Sandra Steffens

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.

Incidence and long-term prognosis of papillary compared to clear cell renal cell carcinoma – A multicentre study

AIM OF THE STUDY Papillary renal cell carcinoma (pRCC) is the second most common subtype of RCC after the conventional clear cell type (cRCC). However, its characteristics and prognosis have been less intensively investigated. The aim of our study was to examine the tumour characteristics and long-term prognosis of pRCC compared to clear cell RCC (cRCC). METHODS In total, 4941 evaluable patients were subjected to either radical nephrectomy or nephron-sparing surgery for pRCC or cRCC at five centres in Germany (University Hospitals of Hannover, Homburg/Saar, Mainz, Ulm and Marburg) between 1990 and 2010. RESULTS pRCC (n=565) and cRCC (n=4376) patients were comparable with regard to mean age, clinical symptoms, tumour differentiation and regional lymph node metastases. Patients with pRCC had a significantly higher rate of organ confined tumours (pT1-2, N/M0; 74.9% versus 62.9%), less synchronic visceral metastases (9.6% versus 15.2%), and a higher 5-year CSS rate than those with cRCC (85.1% versus 76.9%). Multivariate analysis identified the papillary subtype as a significant positive prognostic factor in localised (HR, 0.45) but as a negative prognostic factor in metastatic tumour stages (HR, 1.37). CONCLUSION pRCC can apparently be differentiated into two subgroups: an organ-confined/localised subgroup with a significantly better prognosis and an advanced/metastatic subgroup with a worse prognosis compared to cRCC.

Progression free survival of first line vascular endothelial growth factor-targeted therapy is an important prognostic parameter in patients with metastatic renal cell carcinoma

PURPOSE Intrinsic resistance in metastatic renal cell carcinoma (mRCC) was recently associated with poor overall survival (OS), suggesting that VEGF inhibitor sensitivity may represent a valuable prognostic marker. We explored the duration of progression free survival (PFS) in first-line treatment and other variables as prognostic markers in mRCC. METHODS Medical records from 119 mRCC patients receiving first line treatment with tyrosine kinase inhibitors (TKI) were retrieved retrospectively. Kaplan-Meier and log-rank analyses were employed on PFS and OS and multivariate Cox proportional hazard model analysed clinical parameters for their prognostic relevance. RESULTS The median PFS of first line treatment was 8.4 months (95% confidence interval 5.8-11) associated with a median OS of 28.2 months (95% CI 20.9-35.4). Second line therapy with another TKI or mTOR-inhibitor was applied to 81 patients (68%). PFS of any second line therapy was 5.1 and 3.7 months in first line treatment responders and non-responders (p = 0.3), respectively. Univariate analyses revealed bone metastases, prior cytokine treatment, Memorial Sloan Kettering cancer centre (MSKCC) score, objective response rate, Eastern Cooperative Oncology Group (ECOG) performance status, first line PFS with 6 months taken as cut-off parameter and second line treatment as prognostic variables. Multivariate analyses proved first line PFS above 6 months (95% CI 0.154-0.641; HR 0.314), second line treatment (95% CI 0.162-0.657; HR 0.326), MSKCC score (95% CI 1.07-3.392; HR 1.905) and objective response rate (95% CI 0.358-0.989; HR 0.595) to be independent prognostic markers. CONCLUSIONS The duration of first line PFS is an independent prognostic variable but not predictive for subsequent therapy.

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.

Preoperative serum C- reactive protein: a prognostic marker in patients with upper urinary tract urothelial carcinoma

BackgroundTo analyse the prognostic significance of preoperative C-reactive protein (CRP) serum level in patients with upper urinary tract urothelial carcinoma (UUT-UC).MethodsWe evaluated 158 UUT-UC patients who had undergone surgery in the University Hospital of Hannover (MHH). 143 (89.4%) suffered from cancer in the renal pelvis, 13 (8.1%) patients presented with tumour located in the ureter. A preoperative CRP value was available for 115 patients. The mean (median) follow-up for these patients was 28.3 (15.1) months.ResultsThe median (mean) CRP value of all evaluable patients was 10.0 (40.7) mg/l. The CRP-level, stratified into two subgroups (CRP ≤5 vs. >5 mg/l), correlated significantly with muscle invasive tumour stage (36.4 vs. 78.9%; p<0.001), the risk of presenting nodal disease (4.5 vs. 26.8%; p=0.002) and distant metastasis (2.3 vs. 16.9%; p<0.016). The Kaplan-Meier 5-year cancer specific survival (CSS) rates were 54.2 and 26.4% for patients with preoperative CRP levels ≤ and >5 mg/l, respectively (p<0.006). Next to age and the presence of metastasis, multivariate analysis also identified CRP as a continuous variable as an independent prognosticator for CSS.ConclusionsA high preoperative serum CRP level is associated with locally advanced and metastatic disease in patients with UUT-UC. Its routine use could allow better risk stratification and risk-adjusted follow-up of UUT-UC patients.

High CRP values predict poor survival in patients with penile cancer

BackgroundHigh levels of circulating C-reactive protein (CRP) have recently been linked to poor clinical outcome in various malignancies. The aim of this study was to evaluate the prognostic significance of the preoperative serum CRP level in patients with squamous cell carcinoma (SCC) of the penis.MethodsThis retrospective analysis included 79 penile cancer patients with information about their serum CRP value prior to surgery who underwent either radical or partial penectomy at two German high-volume centers (Ulm University Medical Center and Hannover Medical School) between 1990 and 2010. They had a median (mean) follow-up of 23 (32) months.ResultsA significantly elevated CRP level (>15 vs. ≤ 15 mg/l) was found more often in patients with an advanced tumor stage (≥pT2) (38.9 vs. 11.6%, p=0.007) and in those with nodal disease at diagnosis (50.0 vs. 14.6%, p=0.007). However, high CRP levels were not associated with tumor differentiation (p=0.53). The Kaplan-Meier 5-year cancer-specific survival (CSS) rate was 38.9% for patients with preoperative CRP levels above 15 mg/l and 84.3% for those with lower levels (p=0.001). Applying multivariate analysis and focusing on the subgroup of patients without metastasis at the time of penile surgery, both advanced local tumor stage (≥pT2; HR 8.8, p=0.041) and an elevated CRP value (>15 mg/l; HR 3.3, p=0.043) were identified as independent predictors of poor clinical outcome in patients with penile cancer.ConclusionsA high preoperative serum CRP level was associated with poor survival in patients with penile cancer. If larger patient populations confirm its prognostic value, its routine use could enable better risk stratification and risk-adjusted follow-up of patients with SCC of the penis.

Neoadjuvant therapy of renal cell carcinoma: a novel treatment option in the era of targeted therapy?

The study was carried out to evaluate the effectiveness, toxicity and optimal duration of neoadjuvant therapy for patients with organ‐confined or locally advanced renal cell carcinoma in the era of targeted agents. A literature review was carried out using Medline/Pubmed articles, as well as congress reports from the last five American Society of Clinical Oncology, American Urological Association and European Association of Urology Annual Meetings. Neoadjuvant targeted therapy is feasible and shows toxicity similar to that seen in a palliative setting. Most studies recommend an application for 2–4 months. The current data situation is best for sunitinib. Surgery can apparently be carried out the day right after discontinuing the drug. However, even sunitinib leads to only a mean 10% decrease in primary tumor size, and one‐quarter to one‐fifth of all patients show local tumor progression during treatment. Few patients (approximately 12%) with a vena cava tumor thrombus achieve a significant decrease in its level under neoadjuvant therapy; here too, progression is observed in a significant number of cases. Even the new targeted agents show limited effectiveness in achieving relevant remissions of the primary tumor. Furthermore, tumor progression is seen in a significant percentage of patients during neoadjuvant therapy. Thus, even today in the era of targeted agents, a neoadjuvant approach should only be made in patients with localized or locally advanced renal cell carcinoma, which primarily seem to be absolutely inaccessible by (partial) nephrectomy.

Small renal cell carcinomas - How dangerous are they really? Results of a large multicenter study

AIM OF THE STUDY Modern diagnostic ultrasound and cross-sectional imaging has enabled the detection of increasing numbers of renal tumours. The aim of this study was to investigate the tumour- and patient-specific characteristics and prognosis of small renal cell carcinomas (RCCs) after surgical resection. METHODS The study included 2197 patients who underwent surgical resection of histologically confirmed RCC ⩽ 4 cm between 1990 and 2011. Median (mean) follow-up was 56.2 (65.5) months. RESULTS At the time of surgery, tumours were staged as pT ⩾ 3a in 175 (8.0%) cases, 134 (6.2%) were poorly differentiated and 75 (3.5%) were metastasised. The larger the tumour size, the higher was the risk of presenting with stage pT ⩾ 3a (p<0.001), poor tumour differentiation (p = 0.004), microscopic vascular involvement (p = 0.001) and collecting system invasion (p = 0.03). The 5-year cancer-specific survival (CSS) rate was 93.8% for stage pT1a versus 79.4% for stage pT ⩾ 3a (p<0.001), and it was 93.7% for G1-2 versus 76.8% for G3-4 differentiation (p<0.001). Multivariate analysis identified age in years (hazard ratio (HR) 1.04, p<0.001), metastatic disease (HR 12.5, p < 0.001), tumour differentiation (HR 2.8, p<0.001) and non-clear cell histology (HR 0.51, p = 0.02) as independent prognosticators for CSS in patients with small RCC. Interestingly, the 5-year cancer-specific mortality rate for pT1a N/M0 patients was 5.8%. CONCLUSIONS This large multicenter study has clearly shown that, though most small RCC have a low pathological stage and a good prognosis, there is also a small but significant subgroup of these tumours that are already locally advanced or poorly differentiated.

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.