Hendrik Eggers

Validation of CRP as prognostic marker for renal cell carcinoma in a large series of patients

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.

Does Obesity Influence the Prognosis of Metastatic Renal Cell Carcinoma in Patients Treated with Vascular Endothelial Growth Factor–Targeted Therapy?

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 long-term 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 according to the European average for men (1.98 m(2)) and women (1.74 m(2)). VFA and SFA were dichotomized using the median of the observed distribution as the cutoff. The primary endpoints of this study were time to progression and overall survival time. RESULTS AND LIMITATIONS The whole population had median progression-free and overall survival times of 8.3 months and 20.5 months, respectively. In contrast to BMI and BSA, higher than average VFA and SFA levels were significant predictors of longer progression-free and overall survival times. The major limitations of this study are its retrospective design and its heterogeneous patient population. CONCLUSION This is the first study to identify high VFA and SFA levels as positive predictive biomarkers for patients who receive first-line antiangiogenic agents for metastatic RCC.

Caveolin 1 protein expression in renal cell carcinoma predicts survival

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.

GATA5 CpG island methylation in renal cell cancer: a potential biomarker for metastasis and disease progression.

Whats known on the subject? and What does the study add?

Prognostic and diagnostic relevance of hypermethylated in cancer 1 (HIC1) CpG island methylation in renal cell carcinoma.

The tumour suppressor gene hypermethylated in cancer 1 (HIC1) is a transcriptional repressor, which functionally cooperates with p53. Loss of HIC1 function is associated with the development of various tumor entities. The aim of this study was to elucidate the relevance of CpG island (CGI) methylation of HIC1 in renal cell carcinoma (RCC). DNA methylation of HIC1 was analysed in a total of 98 tumor and 70 tumor adjacent normal specimens. After conducting bisulfite conversion, relative methylation levels were quantitated using pyrosequencing. Relative methylation values were compared for paired tumor and normal specimen and for correlation with clinico-pathologic and follow-up data of patients. Tumor-specific hypermethylation could not be detected for the subregion of the HIC1 - CGI analyzed in this study. Comparing the level of methylation in tumors to clinicopathological data solely, patients without lymph node metastases demonstrated a higher level of methylation compared to patients with lymph node metastases (p=0.030). Patients recurrence-free survival (p=0.0074) both in univariate as well as bivariate cox regression analysis. This study identifies HIC1 hypermethylation in tumors as an independent predictor of reduced recurrence-free survival, which fits into our current understanding of hypermethylated HIC1 being a marker for poor prognosis. Therefore, HIC1 - CGI methylation could be a candidate marker to improve individualized therapy and risk stratification.

Caveolin 1 mRNA is overexpressed in malignant renal tissue and might serve as a novel diagnostic marker for renal cancer.

BACKGROUND & AIM Caveolae 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 expression of caveolin (CAV)1 in the development of renal cell cancer (RCC) and to determine a possible prognostic relevance for optimal clinical management. MATERIAL & METHODS 109 RCC and 81 corresponding normal tissue specimens from the same kidney were collected from patients undergoing surgery for renal tumors and subjected to total RNA extraction. Quantification of CAV1 mRNA expression was performed using real-time reverse transcription PCR with three endogenous controls for renal proximal tubular epithelial cells and the ΔΔCt method for calculation of relative quantities. Expression levels were correlated to clinical variables. RESULTS Tissue-specific mean CAV1 expression was significantly increased in RCC compared with normal renal tissue (p = 0.0003; paired Wilcoxon rank sum test). CAV1 expression was increased 1.9-fold in clear cell RCC compared with papillary RCC (p = 1.48 × 10(-7); unpaired Wilcoxon rank sum test). Patients with advanced disease had higher CAV1 expression when compared with organ-confined disease (p = 0.019; unpaired Wilcoxon rank sum test). Moreover, mean tissue-specific CAV1 expression was increased in patients with distant metastasis at the time of diagnosis compared with patients without metastasis (p = 0.0058; unpaired Wilcoxon rank sum test). CONCLUSION To our knowledge, this is the first study to show that CAV1 mRNA expression, using quantitative real-time PCR, is significantly higher in RCC compared with normal renal tissue and increases with tumor stage. CAV1 mRNA expression might serve as a candidate biomarker for objective prognosis indicating RCC aggressiveness. Our data encourage further investigations to determine the role of CAV1 in RCC.

Predictive Factors for Second-Line Therapy in Metastatic Renal Cell Carcinoma: A Retrospective Analysis

Currently, about 50% of patients with metastatic renal cell carcinoma (mRCC) receive a second-line therapy. Therefore, the choice at each subsequent treatment line remains an important issue. In this retrospective study, we sought to identify pretreatment clinical parameters that could predict the likelihood of a patient receiving a second-line therapy. One hundred and sixty-one mRCC patients who received targeted therapy were evaluated. Descriptive statistics, Kaplan–Meier overall survival (OS), Cox regression, and binary logistic regression models were used for data analysis. Second-line therapy was given to 105 patients (65%). Patients with grade 1 tumor received second-line therapy more frequently than those with grade 2/3 tumors (P = 0.03). Only tumor grade was significantly different between patients receiving, or not receiving, second-line treatment. Median OS was significantly superior in patients receiving second-line therapy (32 versus 14 months; P = 0.007; hazard ratio [HR], 1.75; P = 0.008), patients with grade 1 tumors (130 versus 29 months in G2/3 tumors; HR, 3.85; P = 0.009), and in patients without early tumor progression (41 versus 11 months; HR, 5.04; 95% confidence interval [CI], 3.06–8.31; P < 0.001). In binary logistic regression, we identified early progression to be significantly associated with a higher probability of not receiving a second-line therapy (HR, 2.50; 95% CI, 1.01–6.21; P = 0.048). This study hypothesizes that pretreatment grade and early progression are predictive parameters for the selection of patients for second-line therapy.

Oxaliplatin pharmacokinetics on hemodialysis in a patient with diffuse large B cell lymphoma

Dear Editor, Oxaliplatin is a widely used chemotherapeutic agent in diverse anticancer regimens [1]. As oxaliplatin is eliminated from the body mainly by the kidneys and its clearance strongly correlates with glomerular filtration rate (GFR), patients with renal insufficiency or end stage renal disease (ESRD) are especially prone to accumulation and drugrelated toxicity [2]. However, the role of extra-corporal renal replacement therapy in oxaliplatin clearance is not clear. So far, pharmacokinetic data is limited to single hemodialysis (HD) treatment cycles and their respective effect on plasma total and plasma free platinum levels [3, 4]. However, there is no data available on the absolute clearance of oxaliplatin from the body by HD, and HD dose as a parameter of oxaliplatin clearance has not been studied so far. Furthermore, long-term effects of HD on oxaliplatin elimination and necessary dose adjustments are lacking. We analyzed oxaliplatin clearances in a 61-year-old anuric HD patient who was referred to our tertiary care hospital in April 2014 with cervical, supraclavicular, and retroperitoneal lymphadenopathy. Histology revealed follicular lymphoma grade 3A, stage IIIA. Due to additional cardiovascular comorbidity, the patient received six courses of rituximab and bendamustine, which led to partial remission as best response. Despite rituximab maintenance, clinical relapse with recurrence in the known localisations plus splenic infiltration and histopathological transformation to diffuse large B cell lymphoma occurred in September 2015. Second-line treatment with rituximab, gemcitabine, and oxaliplatin was chosen. Because of ESRD secondary to polycystic kidney disease requiring regular home HD since 2002 and lack of evidence for long-term oxaliplatin clearance, dosage of oxaliplatin was reduced to 50 mg/m (50 % reduction, Fig. 1b). Sample collection comprised spent dialysate, ultrafiltrate, and serum. Results (Fig. 1a) show a Cmax of total predialyzer serum platinum (1093 μg/L) within the therapeutic range (500–5000 μg/L) before start of HD and a rapid exponential decline during 5 h of HD, which is in line with data from the literature [4]. Preand post-dialyzer platinum concentrations converged after 4–5 h of dialysis with ΔAUC (AUCpre−AUCpost) representing platinum removal on HD. Concentrations after the first and before the second HD did not change significantly, indicating that no additional elimination occurred between day 1 and 2 after oxaliplatin application. Although calculated dialyzer clearance of oxaliplatin (CLdial) was relatively low (28.43 mL/ min), daily dialysis over five consecutive days clearly showed a significant reduction of long-term platinum serum concentration (Fig. 1b). Interestingly, total amounts of platinum in ultrafiltrate (153 μg) and spent dialysate (4815 μg) were unexpectedly low, which may be * Michael S. Balzer balzer.michael@mh-hannover.de

Do body mass index (BMI) and body surface area (BSA) influence the outcome of metastatic renal cell carcinoma

e15162 Background: Obesity increases the risk of developing renal cell carcinoma (RCC); however, it remains unclear whether obesity is associated with RCC aggressiveness and survival. A recently published study even proposed Obesity as a independent (positive) prognostic factor for localized renal cell carcinoma (RCC; Waalkes et al.). Additionally at the ASCO annual meeting 2010 Choueiri et al. presented data indicating that obesity might be associated with a favorable prognosis in patients with metastasized RCC (mRCC). METHODS On basis of two study groups we evaluated if BMI or a BSA above average (>1.98 m2 for male, >1.74 m2 for women in the EU) is of prognostic relevance for patients with mRCC. RESULTS Group A (n=293): Patients with primary mRCC treated between 1990 and 2005 with palliative nephrectomy in the cytokine era. Group B (n=107): mostly mRCC-patients treated with nephrectomy and 1st line therapy with TKI from 2006 to 2009. Mean Age, BMI and BSA in groups A (respectively B) was 61.9 years (61.0 years), 25.5 kg/m2 (25.7 kg/m2) and 1.93 m2 (1.97 m2). 28.4% (33.6%) were women and 9.7% (15%) were classified as non-clear cell (ncRCC) malignancies. In Kaplan Meier Analysis there was no evidence for group A and B that BMI (p=0,89 / 0,95) or BSA (p=0,86 / 0,7; Mantel-Cox) had any influence on prognosis of patients with mRCC. In multivariate analysis BMI and BSA also failed to prove as independent prognostic factors. Solely the subgoup of ncRCC in group A was related to a significantly worse prognosis. CONCLUSIONS The evaluation of two large study populations treated in the era of cytokines and TKIs was not able to show a prognostic relevance of obesity in mRCC.