Non-metastatic Clear Renal Cell Carcinoma Research Articles

Tumor Infiltrating Mast Cells (TIMs) Confers a Marked Survival Advantage in Nonmetastatic Clear-Cell Renal Cell Carcinoma.

The role played by the innate immune system in determining the clinical outcome of clear-cell renal cell carcinoma (ccRCC) was still blurred. This study was designed to investigate the prognostic significance of tumor infiltrating mast cells (TIMs) in ccRCC. The study retrospectively enrolled a training set (474 patients) and a validation set (188 patients) with nonmetastasis (pT1-4N0M0) ccRCC from two institutional medical centers of China. TIMs was evaluated by immunohistochemical staining of tryptase and its association with clinicopathologic features and prognosis were evaluated. In ccRCC tissues, TIMs ranged from 0 to 103 cells/mm2 and 0 to 113 cells/mm2 in the training set and validation set, respectively. TIMs was negatively correlated with tumor size (P<0.001 and P<0.001, respectively), pathological T stage (P=0.005 and P=0.007, respectively) and Fuhrman grade (P<0.001 and P<0.001, respectively). Patients with abundant TIMs infiltration showed significantly longer cancer-specific survival in the training cohort and the validation cohort (P<0.001 and P<0.001). Patients with abundant mast cell infiltration showed significantly longer overall survival in the TCGA cohort (P<0.001). Moreover, multivariate analysis identified TIMs as an independent prognostic factor for cancer-specific survival (CSS) and relapse-free survival (RFS). Also, TIMs was significantly correlated with CSS and RFS of the mediate and high-risk patients in the training cohort and the validation cohort. TIMs density is a powerful independent prognostic factor for CSS and RFS in patients with nonmetastasis (pT1-4N0M0) ccRCC.

833P - Retrospective analysis of metastatic non-clear cell renal carcinoma (NCCRC): the Spanish Grupo Centro Experience

833P - Retrospective analysis of metastatic non-clear cell renal carcinoma (NCCRC): the Spanish Grupo Centro Experience

CCL2/CCR2 axis is associated with postoperative survival and recurrence of patients with non-metastatic clear-cell renal cell carcinoma

PurposeChemokine (C-Cmotif) ligand 2 (CCL2) is a major chemokine that recruit monocytes and macrophages to the sites of inflammation. Recent researches have clarified that overexpression of CCL2 is associated with unfavorable prognosis in various cancer types. In this study, we aim to determine the prognostic value of CCL2 expression as well as its receptor C-C motif receptor type 2 (CCR2) in patients with non-metastatic clear cell renal cell carcinoma (ccRCC) after surgery.ResultsBoth high CCL2 and CCR2 expression were remarkably correlated with shortened survival time (P < 0.001 and P < 0.001, respectively) and increased risk of recurrence (P = 0.001 and P = 0.003, respectively). The combination of CCL2 and CCR2 expression (CCL2/CCR2 signature) could offer a better prognostic stratification. Furthermore, multivariate analyses identified CCL2/CCR2 signature as an independent risk factor for overall survival (OS) and recurrence-free survival (RFS) (P = 0.007 and P = 0.043, respectively). The incorporation of CCL2/CCR2 signature would refine individual risk stratification and predictive accuracy of the well-established models.Materials and MethodsWe retrospectively examined the intratumoral expression of CCL2 and CCR2 by immunohistochemical staining in 268 histologically proven non-metastatic ccRCC patients receiving surgery in a single institution between 2001 and 2004. Kaplan-Meier analysis and Cox regression were applied to determine the prognostic value of CCL2 and CCR2 expression. Concordance index was calculated to compare predictive accuracy of the established models.ConclusionsCombined CCL2 and CCR2 expression emerges as an independent prognostic factor for non-metastatic ccRCC patients after surgical treatment.

High expression of galectin-7 associates with poor overall survival in patients with non-metastatic clear-cell renal cell carcinoma.

BackgroundGalectin-7, has a controversial role in tumor progression, can either suppress tumor growth or induce chemoresistance depends on different tumor histology types. The aim was to appraise Galectin-7 expression on the overall survival (OS) of patients with non-metastatic clear cell renal cell carcinoma (ccRCC) following surgery.ResultsHigh galectin-7 expression was specifically correlated with necrosis (P = 0.015). Multivariate analysis confirmed galectin-7 as an independent prognosticator for OS (P = 0.005). High galectin-7 expression suggested poor OS (P < 0.001), particularly with UISS intermediate and high score groups. Notably, the predictive accuracy of the traditional prognostic scores was improved when combined with galectin-7 expression.Materials and MethodsWe retrospectively enrolled 416 patients who underwent nephrectomy at a single institute between 2008 and 2009 and detected their intratumor galectin-7 expression by immunohistochemistry. Kaplan-Meier method was conducted to plot survival curves and multivariate cox regression analysis for potential independent prognostic factors on OS. A nomogram was constructed with concordance index (C-index) and Akaike's Information Criteria (AIC) to appraise prognostic accuracy of different models.ConclusionsHigh galectin-7 expression is an independent adverse predictor for survival. Evaluation of galectin-7 could help guide postsurgical management for non-metastatic ccRCC patients.

Vimentin over-expression and carbonic anhydrase IX under-expression are independent predictors of recurrence, specific and overall survival in non-metastatic clear-cell renal carcinoma: a validation study.

Clinical outcomes prognostic markers are awaited in clear-cell renal carcinoma (ccRCC) to improve patient-tailored management and to assess six different markers' influence on clinical outcomes from ccRCC specimen and their incremental value combined with TNM staging. This is a retrospective, multicenter study. One hundred and forty-three patients with pT1b-pT3N0M0 ccRCC were included. Pathology specimens from surgeries were centrally reviewed, mounted on a tissue micro-array and stained with six markers: CAIX, c-MYC, Ki67, p53, vimentin and PTEN. Images were captured through an Ultra Fast Scanner. Tumor expression was measured with Image Pro Plus. Cytoplasmic markers (PTEN, CAIX, vimentin, c-MYC) were expressed as surface percentage of expression. Nuclear markers (Ki67, p53) were expressed as number of cells/mm2. Clinical data and markers expression were compared with clinical outcomes. Each variable was included in the Cox proportional multivariate analyses if p<0.10 on univariate analyses. Discrimination of the new marker was calculated with Harrell's concordance index. At median follow-up of 63months (IQR 35.0-91.8), on multivariate analysis, CAIX under-expression and vimentin over-expression were associated with worse survival (recurrence, specific and overall survival). A categorical marker CAIX-/Vimentin+with cutoff points for CAIX and vimentin of 30 and 50%, respectively, was designed. The new CAIX-/Vimentin+marker presented a good concordance and comparable calibration to the reference model. Limitations are the retrospective design, the need for external validation and the large study period. Using an automated technique of measurement, CAIX and vimentin are independent predictors of clinical outcomes in ccRCC.

Elevated expression of IFN-inducible CXCR3 ligands predicts poor prognosis in patients with non-metastatic clear-cell renal cell carcinoma.

IFN-inducible CXCR3 ligands (ICL), namely CXCL9, CXCL10 and CXCL11, exhibit pleiotropic roles in orchestrating immunity and angiogenesis. However, the prognosis value of them in renal cell carcinoma (RCC) was still obscure. Thus, we retrospectively used immunohistochemistry approach to evaluate the impact of these ligands on recurrence and survival of non-metastatic clear cell RCC (ccRCC) patients after nephrectomy. We systemically built a prespecified ICL score based on these ligands, and found specimens with high ICL score were prone to possess high Fuhrman grade, necrosis, and high-risk level of SSIGN. Moreover, ICL score stratified patients into different risk subgroups, and remained an independent adverse prognosticator for overall survival (OS) and recurrence-free survival (RFS). Meanwhile, in TCGA database, the increasing ICL mRNA predicted poor survival and early recurrence. Furthermore, after adding ICL score into SSIGN, the C-index for OS and RFS increased from 0.705 to 0.746 and 0.712 to 0.765, respectively. In conclusion, the ICL score based on expression of CXCL9, CXCL10 and CXCL11 stratified non-metastatic ccRCC patients into different risk subgroups of recurrence and death, which might benefit preoperative risk stratification and guide immune therapy in the future.

Prognostic significance of modified Glasgow Prognostic Score in patients with non-metastatic clear cell renal cell carcinoma

Objective The aim of this study was to evaluate the usefulness of the modified Glasgow Prognostic Score (mGPS) as a prognostic factor in patients with non-metastatic clear cell renal cell carcinoma (RCC).Materials and methods Between June 1994 and July 2012, 469 patients with RCC underwent radical or partial nephrectomy at two hospitals. Among these patients, 65 with non-clear cell type histology and 16 with lymph-node or distant metastasis were excluded. The medical records of the remaining 388 patients were retrospectively reviewed. The mGPS was calculated using a selective combination of C-reactive protein (CRP) and albumin as previously described. The prognostic significance of various clinicopathological variables including mGPS was analyzed using univariate and multivariate analyses.Results Of the total 388 patients, 40 patients (10.3%) developed local recurrence or distant metastasis and 18 patients (4.6%) died of disease during the follow-up period. The univariate analysis identified CRP, mGPS, thrombocytosis, T stage, Fuhrman’s nuclear grade and lymphovascular invasion as significant prognostic factors for recurrence-free survival (RFS) and cancer-specific survival (CSS). The multivariate analysis indicated that mGPS (p < 0.001), T stage (p = 0.024) and lymphovascular invasion (p = 0.046) were independent prognostic factors for RFS, whereas mGPS (p = 0.001) was the only independent prognostic factor for CSS.Conclusions The mGPS is an independent prognostic factor for RFS and CSS in patients with non-metastatic clear cell RCC treated with radical or partial nephrectomy. These findings suggest that mGPS should be used for predicting recurrence or survival in patients undergoing nephrectomy for non-metastatic clear cell RCC.

Decreased Expression of SETD2 Predicts Unfavorable Prognosis in Patients With Nonmetastatic Clear-Cell Renal Cell Carcinoma.

DNA sequencing revealed that mutations in SETD2 occur in 3% to 12% of clear-cell renal cell carcinoma (ccRCC) cases and are associated with poor clinical outcome. In this study, we used an immunohistochemistry (IHC) assay to evaluate the impact of SETD2 loss, with expression of H3K36me3, a nonredundantly histone modification by SETD2, on recurrence and survival of nonmetastatic ccRCC patients after nephrectomy.SETD2 and H3K36me3 were assessed in 192 nonmetastatic ccRCC patients enrolled retrospectively from a single institution. Kaplan-Meier and Cox regression analysis were used to associate prespecified SETD2/H3K36me3 score with overall survival (OS) and recurrence-free survival (RFS). And a nomogram was constructed to predict OS at 10 years.Patients with low expression of SETD2 were prone to possess large tumor size and advanced pT stage. And low H3K36me3 expression was associated with larger tumor size. A prespecified combined score based on SETD2 and H3K36me3 expression remained an independent prognosticator for OS and RFS, which was associated with tumor size, pT stage, and sarcomatoid. Furthermore, using prespecified SETD2/H3K36me3 score could stratify nonmetastatic ccRCC patients into different risk subgroups, especially in patients dichotomized by pT stage and Fuhrman grade, respectively. Finally, the C-index for predicting OS increased from 0.727 to 0.747, after adding SETD2/H3K36me3 score to pT stage and Fuhrman grade.The combined score based on expression of SETD2 and H3K36me3 using IHC could predict poor clinical outcomes in nonmetastatic ccRCC patients, and it may benefit preoperative risk stratification and guide treatment planning in the future.

Current and future strategies in nonclear-cell metastatic renal cell carcinoma.

Therapeutic options for patients with metastatic nonclear-cell renal cell carcinoma (non-ccRCC) are limited and display minimum benefit. Conducting clinical trials in these rare and heterogeneous diseases without identified key biological drivers is a challenge for drug development. A growing body of prospective dedicated clinical trials and large molecular characterization initiatives are raising new expectations in non-ccRCC. The first randomized phase II study in non-ccRCC failed to demonstrate the benefit of everolimus over sunitinib in first-line setting, although this study was small and was not supposed to draw final conclusions. Single-arm phase II trials have reported the results of sunitinib or everolimus in the papillary. The potential role of a sunitinib-gemcitabine combination has been investigated in RCC with sarcomatoid features. In parallel, the molecular characterization of non-ccRCC has been initiated, highlighting the heterogeneity of the distinct subtypes. Current efforts to develop clinical trials in non-ccRCC have provided preliminary results with approved agents. The molecular characterization programs have not yet translated into clinical meaningful results, but MET proto-oncogene inhibition holds promises in the population of papillary RCC. Non-ccRCC management raises the challenge of structuring networks to optimize pathological diagnosis, target identification, and for dedicated clinical trials design.

CXC chemokine receptor 2 is associated with postoperative recurrence and survival of patients with non-metastatic clear-cell renal cell carcinoma

BackgroundAberrant CXC chemokine receptor 2 (CXCR2) expression has been shown to promote angiogenesis and proliferation in renal cell carcinoma (RCC). Our current study aims to evaluate the prognostic significance of CXCR2 in patients with non-metastatic clear-cell renal cell carcinoma (ccRCC). MethodsWe retrospectively enrolled 375 patients with non-metastatic ccRCC undergoing nephrectomy at Zhongshan Hospital, Fudan University between 2003 and 2008. The cohort was split into a training set (n=184) and a validation set (n=191). CXCR2 expression was assessed by immunohistochemical staining and its association with clinicopathologic features and prognosis were evaluated. ResultsCXCR2 expression was significantly associated with tumour size (P=0.036 and P=0.016, respectively) and Fuhrman grade (P=0.009 and P=0.001, respectively) in the training and validation sets. Moreover, high CXCR2 expression indicated poor overall survival (OS) (P<0.001 and P=0.001, respectively) and recurrence-free survival (P<0.001 and P<0.001, respectively) in the training and validation sets. The incorporation of CXCR2 into the T stage and Fuhrman grade would help to refine individual risk stratification. Furthermore, CXCR2 expression was identified as an independent adverse prognostic factor for survival (P<0.001) and recurrence (P<0.001). A predictive nomogram was generated with identified independent prognosticators to assess patient recurrence-free survival at 5 and 10years. ConclusionsCXCR2 is a potential independent adverse prognostic biomarker for recurrence and survival of patients with non-metastatic ccRCC after nephrectomy.

Expression pattern of autophagy-related markers in non-metastatic clear cell renal cell carcinoma: association with disease recurrence following radical nephrectomy.

To evaluate the expression of multiple molecular markers associated with autophagy, a cellular degradation pathway for the clearance of damaged or superfluous proteins and organelles, in clear cell renal cell carcinoma (CCRCC) in order to identify the prognostic significance of these markers in patients undergoing radical nephrectomy. Expression levels of five markers, including autophagy-related gene 5 (Atg5), Atg9, Beclin 1, microtubule-associated protein light chain 3 (LC3), and UNC-51-like kinase 1 (ULK1), in radical nephrectomy specimens from a total of 100 patients with non-metastatic CCRCC were measured by immunohistochemical staining. All the five markers were significantly correlated with some pathological factors reflecting an aggressive phenotype, including the pathological T stage, tumor grade, and microvascular invasion. During the follow-up period of this series (median 58.0 months), disease recurrence developed in 41 of the 100 patients, with a 5-year recurrence-free survival (RFS) rate of 61.3%. On univariate analysis, expression levels of Atg5 and Beclin 1, in addition to the pathological T stage, microvascular invasion, and preoperative CRP level, were identified as significant predictors of disease recurrence. Of these factors, the expression of Beclin 1 and preoperative CRP level were independently correlated with RFS on multivariate analysis. These findings suggest that the combined assessment of expression levels of autophagy-associated markers, particularly Beclin 1, in radical nephrectomy specimens with conventional prognostic parameters, would contribute to the precise prediction of postoperative disease recurrence in patients with non-metastatic CCRCC.

Low preoperative lymphocyte-monocyte ratio (LMR) represents a potentially poor prognostic factor in nonmetastatic clear cell renal cell carcinoma

ObjectivesTo explore the potential prognostic significance of the lymphocyte-monocyte ratio (LMR) in patients with nonmetastatic renal cell carcinoma (RCC), as the LMR has been repeatedly proposed to have a negative effect on patient׳s survival in various hematological and solid cancers. However, findings about LMR׳s prognostic significance in RCC have not been reported yet. Methods and materialsWe retrospectively evaluated the prognostic significance of the LMR in a cohort comprising 678 patients with nonmetastatic clear cell RCC, who were operated between 2000 and 2010 with curative radical or partial nephrectomy at a single tertiary academic center. Preoperative LMR was calculated 1 day before surgical intervention. Patients were categorized using an LMR cutoff of 3.0. Cancer-specific survival (CSS), metastasis-free survival, and overall survival were assessed using the Kaplan-Meier method. To evaluate the independent prognostic significance of the LMR, multivariate Cox regression models were applied. Additionally, the influence of the LMR on the predictive accuracy of the Leibovich prognosis score was determined using the Harrell concordance index (c-index) and decision curve analysis. ResultsLow LMR was statistically significantly associated with older patients (≥65y), high tumor grade (G3+G4), advanced pathologic T category (pT3+pT4), the presence of histologic tumor necrosis, and male gender (P<0.05). Multivariate analysis identified a low LMR as an independent prognostic factor for patients׳ CSS (hazard ratio = 2.33; 95% CI: 1.10–4.94; P = 0.027). The estimated c-index was 0.83 using the Leibovich prognosis score and 0.86 when the LMR was added. ConclusionsRegarding CSS of patients with RCC, a decreased LMR represents an independent prognostic factor. Adding the LMR to well-established prognostic models, such as the Leibovich prognosis score, might improve their predictive ability.

Serum level and immunohistochemical expression of vascular endothelial growth factor for the prediction of postoperative recurrence in renal cell carcinoma.

BackgroundVascular endothelial growth factor (VEGF) plays a major role in angiogenesis. One of the functions of VEGF is to regulate neovascularization in clear cell renal cell carcinoma (CCRCC). The objective of our study was to examine whether before nephrectomy serum levels of VEGF or expression of VEGF using immunohistochemistry (IHC) could predict postoperative recurrence in nonmetastatic CCRCC.ResultsTwelve patients (14.5%) had recurrence during a mean follow-up of 52.6 ± 31.2 months. The serum VEGF level was significantly higher in patients with recurrence than in those without recurrence (P = 0.038). High serum VEGF levels were above 416 pg/mL; this value was chosen based on a receiver operating characteristic analysis. The recurrence-free survival rate in patients with a high serum VEGF level was significantly lower than in those with a low serum VEGF level (P = 0.003). In total, tumors from 26 patients (31.3%) showed overexpression of VEGF using IHC. The recurrence-free survival rate in the IHC-positive group was significantly lower than that in the IHC-negative group (P = 0.044). Multivariate analysis indicated that preoperative serum VEGF levels (P = 0.013) and female gender (P = 0.004) were independent predictors of postoperative recurrence in nonmetastatic CCRCC.ConclusionsPreoperative serum VEGF levels is a useful predictor compared with IHC analysis of VEGF of postoperative recurrence in nonmetastatic CCRCC.

Sunitinib in patients with metastatic non-clear renal cell carcinoma: A multicentric retpospective Turkish Oncology Group (TOG) trial.

e15602 Background: Most of the randomizedstudies that have evaluated the clinical outcome of anti-VEGF treatment in metastatic renal cell carcinoma (RCC) were focused mostly on the clear cell histo...

MP59-04 PREOPERATIVE NEUTROPHIL LYMPHOCYTE RATIO IS AN INDEPENDENT PREDICTOR OF CANCER SPECIFIC SURVIVAL IN PATIENTS WITH NONMETASTATIC CLEAR CELL RENAL CARCINOMA UNDERGOING RADICAL NEPHRECTOMY

You have accessJournal of UrologyKidney Cancer: Localized IV1 Apr 2014MP59-04 PREOPERATIVE NEUTROPHIL LYMPHOCYTE RATIO IS AN INDEPENDENT PREDICTOR OF CANCER SPECIFIC SURVIVAL IN PATIENTS WITH NONMETASTATIC CLEAR CELL RENAL CARCINOMA UNDERGOING RADICAL NEPHRECTOMY Boyd Viers, R. Houston Thompson, Stephen Boorjian, Christine Lohse, Bradley Leibovich, and Matthew Tollefson Boyd ViersBoyd Viers More articles by this author , R. Houston ThompsonR. Houston Thompson More articles by this author , Stephen BoorjianStephen Boorjian More articles by this author , Christine LohseChristine Lohse More articles by this author , Bradley LeibovichBradley Leibovich More articles by this author , and Matthew TollefsonMatthew Tollefson More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1800AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Introduction and Objectives The neutrophil-lymphocyte ratio (NLR) is an indicator of the systemic inflammatory response. An increased pretreatment NLR has been associated with adverse outcomes, in other malignancies, but its role in nonmetastatic (M0) clear cell renal cell carcinoma (ccRCC) remains unclear. As such, we evaluate the ability of preoperative NLR to predict oncologic outcomes in patients with M0 ccRCC undergoing radical nephrectomy (RN). Methods From 1995 to 2008, 952 patients underwent RN for M0 ccRCC. Of these, 827 (87%) had preoperative NLR collected within 90 days prior to RN. NLR was analyzed as a continuous variable and using a cutpoint of 4.0. Multivariate analysis to evaluate the association of NLR with death from RCC was performed adjusting for the SSIGN score (tumor stage, lymph node status, size, nuclear grade and necrosis). Results At a median follow up 9.1 years, 345 (36%), 265 (28%) and 485 (51%) patients had distant metastasis, death from RCC and all-cause mortality, respectively. Those with NLR ≥ 4 had increased tumor size, nuclear grade, necrosis and sarcomatoid features (all P<0.001). Preoperative NLR ≥ 4.0 versus < 4.0 was associated with significantly adverse 10-year progression-free (52% versus 66%; P<0.001) and cancer-specific survival (58% versus 74%; P<0.001). After controlling for the SSIGN score, NLR as a continuous variable (HR for a 1-unit increase of 1.02, P=0.010) and ≥ 4.0 (HR 1.42, P=0.010) were independent predictors of death from RCC. Conclusions Our results suggest that NLR is independently associated with an increased risk of cancer specific mortality among patients with clinically localized ccRCC undergoing nephrectomy. While external validation is needed, NLR appears to be a marker of biologically aggressive RCC and may be useful in patient risk stratification. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e651 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Boyd Viers More articles by this author R. Houston Thompson More articles by this author Stephen Boorjian More articles by this author Christine Lohse More articles by this author Bradley Leibovich More articles by this author Matthew Tollefson More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

High preoperative monocyte-lymphocyte ratio (MLR) as a prognostic factor in nonmetastatic clear cell renal cell carcinoma.

534 Background: The ratio of peripheral blood absolute monocyte count to absolute lymphocyte count (MLR) has been proposed as a negative impact for patient’s survival in haematological cancers. However, findings about MLR’s potential prognostic significance in non-metastatic renal cell carcinoma (RCC) patients have not been reported yet. Methods: We retrospectively evaluated the prognostic significance of the MLR in a cohort comprising of 678 consecutive non-metastatic clear cell RCC patients, operated between 2000 and 2010 with curative radical or partial nephrectomy at a single tertiary academic centre. Pre-treatment MLR was calculated one day before surgical intervention. Patients were categorised using an MLR cut-off of 0.35. Cancer-specific- (CSS), metastasis-free- (MFS), as well as overall survival (OS) were assessed using the Kaplan-Meier method. To evaluate the independent prognostic significance of the MLR, multivariate Cox regression models were applied for all three endpoints. Additionally, the influence of the MLR on the predictive accuracy of the Leibovich prognosis score was determined by Harrell’s concordance index (c-index) and decision curve analysis (DCA). Results: An increased MLR was statistically significantly associated with poor outcomes for all three endpoints in univariable analyses (all p≤0.006). Multivariable analyses identified an increased MLR as an independent prognostic factor for patients’ CSS [HR=2.33, 95%CI=1.10-4.94, p=0.027], but not for MFS [HR=1.59, 95%CI=0.94-2.69, p=0.087], nor for OS [HR=1.37, 95%CI=0.93-2.03, p=0.112]. The estimated c-index was 0.83 using the Leibovich prognosis score and 0.86 when MLR was added. Conclusions: Regarding RCC patients’ CSS, an increased MLR represented an independent prognostic factor. Adding the MLR to well-established prognostic models such as the Leibovich prognosis score might improve their predictive ability.

A phase II clinical trial examining the impact of neoadjuvant axitinib on primary tumor response in patients with locally advanced clear cell renal cell carcinoma.

4516 Background: Previous studies have shown minimal impact of TKIs on primary renal tumor downsizing. Axitinib is a VEGFR TKI that has been recently approved for use in patients with metastatic clear cell renal cell carcinoma (RCC). In this prospective phase II trial, we sought to investigate the safety and role of axitinib in downsizing tumors in patients with non-metastatic renal cell carcinoma, prior to undergoing surgical resection. Methods: Patients with locally advanced (clinical stage T2-T3b N0 M0) biopsy-proven clear cell RCC were eligible for this phase II clinical trial. The primary outcome was objective response rate (using RECIST) following the administration of axitinib for 12 weeks prior to undergoing radical nephrectomy. Secondary outcomes included safety, tolerability, and feasibility of administration of axitinib in this patient population. Patients were given axitinib 5mg PO BID, and dose titration was allowed. Axitinib was continued until 36 hours prior to surgery. A dedicated radiologist independently reviewed all CT scans to evaluate for response using RECIST. Results: The study goal of enrolling 24 patients has been recently reached. At present, nineteen patients have completed the studies required for assessment of the primary outcome and are hereby reported. Fifteen patients were males, and four were females. Median age was 61 years (range 42-83 years). All patients had biopsy-proven clear cell RCC. All 19 patients continued axitinib for 12 weeks, and underwent surgery as planned without delay. Adverse events of any grade were: arthralgia in 6, hypothyroidism in 14, fatigue in 15, and hypertension in 16 patients. No wound complications occurred after surgery. Nine patients (47%) experienced a partial response by RECIST, and 10 patients had stable disease. There was no progression of disease while on axitinib. Conclusions: Axitinib is well tolerated in the neoadjuvant setting in patients with planned surgery for locally advanced non-metastatic clear cell RCC. The drug showed tumor downsizing activity when given for 12 weeks prior to surgery. Adverse events of any grade were common and easily manageable with routine care. Clinical trial information: NCT01263769.

Validation of the pre-treatment neutrophil–lymphocyte ratio as a prognostic factor in a large European cohort of renal cell carcinoma patients

Background:The neutrophil–lymphocyte ratio (NLR) has been proposed as an indicator of systemic inflammatory response. Several studies suggest a negative impact of increased NLR for patient's survival in different types of cancer. However, previous findings from small-scale studies revealed conflicting results about its prognostic significance with regard to different clinical end points in non-metastatic renal cell carcinoma (RCC) patients. Therefore, the aim of our study was the validation of the prognostic significance of NLR in a large cohort of RCC patients.Methods:Data from 678 consecutive non-metastatic clear cell RCC patients, operated between 2000 and 2010 at a single centre, were evaluated retrospectively. Cancer-specific, metastasis-free, as well as overall survival (OS) were assessed using the Kaplan–Meier method. To evaluate the independent prognostic significance of NLR, multivariate Cox regression models were applied for all three different end points. Influence of the NLR on the predictive accuracy of the Leibovich prognosis score was determined by Harrell's concordance index.Results:Multivariate analysis identified increased NLR as an independent prognostic factor for overall (hazard ratio (HR)=1.59, 95% confidence interval (CI)=1.10–2.31, P=0.014), but not for cancer-specific (HR=1.59, 95% CI=0.84–2.99, P=0.148), nor for metastasis-free survival (HR=1.39, 95% CI=0.85–2.28, P=0.184). The estimated concordance index was 0.79 using the Leibovich risk score and 0.81 when NLR was added.Conclusion:Regarding patients' OS, an increased NLR represented an independent risk factor, which might reflect a higher risk for severe cardiovascular and other comorbidities. Adding the NLR to well-established prognostic models such as the Leibovich prognosis score might improve their predictive ability.

血清VEGF（Vascular Endothelial Growth Factor）による腎細胞癌術後再発の予測

Vascular endothelial growth factor (VEGF) is known as one of the key molecules in molecular targeting therapy for patients with renal cell carcinoma (RCC). Several studies have shown that VEGF might be useful for predicting prognosis in RCC. We examined whether pretreatment serum VEGF can be used as a predictor of recurrence-free survival in non-metastatic RCC. We studied 85 patients with non-metastatic clear cell RCC who underwent nephrectomy between 2001 and 2010. Serum samples were collected for VEGF before operation. We evaluated the recurrence-free survival by univariate and multivariate analysis. 9 patients (10.6%) showed recurrence. Serum level of VEGF in patients with recurrence showed significantly higher than those in patients without recurrence (p = 0.0310). A cutoff level of 416 pg/mL for the separation of low and high serum VEGF levels was established based on the receiver operating characteristic (ROC) curve. The recurrence-free survival rate was significantly lower in patients with a high serum VEGF level (p = 0.0039). Multivariate analysis showed that pretreatment serum VEGF value was a significant predictor of postoperative recurrence in non-metastatic clear cell RCC (p = 0.0062). Pretreatment level of serum VEGF might be useful for prediction of postoperative recurrence in non-metastatic clear cell RCC.

Plasma cytokines and angiogenic factors (CAFs) for evaluation of risk of recurrence and classification of patients (pts) with nonmetastatic renal cell carcinoma (RCC).

e15075 Background: Although recent years have brought great progress into understanding the pathogenesis of RCC and multiple promising biomarkers, no tumor tissue or blood-based test has yet been established to assist in the clinical determination of prognosis. Whether CAFs can be used to classify RCC pts and the set of CAFs that is host vs. tumor-dependent remain unclear. The main objectives of this exploratory analysis were to identify CAFs predictive of recurrence, and to gain insight into coordinated regulation and tumor dependency of individual factors by comparing CAFs pre- and post-nephrectomy (Nx) in RCC pts. Methods: Plasma samples were obtained before and up to 1 year after Nx from 52 pts with sporadic, non-metastatic RCC with dominant clear cell histology. Pts were categorized based on pathologic staging (pT1/pT2 as low-risk [LR] for recurrence, n=32; pT3/pT4 as high-risk [HR], n=20). Multiplex bead suspension arrays and ELISA were used to measure concentrations of 58 CAFs including angiogenesis and invasion mediators (VEGF, VEGF-C, soluble CAIX [sCA9], HGF and TGF-b1, among others), and multiple inflammatory and/or immunomodulatory chemokines and interleukins (IL). t-test and Wilcoxon signed rank or rank-sum tests were respectively used to assess changes in CAFs between pre- and post-Nx or to compare CAFs between subgroups of pts. Results: The concentrations of IL-8 and sCA9, among others, were significantly higher in HR vs. LR RCC pts pre-Nx (P&lt;0.01). The pre-Nx concentrations of e-selectin were lower in RCC pts with eventual disease recurrence (P=0.027). Several CAFs decreased significantly post-Nx, including sCA9 and endoglin, whereas others increased, such as stem cell factor, IL-12, IL-18 and vascular cell adhesion molecule-1. Angiogenic and hypoxia-regulated CAFs such as OPN, sCA9, HGF, endoglin and collagen type IV grouped together using unsupervised hierarchical clustering. Conclusions: Pre-Nx CAFs associated with risk for recurrence could be useful in risk stratification of non-metastatic clear cell RCC pts. Some tumor-dependent angiogenic CAFs are coordinately regulated in these pts.