Leibovich Score Research Articles

Computerized Image Analysis of Tumor Cell Nuclear Morphology Can Improve Patient Selection for Clinical Trials in Localized Clear Cell Renal Cell Carcinoma

Background: Clinicopathological scores are used to predict the likelihood of recurrence-free survival for patients with clear cell renal cell carcinoma (ccRCC) after surgery. These are fallible, particularly in the middle range. This inevitably means that a significant proportion of ccRCC patients who will not develop recurrent disease enroll into clinical trials. As an exemplar of using digital pathology, we sought to improve the predictive power of “recurrence free” designation in localized ccRCC patients, by precise measurement of ccRCC nuclear morphological features using computational image analysis, thereby replacing manual nuclear grade assessment. Materials and Methods: TNM 8 UICC pathological stage pT1-pT3 ccRCC cases were recruited in Scotland and in Singapore. A Leibovich score (LS) was calculated. Definiens Tissue studio® (Definiens GmbH, Munich) image analysis platform was used to measure tumor nuclear morphological features in digitized hematoxylin and eosin (H&E) images. Results: Replacing human-defined nuclear grade with computer-defined mean perimeter generated a modified Leibovich algorithm, improved overall specificity 0.86 from 0.76 in the training cohort. The greatest increase in specificity was seen in LS 5 and 6, which went from 0 to 0.57 and 0.40, respectively. The modified Leibovich algorithm increased the specificity from 0.84 to 0.94 in the validation cohort. Conclusions: CcRCC nuclear mean perimeter, measured by computational image analysis, together with tumor stage and size, node status and necrosis improved the accuracy of predicting recurrence-free in the localized ccRCC patients. This finding was validated in an ethnically different Singaporean cohort, despite the different H and E staining protocol and scanner used. This may be a useful patient selection tool for recruitment to multicenter studies, preventing some patients from receiving unnecessary additional treatment while reducing the number of patients required to achieve adequate power within neoadjuvant and adjuvant clinical studies.

UK Multicenter Prospective Evaluation of the Leibovich Score in Localized Renal Cell Carcinoma: Performance has Altered Over Time

ObjectiveTo examine changes in outcome by the Leibovich score using contemporary and historic cohorts of patients presenting with renal cell carcinoma (RCC)Patients and MethodsProspective observational multicenter cohort study, recruiting patients with suspected newly diagnosed RCC. A historical cohort of patients was examined for comparison. Metastasis-free survival (MFS) formed the primary outcome measure. Model discrimination and calibration were evaluated using Cox proportional hazard regression and the Kaplan-Meier method. Overall performance of the Leibovich model was assessed by estimating explained variation.ResultsSeven hundred and six patients were recruited between 2011 and 2014 and RCC confirmed in 608 (86%) patients. Application of the Leibovich score to patients with localized clear cell RCC in this contemporary cohort demonstrated good model discrimination (c-index = 0.77) but suboptimal calibration, with improved MFS for intermediate- and high-risk patients (5-year MFS 85% and 50%, respectively) compared to the original Leibovich cohort (74% and 31%) and a historic (1998-2006) UK cohort (76% and 37%). The proportion of variation in outcome explained by the model is low and has declined over time (28% historic vs 22% contemporary UK cohort).ConclusionPrognostic models are widely employed in patients with localized RCC to guide surveillance intensity and clinical trial selection. However, the majority of the variation in outcome remains unexplained by the Leibovich model and, over time, MFS rates among intermediate- and high-risk classified patients have altered. These findings are likely to have implications for all such models used in this setting.

978P - Algorithms derived from quantitative pathology can be a gatekeeper in patient selection for clinical trials in localised clear cell renal cell carcinoma (ccRCC)

BackgroundIdentifying low risk of disease recurrence in localised ccRCC is key for gatekeeping in the adjuvant therapy enrolment. Uncertainty increases the number of patients required for accrual to achieve statistical power. Current scoring systems are good at identifying very low and very high risk cohorts, but have not been proved to be as effective at accurately predicting disease recurrence in intermediate groups. These patients are perhaps those likely to benefit from intervention in addition to surgery, but many may be treated unnecessarily. Using digital pathology, image analysis and machine learning we sought to stratify for risk in this intermediate category. MethodsDefiniens Tissue studio and Developer XD were utilised for object thresholding to measure tumour cell nuclear morphological features on H&E digitised images from 120 ccRCC training set from UK and 217 ccRCC validation set from Singapore. Multiplexed immunofluorescence (mIF) was performed on 120 cases to co-detect neo-vasculature and pan-T cells. An algorithm was derived to measure spatial relationships between blood vessels and T cells. A statistical model was developed by generalised linear model with spatially adaptive local smoothing algorithm, having specificity prefixed (0.8-1) plus cross validation. ResultsReplacing manual nuclear grade with AI aided tumour cell nuclear morphological features improved the specificity of Leibovich score (LS) from 0.76 to 0.86 and from 0.84 to 0.94 in training and validation sets, respectively. Moreover, tumour microenvironment (TM) parameters significantly improved the specificity up to 0.93 in the training set. The negative predictive values of both LS 5 and 6 were zero, but by applying the algorithm the specificity for LS 5 and 6 cases became 0.93 and 0.40 respectively. ConclusionsBy applying image analysis it is possible to identify lower risk for recurrence patients in a conventionally identified intermediate risk group based on routine ccRCC H&E images, and multiplexed TM features. This approach to pathology should help refine selection of patients for clinical trials and form the basis of future AI-enabled prognostic and predictive algorithms in ccRCC. Legal entity responsible for the studyAuthors. FundingRenal Cancer Research Fund and NHS Lothian. DisclosureAll authors have declared no conflicts of interest.

4-miRNA Score Predicts the Individual Metastatic Risk of Renal Cell Carcinoma Patients.

In order to improve individual prognostication as well as stratification for adjuvant therapy in patients with clinically localized clear cell renal cell carcinoma (ccRCC), reliable prognostic biomarkers are urgently needed. In this study, microRNAs (miRNAs) have emerged as promising candidates. We investigated whether a combination of differently expressed miRNAs in primary tumors can predict the individual metastatic risk. Using two prospectively collected biobanks of academic centers, 108 ccRCCs were selected, including 57 from patients with metastatic disease at diagnosis or during follow-up and 51 without evidence of metastases. Fourteen previously identified candidate miRNAs were tested in 20 representative formalin-fixed and paraffin embedded samples in order to select the best discriminators between metastatic and nonmetastatic ccRCC. These miRNAs were approved in 108 tumor samples. We evaluated the association of altered miRNA expression with the metastatic potential of tumors using quantitative polymerase chain reaction. A prognostic 4-miRNA model has been established using a random forest classifier. Cox regression analyses were performed for correlation of the miRNA model and clinicopathological parameters to metastasis-free and overall survival. Nine miRNAs indicated significant expression alterations in the small cohort. These miRNAs were validated in the whole cohort. The established 4-miRNA score (miR-30a-3p/-30c-5p/-139-5p/-144-5p) has been identified as a superior predictor for metastasis-free survival (hazard ratio 12.402; p = 7.0E-05) and overall survival (p = 1.1E-04) compared with clinicopathological parameters, and likewise in the Leibovich score subgroups. We identified a 4-miRNA model that was found to be superior to clinicopathological parameters in accurately predicting individual metastatic risk and can support patient selection for risk-stratified follow-up and adjuvant therapy studies.

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

Renal cell carcinoma (RCC) accounts for 2%–3% of all adultmalignancies, representing the seventh most common cancer inmen and the ninth most common cancer in women [1].Worldwide, there are ∼209000 new cases and 102000 deathsper year. The incidence of all stages of RCC has increased overthe past several years, contributing to a steadily increasing mor-tality rate per unit population. Active and passive cigarettesmoking is an established risk factor for RCC as well as hyper-tension. However, anti-hypertensive medications such as diure-tics are not independently associated with RCC development.RCC also appears to be more common in patients with obesity,end-stage renal failure, acquired renal cystic disease and tuber-ous sclerosis.Approximately 2%–3% of RCC are hereditary and severalautosomal dominant syndromes are described, each with a dis-tinct genetic basis and phenotype, the most common one beingVon Hippel Lindau disease.In recent years, many new genes associated with RCC havebeen reported (such as PBRM1, SETD2, BAP1). Their roles inpathogenesis and as prognostic biomarkers are currently underinvestigation.

Metastatic risk stratification of clear cell renal cell carcinoma patients based on genomic aberrations.

Prognostic markers for the definition of the individual metastatic risk in renal cell carcinoma are still missing. The aim of our study was to establish a total number of specific aberrations (TNSA) genetic score as a new prognostic test for metastatic risk evaluation. Fluorescence in situ hybridization (FISH) was performed on isolated cell nuclei of 100 ccRCCs (50 M1/50 M0) and 100 FFPE sections (second cohort, 32 M1/68 M0). For each chromosomal region (1q21.3, 7q36.3, 9p21.3p24.1, 20q11.21q13.32) cut-off values were determined by receiver-operator curve (ROC)-curve analysis. TNSA was calculated based on the dichotomized specific CNVs. The prognostic significance of CNVs was proven by Cox and logistic regression. TNSA was the best predictor of metastasis and recurrence free survival in both cohorts. We derived an algorithm for risk stratification by combining TNSA and T-category, which increased the prognostic accuracy to 87% (specificity = 86%, sensitivity = 88%). This model divides patients into two risk groups with significantly different RFS, CSS, and OS (P = 3.8×10-5 , P = 5×10-6 and P = 3.57×10-8 respectively). The genetic risk model was superior to Leibovich score and was able to identify patients with metachronous metastatic spread which were incorrectly classified as "low" or "intermediate risk." We present a new tool for individual risk stratification by combining genetic alterations with clinico-pathologic parameters. Interphase FISH proves to be a dependable method for prognostic evaluation in primary tumor tissue on isolated cell nuclei as well as on FFPE sections. Especially in organ-confined tumors the genetic score seems to be an important tool to identify patients at high risk for metastatic disease.

External validation of the updated Leibovich prognostic models for clear cell and papillary renal cell carcinoma in an Asian population

PurposeThe Leibovich model was updated to prognosticate oncological outcomes in postnephrectomy nonmetastatic renal cell carcinoma (RCC) for each major histological subtype including clear cell (ccRCC), papillary (papRCC), and chromophobe RCC. We evaluated its performance in an independent population of predominantly Asian patients from Singapore. Materials and MethodsNine hundred and forty two binephric patients with nonmetastatic unilateral RCC treated with radical/partial nephrectomy from 1990 to 2015 from Singapore were retrospectively reviewed. Based on the Leibovich model, ccRCC patients were scored from 0 to 25 and papRCC patients divided into 3 risk groups. Primary outcomes of progression-free survival (PFS) and cancer-specific survival (CSS) were assessed with the Kaplan–Meier method. Receiver operating characteristic curves and calibration plots were obtained to determine discrimination and calibration respectively. ResultsEight hundred and twenty nine patients (88%) had ccRCC where 16.2% experienced disease progression while 11.9% died of RCC over a median follow-up of 76 (42–117) months. There was good discrimination (c-index 0.81 for PFS, 0.83 for CSS) and calibration (PFS calibration-in-the-large 0.002 and calibration slope 0.99, CSS calibration-in-the-large 0.005 and calibration slope 0.96). One hundred and thirteen patients (12%) had papRCC, where 18.6% progressed while 14.2% died from RCC over a median follow-up of 69.5 (36.0–112.0) months. Discrimination was slightly weaker (c-index 0.72 for PFS, 0.74 for CSS), and the model was only calibrated for CSS (calibration-in-the-large 0.002, calibration slope 0.98), not for PFS (calibration-in-the-large 0.09, calibration slope 1.93). ConclusionsThe updated Leibovich score is applicable for prognostication of progression and death in both ccRCC and papRCC, even when applied to an independent population of Asian patients. Further validation is required to ensure accuracy in prognosticating PFS for papRCC.

Kidney transplantation in patients with previous renal cancer: a critical appraisal of current evidence and guidelines.

Due to the increasing occurrence of renal cell carcinoma (RCC) in the general population and the high prevalence of chronic kidney disease among cancer patients, many people with a previous RCC may eventually require renal replacement therapy including kidney transplantation. They should accordingly be evaluated to assess their life expectancy and the risk that the chronic immunosuppressive therapy needed after grafting might impair their long-term outcome. Current guidelines on listing patients for renal transplantation suggest that no delay is required for subjects with small or incidentally discovered RCC, while the recommendations for patients who have been treated for a symptomatic RCC or for those with large or invasive tumours are conflicting. The controversial results reported by even recent studies focusing on the cancer risk in kidney graft recipients with a prior history of malignancy do not help to clarify the doubts arising in everyday clinical practice. Several tools, including integrated scoring systems, are currently available to assess the prognosis of patients with a previous RCC and, although they have not been validated in subjects receiving long-term immunosuppressive drugs, they can be used to identify patients suitable to be listed for grafting. Among these, the Leibovich score is currently the most widely used as it has proved simple and reliable enough and helps categorize renal transplant candidates. According to this system, subjects with a score from 0 to 2 are at low risk and may be listed without delay, while those with a score of 6 or higher should be excluded from grafting. In addition, other factors have an established positive prognostic value, including chromophobe or clear cell papillary tumour, or G1 grade cancer; on the contrary, medullary or Bellini's duct carcinoma or those with sarcomatoid dedifferentiation at histological examination should be excluded. All other patients would be better submitted to careful individual evaluation by an Oncologist before being listed for renal transplantation, pending studies specifically focusing on cancer risk evaluation in people already treated for malignancy receiving long-term immunosuppressive therapy.

Perspectives on Adjuvant Therapy in Renal Cell Carcinoma

Perspectives on Adjuvant Therapy in Renal Cell Carcinoma

Long-term Outcomes of Follow-up for Initially Localised Clear Cell Renal Cell Carcinoma: RECUR Database Analysis

BackgroundOptimal follow-up (FU) strategy to detect potentially curable (PC) recurrences after treatment of localised clear cell renal cell carcinoma (ccRCC) is unclear. This study retrospectively analysed a large international database to determine recurrence patterns and overall survival (OS), as part of a wider project to issue recommendations on FU protocols. ObjectiveTo analyse associations between RCC recurrences in patients with ccRCC, their risk group stratifications, treatments, and subsequent outcomes. Design, setting, and participantsNonmetastatic ccRCC patients treated with curative intent between 1 January 2006 and 31 December 2011, with at least 4 yr of FU, were included. Patient, tumour and recurrence characteristics, Leibovich score, and management and survival data were recorded. Isolated local, solitary, and oligometastatic (three or fewer lesions at a single site) recurrences were considered PC, while all others were probably incurable (PI). InterventionPrimarily curative surgical treatment of ccRCC while at recurrence detection metastasectomy, systemic therapy, best supportive care, or observation. Outcome measurements and statistical analysisIncidence, time to recurrence (TTR), and OS were measured. Competing risk analysis, Kaplan-Meier, and Cox regression models were used. Results and limitationOf 1265 patients with ccRCC, 286 had a recurrence, with 131 being PC and 155 PI. Five-year cumulative risks of recurrence for low- (n=53), intermediate- (n=105), and high-risk (n=128) patients were, respectively, 7.2%, 23.2%, and 61.6%, of whom 52.8%, 37.1%, and 30.5% were PC, respectively. Median TTR was 25.0 for PC patients versus 17.3 mo for PI patients (p=0.004). Median OS was longer in PC compared with that in PI patients (p<0.001). Competing risk analysis showed highest risk of ccRCC-related death in younger and high-risk patients. Limitations were no data on comorbidities, retrospective cohort, and insufficient data excluding 12% of cohort. ConclusionsLow-risk group recurrences are rare and develop later. Treatment of recurrences with curative intent is disappointing, especially in high-risk patients. An age- and risk score-dependent FU approach is suggested. Patient summaryWe analysed data from eight European countries, and found that the incidence of the kidney cancer recurrence and patient survival correlated with clinical factors known to predict cancer recurrence reliably and age. We conclude that these factors should be used to design follow-up strategies.

Potentially curable recurrent disease after surgically managed non-metastatic renal cell carcinoma in low-, intermediate- and high-risk patients.

Guidelines recommend risk-adapted follow-up (FU) strategies after (partial) nephrectomy in non-metastatic renal cell carcinoma (RCC). Since current systemic therapy does not cure metastatic RCC, only timely detected recurrence accessible for local therapy is potentially curable. This study analyzed the rate and management of potentially curable recurrences per risk group. This is a retrospective study including non-metastatic RCC patients who underwent (partial) nephrectomy from 2004 to 2011, with a minimum follow-up of 4years. Risk stratification was by Leibovich score (clear cell subtype) and UICC/AJCC grading (other subtypes). Recurrence, time to recurrence, symptoms and detection method were documented. Isolated local recurrence, solitary- and oligometastases (≤3 lesions, single site) were considered potentially curable. Among 234 patients, followed during a median of 61.9months, 68 patients (29.1%) developed a recurrence of which 28 (41.2%) were considered potentially curable. The 5-year risk of recurrence for low-, intermediate- and high-risk patients was 7.8, 26.3 and 59.1% of which 71.4, 52.2 and 23.1% were considered potentially curable, respectively. In high-risk patients, incurable recurrence was detected after a median of 7.9 (3.7-17.2) months versus 13.9 (6-41.3) months for potentially curable lesions. Only 13 of potentially curable lesions (46%) received local therapy. FU protocols should be adapted to the recurrence pattern of potentially curable disease. Most of the benefit may be achieved in intermediate-risk and high-risk-patients free of recurrence 1year after surgery. Despite frequent imaging, only 13 patients (5.6% of all patients followed) were managed with local therapy of whom only 4 remained free of disease.

The Presence of Vascular Mimicry Predicts High Risk of Clear Cell Renal Cell Carcinoma after Radical Nephrectomy

Vascular mimicry is a type of tumor cell plasticity. The aim of this study was to determine the prognostic value of vascular mimicry in patients with clear cell renal cell carcinoma. We performed a retrospective cohort study in 387 patients with clear cell renal cell carcinoma who underwent radical nephrectomy at Zhongshan Hospital, Fudan University between 2008 and 2009. Pathological features, baseline patient characteristics and followup data were recorded. Vascular mimicry in clear cell renal cell carcinoma tissue was identified by CD31-periodic acid-Schiff double staining. Univariate and multivariate Cox regression models were used to analyze the impact of prognostic factors on recurrence-free survival. The concordance index and the Akaike information criterion were used to assess the predictive accuracy and sufficiency of different models. Positive vascular mimicry staining occurred in 25 of 387 clear cell renal cell carcinoma cases (6.5%) and it was associated with an increased risk of recurrence (log-rank p <0.001). Incorporating vascular mimicry into pT stage, Fuhrman grade and Leibovich score helped refine individual risk stratification. Moreover, vascular mimicry was identified as an independent prognostic factor (p = 0.001). It was entered into a nomogram together with pT stage, Fuhrman grade, tumor size and necrosis. In the primary cohort the Harrell concordance index for the established nomogram to predict recurrence-free survival was slightly higher than that of the Leibovich model (0.850 vs. 0.823), which failed to reach statistical significance (p = 0.158). Vascular mimicry could be a potential prognosticator for recurrence-free survival in patients with clear cell renal cell carcinoma after radical nephrectomy. Further external validation and functional analysis should be pursued to assess its potential prognostic and therapeutic values for clear cell renal cell carcinoma.

Positive intratumoral chemokine (C-C motif) receptor 8 expression predicts high recurrence risk of post-operation clear-cell renal cell carcinoma patients.

Chemokine (C-C motif) receptor 8 (CCR8) could drive cancer progress through recruiting certain immune cells. Recent evidences revealed the chemotaxis of CCR8+ human malignant tumor cells towards lymph node, and a significantly increased CCR8 expression in renal carcinomas patients. To assess the clinical association between CCR8 expression and the risk of post-surgery recurrence in patients with clear-cell renal cell carcinoma (ccRCC), we detected intratumoral CCR8 expression in 472 post-nephrectomy ccRCC patients retrospectively enrolled. Positive CCR8 staining tumor cell occurred in 26.1% (123 of 472) non-metastatic ccRCC cases, and the positive expression was associated with increased risks of recurrence (Log-Rank P < 0.001). In multivariate analyses, CCR8 expression was identified as an independent prognostic factor (P = 0.008) and entered into a newly-built nomogram together with T stage, Fuhrman grade, tumor size, necrosis and lymphovascular invasion. Calibration curves showed optimal agreement between predictions and observations, while its C-index was higher than that of Leibovich score for predicting recurrence-free survival (RFS) of localised RCC patients (0.854 vs 0.836, respectively; P = 0.044). The practical prognostic nomogram model may help clinicians in decision making and design of clinical studies.

High APOBEC3B expression is a predictor of recurrence in patients with low-risk clear cell renal cell carcinoma

PurposeAPOBEC3B is a member of the cytosine deaminase family, which converts cytosine to uracil during RNA editing and retrovirus or retrotransposon restriction. Recent evidence has revealed that APOBEC3B-catalyzed genomic DNA deamination could provide genetic fuel for cancer development, metastasis, and even treatment resistance. The aim of this study was to assess the association between APOBEC3B expression and the risk of recurrence after surgery in patients with renal cell carcinoma (RCC). MethodsWe retrospectively enrolled 299 consecutive patients with RCC who underwent nephrectomy at a single center in 2008. Clinicopathologic variables and recurrence-free survival (RFS) were recorded. APOBEC3B expression levels were determined by immunohistochemistry in tumor tissues. Kaplan-Meier method was applied to compare survival curves. Cox regression models were fitted to analyze the effect of prognostic factors on RFS. The Harrell concordance index was calculated to assess predictive accuracy. ResultsHigh APOBEC3B expression was associated with an increased risk of recurrence in patients with clear cell RCC (ccRCC) (P<0.001) rather than in patients with non-ccRCC (P = 0.247). After backward elimination, APOBEC3B expression was identified as an independent prognostic factor for RFS in patients with clear cell histology (P = 0.016). The predictive accuracy of the Leibovich prognostic score was improved when APOBEC3B expression was incorporated. Notably, the improvement in prediction mainly took place in patients with low-risk disease defined by the Leibovich score. ConclusionsHigh APOBEC3B expression is an independent predictor of recurrence in patients with ccRCC, and the prognostic value is most prominent in those with low-risk disease.

A 16-gene assay to predict recurrence after surgery in localised renal cell carcinoma: development and validation studies

The likelihood of tumour recurrence after nephrectomy in localised clear cell renal cell carcinoma is well characterised by clinical and pathological parameters. However, these assessments can be improved and personalised by the addition of molecular characteristics of each patient's tumour. We aimed to develop and validate a prognostic multigene signature to improve prediction of recurrence risk in clear cell renal cell carcinoma. In the development stage, we investigated the association between expression of 732 genes, measured by reverse-transcription PCR, and clinical outcome in 942 patients with stage I-III clear cell renal cell carcinoma who had undergone a nephrectomy at the Cleveland Clinic (OH, USA). 516 genes were associated with recurrence-free interval. 11 of these genes were selected by further statistical analyses, and were combined with five reference genes (ie, 16 genes in total), from which a recurrence score algorithm was developed. The recurrence score was then validated in an independent cohort of 626 patients from France with stage I-III clear cell renal cell carcinoma who had also undergone nephrectomy. The association between the recurrence score and the risk of recurrence and cancer-specific survival in the first 5 years after surgery was assessed using Cox proportional hazard regression, stratified by tumour stage (stage I vs stage II vs III). In our primary univariate analysis, the continuous recurrence score (median 37, IQR 31-45) was significantly associated with recurrence-free interval (hazard ratio 3·91 [95% CI 2·63-5·79] for a 25-unit increase in score, p<0·0001). In multivariable analyses, the recurrence score was significantly associated with the risk of tumour recurrence (hazard ratio per 25-unit increase in the score 3·37 [95% CI 2·23-5·08], p<0·0001) after stratification by stage and adjustment for tumour size, grade, or Leibovich score. The recurrence score was able to identify a clinically significant number of both high-risk stage I and low-risk stage II-III patients. A heterogeneity study on separate samples showed little to no intratumoural variability among the 16 genes. Our findings validate the recurrence score as a predictor of clinical outcome in patients with stage I-III clear cell renal cell carcinoma, providing a more accurate and individualised risk assessment beyond existing clinical and pathological parameters. Genomic Health Inc and Pfizer Inc.

Robustness of the 16-gene signature for prediction of recurrence-free interval in localized clear cell renal cell carcinoma.

455 Background: The Renal Cancer assay is a clinically validated RT-PCR assay developed to estimate the risk of recurrence in stage I-III clear cell renal cell carcinoma (ccRCC) patients (pts) treated with nephrectomy. The assay measures expression of 16 genes that are combined to calculate the Recurrence Score result (RS). The RS is associated with recurrence, renal cancer-specific survival and overall survival (all p&lt;0.001) (Escudier, ASCO 2014). The performance of the RS in clinically relevant subgroups, compared to the Leibovich score, and its within-patient variability was examined. Methods: The algorithm, endpoints, methods, and analysis plan were pre-specified prior to merging clinical and molecular data. RT-PCR of RNA from fixed paraffin-embedded ccRCC tissue was performed without knowledge of clinical data. Recurrence-free internval (RFI) was analyzed using Cox regression stratified by stage with data censored at 5 years, and Kaplan-Meier methods. Multivariable models incorporating the Leibovich score were used to assess the additional contribution of the RS to prediction of recurrence. Within- and between-tumor block reproducibility was assessed in an independent study using two separate tumor blocks from 8 pts, where each block was analyzed at 3 depths. Results: RS was generated in 626/645 pts (97%): 398 stage I, 54 stage II, 174 stage III. Median follow up was 5.5 yrs. The RS was significantly associated with risk of recurrence after adjustment for the Leibovich score (HR=4.20, p&lt;0.001). Additionally, the performance of RS was similar across age groups (&lt;60, 60-70 or ≥70), gender, nephrectomy type, tumor size (≤4, 4-7 or &gt;7cm), grade, and presence/absence of invasion (all interaction p&gt;0.29). Within-patient variability in the score (std. dev. of 1.73 and 4.74 RS units for within- and between-tumor block, respectively) was lower than patient-to-patient variability (std. dev. of 15.6 in validation study). Conclusions: The 16-gene signature remains strongly associated with risk of recurrence after adjustment for the Leibovich score and performs consistently across clinically relevant subgroups. Examination of within-patient and between-patient variability indicates that the score is robust to tumor heterogeneity.

Patients' preferences for adjuvant sorafenib after resection of intermediate or high-risk renal cell carcinoma in the SORCE trial: What makes it worthwhile?

415 Background: SORCE is an international, double-blind, placebo-controlled, phase 3 trial comparing adjuvant sorafenib for 1 year, for 3 years, or observation after resection of intermediate or high risk (as per the Leibovich score), localised renal cell carcinoma (RCC). We determined the survival benefits that SORCE participants judged necessary to make adjuvant sorafenib worthwhile 3 months after starting study treatment. Methods: Participants recruited to SORCE from Australia and selected UK sites completed a validated, self-administered questionnaire 3 months after starting study treatment to determine the minimum survival benefits they judged necessary to make adjuvant sorafenib worthwhile. Scenarios used baseline survival times (without adjuvant sorafenib) of 5 and 15 years; and baseline survival rates (without adjuvant sorafenib) of 65% and 85% at 5 years. Preferences were determined for 1 year of adjuvant sorafenib (versus none) and for 3 years of adjuvant sorafenib (versus 1 year). All tests were 2-sided and non-parametric. This substudy of SORCE was conducted by the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP). Results: The 179 participants were mostly male (72%) with a median age of 57 years (range 29 to 78). Participants allocated sorafenib judged larger benefits necessary to make 1 year of adjuvant sorafenib worthwhile than those allocated placebo: median benefit of an extra 1 year versus an extra 1 month for baselines of 5 years (p=0.004) and 15 years (p=0.02); median benefit of an extra 5% versus an extra 1% for baseline of 65% (p=0.03), and an extra 3% versus an extra 1% for a baseline of 85% (p=0.07). Larger survival benefits were judged necessary to make 3 years of adjuvant sorafenib worthwhile (versus 1 year) regardless of treatment allocation: median benefit of an extra 2 months to 1 year for baselines of 5 years (p=0.02) and 15 years (0.02). Conclusions: Experienced toxicity and duration of treatment are important determinants of patients’ preferences for adjuvant sorafenib in RCC.

Interleukin-11 receptor predicts post-operative clinical outcome in patients with early-stage clear-cell renal cell carcinoma.

To investigate the prognostic value of interleukin-11 receptor α chain in patients with early-stage clear-cell renal cell carcinoma. Interleukin-11 receptor α chain, a member of the gp130-dependent receptors, exerts pleiotropic oncogenic activities by promoting proliferation, angiogenesis and metastasis in many cancers. We retrospectively enrolled 293 patients (130 in the training cohort and 163 in the validation cohort) with early-stage (TNM Stage I + II) clear-cell renal cell carcinoma undergoing nephrectomy at a single institution. Clinicopathologic features, recurrence-free survival and overall survival were recorded. Interleukin-11 receptor α chain intensities were assessed by immunohistochemistry in tumor tissues. Kaplan-Meier method was applied to compare survival curves between groups. Cox regression models were used to analyze the impact of prognostic factors on recurrence-free survival and overall survival. The concordance index was calculated to assess predictive accuracy. In both training and validation cohorts, high interleukin-11 receptor α chain expression was associated with early recurrence (P = 0.004 and P = 0.015, respectively) and poor survival (P < 0.001 and P = 0.019, respectively) of patients with early-stage clear-cell renal cell carcinoma. Multivariate analyses confirmed that interleukin-11 receptor α chain expression was an independent prognostic factor for recurrence-free survival (P = 0.004) and overall survival (P = 0.001). The predictive accuracy of the Leibovich prognostic score was improved when interleukin-11 receptor α chain expression was incorporated. Notably, the improvement in prediction mainly took place in patients with low-risk disease defined by the Leibovich score. High Interleukin-11 receptor α chain expression is an independent predictor of poor clinical outcome in patients with early-stage clear-cell renal cell carcinoma, and the prognostic value is more prominent in those with low-risk disease.

Incidental renal neoplasms: is there a need for routine screening? A Danish single-center epidemiological study.

On the basis of associations between tumor size, pathological stage, histological subtype and tumor grade in incidentally detected renal cell carcinoma vs symptomatic renal cell carcinoma, we discussed the need for a screening program of renal cell carcinoma in Denmark. We analyzed a consecutive series of 204 patients with renal tumors in 2011 and 2012. The tumors were classified according to detection mode: symptomatic and incidental and compared to pathological parameters. Eighty-nine patients (44%) were symptomatic, 113 (55%) were incidental. Information was not available in two patients. In the incidental group, the size (p<0.05), pathological stage (p<0.001), Fuhrman grading (p<0.0001) and Leibovich score (p<0.0001) were lower than in those causing symptoms. Significantly less in the incidental group had metastasis at follow-up (p<0.0001). Incidentally discovered RCC constitute a major part of kidney tumors. They have a more favorable prognosis than symptomatic tumors and seem to be discovered in an earlier phase. Needle core biopsy is an accurate technique for distinguishing between malignant and benign tumors and is recommendable for smaller incidental tumors. Screening may help detect RCC at an earlier stage.

Can the Leibovich score for clear cell renal cell carcinoma (ccRCC) be accurately reported by a general pathologist?

To evaluate the accuracy of reporting of the Leibovich score (LS) by general pathologists at our centre by comparing the LS in their initial reports with the LS in subsequent review reports by our specialist urological pathologists. We also assessed whether a revision in the LS subsequently altered the risk group. In all, 54 consecutive patients had had their initial histology after nephrectomy reported by a general pathologist between August 2008 and March 2012. The histological slides were subsequently re-reviewed by the two specialist urological pathologists and revised LS were given if appropriate. The cases were then discussed at the Uro-oncology Multi disciplinary meeting (MDT) and the reason for the revised LS was discussed with the participating panel and reviewed by the uropathologist. The general pathologists allocated the 54 patients into low- (13 patients), intermediate- (25) and high-risk (16) categories. After a review of the slides by the specialist urological pathologists and discussion at the MDT meeting the LS was revised in 23 patients (42.6%). The 23 patients who had their LS revised were divided into two groups for the purpose of the present study. On revision of the LS a total of eight patients (14.8%) changed their prognostic group. The change in the prognostic group in the eight patients was increased from intermediate- to high-risk in four patients. There was a reduction in the LS in four patients, which was from high- to intermediate-risk category in one patient and intermediate- to low-risk in three patients. In the present study, histopathology review by a specialist urological pathologist led to a change in LS in 42.6% of cases leading a change in risk grouping in 14.8% of cases. This level of discrepancy is not insignificant. However, the few cases evaluated in the present study does limit robust conclusions and further studies are needed to investigate this issue, so that recommendations can be made to enhance diagnostic accuracy and reproducibility.