Clear Renal Cell Carcinoma Patients Research Articles

Delta-like ligand 4: A predictor of poor prognosis in clear cell renal cell carcinoma.

Delta-like ligand 4 (Dll4)-Notch signaling is important in tumor angiogenesis; however, the prognostic value of D114 detection in patients with clear cell renal cell carcinoma (CCRCC) remains unclear. The present study aimed to determine whether the presence of high Dll4 expression levels was correlated with poor prognosis in CCRCC following curative resection. The D114 expression levels in four paired samples of CCRCC tissues and adjacent normal renal tissues were assayed by western blotting. Surgical specimens comprised 121 CCRCC tissue samples and 65 normal renal tissue samples, obtained from patients with CCRCC. The specimens were immunohistochemically assessed to determine Dll4 and vascular endothelial growth factor receptor 2 (VEGFR-2) expression levels. The prognostic significance of Dll4 expression levels was evaluated by the Kaplan-Meier method and Cox regression analysis. The correlation between Dll4 expression levels and VEGFR-2 expression levels, tumor stage, tumor grade and metastasis, was examined by χ2 test and multivariate logistic regression. As determined by the western blotting results, Dll4 protein expression levels were significantly increased in CCRCC tissues compared with those in adjacent non-cancerous tissues. From the analysis of the surgical specimens, 53 (43.8%) CCRCC patients exhibited immunohistochemically high Dll4 expression levels and 68 (56.2%) patients exhibited low Dll4 expression levels. The survival curves revealed that the patients with high Dll4 expression levels had significantly shorter survival times than the patients with low Dll4 expression levels (P<0.001). Multivariate survival analysis demonstrated that the presence of high Dll4 expression levels was independently associated with reduced overall survival and progression-free survival times (P=0.021 and 0.034, respectively). A positive correlation was also identified between Dll4 and VEGFR-2 expression levels (P=0.001). In conclusion, the results show that the presence of high Dll4 expression levels was clearly associated with high VEGFR-2 expression levels, tumor grade, tumor stage and poor prognosis in CCRCC patients. Therefore, inhibition of Dll4 may exert potent growth inhibitory effects on tumors resistant to anti-VEGF therapies for CCRCC.

MiR149 rs71428439 polymorphism and risk of clear cell renal cell carcinoma: a case-control study.

Clear cell renal cell carcinoma (CCRCC) is the most common subtype of renal cell cancer and accounts for 70% of renal cell cancer. CCRCC remains an enigmatic tumor type, as the molecular genetic mechanisms are still unclear. MicroRNA (miR) 149 functions as a tumor suppressor and plays an important role in the carcinogenesis of renal cells. In this study, we enrolled 1,000 CCRCC patients and 1,000 cancer-free controls to evaluate the association of miR149 rs71428439 with the risk of CCRCC by a case-control study to determine the effects on CCRCC risk. miR149 rs71428439 was significantly associated with increased CCRCC risk (odds ratio (OR) for trend = 1.53, P for trend = 4.04 × 10(-11)), with ORs (95% confidence intervals (CIs)) of 1.42 (1.17-1.72) associated with AG genotype and 2.27 (1.76-2.94) associated with GG genotype, compared with subjects with AA genotype. The expression levels of miR149 in cancer tissues were significantly lower than those in adjacent normal tissues (P = 0.005), and per G allele has significantly lower miR149 levels in both tumor tissues and adjacent normal tissues. Our data suggest that the GG genotypes of miR149 rs71428439 predispose their carriers to CCRCC, and miR149 rs71428439 may be a new biomarker for predicting the risk of CCRCC.

Expression of Neural Wiskott-Aldrich Syndrome Protein in Clear Cell Renal Cell Carcinoma and Its Correlation with Clinicopathological Features

Introduction: Neural Wiskott-Aldrich syndrome protein (N-WASP) expression is associated with tumor cell invasion and migration. However, its expression status in clear cell renal cell carcinoma (CCRCC) remains unclear. We examined the level of N-WASP in CCRCC and its association with clinicopathological features characteristic. Materials and Methods: 73 CCRCC patients who underwent radical nephrectomy or partial nephrectomy were enrolled. Immunohistochemical staining for N-WASP was performed on tissue microarrays constructed from tumor and para-tumor tissue obtained from these patients. The difference in N-WASP expression between tumor tissue and adjacent normal renal tissue was examined. Correlations between N-WASP expression in the tumor and clinicopathological parameters were analyzed and the relationship between N-WASP expression and overall survival also assessed. Uni- and multivariate survival analyses were performed. Results: N-WASP expression was significantly reduced in tumor tissues and was significantly related to the histological grade of CCRCC. A higher level of N-WASP expression in the tumor was associated with relatively poor survival in CCRCC patients. The level of N-WASP expression, age at time of surgery, and histological grade were all responsible for clinical outcome in CCRCC patients. N-WASP was an independent predictor for overall survival. Conclusions: N-WASP was downregulated in CCRCC and could serve as a prognostic biomarker for predicting clinical outcome of CCRCC.

Relationship between survivin/HLA classI molecules expression and survival of patients withc lear cell er nal cell carcinoma

Objective To investigate the expression of survivin/Human leukocyte antigen class I （ HLA-Ⅰ） proteins and its physiological significance in clear cell renal cell carcinoma （ CCRCC ） . Methods Immunohistochemistry was used to analyze survivin/HLA-Ⅰ protein expression in 90 cases of CCRCC and 10 normal tissues to study relationships with clinical symptoms and disease prognosis . Resutl s The level of survivin protein expression was found to be significantly higher in CCRCC tissues 82.2%（ 74/90） than in normal tissues（ 0/10）.However, the relative amount of HLA-Ⅰprotein in colorectal cancer tis-sue was also found to be significantly lower 67.8%（61/90） than in normal tissues 90%（9/10）.Survivin expression was associated with tumor grade , stage,and lymph node metastasis （ P=0.000, P=0.016, and P=0.001, respectively ） .Conversely , lost HLA-Ⅰexpression did not have any associations with clinicopath-ological data （P〈0.05）.Survivin negative patients （25.0%, 4/16） had a higher tumor-free survival rate than patients （52.7%, 39/74）with survivin expression （P=0.037）.Patients （27.6%, 8/29） with normal HLA-Ⅰlevels had a higher tumor-free survival rate than those （ 60.7%, 37/61） with reduced HLA-Ⅰlev-els （P=0.020）.The univariate and multivariate analyses indicated that expression of survivin and HLA indi -vidually and in combination were independent predictors for CCRCC patient survival . Conclusions Over-expression of survivin but reduced HLA-Ⅰ expression is associated with CCRCC development and progres-sion. Key words: Clear cell renal cell carcinoma; Survivin; HLA class I molecules; Immunohisto-chemistry; Prognosis

EZH2 promotes tumor progression by increasing VEGF expression in clear cell renal cell carcinoma.

The present study is to evaluate the expression level of enhancer of zeste homolog 2 (EZH2) and vascular endothelial growth factor (VEGF), and analyze their correlations with clinicopathological characteristics and survival in patients with clear cell renal cell carcinoma (CCRCC). The effect of EZH2 on apoptosis and cell proliferation in 786-O renal cancer cell line is investigated. The expression level of EZH2 and VEGF was detected in 185 primary CCRCC patients' tissues using tissue microarray and immunohistochemistry. Small interfering RNA or enhanced green fluorescent protein transfection was employed to investigate the effect of EZH2 inhibition or overexpression on VEGF expression, apoptosis and cell proliferation in 786-O cells using flow cytometry, immunofluorescence microscopy, quantitative real-time reverse-transcription polymerase chain reaction and Western blot analysis. High expression level of EZH2 and VEGF was observed in advanced CCRCC and correlated with the TNM stage (p=0.013, p=0.001) and distant metastasis (p=0.011, p=0.038), respectively. EZH2 was positively correlated with VEGF in CCRCC tissues (correlation coefficient=0.850, p<0.001). Kaplan-Meier survival analysis revealed that patients with positive EZH2 expression had a shorter overall survival time compared to patients with negative EZH2 expression (34.3 vs. 67.2, p<0.001). In 786-O cells, EZH2 silencing inhibited VEGF expression and cell proliferation while increasing apoptosis (p<0.001). EZH2 overexpression promoted VEGF expression and cell proliferation while inhibiting apoptosis (p<0.001). EZH2 correlates positively with VEGF and associates with adverse clinicopathologic characteristics and shorter survival time in CCRCC patients. EZH2 accelerates antiapoptosis and cell cycle in 786-O cells.

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.

Expression of CD9 and CD82 in clear cell renal cell carcinoma and its clinical significance

CD9 and CD82, members of the tetraspanin family, act as metastasis suppressors in many human malignant tumors, but the role of these molecules is not well known in clear cell renal cell carcinoma (CCRCC). This study was designed to evaluate the immunohistochemical expression of CD9 and CD82 in 644 cases of CCRCC and to determine the clinicopathologic and prognostic significance of their expression. The percentage of positive tumor cells was evaluated, and the expression was classified into 2 categories: low expression (less than 10% positive cells) or high expression (more than 10% positive cells) for CD9 expression and negative (no positive cells) or positive for CD82 expression. CD9 high expression was found in 303 (47.0%) patients, and CD82 positivity was found in 98 (15.2%) patients. High expression of CD9 was statistically associated with older patients (p=0.003). The cases showing positive immunoreactivity for CD82 exhibited a high stage (p<0.001) and high nuclear grade (p<0.001). The overall, cancer-specific and progression-free survival rates were significantly higher in patients with a CD82-negative profile compared to patients with a CD82-positive profile (p<0.001). Although the biological function of CD82 in CCRCC remains unclear, the CCRCC patients with CD82 positive expression show poor prognosis.

Combination of expression levels of miR-21 and miR-126 is associated with cancer-specific survival in clear-cell renal cell carcinoma

BackgroundRenal cell carcinoma (RCC) is marked by high mortality rate. To date, no robust risk stratification by clinical or molecular prognosticators of cancer-specific survival (CSS) has been established for early stages. Transcriptional profiling of small non-coding RNA gene products (miRNAs) seems promising for prognostic stratification. The expression of miR-21 and miR-126 was analysed in a large cohort of RCC patients; a combined risk score (CRS)-model was constructed based on expression levels of both miRNAs.MethodsExpression of miR-21 and miR-126 was evaluated by qRT-PCR in tumour and adjacent non-neoplastic tissue in n = 139 clear cell RCC patients. Relation of miR-21 and miR-126 expression with various clinical parameters was assessed. Parameters were analysed by uni- and multivariate COX regression. A factor derived from the z-score resulting from the COX model was determined for both miRs separately and a combined risk score (CRS) was calculated multiplying the relative expression of miR-21 and miR-126 by this factor. The best fitting COX model was selected by relative goodness-of-fit with the Akaike information criterion (AIC).ResultsRCC with and without miR-21 up- and miR-126 downregulation differed significantly in synchronous metastatic status and CSS. Upregulation of miR-21 and downregulation of miR-126 were independently prognostic. A combined risk score (CRS) based on the expression of both miRs showed high sensitivity and specificity in predicting CSS and prediction was independent from any other clinico-pathological parameter. Association of CRS with CSS was successfully validated in a testing cohort containing patients with high and low risk for progressive disease.ConclusionsA combined expression level of miR-21 and miR-126 accurately predicted CSS in two independent RCC cohorts and seems feasible for clinical application in assessing prognosis.

Tyrosine Kinase Inhibitor Sorafenib Decreases 111In-Girentuximab Uptake in Patients with Clear Cell Renal Cell Carcinoma

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of metastatic clear cell renal cell carcinoma (RCC). Although TKIs have demonstrated good clinical efficacy, the lack of complete responses, the chronic nature of the treatment, and the side effects are clear disadvantages. An interesting new approach in the treatment of clear cell RCC is antibody-mediated therapy with the chimeric anti-carbonic anhydrase IX (CAIX) antibody girentuximab (cG250). As the results of several girentuximab trials become available, the question arises of whether TKI treatment can be combined with girentuximab-based therapy. In this study, we assessed the effect of the widely used TKI sorafenib on the tumor-targeting potential of (111)In-labeled girentuximab. (111)In-girentuximab imaging was performed on 15 patients suspected of having a renal malignancy, with surgery being part of their treatment plan. Of these, 10 patients were treated in a neoadjuvant setting with sorafenib (400 mg orally twice daily). Five patients received treatment during 1 wk, and 5 patients received treatment during 4 wk. In both sorafenib-treated groups, baseline and posttreatment tumor targeting of (111)In-girentuximab were compared. Surgery was performed 3 d after the last image acquisition. Five additional patients were included as a control group and had only a single (111)In-girentuximab injection and scintigraphy without any treatment. Distribution of (111)In-girentuximab was determined scintigraphically ex vivo in a 1-cm lamella of the resected tumorous kidney. Expression of CAIX and of the vascular marker CD31 was determined immunohistochemically on specimens of both tumor and normal kidney tissue. Treatment with sorafenib resulted in a marked decrease of (111)In-girentuximab uptake in the tumor in clear cell RCC patients, especially in the group treated for 4 wk (mean change in both sorafenib-treated groups, -38.4%; range, +9.1% to -79.4%). Immunohistochemical analysis showed markedly reduced CD31 expression and vessel density in the sorafenib-treated groups but no differences in CAIX expression between the sorafenib-treated groups and the nontreated patients. Treatment with sorafenib resulted in a treatment duration-dependent significantly decreased uptake of (111)In-girentumab in clear cell RCC lesions. These results indicate that the efficacy of antibody-mediated treatment or diagnosis modalities is hampered by TKI treatment.

Clinical significance of serum soluble T cell regulatory molecules in clear cell renal cell carcinoma.

To clarify the role of serum soluble T cell regulatory molecules in clear cell renal cell carcinoma (CCRCC), we measured the serum levels of soluble interleukin-2 receptor (sIL-2R), soluble B7-H3 (sB7-H3), and soluble cytotoxic T lymphocyte associated antigen-4 (sCTLA-4) in 70 CCRCC patients and 35 healthy controls. We investigated correlations between the serum levels of these soluble T cell regulatory molecules and the pathological grade, clinical stage, and prognosis of CCRCC. We also assessed the relations among each of these soluble molecules. As a result, the serum level of sIL-2R was significantly higher in CCRCC patients than in healthy controls (P < 0.05). In addition, elevation of serum sIL-2R was significantly correlated with the clinical stage (P < 0.001), and the survival of patients with high sIL-2R levels was shorter than that of patients with low sIL-2R levels (P < 0.05). Furthermore, the serum level of sB7-H3 was also significantly correlated with the clinical stage (P < 0.05), while the sIL-2R and sB7-H3 levels showed a positive correlation with each other (R = 0.550, P < 0.0001). These results indicate that the serum level of sIL-2R reflects tumor progression in CCRCC patients. In addition, the possibility was suggested that the IL-2/IL-2R and B7-H3 pathways may be involved in the progression of CCRCC.

Aberrant methylation of PCDH8 is a potential prognostic biomarker for patients with clear cell renal cell carcinoma.

BackgroundPCDH8 is a tumor suppressor that regulates cell adhesin, proliferation, and migration. It is often inactivated by aberrant promoter methylation in several human cancers, including clear cell renal cell carcinoma (CCRCC). The clinical significance of PCDH8 methylation in CCRCC remains unclear. The aim of this study was to investigate the relationship between PCDH8 methylation and clinicopathological characteristics as well as outcome of patients with CCRCC.Material/MethodsThe methylation status of PCDH8 in 153 CCRCC tissues and 97 paired adjacent normal renal tissues were examined using methylation-specific PCR (MSP). Then the relationships between PCDH8 methylation and clinicopathological features as well as progression-free survival of CCRCC patients were evaluated.ResultsPCDH8 methylation was significantly more frequent in CCRCC tissues compared with normal renal tissues. Moreover, PCDH8 methylation was significantly correlated with advanced clinical stage (P=0.0141), higher grade (P=0.0190), and lymph node metastasis (P=0.0098). In addition, multivariate analysis showed that PCDH8 methylation was independently associated with poor progression-free survival (P=0.0316).ConclusionsPCDH8 methylation is a frequent event in CCRCC and is correlated with unfavorable clinicopathological features. Moreover, PCDH8 methylation may be a useful biomarker to predict the progression of CCRCC.

Gene and isoform expression signatures associated with tumor stage in kidney renal clear cell carcinoma

BackgroundIdentification of expression alternations between early and late stage cancers is helpful for understanding cancer development and progression. Much research has been done focusing on stage-dependent gene expression profiles. In contrast, relatively fewer studies on isoform expression profiles have been performed due to the difficulty of quantification and noisy splicing. Here we conducted both gene- and isoform-level analysis on RNA-seq data of 234 stage I and 81 stage IV kidney renal clear cell carcinoma patients, aiming to uncover the stage-dependent expression signatures and investigate the advantage of isoform expression profiling for identifying advanced stage cancers and predicting clinical outcome.ResultsBoth gene and isoform expression signatures are useful for distinguishing cancer stages. They provide common and unique information associated with cancer progression and metastasis. Combining gene and isoform signatures even improves the classification performance and reveals additional important biological processes, such as angiogenesis and TGF−beta signaling pathway. Moreover, expression abundance of a number of genes and isoforms is predictive of the risk of cancer death in an independent dataset, such as gene and isoform expression of ITPKA, the expression of a functional important isoform of UPS19.ConclusionIsoform expression profiling provides unique and important information which cannot be detected by gene expression profiles. Combining gene and isoform expression signatures helps to identify advanced stage cancers, predict clinical outcome, and present a comprehensive view of cancer development and progression.

Acetylation status of P53 and the expression of DBC1, SIRT1, and androgen receptor are associated with survival in clear cell renal cell carcinoma patients

Recently, the important role of silent mating type information regulation 2 homolog 1 (SIRT1) and deleted in breast cancer 1 (DBC1) in human cancer has been extensively studied and their role has been closely related with the control of P53 and androgen receptor (AR) functions. However, their role in clear cell renal cell carcinoma (CRCC) is still unknown. We evaluated the expression of SIRT1, P53, acetylated-P53, DBC1 and AR and their prognostic significance in 200 CRCC patients. The expression of SIRT1, P53, DBC1, and AR significantly correlated with each other and all of them predicted shorter overall survival (OS), relapse-free survival (RFS), and cancer-specific survival (CSS). In contrast, the expression of acetylated-P53 predicted favourable OS, RFS, and CSS. Combined expression pattern of acetylated-P53 and P53 (Ac-P53/P53) also closely correlated with survival of CRCC patients. Multivariate analysis revealed DBC1, acetylated-P53, and Ac-P53/P53 expression as independent prognostic indicators for OS and RFS, and Ac-P53 expression as an independent prognostic indicator for CSS. This study demonstrates that the acetylation status of P53 and the expression of SIRT1, DBC1, and AR could be new prognostic indicators for CRCC and suggest that SIRT1-P53 and DBC1-AR related pathways could be new therapeutic targets for the treatment of CRCC.

The Role of Aberrant VHL/HIF Pathway Elements in Predicting Clinical Outcome to Pazopanib Therapy in Patients with Metastatic Clear-Cell Renal Cell Carcinoma

Inactivation of von Hippel-Lindau (VHL) gene in clear-cell renal cell carcinoma (RCC) leads to increased levels of hypoxia-inducible factors (HIF) and overexpression of HIF target genes, such as VEGF and others. VEGF-targeted agents are standard in advanced clear-cell RCC but biomarkers of activity are lacking. We analyzed tumor tissue samples from metastatic clear-cell RCC patients who received pazopanib as part of clinical trial VEG102616. We evaluated several components of the VHL/HIF pathway: VHL gene inactivation (mutation and/or methylation), HIF-1α and HIF-2α immunohistochemistry staining, and HIF-1α transcriptional signature. We evaluated the association of these biomarkers with best overall response rate (ORR) and progression-free survival (PFS) to pazopanib, a standard first-line VEGF-targeted agent. The VEG102616 trial enrolled 225 patients, from whom 78 samples were available for tumor DNA extraction. Of these, 70 patients had VHL mutation or methylation. VHL gene status did not correlate with ORR or PFS. Similarly, HIF-1α (65 samples) and HIF-2α (66 samples) protein levels (high vs. low) did not correlate with ORR or PFS to pazopanib. The HIF-1α transcriptional signature (46 samples) was enriched in tumors expressing high HIF-1α levels. However, the HIF-1α gene expression signature was not associated with clinical outcome to pazopanib. In patients with advanced clear-cell RCC, several potential biomarkers along the VHL/HIF-1α/HIF-2α axis were not found to be predictive for pazopanib activity. Additional efforts must continue to identify biomarkers associated with clinical outcome to VEGF-targeted agents in metastatic RCC.

Prospective assessment of circulating endothelial cells (CECs) as pharmacodynamic marker in first line clear cell renal cell carcinoma (CCRCC): The CIRCLES study (SOGUG 2011-01).

e15586 Background: Angiogenesis inhibitors have become a cornerstone in the management of CCRCC. Since CECs counts have been proposed as a surrogate biomarker of antiangiogenic activity they could potentially be used to assess the efficacy of such drugs. Methods: An observational prospective multicenter study was designed. Patients with confirmed CCRCC on first line treatment (any drug) who have not progressed after 3 months on therapy were considered eligible. CECs (CD146+, CD 105+,CD 45- DAPI + cells assessed by the Cell Search system), were determined every 6 weeks for 15 months or radiological tumor progression. External monitoring of clinical data was performed. Results: 75 patients (29% female, 71% male) were included between June 2011 and January 2013 from 11 Spanish institutions. Median age was 62 years (range 37-81). Distribution of patients according to MSKCC risk cathegories was: good 32%, intermediate 66% and poor 1.5%. 90% of patients have received sunitinib, 6% pazopanib, 1% temsirolimus, and was not available in 3%. With a median follow-up of 7 months (range 0-11.8) 13 patients have progressed and median progression free survival (PFS) has not been reached. At baseline median CECs count was 47 cells/4 ml (range 4-485). A trend towards worse PFS has been identified in patients with basal CEC levels below the median (p= 0.063 Breslow test). When baseline CEC counts were compared to counts at tumor progression no significant difference was found. Patient and/or tumor characteristics (sex, MSKCC prognostic cathegory, number of metastatic sites, and prior response to therapy) did not seem to influence CECs levels at baseline. Conclusions: CEC counts remain estable in CCRCC patients treated with antiangiogenic inhibitors whohad not progressed to first line therapy. Low CEC counts seem to identify a population with shorter response to therapy. Thus, CEC could be a reliable pharmacodynamic marker able to assess the antiangiogenic activity of a drug. Long-term follow-up results will be presented.

Expression of Opa interacting protein 5 (OIP5) is associated with tumor stage and prognosis of clear cell renal cell carcinoma

Opa interacting protein 5 (OIP5), overexpressed in some types of human cancers, has been reported to be associated with the carcinogenesis of human cancer. However, the biological function and clinical significance of OIP5 in human Clear Cell Renal Cell Carcinoma (CCRCC) remains unknown. In the present study, we found the expression of OIP5 was markedly upregulated in surgical CCRCC specimens and CCRCC cell lines. Immunohistochemical analysis revealed that paraffin-embedded archival CCRCC specimens exhibited higher levels of OIP5 expression than normal renal tissues. Further statistical analysis suggested the upregulation of OIP5 was positively correlated with the Fuhrman grade (P=0.02), T classification (P=0.015), N classification (P=0.018) and clinical stage (P=0.035). Also, patients with high OIP5 expression dramatically exhibited shorter survival time (P=0.001). In addition, the OIP5 expression was an independent prognostic marker of overall survival of CCRCC patients in a multivariate analysis (P=0.008). Experimentally, we demonstrated that silencing OIP5 in CCRCC cell lines by specific siRNA clearly inhibited cell growth. In conclusion, our findings suggested that OIP5 could be a valuable marker of CCRCC progression and prognosis, and a promising therapeutic target for CCRCC.

466 EXPRESSION LEVEL OF GLI2 IN RADICAL NEPHRECTOMY SPECIMENS AS A PROGNOSTIC PREDICTOR IN PATINETS WITH METASTATIC RENAL CLEAR CELL CARCINOMA TREATED WITH SUNITINIB

You have accessJournal of UrologyKidney Cancer: Basic Research (III)1 Apr 2013466 EXPRESSION LEVEL OF GLI2 IN RADICAL NEPHRECTOMY SPECIMENS AS A PROGNOSTIC PREDICTOR IN PATINETS WITH METASTATIC RENAL CLEAR CELL CARCINOMA TREATED WITH SUNITINIB Junya Furukawa, Masafumi kumano, Ken-ichi Harada, Mototsugu Muramaki, Hideaki Miyake, and Masato Fujisawa Junya FurukawaJunya Furukawa Kobe, Japan More articles by this author , Masafumi kumanoMasafumi kumano Kobe, Japan More articles by this author , Ken-ichi HaradaKen-ichi Harada Kobe, Japan More articles by this author , Mototsugu MuramakiMototsugu Muramaki Kobe, Japan More articles by this author , Hideaki MiyakeHideaki Miyake Kobe, Japan More articles by this author , and Masato FujisawaMasato Fujisawa Kobe, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1857AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Gli transcription factors mediate hedgehog signaling and especially, Gli2 seems to be the major nuclear effector of hedgehog signaling. Gli2 in carcinogenesis have been shown in several human cancers. The objective of this study is to investigate the expression levels of Gli2 in radical nephrectomy specimens from patients with metastatic renal clear cell carcinoma (RCC) treated with sunitinib in order to identify factors predicting susceptibility to this agent. METHODS This study included a total of 40 consecutive patients undergoing radical nephrectomy, who were diagnosed as having metastatic RCC and subsequently treated with sunitinib. Gli1, Gli2 and major molecular targets of sunitinib such as VEGFR-1, VEGFR-2, PDGF-alpha and PDGF-beta expression level in primary RCC specimens were assessed by immunohistochemical staining. RESULTS The expression level of VEGFR-1, VEGFR-2, and Gli2, Memorial Sloan-Kettering Cancer Center risk classification, pretreatment serum calcium and c-reactive protein level were significantly associated with the progression-free survival (PFS) on univariate analysis. Of these significant factors, only Gli2 expression appeared to be independently related to PFS on multivariate analysis. In fact, PFS in patients with strong expression of Gli2 was significantly poor compared with that in those with weak expression of Gli2. CONCLUSIONS These findings suggest that it would be useful to consider expression levels of potential molecular marker, Gli2, as well as conventional clinical parameters to select metastatic RCC patients likely to benefit from treatment with sunitinib. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e191-e192 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Junya Furukawa Kobe, Japan More articles by this author Masafumi kumano Kobe, Japan More articles by this author Ken-ichi Harada Kobe, Japan More articles by this author Mototsugu Muramaki Kobe, Japan More articles by this author Hideaki Miyake Kobe, Japan More articles by this author Masato Fujisawa Kobe, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Onconeuronal antigen Cdr2 correlates with HIF prolyl-4-hydroxylase PHD1 and worse prognosis in renal cell carcinoma

Neoplastic expression of the onconeuronal cerebellar degeneration-related antigen Cdr2 in ovary and breast tumors is associated with paraneoplastic cerebellar degeneration (PCD). Cdr2 protein expression is normally restricted to neurons, but aberrant Cdr2 expression has mainly been described for breast and ovarian tumors. Previously, we found strong Cdr2 protein expression in the papillary subtype of renal cell carcinoma (pRCC) and showed that Cdr2 interacts with the hypoxia-inducible factor (HIF) prolyl-4-hydroxylase PHD1. High Cdr2 protein levels are associated with decreased HIF-dependent gene expression in cells as well as in clinical pRCC samples, providing a possible explanation why pRCCs are the most hypovascular renal tumors. Here, we demonstrate that strong Cdr2 protein expression in clinical samples from pRCC patients correlates with elevated PHD1 protein levels, suggesting that increased PHD1 activity attenuates HIF-dependent gene expression. Interestingly, survival analysis revealed a significant correlation between high levels of Cdr2 expression and worse patient outcome in clear cell (cc) RCC patients. These findings provide evidence that Cdr2 might represent an important tumor antigen in kidney cancer and possibly in other cancer types as well. In contrast to ovary and breast tumor patients who develop PCD, no Cdr2 auto-antibodies were detected in the serum of pRCC patients, which is in line with the fact that pRCC patients have not been reported to display paraneoplastic neurodegenerative syndromes. This suggests that, despite a shared target antigen, tumor immunity and autoimmunity only partially overlap, and also highlights to which extent immuno-surveillance against cancer can be clinically silent.

Prospective assessment of circulating endothelial cells (CECs) as early markers of clear cell renal cell carcinoma (CCRCC) progression in first-line setting: The Circles study (SOGUG 2011-01).

436 Background: Angiogenesis inhibitors have become a cornerstone in the management of clear cell renal cell carcinoma (CCRCC). Since circulating endothelial cells (CECs) counts have been proposed as surrogate biomarkers of angiogenesis, they could potentially be used to assess the activity of such drugs. Methods: An observational prospective study is being performed in 11 institutions members of the SOGUG group. Patients with confirmed CCRCC on first-line treatment who have not progressed after 3 months of therapy are considered eligible. CECs (CD 105+,CD 45-, DAPI + cells assessed by the Cell Search system), are determined every 6 weeks for 15 months or radiological tumor progression. Results: Up to 64 of the 75 scheduled patients have already been recruited. Mean age was 64 years, 73% were men and 27% women. Distribution upon MSKCC risk cathegories was: good 30%, intermediate 58%, poor 3% and not available (N/A) 9%. 57 (90%) patients received sunitinib, 3 (5%) pazopanib, 1 (2%) temsirolimus and was N/A in 3 (5%). The CECs counts were determined in 60 patients. At baseline median was 47 cells/4 ml (range 4-480). When comparing patients who experienced tumor progression while on study (11 cases) with patients who did not (28 CECs/4 ml vs. 73 CECs/4ml respectively), a significant difference was found (p = 0.002, t-student). Several exploratory analysis regarding concomitant conditions and patients and tumor characteristics showed that cases with heavily treated hypertension (8 in 60 patients) had lower baseline CECs counts, though without statistical significance (p = 0.068, t-student). Conclusions: Our data point to a different behaviour of CECs counts among CCRCC patients tretated with anitangiogenic drugs that could lead to identify specific subpopulations. Mature results will be presented at the meeting.

Outcomes of patients with metastatic renal cell cancer treated with sunitinib in clinical practice at a reference cancer centre in Manchester, United Kingdom.

477 Background: The development of anti-angiogenic therapy produced a change in the treatment of metastatic renal cancer (mRCC). There are now a range of drugs available with sunitinib being the most widely used first-line anti-angiogenic therapy. In the United Kingdom, until the advent of pazopanib it was the only such drug routinely funded by the NHS. The aim of this study was to audit the clinical outcomes of patients on routine treatment with sunitinib, to compare them with those obtained on trials and to analyze different subsets of patients. Methods: A database of mRCC patients treated at The Christie was set up to record clinical outcomes. Long-term follow-up data is available. Here we present a detailed analysis of 395 patients treated with sunitinib as a first-line anti-angiogenic therapy from 2005 to 2012. 397 patients treated out of a clinical trial. The outcomes were analysed according to various prognostic features. Results: The median OS of all patients audited was 18 months (m) with a PFS of 10.5m. This included clear cell RCC (n=305) and non-clear cell RCC (n=52). OS of clear cell RCC patients who received treatment second-line after cytokine therapy failure was 20.5m, longer than those treated first line 18.6m. This may be because we offer High-Dose IL2 to selected patients and these patients have a longer OS (24m) measured from the start of sunitinib. Baseline performance status was a predictor of outcome with OS being 23.5m for WHO PS 0/1 and 5.9m for WHO PS 2/3. Elderly age was not a predictor of poor outcome as the OS of patients &lt;60, 60-70, and &gt;70 was 15, 23, and 22m respectively. Time from nephrectomy to treatment with sunitinib had an influence on outcome with OS being 15, 24, and 48m for those &lt;1, 1-5, and &gt;5 years since nephrectomy. Further detailed analysis will be presented. Conclusions: Overall, the outcomes of patients treated in routine clinical practice were very similar to comparable groups treated on trials. Interestingly, the outcome post cytokine patients were particularly good but this may reflect particularly, careful choice of patients who receive cytokines since 2008.