. On univariate survival analysis of the scoring systems, Kattan (P<0.05), UISS (P<0.001), SSIGN (P<0.001) and Leibovich (P<0.001) were significantly associated with cancer-specific survival. Using cancer-specific mortality at 4 years as an endpoint, the area under the receiver operator curve was 0.726 (95% CI 0.629–0.822; P=0.001) for Kattan, 0.776 (95% CI 0.671–0.880; P<0.001) for UISS, 0.812 (95% CI 0.733–0.892; P<0.001) for SSIGN, 0.778 (95% CI 0.666–0.889; P<0.001) for Leibovich and 0.800 (95% CI 0.687–0.912; P<0.001) for the mGPS scoring system. On multivariate analysis of significant independent scoring systems and mGPS, UISS (HR 3.08, 95% CI 1.54–6.19, P=0.002) and mGPS (HR 5.13, 95% CI 2.89–9.11, P<0.001) were significant independent predictors of cancer-specific survival.Conclusions:The present prospective study shows that the mGPS, an inflammation-based prognostic score, is at least equivalent to and independent of other current validated prognostic scoring systems for patients undergoing curative nephrectomy for renal clear cell cancer. The mGPS is simple, measured preoperatively, based on well-standardised, widely available protein assays, and therefore provides an objective and rational basis before treatment for future staging systems in patients with operable renal cancer.

1770 CANCER-SPECIFIC SURVIVAL OUTCOMES OF SUNITINIB TREATMENT IN UISS RISK-STRATIFIED METASTATIC RCC PATIENTS

You have accessJournal of UrologyKidney Cancer: Advanced1 Apr 20111770 CANCER-SPECIFIC SURVIVAL OUTCOMES OF SUNITINIB TREATMENT IN UISS RISK-STRATIFIED METASTATIC RCC PATIENTS Edward Rampersaud, Tobias Klatte, Frederic Pouliot, David Li, Christine Anterasian, Nazy Zomorodian, Fairooz Kabbinavar, David Miller, Arie Belldegrun, and Allan Pantuck Edward RampersaudEdward Rampersaud Los Angeles, CA More articles by this author , Tobias KlatteTobias Klatte Los Angeles, CA More articles by this author , Frederic PouliotFrederic Pouliot Los Angeles, CA More articles by this author , David LiDavid Li Los Angeles, CA More articles by this author , Christine AnterasianChristine Anterasian Los Angeles, CA More articles by this author , Nazy ZomorodianNazy Zomorodian Los Angeles, CA More articles by this author , Fairooz KabbinavarFairooz Kabbinavar Los Angeles, CA More articles by this author , David MillerDavid Miller Ann Arbor, MI More articles by this author , Arie BelldegrunArie Belldegrun Los Angeles, CA More articles by this author , and Allan PantuckAllan Pantuck Los Angeles, CA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.2098AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Prior to the advent of targeted therapies, immunotherapy such as interleukin-2 (IL-2) served as the best available therapy for patients with metastatic kidney cancer. In addition to better tolerability, newer “targeted” treatment options should ideally provide similar or better survival benefits as those achieved with aggressive surgical resection and immunotherapy. We therefore sought to determine how patients treated with sunitinib fared compared to immunotherapy using a large mature cohort of patients treated at a single institution as a benchmark. METHODS A prospective database including clinical and pathological variables for 1683 patients with RCC was queried. 305 IL-2 treated patients and 51 sunitinib treated patients with metastatic RCC treated in the first-line setting following cytoreductive nephrectomy were identified and stratified using the UCLA Integrated Staging System (UISS) into low-, moderate-, and high-risk groups, and treatment response and disease specific survival (DSS) were assessed. RESULTS Overall median survival for the entire cohort was 21.5 months in IL-2 treated patients and 19.3 months in sunitinib treated patients (p=0.7693). When stratified by UISS risk group, similar survival outcomes were observed between the two treatment groups: low risk (39.7 months vs. not reached, p=0.2940), intermediate risk (20.9 vs. 17.7 months, p=0.5383), and high risk (10.5 vs. 7.6 months, p=0.2993). Patients treated with IL-2 group demonstrated a 7.3% complete response (CR) rate whereas there were no CRs following treatment with sunitinib (p<0.001). Clinical benefit (CR+ PR + SD) rate was 55% for IL-2 compared to 84% for sunitinib. Survival in those having stable disease following IL-2 was 31.6 months versus 24.8 months after (p=0.007). Excluding non-responders, median survival for IL-2 patients (n=167) was 36 months compared to 26 months for sunitinib patients (n=37) (p=0.06). CONCLUSIONS Targeted agents have proven attractive due to their relative ease of administration. At UCLA, patients treated with sunitinib for metastatic RCC more frequently achieved a clinical benefit than those treated with IL-2, yet overall survival between the two groups was similar. Benefit in treatment response, however, was at the expense of complete responses and required a trade-off of acute for chronic toxicities. Excluding non-responders, IL-2 related survival exceeded that of sunitinib by 10 months. As our ability to select patients likely to respond to IL-2 improves, a substantial number of patients remain good candidates for IL-2 based therapy. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e710 Peer Review Report Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Edward Rampersaud Los Angeles, CA More articles by this author Tobias Klatte Los Angeles, CA More articles by this author Frederic Pouliot Los Angeles, CA More articles by this author David Li Los Angeles, CA More articles by this author Christine Anterasian Los Angeles, CA More articles by this author Nazy Zomorodian Los Angeles, CA More articles by this author Fairooz Kabbinavar Los Angeles, CA More articles by this author David Miller Ann Arbor, MI More articles by this author Arie Belldegrun Los Angeles, CA More articles by this author Allan Pantuck Los Angeles, CA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

539 VALIDATION OF PROGNOSTIC MODELS FOR NONMETASTATIC RENAL CELL CARCINOMA AFTER NEPHRECTOMY IN A MEDITERRANEAN CAUCASIAN POPULATION

INTRODUCTION AND OBJECTIVES: To determine the applicability of the current prognostic models to predict disease recurrencefree survival (RFS) and cancer-specific survival (CSS) after nephrectomy in nonmetastatic renal cell carcinoma (RCC) in a Mediterranean Caucasian population. METHODS: We retrospectively reviewed the clinical and pathological variables of 305 patients treated with nephrectomy (partial or radical) for RCC. Three models were used to predict RFS (Kattan nomogram, Sorbellini model and Leibovich model), and three ones to predict CSS: the University of California at Los Angeles Integrated Staging System (UISS) model, the Stage, Size, Grade and Necrosis (SSIGN) model and the Karakiewicz nomogram. Survival was estimated using the Kaplan-Meier method. The predictive ability of the different scores was evaluated using the Harrell concordance index. RESULTS: With a median follow-up of 50.7 months, 41 patients (15.1%) died of RCC and in 54 (19.9%) the disease progressed. The 5-years CSS and RFS rates were 84.9% and 77.5%, respectively. Among the features included in the models, the Eastern Cooperative Oncology Group Performance Score (ECOG PS), pathological T (pT) stage, tumor size in surgical specimen, nuclear grade and pathological necrosis were significantly associated with RFS and CSS on univariate analysis. The ECOG PS, pT stage and nuclear grade also influenced in the multivariate analysis (Table 1). The c-indexes for RFS at 5 years were 0.626 for the Kattan nomogram and 0.696 for the Sorbellini model. The Leibovich nomogram presented c-indexes for RFS at 1, 3 and 5 years of 0.807, 0.728 and 0.721 respectively. The c-indexes for CSS were 0.774, 0.773, 0.772, 0.760 and 0.760 at 1, 2, 3, 4 and 5 years respectively for the UISS model, 0.831, 0.819 and 0.795 at 1, 3 and 5 years respectively for the SSIGN nomogram, and 0.752, 0.753 and 0.767 at 1, 2 and 5 years respectively for the Karakiewicz model. CONCLUSIONS: The current prognostic models are therefore validated in the Mediterranean Caucasian population with nonmetastatic RCC treated by surgery. The Leibovich nomogram was found to be most accurate to predict RFS, and SSIGN model to predict CSS. The most influential features in our population, both in RFS and CSS, were nuclear grade, ECOG PS and pT stage.

Quality of pathological reporting for renal cell cancer: implications for systemic therapy, prognostication and surveillance

• To evaluate whether current nephrectomy pathology reports are sufficient to allow clinicians to use prognostic nomograms, tailor surveillance, enroll patients into adjuvant trials and select systemic therapy for renal cell carcinoma (RCC). • Nephrectomy pathology reports were obtained from the LA County Tumor Registry. Key reporting elements identified by the College of American Pathology (CAP) and utilized in RCC prognostic models were abstracted. Hospital type was coded as community, teaching or cancer centre. • Reporting quality was assessed across hospital type and year. • A total of 317 of 344 sampled reports (92.2%) met the inclusion criteria. Tumour size and margin status were commonly reported. Some 90.2% and 84.2% of reports provided data on histology and Fuhrman grade. Tumour classification was omitted in 27.8%. • Microvascular invasion and necrosis were infrequently reported (44.5% and 25.6%, respectively). Only 59.9% of reports met CAP guidelines for tumour classification, margin, size, histology and grade. • Two prognostic nomograms (Stage, Size, Grade and Necrosis system and Kattan) could rarely be utilized (15.8% and 12.3%, respectively), whereas the UCLA Integrated Staging System could be used frequently (65.6%). There were discrepancies satisfying CAP guidelines between community, teaching and cancer centre hospitals, with 54.7%, 70.5% and 75% of reports meeting CAP criteria (P= 0.0102). • Current RCC pathology reporting fails to satisfy CAP guidelines, does not permit the use of prognostic systems, and may hinder enrollment into adjuvant trials and the selection of systemic therapy. Important reporting discrepancies exist between hospital types, with cancer centres performing best. • Quality improvement initiatives to encourage consistent, comprehensive and clinically relevant pathology reports would improve the quality of RCC patient care.

Neoadjuvant targeted therapy in renal cell carcinoma

we read with interest the article published by vincenzo Ficarra and Giacomo novara (Kidney cancer: neoadjuvant targeted therapies in renal cell carcinoma. Nat. Rev. Urol. 7, 63–64; 2010).1 in the past few years, randomized trials have shown the efficacy of targeted therapies in renal cell carcinoma (rCC); these results have dramatically changed the therapeutic approach. it is important to draw attention to the following issues. First, the appropriateness of using tnM staging to determine eligibility of patients for neoadjuvant treatment. it has been shown that the tnM system is not sufficient for risk stratification of patients with resected or advanced rCC. a combination of clinical and histological factors, such as tnM staging, Fuhrman’s tumor grade and eastern Cooperative Oncology Group (eCOG) performance status, have more relevant prognostic value in terms of survival, according to the uCLa integrated staging system (uiss).2 Patients with nonmetastatic highrisk disease have a high rate of systemic failure, suggesting the presence of occult metastases at diagnosis that are not detectable using current imaging methods. Moreover, similar survival curves have been published for nonmetastatic high-risk patients and metastatic low-risk patients.3 neoadjuvant therapy is commonly used in an effort to downstage locally advanced tumors, as well as to improve survival. Parameters in current use—including large tumor size, involvement of vital structures, and bulky lymphadenopathy—may not be sufficient to identify patients who are eligible for medical treatment. Precisely defining the uiss risk class could be more useful in the presurgical decisionmaking phase. Considering the lack of data supporting adjuvant treatments in patients with rCC, neoadjuvant medical therapy that has the effect of delaying nephrectomy could facilitate earlier onset of systemic disease control. Considerable doubt remains regarding the poor response rate of primary tumors treated with targeted agents, relative to the higher overall response rate reported in a number of phase iii trials of bevacizumab plus interferon, or sunitinib, in metastatic rCC. 91% of patients treated with sunitinib in phase iii trials had previously undergone nephrectomy; as such, comparable data on primary tumor shrinkage are not available.4 it is possible that the poor response of primary tumors, as published in preliminary reports, is not a function of limited efficacy of anti-angiogenic treatment. rather, it might be ascribed to a reduced ratio of neoplastic tissue to tumor necrosis, which is usually present at the center of the primary disease site.5 the superior response rate observed in the metastatic setting could be a function of the higher burden of non-necrotic tumor. in the neoadjuvant setting, a 15% reduction in tumor size is not considered an exciting result, even though a mean size decrease of 10% has been reported to be an optimal criterion for identification of patients with metastatic rCC who will derive benefit from sunitinib treatment in terms of progression-free and overall survival.6,7 whether the achieved degree of tumor downsizing is sufficient to facilitate surgery is an unresolved issue, as is the optimal timing of neoadjuvant treatment. in conclusion, the rapidity of recent advances in rCC management make it difficult to establish a therapeutic algorithm that accounts for the numerous and evolving prognostic/predictive factors. the use of targeted therapies in a neoadjuvant setting, with the aims of significantly reducing tumor volume before surgery and gaining better control of disease in high-risk patients, is a fascinating future option. these theoretical advantages could balance the published possible risk of perioperative complications associated with neoadjuvant anti-angiogenic therapies.

Abstract LB-275: 5-miRNA signature to predict clear cell renal cell carcinoma metastasis and prognosis

Abstract Introduction: Clear cell renal cell carcinoma (ccRCC) represents the most common renal cancer histology. In the setting of metastatic disease, few patients achieve a durable remission with currently available therapies. Early determination of metastatic potential may help guide therapy and improve clinical outcome. MicroRNA (miRNA) is a group of small non-coding RNAs that regulate gene expression during development and differentiation. miRNA expression is altered in malignant tissue, and signatures based on miRNA expression can aid in diagnosis and prognostication. In this study, we have characterized ccRCC miRNA expression in a 28-sample training cohort using microarray technology. From this, we have developed a 5-miRNA expression signature to predict the risk of metastasis and overall prognosis. This signature has been further validated by an independent 34-sample testing cohort. Study Design: Training and testing cohorts were established, comprised of 28 and 34 ccRCC frozen tissue specimens, respectively. The training cohort included specimens from patients characterized as stage I (T1; n=14) and stage IV (M1; n=14). The testing cohort included specimens from patients with (n=20) and without (n=14) metastatic disease. All cases used for the testing cohort had been followed for at least 5 years if there was no tumor metastasis reported. Total RNAs of these samples were analyzed using Agilent miRNA microarray (probes for 723 human miRNAs, Sanger miRBase 10.1). Results: (1) Differentially expressed miRNAs between metastatic ccRCCs and their non-metastatic counterparts in the training cohort were identified, using the criteria of fold change &amp;gt;1.5 (p value &amp;lt;0.05 by ANOVA). The 28 samples in the cohort were found to form distinct groups with different miRNA expression profiles using hierarchical clustering method. (2) A 5-miRNA ccRCC metastasis-specific signature has been identified using a customized computational method, which was based on logistic regression and Linear Discriminant Analysis classification, by comparing miRNA expression between metastatic and non-metastatic samples. (3) The signature has been successfully validated in the 34-sample testing cohort. With the clinical follow-up information (&amp;gt; 5 years if no metastasis reported), the signature had very high sensitivity (77%) and specificity (100%) when it was used to predict the tumor status of metastasis and metastatic potential. (4) This 5-miRNA signature may supplement widely used prognostic tools in RCC, such as the UCLA Integrated Staging System (UISS). The 5-miRNA signature stratified outcome within groups classified as high, intermediate or low risk by this schema. Conclusions: We have developed a 5-miRNA expression signature to determine ccRCC metastasis and prognosis. With further validation in larger cohorts, the signature may be applied towards early prediction of metastatic potential, and may augment currently available risk stratification tools for RCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-275.

Prognostic factors in renal cell carcinoma

Renal cell carcinoma (RCC) is a very heterogeneous disease with widely varying prognosis. An accurate knowledge of the individual risk of disease progression and mortality after treatment is essential to counsel patients, plan individualized surveillance protocols and select patients for adapted treatment schedules and new clinical trials. A systematic review of the literature on prognostic factors of localized and metastatic RCC was performed. Prognostic factors in RCC include anatomical (TNM classification, tumor size), histological (Fuhrman grade, histologic subtype), clinical (symptoms and performance status), and molecular features. All these features are not perfectly accurate when used alone. Therefore an increasing number of prognostic models or nomograms that include several combined prognostic features have been designed in order to improve predictive accuracy. UCLA Integrated Staging System (UISS) and the Mayo Clinic's SSIGN score are the two most used prognostic models for localized RCC. In the setting of metastatic RCC the classical anatomical and histological tumor features have little predictive value. However, accurate prognostic models have been designed to predict response to therapy, and progression-free and overall survival. The two most used tools to predict response to immunotherapy are the model designed by the French Group of Immunotherapy and the Motzer's model. The advent of tyrosine kinase inhibitors and antiangiogenic drugs have deeply changed the treatment of metastatic RCC. Predictive tools that are adapted to the modern targeted therapies are now needed. There is increasing knowledge on prognostic factors of localized and metastatic RCC. Several predictive models have been developed by combining different prognostic features and are valuable tools for patient counseling, treatment decision-making and trial design. Further research is needed to assess whether the combination of classical prognostic factors with molecular features and information from gene and protein expression profiling can increase the predictive accuracy of the current prognostic models.