Background. Obesity increases the risk for renal cell carcinoma (RCC). However, it has only recently been identified as an independent positive prognostic factor for localized RCC.Objective. To determine whether obesity influences longterm prognosis in metastatic RCC patients receiving vascular endothelial growth factor-targeted therapy.Design, Setting, and Participants. In 116 patients with metastatic RCC who received antiangiogenic agents (sunitinib, sorafenib, axitinib, bevacizumab) in 2005-2010, we evaluated whether body mass index (BMI), a body surface area (BSA) above the European average, the visceral fat area (VFA), or s.c. fat area (SFA) were of predictive relevance.Measurements. BMI was categorized based on current World Health Organization definitions. BSA was stratified

BackgroundTo evaluate the prognostic significance of the pre-operative C-reactive protein (CRP) serum level in patients with renal cell cancer (RCC).MethodsWe evaluated 1,161 RCC patients with complete patient and tumour specific characteristics as well as information about their pre-operative CRP-level, who had undergone either radical nephrectomy or nephron-sparing surgery at two German high-volume centres (University Hospitals of Hannover and Ulm). The mean follow-up was 54 months.ResultsThe CRP-level, stratified to three subgroups (CRP ≤ 4, 4–10, and >10 mg/l), correlated significantly with tumour stage (p < 0.001), the risk of presenting nodal disease (2.1, 3.1, and 16.4%) and distant metastasis (2.9, 8.6, and 30.0%; p < 0.001). The Kaplan-Meier 5-year cancer specific survival (CSS) rates were 89.4, 77.9, and 49.5%, respectively (p < 0.001). Multivariate analysis identified CRP as an independent prognosticator for CSS as well as overall survival (p < 0.001). Patients with a CRP of 4–10 and >10 mg/l had a 1.67 and 2.48 fold higher risk of dying due to their RCC compared to those with a pre-operative CRP ≤4 mg/l, respectively.ConclusionsA high preoperative serum CRP level is an independent predictor of poor survival in patients with RCC. Its routine use could allow better risk stratification and risk-adjusted follow-up of RCC patients.

Until today, there is no reliable prognostic or predictive parameter for the prognosis of patients with metastatic urothelial cancer of the bladder prior to chemotherapy. Recently, serum C-reactive protein (CRP) level has been shown to be associated with survival of patients with various malignancies including localized and metastatic renal cell carcinoma, upper urinary tract as well as penile cancer. The aim of this study was to evaluate the prognostic impact of the pretreatment CRP serum level in patients with metastatic urothelial cancer of the bladder. We retrospectively evaluated 34 patients with metastatic urothelial cancer of the bladder and information about the CRP level prior to chemotherapy. The CRP level was correlated with patient- and tumor-specific characteristics. Kaplan-Meier and log-rank analyses were employed to calculate progression-free (PFS) and overall survival (OS). Receiver operating characteristics (ROC) analysis was used to determine an optimal prognostic CRP cutoff value to predict cancer-specific death. The median PFS to first-line chemotherapy and the OS for the whole cohort were 3.3 and 24.3 months, respectively. Serum CRP in mg/l was significantly associated with patients' survival (HR 1.02, p < 0.001, univariate Cox-regression). ROC analysis identified a CRP value of 80 mg/l to be the optimal cutoff. The median PFS was 4.5 and 3.0 months (p = 0.08; Mann-Whitney test), and the calculated 1-year OS was 82.6 and 22.2 % for patients with a CRP <80 and ≥80 mg/l, respectively (log-rank, p < 0.001). In contrast, neither T-stage, tumor grade, sex, age nor the body mass index was related to the CRP level or associated with overall survival. This is the first analysis revealing that the CRP value prior to systemic treatment might be of prognostic significance and could enable better risk stratification for patients with metastatic urothelial cancer of the bladder.

Abstract. Fibronectin 1 (FN1) is a glycoprotein that is involved in cell adhesion and migration processes including embryogenesis, wound healing, blood coagulation, host defenses and metastasis. The aim of this study was to elucidate the FN1 protein expression in renal cell carcinoma (RCC) and to determine its potential prognostic relevance. A total of 270 clear cell RCC tissue specimens were collected from patients undergoing surgery for renal tumors. Biomarker expression was determined by immunohistochemistry and correlated with clinical variables. Survival analysis was carried out for 153 patients with complete follow-up data and pathologically proven clear cell carcinoma of the kidney. The follow-up group had a mean follow-up period of 83.8 months (IQR 26.2-136.2 months). The calculated median 5-year overall and tumor-specific survival rate of all 153 evaluable patients was 66.6 and 71.0%, respectively. A higher diseaserelated mortality rate was observed among patients with cytoplasmic FN1 expression (41.3 vs. 24.7%, p=0.039, Fisher's exact test). No significant correlation was found between FN1 staining and patient characteristics such as age, gender, tumor differentiation and visceral metastasis. However, there was a trend for FN1 expression and correlation with tumor stage and lymph node metastasis (p=0.085 and p=0.203; respectively). The Kaplan-Meier analysis revealed significant differences in the 5-year tumor-specific survival for patients with and without cytoplasmic FN1 expression (64.8 vs. 77.7%; p=0.035, log-rank test). However, results of the multivariate Cox regression analysis showed that FN1 expression was not an independent marker of either overall or tumor-specific survival. In conclusion, FN1 protein expression in RCC is associated with a higher disease-related mortality rate, indicating a possible role in RCC progression. Therefore, our data on FN1 encourage further investigations to determine the role of FN1 in RCC.

BackgroundCaveolae play a significant role in disease phenotypes such as cancer, diabetes, bladder dysfunction, and muscular dystrophy. The aim of this study was to elucidate the caveolin-1 (CAV1) protein expression in renal cell cancer (RCC) and to determine its potential prognostic relevance.Methods289 clear cell RCC tissue specimens were collected from patients undergoing surgery for renal tumors. Both cytoplasmic and membranous CAV1 expression were determined by immunohistochemistry and correlated with clinical variables. Survival analysis was carried out for 169 evaluable patients with a median follow up of 80.5 months (interquartile range (IQR), 24.5 - 131.7 months).ResultsA high CAV1 expression in the tumor cell cytoplasm was significantly associated with male sex (p = 0.04), a positive nodal status (p = 0.04), and poor tumor differentiation (p = 0.04). In contrast, a higher than average (i.e. > median) CAV1 expression in tumor cell membranes was only linked to male sex (p = 0.03). Kaplan-Meier analysis disclosed significant differences in 5-year overall (51.4 vs. 75.2%, p = 0.001) and tumor specific survival (55.3 vs. 80.1%, p = 0.001) for patients with higher and lower than average cytoplasmic CAV1 expression levels, respectively. Applying multivariable Cox regression analysis a high CAV1 protein expression level in the tumor cell cytoplasm could be identified as an independent poor prognostic marker of both overall (p = 0.02) and tumor specific survival (p = 0.03) in clear cell RCC patients.ConclusionOver expression of caveolin-1 in the tumour cell cytoplasm predicts a poor prognosis of patients with clear cell RCC. CAV1 is likely to be a useful prognostic marker and may play an important role in tumour progression. Therefore, our data encourage further investigations to enlighten the role of CAV1 and its function as diagnostic and prognostic marker in serum and/or urine of RCC patients.

What's known on the subject? and What does the study add? GATA5 CpG island (CGI) methylation and transcriptional inactivation is involved in colorectal and gastric cancer. Whether DNA methylation of GATA5 affects clinical pathology is still unclear. In the present study, we analysed, for the first time, CGI methylation in RCC and its association with clinicopathological parameters and progression‐free survival of patients. We show for the first time GATA5 CGI hypermethylation in RCC. Moreover, we found out that increased methylation is statistically associated with status of metastasis, progressive disease and shortened progression‐free survival. The present study underline the necessity for further functional investigations as well as prospective survival analyses to clarify whether GATA5 promoter methylation can provide independent information for future clinical management of patients with RCC. OBJECTIVE To investigate whether GATA5 CpG island (CGI) methylation occurs in renal cell carcinoma (RCC) and is associated with clinical, histopathological characteristics or progression‐free survival of patients. PATIENTS AND METHODS Methylation was quantified in 117 RCC samples and 89 paired adjacent normal tissues using quantitative combined bisulphite restriction analysis (COBRA). COBRA was evaluated in advance by pyrosequencing analyses of control RCC cell lines (coefficient of correlation, R= 0.95). Statistical analyses were carried out using the paired t‐test for matched tumour tissue (TU) and adjacent normal tissue (adN) samples, logistic regression for comparisons of independent sample groups and Cox regression for analysis of progression‐free survival. RESULTS In the present study, we found a significant higher mean relative methylation in TU (20.4%) than in adN (7.9%, P < 0.001) in paired samples of all RCCs. Increased GATA5 methylation in tumours was associated with metastasis (P= 0.005) and decreased progression‐free survival (P= 0.005, HR = 4.59) in the clear‐cell RCC (ccRCC) group. CGI methylation in advanced ccRCCs (pT ≥3 and/or N1, M1 or G2–3/G3) exceeds those detected in localized tumours (pT ≤2, N0, M0, G1/G1–2) (27.8% vs 11.0%, P < 0.001). CONCLUSIONS The association of GATA5 hypermethylation with metastasis and progression‐free survival of patients indicates that epigenetic alterations of GATA5 participate in renal cell carcinogenesis. Moreover, GATA5 CGI methylation could serve as a biomarker for tumour progression, although prospective and functional investigations are necessary to clarify whether independent information for future clinical management of patients with RCC can be obtained.

The immunological checkpoints of programmed death 1 and its ligand (PD-L1) are currently in focus as novel therapeutic targets in renal cell carcinoma (RCC). The aim of this study was to evaluate the prognostic association of PD-L1 expression in clear cell (cc) RCC with clinical parameters, tumor aggressiveness and overall survival (OS). Patients who underwent renal surgery due to RCC between 1994 and 2003 were retrospectively evaluated. Tumor specimens were analyzed for PD-L1 expression by immunohistochemistry. One hundred and seventy-seven ccRCC patients were eligible for analysis, in which 140 (79.1 %) were negative and 37 (20.9 %) were positive for PD-L1 expression. PD-L1 positivity was associated with female gender (p = 0.001), lymph node metastasis (p = 0.004), distant metastasis (p = 0.002), higher AJCC stage (p = 0.004), as well as advanced disease (pT3/4 and/or N+ and/or M1) (p < 0.001). Kaplan-Meier analysis revealed a significantly diminished 5- and 10-year overall survival of 46.7 and 28.3 % for PD-L1(+) compared to PD-L1(-) tumors with 66 and 53.4 % (p = 0.005), respectively. Univariate analysis showed a significant negative association of OS with PD-L1 positivity [p = 0.005; HR: 2 (95 % CI 1.2-3.3)], even though PD-L1 positivity only tends to predict independently the OS using multivariate analyses [p = 0.066; HR: 1.6 (95 % CI 0.98-2.7)]. PD-L1 expression in ccRCC is associated with parameters of aggressiveness, as well as with poor OS, even though PD-L1 status was not identified as a significant independent prognostic parameter. However, further studies in larger cohorts are warranted.

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