Factor In Renal Cell Carcinoma Research Articles

Abstract A75: Preexisting kidney disorders and risk of renal cell carcinoma: Results from a population-based case-control study of Caucasians and African Americans

Abstract Background: In the United States, the incidence of renal cell carcinoma (RCC) is higher among African Americans (AA) than among Caucasians. However, few studies have investigated potential risk factors that may contribute to racial disparities in RCC incidence. Established risk factors for RCC include smoking, obesity, and hypertension. Beyond these factors the etiology of RCC remains largely unknown, though previous observations suggest that patients with end-stage renal disease on long-term dialysis may be at increased risk of developing RCC. Methods: We conducted an investigation of RCC risk in relation to pre-existing kidney disorders in a population-based case-control study of AAs and Caucasians in the metropolitan regions of Chicago and Detroit. Personal interviews were conducted to obtain information on history of kidney disorders and other covariates from 1,217 RCC cases (361 AAs and 856 Caucasians) and 1,235 controls (523 AAs and 712 Caucasians). Odds ratios (OR) and 95% confidence intervals (CI) were estimated using sample weighted unconditional logistic regression models adjusted for age, sex, race, level of education, smoking status, body mass index, history of hypertension, family history of cancer, and study center. Analyses stratified by race and time since kidney disease diagnosis were also performed. Results: A statistically significant increased risk of RCC was observed among subjects who had been previously diagnosed with chronic renal failure (OR 4.7, 95% CI 2.2–10.1) or were on dialysis (OR 18.0, 95% CI 3.6–91.1). Stronger associations were observed among subjects who had renal failure or were on dialysis 10 or more years prior to RCC diagnosis. The association between chronic renal failure and RCC was considerably stronger among AAs than among Caucasians (ORs of 8.7 and 2.0, respectively; P-interaction=0.03). Among AAs, history of kidney stones, kidney cysts, and nephrotic syndrome were all associated with an elevated risk of RCC (OR≥2.0), though these findings were not statistically significant. Conclusions: The results of this large population-based study suggest that chronic renal failure and dialysis may be important risk factors for RCC development in both AAs and Caucasians. Our findings of differences in risk estimates by race, to our knowledge the first such report, require replication. Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A75.

Unraveling the Role of Hypoxia-Inducible Factor in Renal Cell Carcinoma: A Biological and Therapeutic Perspective

The genetic control of hypoxia-inducible factor (HIF) has long been associated with the pathogenesis of clear cell renal cell carcinoma. Only recently have the complex genetics and biology of relevant HIF subtypes been unraveled, leading to potential novel strategies for treating this disease.

Population based analysis of survival in patients with renal cell carcinoma and venous tumor thrombus

ObjectivesTo identify prognostic factors for renal cell carcinoma (RCC) with venous tumor thrombus (VTT) and determine the significance of thrombus level on survival. Materials and methodsPatients within the Surveillance, Epidemiology, and End Results (SEER) database with RCC and VTT were identified and included if managed surgically. The Kaplan-Meier method and Cox regression analyses were performed to identify factors associated with disease-specific survival. ResultsA total of 1,875 patients met the inclusion criteria. One-year survival for patients undergoing surgery was 60% for patients with metastases and 90% for those without. Factors associated with worse survival included larger tumor size (HR 1.2, 95% CI 1.0–1.4), medullary, collecting duct, or sarcomatoid histology (HR 2.2, 95% CI 1.5–3.3), Fuhrman grade 3 (HR 2.2, 95% CI 1.5–3.3) or grade 4 (HR 2.9, 95% CI 1.8–4.5) tumors, positive lymph nodes (HR 1.5, 95% CI 1.0–2.0), and metastases (HR 3.5, 95% CI 2.6–4.8). Thrombus level above the diaphragm (T3c) was not significantly associated with worse survival (HR 1.4, 95% CI 0.8–2.5). ConclusionsIn this large, population-based study of patients with RCC and VTT, we identify several disease-specific factors strongly associated with cancer-specific mortality. After controlling for adverse prognostic factors, thrombus level was not associated with worse outcome.

MicroRNAs as Regulators of Signal Transduction in Urological Tumors

MicroRNAs (miRNAs) are short noncoding RNAs that have been shown to play pivotal roles in carcinogenesis. In the past decade, miRNAs have been the focus of much research in oncology, and there are great expectations for their utility as cancer biomarkers and therapeutic targets. In this review we examine how miRNAs can regulate signal transduction pathways in urological tumors. We performed in silico target prediction using TargetScan 5.1 to identify the signal transduction targets of miRNA, and we summarize the experimental evidence detailing miRNA regulation of pathways analyzed herein. miRNAs, which have been shown to be dysregulated in bladder, prostate, and renal cell cancer, are predicted to target key proteins in signal transduction. Because androgen receptor signaling is a major regulator of prostate cancer growth, its regulation by miRNAs has been well described. In addition, members of the phosphatidylinositol 3-kinase/Akt (RAC-alpha serine/threonine-protein kinase) signaling pathway have been shown to be susceptible to miRNA regulation. In contrast, there are very few studies on the impact of miRNA regulation on signaling by VHL (von Hippel-Lindau tumor suppressor) and vascular endothelial growth factor in renal cell carcinoma or by fibroblast growth factor receptor 3 and p53 in bladder cancer. Many miRNAs are predicted to target important signaling pathways in urological tumors and are dysregulated in their respective cancer types; a systematic overview of miRNA regulation of signal transduction in urological tumors is pending. The identification of these regulatory networks might lead to novel targeted cancer therapies. In general, the targeting of miRNAs is a valuable approach to cancer therapy, as has been shown recently for various types of cancer.

Cigarette Smoking Is Associated With Advanced Renal Cell Carcinoma

Cigarette smoking is a recognized risk factor for renal cell carcinoma (RCC), but little data are available on the association between smoking and RCC biology. We investigated the association between cigarette smoking and RCC stage in a large contemporary multiethnic surgical cohort. We retrospectively reviewed the demographic, clinical, and pathologic data of patients undergoing surgery for RCC between 2000 and 2009. Advanced RCC was defined as metastatic disease, pathologic stage ≥ T3, and/or lymph node involvement. Self-reported smoking history included smoking status, duration, intensity, cumulative exposure, and cessation. Patient and tumor characteristics were compared between the groups in univariate and multivariate analyses. Of the 845 eligible patients, 19.4% and 29.1% were current and former smokers, respectively, and 207 patients (24.5%) had advanced disease. In both univariate and multivariate analyses, smoking was consistently associated with advanced RCC, and cessation reversed the risk. Current and former smokers had 1.5- and 1.6-fold increased odds of advanced disease, respectively. Heavier smoking (longer duration and exposure) was associated with increased risk of advanced RCC, whereas durable cessation reduced the odds of advanced disease. Cigarette smoking is an independent risk factor for advanced RCC. Heavier smoking increases the likelihood of advanced disease. Durable smoking cessation attenuated the risk of advanced disease. Given that cigarette smoking is among the few modifiable risk factors for RCC, our results reinforce the importance of smoking cessation and encourage further investigation of the association between smoking and RCC biology.

Abstract 5169: Simple perioperative algorithm for serum C-reactive protein: A potent, independent, adverse prognostic factor for renal cell carcinoma

Abstract Introduction: Approximately 20 to 30% of patients who undergo nephrectomy with curative intent for kidney cancer will recur and die of the disease. No adjuvant therapy has been shown to reduce the risk of relapse. Risk of recurrence is largely based on T stage, Fuhrman nuclear grade and nodal status allowing the frequency of surveillance to be adjusted based on low, intermediate and high risk categories. Though C-reactive protein (CRP) has long been recognized as an adverse prognostic factor for clear cell renal cell carcinoma (ccRCC), it has not been incorporated into the risk stratification protocols of current adjuvant clinical trials. Methods: Patients with clinically localized (T1-T3N0M0) ccRCC were followed for 1 year postoperatively. Metastases were identified radiographically and mortality confirmed with the social security death registry. Univariate and multivariate binary logistic regression analyses examined 1-year relapse-free survival (RFS) and overall survival (OS) across patient and disease characteristics. Serum CRP levels were measured prior to nephrectomy and approximately one month after surgery. Patients were assigned retrospectively to the pCRP(+) group if the perioperative (either preoperative or postoperative) serum CRP level was >10 mg/L. All others were assigned to the pCRP(−) group. Results: Of the 109 patients in the study, 17 patients (15.6%) developed metastases and 6 died (5.5%). The pCRP algorithm was employed to ascertain risk of recurrence with 25 patients assigned to the high risk category and 84 patients to the low risk category. Fourteen of 25 patients in the pCRP(+) group recurred at 1 year including all 6 who died. Only 3 of the remaining 84 patients in the pCRP(−) group recurred with no deaths. The sensitivity and specificity of the pCRP algorithm for metastasis were 82% and 88%, respectively, with a positive predictive value (PPV) of 56% and a negative predictive value (NPV) of 96%. The sensitivity and specificity of the pCRP algorithm for mortality were 100% and 82%, respectively, with a PPV of 24% and a NPV of 100%. The p values for metastasis and mortality were both <0.0001. The pCRP algorithm appears to be independent of T-stage and Furhman nuclear grade. Conclusions: When applied retrospectively, the pCRP algorithm accurately identified patients among those considered to be at low risk of recurrence whose actual risk was, in fact, extremely high. The pCRP algorithm also identified patients considered to be at high risk whose actual risk may be somewhat lower. The high NPV of the pCRP algorithm may allow patients in the pCRP(−) group to be spared the potential toxicity and expense of adjuvant therapy. External validation of the pCRP algorithm is needed to establish CRP as a clinically relevant biomarker with a potential role as a novel therapeutic target for ccRCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5169. doi:10.1158/1538-7445.AM2011-5169

Abstract 5215: Detection of circulating tumor cells in peripheral blood of patients with renal cell carcinoma

Abstract Detection of circulating tumor cells in peripheral blood of patients with renal cell carcinoma The aim of this study was to evaluate the clinical relevance of the presence of disseminated tumor cells in peripheral blood, so called circulating tumor cells (CTCs), for renal cell carcinoma (RCC) patients. 233 peripheral blood samples from 154 RCC patients were investigated for the presence of disseminated tumor cells (DTCs) by autoMACS technique and immunocytochemical (ICC) staining of cytokeratin. The frequency of CTCs was analyzed statistically for correlation with relevant clinical data. Two kinds of tumor cells were detected: those with expression of cytokeratin 8/18 (CK+), but also cells without a detectable CK+ expression, which we called large blue stained (Bl+) cells with a tumor-like morphology. After following the CD45 autoMACS depletion protocol, we identified CTCs in 96 out of 233 peripheral blood samples (41%), which originated from 81 out of 154 (53%) RCC patients. A significant correlation between the detection of CTCs and positive lymph node status (p < 0.001; Chi-square test) and the presence of synchronous metastases at the time of primary tumor resection (p < 0.02; Chi-square test) was found. In a multivariate Cox's regression hazard model, presence of CK+ CTCs was significantly correlated with poor overall survival for RCC patients (RR=2.3; p < 0.05). The presence of CTCs correlated to lymph node status and presence of synchronous metastases in RCC. It is important to evaluate CK+ and Bl+ tumor cells together to determine the role of CTCs in tumor behavior and disease progression. Detection of CK+ CTCs in peripheral blood is a significant and independent prognostic factor for RCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5215. doi:10.1158/1538-7445.AM2011-5215

Extracellular proteases in renal cell carcinoma.

363 Background: Tumor growth and metastasis relies on extracellular matrix remodeling, which is primarily mediated by the matrix metalloproteinase (MMP) family of enzymes. Extracellular matrix metalloprotease inducer (EMMPRIN, E) is a glycoprotein also implicated in tumor progression and has been shown to function in concert with MMPs. MMPs and E are highly expressed on the surface of many malignant tumors, including renal cell carcinoma (RCC). We investigated whether MMPs and E represent molecular prognostic factors in RCC. Methods: Protein expression was evaluated in 77 patients with immunohistochemical analysis of a tissue microarray (TMA) consisting of two tumor samples and an adjacent normal renal sample from each patient. Tumors represented on the TMA were clear cell (57), chromophobe (9), papillary (4), oncocytomas (3), clear cell with sarcomatoid differentiation (2), and metastatic (2). Protein expression scores were correlated with clinical outcomes to determine prognostic significance by univariate and multivariate analyses. Results: Using univariate analysis of all RCC tumors, membranous E correlated with overall survival (OS), metastasis-free survival (MFS), size, stage and overall 5-yr survival. Cytoplasmic E correlated with OS, MFS, size, grade, stage and 5-yr survival. Membranous MT1-MMP correlated with MFS, and endothelial MMP-2 correlated with grade. In multivariate analysis, membranous E was an independent indicator of stage, whereas cytoplasmic E was an independent indicator for size, stage, grade and MFS. In the clear cell population, membranous MT1-MMP correlated with OS and MFS, and endothelial MMP-2 correlated with grade in univariate analysis. In multivariate analysis, membranous MT1-MMP was an independent indicator for MFS. Conclusions: We identified EMMPRIN as an independent prognostic indicator for size, grade, stage, and MFS in RCC. While MT1-MMP and MMP-2 both significantly correlated with disease outcome in the clear cell RCC population, only MT1-MMP was an independent prognostic factor for MFS. We conclude that MMPs and E mediate important steps in RCC progression. Further investigation is warranted using larger datasets and a prospective study to determine the strength of the prognostic significance of these findings. No significant financial relationships to disclose.

Tumor biology and prognostic factors in renal cell carcinoma.

In the past 15 years, there has been an increased understanding of the tumor biology of renal cell carcinoma (RCC). The identification of vascular endothelial growth factor (VEGF), its related receptor (VEGFR), and the mammalian target of rapamycin as dysregulated signaling pathways in the development and progression of RCC has resulted in the rational development of pharmaceutical agents capable of specifically targeting key steps in these pathways. Clinical trials have demonstrated survival benefit with these agents, particularly in clear cell RCC patients. However, metastatic RCC will progress in all patients, resulting in a critical need to determine patient risk and optimize treatment. The goal of this article is to highlight the significant breakthroughs made in understanding the critical genetic alterations and signaling pathways underlying the pathogenesis of RCC. The discovery of prognostic factors and development of comprehensive nomograms to stratify patient risk and predictive biomarkers to facilitate individualized treatment selection and predict patient response to therapy also are reviewed.

Native Renal Cysts and Dialysis Duration Are Risk Factors for Renal Cell Carcinoma in Renal Transplant Recipients

Urinary tract cancers are the third most common cancers in renal transplant recipients (RTX). This study examined the impact of dialysis duration and native renal cyst(s) (NRC) on renal cell carcinoma (RCC) occurrence among 1036 RTX followed-up from 1995 to July 2007. Abdominal ultrasonography was planned within 1-month of transplant, then every 5 years, or 2 years if renal cysts developed. Based on presence and time of development of NRC, RTX were grouped into those with no (No-NRC), new (New-NRC), preexisting (Pre-NRC) and time-indeterminate NRC (TI-NRC). Ten asymptomatic RTX were diagnosed with RCC at a median of 5.8 years posttransplant and had 5-year graft and patient survivals of 90% and 100%, respectively, following appropriate therapy. RCC occurred only in Pre-NRC and TI-NRC who had significantly longer dialysis duration than No- or New-NRC (6.7 ± 3.9 and 3.3 ± 3.2 vs. 2.7 ± 3.1 and 2.6 ± 2.4 years, respectively). These results suggest that NRC and increased dialysis duration are risk factors for RCC posttransplant. Since early treatment of RCC gives excellent outcomes, regular ultrasonography performed within a month of transplantation, then every 5 years for those without cysts and every 2 years for those with cysts for early detection of RCC is recommended.

The Clinical Association of Autosomal Dominant Polycystic Kidney Disease and renal cell Carcinoma

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is not currently considered to be a risk factor for renal cell carcinoma (RCC). We present data from our institution demonstrating incidence of RCC with ADPKD above the incidence rate for RCC in the general population, as well as that in patients with end-stage renal disease (ESRD). The discussion relates our findings in the context of the current literature including recent case reports published in this entity.

The role of diabetes mellitus in localized and metastatic renal cell carcinoma

Introduction & Objectives: Until recently, the incidence of renal cell carcinoma (RCC) has been increasing worldwide, mainly in western countries, at a rate between 2% and 4% per year. However, the reason for this dramatic increase in number has not been fully understood. Diabetes mellitus (DM) is a known risk factor for RCC, but the impact of DM on the prognosis of RCC is unclear. In the present study, we investigated the potential influence of DM on clinicopathological features of localized and metastatic RCC. Material & Methods: We evaluated 863 patients with primary RCC who had undergone renal surgery between 1991 and 2005 in the University Hospital Hannover; the mean follow-up was 58 months. To test the association of DM with survival end-points, Kaplan-Meier Method and Cox multivariable logistic regression models were applied. Results: In total, we identified 123 diabetic patients who suffered from RCC, 9 patients with diabetes type 1 and 114 with type 2. Patients with DM type 2 presented significantly more often with pT1a tumours at diagnosis (40.0 vs. 31.7%, p = 0.02), had less frequently high grade cancer (G3/4; 10.3 vs. 16.2%, p = 0.03), were older (median, 65.3 vs. 61.6 years; p < 0.001), and had a higher BMI at diagnosis (median, 27.6 vs. 25.8, p < 0.001). However, there was no difference between diabetic and non-diabetic patients concerning sex, histological subtype, lymphatic and distant metastasis. In addition, there was no discrepancy in 5-year cancer specific survival between both groups (62.2 vs. 64.9% for patients without and with DM type 2, respectively). Applying multivariable analysis, unlike age, tumour stage, grade and N/M status, diabetes was not identified as a significant independent prognostic factor. Conclusions: To our knowledge this is the first study to show that even though diabetes is a risk factor for RCC it does not seem to influence its prognoses even though it might be diagnosed earlier in diabetic patients.

Enhancer of zeste homolog 2 (EZH2) expression is an independent prognostic factor in renal cell carcinoma

BackgroundThe enhancer of zeste homolog 2 (EZH2) gene exerts oncogene-like activities and its (over)expression has been linked to several human malignancies. Here, we studied a possible association between EZH2 expression and prognosis in patients with renal cell carcinoma (RCC).MethodsEZH2 protein expression in RCC specimens was analyzed by immunohistochemistry using a tissue microarray (TMA) containing RCC tumor tissue and corresponding normal tissue samples of 520 patients. For immunohistochemical assessment of EZH2 expression, nuclear staining quantity was evaluated using a semiquantitative score. The effect of EZH2 expression on cancer specific survival (CSS) was assessed by univariate and multivariate Cox regression analyses.ResultsDuring follow-up, 147 patients (28%) had died of their disease, median follow-up of patients still alive was 6.0 years (range 0-16.1 years). EZH2 nuclear staining was present in tumor cores of 411 (79%) patients. A multivariate Cox regression analysis revealed that high nuclear EZH2 expression was an independent predictor of poor CSS (> 25-50% vs. 0%: HR 2.72, p = 0.025) in patients suffering from non-metastatic RCC. Apart from high nuclear EZH2 expression, tumor stage and Fuhrman's grading emerged as significant prognostic markers. In metastatic disease, nuclear EZH2 expression and histopathological subtype were independent predictive parameters of poor CSS (EZH2: 1-5%: HR 2.63, p = 0.043, >5-25%: HR 3.35, p = 0.013, >25%-50%: HR 4.92, p = 0.003, all compared to 0%: HR 0.36, p = 0.025, respectively).ConclusionsThis study defines EZH2 as a powerful independent unfavourable prognostic marker of CSS in patients with metastatic and non-metastatic RCC.

Factors affecting outcome in renal cell carcinoma

To review the latest status on prognostic factors in renal cell carcinoma (RCC). Many predictive and prognostic factors can help differentiate between favorable and unfavorable RCC phenotypes. There currently exist several clinical and/or pathological, and biological factors, which have been exclusively tested and used in predictive and prognostic models. Nonetheless, the search for highly informative and reliable factors of disease characteristics and progression continues. Over the last decade, an increase occurred in the number of models that can predict the treated natural history of RCC. Many of these novel models and previously developed models are tested in a head-to-head fashion, with the intent of identifying the most accurate and valuable tools for clinical practice. Novel prognostic factors and more up-to-date models are urgently needed for patients with metastatic RCC, especially in the era of targeted therapies. This should represent the focus of contemporary prognostic modeling in RCC.

A case controlled study of acquired risk factors for renal cell carcinoma in a south Asian cohort – is it similar to the west?

Objective: To identify the validity of established western risk factors in renal cell carcinoma in Sri Lanka. Design, setting and methods: A case control study was designed to compare 36 consecutive, renal cell carcinoma (RCC) cases treated at one urology unit of a tertiary referral centre with 72 age, sex matched controls. Well studied risk factors in western countries such as smoking, hypertension, obesity, occupational chemical exposure and use of long term analgesics were included. Data was analyzed with standard matched pair methods. Conditional logistic regression models were used to examine the univariate and multivariate relationships of RCC with various risk factors. Results: There were 28 males and 08 females. Mean age at diagnosis was 56.92 (27-83) years. Obesity (BMI ≥ 30 kg/m2) increased the risk of RCC by 6 folds in comparison to BMI less than 25. Positive occupational exposure was shown to increase the risk of RCC by 3.2 folds (CI = 1.2-8.5) and hypertension by 4.1 folds (95%CI 1.09 - 15.39) after making adjustments for co-founding factors. Interestingly amount of smoking calculated in pack years showed an increasing trend in the odds ratio suggesting increase risk of RCC with smoking, but failed to show a strong association in the univariate analysis. Conclusions: Comparing to the results of western studies present smoking state didn't show a strong positive correlation as a risk factor. However, increasing pack years demonstrated an increased risk. Hypertension, obesity and occupational chemical exposure were shown to increase the risk as found in the west. Other factors such as analgesics, alcohol and social class did not demonstrate a significant correlation. DOI: 10.4038/sljs.v27i2.2098 The Sri Lanka Journal of Surgery 2009: 27: 39-44

281 Cancer: a less depressing outlook? Using antidepressants to induce autophagic programmed cell death in a resistant strain of Burkitt's lymphoma

STAT3, but not ERKs, mediates the IL-6–induced proliferation of renal cancer cells, ACHN and 769P.Although interleukin-6 (IL-6) has been suggested to function as an autocrine growth factor in renal cell carcinoma (RCC), the underlying mechanism responsible for the IL-6–induced proliferation of RCC has not been defined. The aim of this study was to characterize the signaling cascades mediating IL-6–induced proliferation and to investigate the use of effective novel interventions to block the IL-6–induced autocrine growth of renal cancer cells.IL-6–induced proliferation and intracellular signaling cascades were analyzed in four human renal cancer cell lines Caki-1, ACHN, 769P and A498. IL-6–induced activation of STAT3 (signal transducer and activator of transcription-1) and extracellular signal-regulated kinases (ERKs), and the effects of anti–IL-6 neutralizing antibody, Jak inhibitor AG 490, and MEK1 inhibitor PD 98059 were analyzed by Western blotting using phospho-specific antibodies. The DNA-binding activities of STATs were analyzed by EMSA. Apoptosis was determined by using nuclear staining and the TUNEL assay. Changes in the apoptosis-related proteins, bcl-2, bcl-xL, and bax were analyzed by Western blotting.IL-6 induced tyrosine phosphorylation and increased the DNA binding activity of STAT3 and, to a lesser extent, STAT1 in all cell lines except for Caki-1, which did not express the IL-6 receptor subunit gp130. ERKs were constitutively activated in all cell lines and the activation level was not up-regulated further by exogenously added IL-6 nor down-regulated by anti–IL-6 neutralizing antibody. IL-6–induced STAT3 tyrosine phosphorylation and DNA binding activity was inhibited by treatment with Jak specific inhibitor AG 490; however, it was not affected by the MEK1 inhibitor PD 98059. Moreover, treatment with AG 490 inhibited IL-6–induced proliferation of ACHN and 769P cells and induced apoptosis with the down-regulation of bcl-2 and the up-regulation of bax.This study identified STAT3, but not ERKs, to be a major mediator of IL-6–induced proliferation of renal cancer cells. Although ERKs were constitutively activated, ERKs were not found to be essential for the IL-6–induced proliferation and modulation of the STAT3 activity. Because the Jak specific inhibitor AG 490 effectively inhibited the IL-6–induced STAT3 activity and induced apoptosis, the blockade of the STAT3 signaling pathways is considered to be potentially useful as a novel therapeutic approach for RCC.

Hot topics in kidney cancer 2010

The incidence of renal cell carcinoma has increased in recent years, becoming the third most common urologic tumour. This topic issue of the World Journal of Urology provides an updated overview on epidemiology with perspectives on primary prevention by Weikert et al., proceeding from there to an update of imaging and diagnosis by Muller–Lisse. With regard to imaging, it is important for the surgeon to know the reliability of radiological findings in correlation with pathological outcomes. The article by Hong et al. covers this important issue in detail. In some cases with renal lesions of unknown dignity, biopsies are helpful in the preoperative differential diagnosis. In this study by Chyhrai et al., the benefit of multi-colour interphase fluorescence in situ hybridization on fine-needle core biopsies in uncertain renal masses is described. Augmenting prognosis and treatment, Remzi et al. describe the treatment of small renal lesions and possible benign behaviours. Laparoscopic radical nephrectomy is a feasible procedure in treating T1 and T2 tumours and possibly T3 or even more advanced lesions. However, every novel technique has to be evaluated and compared to the standard open procedure in terms of oncological long term outcome. Chen et al. evaluate this question for T1/T2 renal malignancies in a large cohort of patients. Prognostic factors following treatment in localised and advanced disease are of importance, but, unfortunately, the impact and interaction is often unclear. Waalkes et al. demonstrate in a multivariate analysis of a large cohort of patients that the urinary collecting system (UCS) invasion is not an independent prognostic factor in renal cell carcinoma. The treatment of patients with renal cell cancers has evolved substantially during the last decade, mainly due to the introduction of new targeted agents to cure metastatic disease. Less than a decade ago, the progression-free expected survival of patients with metastatic disease was about 3–5 months, with immune therapy. Since the introduction of tyrosine kinase inhibitors, the relapse rate has more than doubled. These important changes in the treatment of advanced renal cancer are discussed in three articles. Finally, Gruschwitz et al. address the role of genetic differentiation for the improvement of histopathological classification of adrenal gland tumours. Nowadays, genetic tests with fine-needle biopsies could be offered in the routine diagnostics of adrenal specimens of unknown origin. We would like to take this opportunity to sincerely thank Professor Dr. Martin Burchardt for inviting us as A. S. Merseburger Department of Urology and Urologic Oncology, Medical School of Hanover [MHH], Carl Neuberg Str. 1, 30625 Hanover, Germany

Highlights of This Issue

Milk consumption has been reported to be a potential risk factor for renal cell carcinoma (RCC). It is unclear if this represents a causal association or is due to confounding or bias. In this study, Timpson and colleagues use genetic variation in lactase persistence as a tool to interrogate these relationships. This hospital-based case-control study utilized observational and phenotypic data as well as the lactase persistence genotype at rs4988235 within the MCM6 gene. The study found no association between the MCM6 genotype and RCC, suggesting that observational associations between milk consumption and RCC may be due to confounding or bias.Despite increasing evidence that physical activity may reduce the risk of endometrial cancer, the role of moderate physical activity in reducing endometrial cancer risk remains uncertain. To help clarify this relationship, John and colleagues conducted a population-based case-control study involving 427 newly diagnosed endometrial cancer cases. Through in-person interviews, the study reports that reduced endometrial cancer risks were associated with greater lifetime physical activity. Interestingly, the relationship was reported for both total physical activity and for moderate intensity physical activity. These findings emphasize the importance of physical activity in lowering the risk of endometrial cancer.Mutagenic heterocyclic amines (HCA) are generated from cooking meats at high temperature and for long duration. Animal studies suggest that HCAs have a role in breast carcinogenesis, and there is epidemiological evidence that higher intake of well-done meat may raise breast cancer risk in humans. To explore the association of HCA intake and breast cancer, Wu and colleagues used data from a cooking method questionnaire administered in 1996 in the Nurses' Health Study. They report that higher intake of HCAs was not associated with elevated risk of breast cancer. In addition, they found that HCA intake was not associated with estrogen receptor-positive/progesterone-positive breast cancer risk.Because of its simplicity, visual inspection of the cervix after acetic acid application (VIA) is widely recommended for cervical cancer screening in resource-limited settings. To evaluate the determinants of positive VIA tests, Vedantham and colleagues compared VIA against Pap cytology and human papillomavirus DNA testing in a peri-urban area in Andhra Pradesh, India. They report that of the 19 women that were diagnosed with cervical intraepithelial neoplasia grade 2 and worse (CIN2+), only 5 were positive by VIA. In addition, VIA positivity was found to be subjective and difficult to evaluate against objective standards. This study cautions against the use of VIA as the primary screening test in resource-limited regions.

Abstract 2231: Detection of circulating tumor cells in peripheral blood of patients with renal cell carcinoma correlates with prognosis

Abstract Purpose. The aim of this study was to evaluate the clinical relevance of the presence of disseminated tumor cells in peripheral blood [so called circulating tumor cells (CTCs)] for renal cell carcinoma (RCC) patients. Methods. 233 peripheral blood samples from 154 RCC patients were investigated for the presence of disseminated tumor cells (DTCs) by autoMACS technique and immunocytochemical (ICC) staining of cytokeratin. The frequency of CTCs was analyzed statistically for correlation with relevant clinical data. Results. Two kinds of tumor cells were detected: those with expression of cytokeratin 8/18 (CK+), but also cells without a detectable CK+ expression, which we called large blue stained (Bl+) cells with a tumor-like morphology. After following the CD45 autoMACS depletion protocol, we identified CTCs in 96 out of 233 peripheral blood samples (41%), which originated from 81 out of 154 (53%) RCC patients. A significant correlation between the detection of CTCs and positive lymph node status (p&amp;lt;0.001; chi2-test) and the presence of synchronous metastases at the time of primary tumor resection (p=0.014; chi2-test) was found. In a multivariate Cox's regression hazard model, presence of CK+ CTCs was significantly correlated with poor overall survival for RCC patients (RR=2.3; P=0.048). Conclusions. The presence of CTCs correlated to lymph node status and presence of synchronous metastases in RCC. It is important to evaluate CK+ and Bl+ tumor cells together to determine the role of CTCs in tumor behavior and disease progression. Detection of CK+ CTCs in peripheral blood is a significant and independent prognostic factor for RCC. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2231.

Prognostic factors in renal cell carcinoma

Renal cell carcinoma (RCC) is a very heterogeneous disease with widely varying prognosis. An accurate knowledge of the individual risk of disease progression and mortality after treatment is essential to counsel patients, plan individualized surveillance protocols and select patients for adapted treatment schedules and new clinical trials. A systematic review of the literature on prognostic factors of localized and metastatic RCC was performed. Prognostic factors in RCC include anatomical (TNM classification, tumor size), histological (Fuhrman grade, histologic subtype), clinical (symptoms and performance status), and molecular features. All these features are not perfectly accurate when used alone. Therefore an increasing number of prognostic models or nomograms that include several combined prognostic features have been designed in order to improve predictive accuracy. UCLA Integrated Staging System (UISS) and the Mayo Clinic's SSIGN score are the two most used prognostic models for localized RCC. In the setting of metastatic RCC the classical anatomical and histological tumor features have little predictive value. However, accurate prognostic models have been designed to predict response to therapy, and progression-free and overall survival. The two most used tools to predict response to immunotherapy are the model designed by the French Group of Immunotherapy and the Motzer's model. The advent of tyrosine kinase inhibitors and antiangiogenic drugs have deeply changed the treatment of metastatic RCC. Predictive tools that are adapted to the modern targeted therapies are now needed. There is increasing knowledge on prognostic factors of localized and metastatic RCC. Several predictive models have been developed by combining different prognostic features and are valuable tools for patient counseling, treatment decision-making and trial design. Further research is needed to assess whether the combination of classical prognostic factors with molecular features and information from gene and protein expression profiling can increase the predictive accuracy of the current prognostic models.