Factor In Renal Cell Carcinoma Research Articles

Calcium-sensing receptor (CaSR) promotes development of bone metastasis in renal cell carcinoma.

Bone metastasis is an important prognostic factor in renal cell carcinoma (RCC). The calcium-sensing receptor (CaSR) has been associated with bone metastasis in several different malignancies. We analyzed the impact of CaSR in bone metastasis in RCC in vitro and in vivo. The RCC cell line 786-O was stably transfected with the CaSR gene and treated with calcium alone or in combination with the CaSR antagonist NPS2143. Afterwards migration, adhesion, proliferation and prominent signaling molecules were analyzed. Calcium treated CaSR-transfected 768-O cells showed an increased adhesion to endothelial cells and the extracellular matrix components fibronectin and collagen I, but not to collagen IV. The chemotactic cell migration and proliferation was also induced by calcium. The activity of SHC, AKT, ERK, P90RSK and JNK were enhanced after calcium treatment of CaSR-transfected cells. These effects were abolished by NPS2143. Development of bone metastasis was evaluated in vivo in a mouse model. Intracardiac injection of CaSR-transfected 768-O cells showed an increased rate of bone metastasis. The results indicate CaSR as an important component in the mechanism of bone metastasis in RCC. Therefore, targeting CaSR might be beneficial in patients with bone metastatic RCC with a high CaSR expression.

Acetyl-CoA synthetase 2 enhances tumorigenesis and is indicative of a poor prognosis for patients with renal cell carcinoma

BackgroundAcetyl-CoA synthetase 2 (ACSS2) is highly expressed in various cancers, whereas ACSS2 expression and function in renal cell carcinoma (RCC) are unknown. MethodsWe investigated ACSS2 expression in 198 human RCC tissues using immunohistochemistry, and analyzed its clinicopathological correlation and prognostic relevance. Overexpression and knockdown of ACSS2 were used to investigate the proliferation, migration and invasion of human RCC 786-O, 769-P, and ACHN cell lines. ResultsHigh-ACSS2 expression was associated with advanced T stage (P = 0.008), advanced tumor-node-metastasis stage (P = 0.015) and high University of California, Los Angeles, Integrated Staging System score category (P = 0.009). Multivariate analysis identified high-ACSS2 expression as a poor prognostic factor for recurrence-free survival (hazard ratio [HR] = 1.83, P = 0.038) and overall survival (HR = 1.60, P = 0.043). Cell-based functional assays showed that ACSS2 knockdown inhibited RCC cell growth, migration, and invasion, whereas overexpression of ACSS2 enhanced these effects. ACSS2 silencing inhibited PI3K/AKT signaling pathway. ConclusionACSS2 may increase tumor progression and aggressive behavior and be an independent prognostic factor in RCC.

Immunologic profile and prognostic significance of tumor-infiltrating lymphocytes in renal cell carcinoma.

673 Background: Renal cell carcinoma (RCC) has been shown to be a genetically and morphologically heterogeneous cancer. As studies show the significance of tumor-infiltrating lymphocytes (TIL) in cancer, it is critical to examine how the phenotype of TILs manifests in RCC. Such analysis may help explain the role of the immune landscape in developing resistance and its contribution to the high treatment failure observed in immunotherapy for RCC. This study compares the immune phenotype of primary tumors, venous tumor thrombi (VTT), and metastases, as well as multiple sites within primary tumors, and investigates whether inter- and intra-tumoral immune heterogeneity is present in RCC. The association of TIL levels and clinical prognosis will also be assessed and compared with current RCC prognostic scores. Methods: Our cohort included 15 VTT and 6 metastases (3 adrenal, 2 bone, 1 liver) with 20 matched primary tumors, as well as 25 non-metastatic primary tumors. The RCC tissue was collected and digested into single cell suspensions. Suspensions were stained for TIL surface markers and processed using flow cytometry. The data was analyzed to capture %CD8+ and %CD4+ in total tumor. The %CD28+ and %PD1+ of CD8+ cells were measured to describe the co-stimulatory and co-inhibitory receptor expression, respectively. Clinical data was obtained to calculate the Mayo Stage, Size, Grade, and Necrosis (SSIGN) and UCLA Integrated Staging System (UISS) scores for each patient and to evaluate recurrence. Results: Immunologic concordance was observed in all measured parameters (%CD8+, %CD4+, %CD28+, and %PD1+) for primary tumors and VTT, for primary tumors and their metastases, and for different sites within 10 primary tumors. In our overall cohort, %CD8+ was found to be inversely associated with recurrence (p = 0.02). Furthermore, %CD8+ was not significantly associated with patient Mayo SSIGN and UISS scores. Conclusions: Despite the genetic and morphologic heterogeneity seen in RCC, immunologic concordance was observed for both inter- and intra-tumoral analysis. The association between %CD8+ and recurrence presents a novel and objective immune-based prognostic factor for RCC, independent of Mayo SSIGN and UISS scores.

High expression of F2RL3 correlates with aggressive features and poor survival in clear cell renal cell carcinoma.

Background: Specific lifestyle factors including tobacco-exposure are vital etiologic factors for renal cell carcinoma (RCC), F2R Like Thrombin/Trypsin Receptor 3 (F2RL3) is associated with smoking but it is unknown whether its expression translate into poor survival of clear cell RCC (ccRCC). In the current study, the expression profiling and prognostic value of F2RL3 in Chinese patients with ccRCC were investigated.Methods: Using Quantitative PCR analysis and immunohistochemistry, the relative expression levels of F2RL3 in 367 paired ccRCC and adjacent normal tissues were calculated. Cox regression analysis was used to identify independent prognostic factors and Kaplan-Meier analysis and a log-rank test were employed to evaluate the prognostic value of F2RL3.Results: We observed that high expression of F2RL3 mRNA and protein were strongly correlated with shorten progression-free survival (PFS) of ccRCC with hazard ratios (HR; 95% confidence interval (CI)) of 2.060 (1.410-3.009) and 1.657 (1.193-2.300), respectively, as well as with poor overall survival (OS) with HRs (95%CI) of 2.826 (1.713-4.662) and 1.712 (1.140-2.569), respectively. After adjustment for confounding factors including smoking status, elevated HRs (95%CI) of 2.113 (1.445-3.089) and 1.692 (1.218-2.352) were presented for PFS, respectively, and 2.936 (1.777-4.851) and 1.811 (1.203-2.725) were present for OS, respectively. Meanwhile, increased F2RL3 mRNA and protein level were reported to significantly associate with smoking-exposure and well-known prognostic factors (higher TNM stage and ISUP grade).Conclusion: These findings suggested that F2RL3 mRNA and protein level in ccRCC is a robust predictor of poorly prognostic phenotype. Exploring the causal relevance of F2RL3 in ccRCC development further warrants in the future study.

The clinical use of the platelet to lymphocyte ratio and lymphocyte to monocyte ratio as prognostic factors in renal cell carcinoma: a systematic review and meta-analysis.

Conflicting evidence exists regarding the effect of platelet to lymphocyte ratio (PLR) and lymphocyte to monocyte ratio (LMR) on the prognosis of renal cell carcinoma (RCC) patients. Here we quantify the prognostic impact of these biomarkers and assess their consistency in RCC. Eligible studies were retrieved from the PubMed, Embase and Web of Science databases. Pooled hazard ratios (HRs), odds ratios (ORs), and 95% confidence intervals (CIs) were calculated. Sixteen studies containing 6,223 patients met criteria for inclusion. Overall, elevated PLR was associated with poorer overall survival (OS, HR 1.76, 95% CI 1.41–2.19, P < 0.001), progression-free survival (PFS, HR 2.81, 95% CI 1.40-5.63, P = 0.004) and recurrence-free survival (RFS, HR 2.64, 95% CI 1.35–5.14, P = 0.004). Conversely, high LMR was correlated with more favorable OS (HR 0.62, 95% CI 0.51–0.77, P < 0.001) and RFS (HR 0.53, 95% CI 0.42–0.67, P < 0.001). Moreover, low LMR was significantly associated with some clinicopathological characteristics that are indicative of poor prognosis and disease aggressiveness. By these results, elevated PLR was associated with poor outcomes, while high LMR correlated with more favorable survival in RCC patients. Pretreatment PLR and LMR can serve as prognostic factors in RCC patients.

Potential Susceptibility Loci Identified for Renal Cell Carcinoma by Targeting Obesity-Related Genes.

Background: Obesity is an established risk factor for renal cell carcinoma (RCC). Although genome-wide association studies (GWAS) of RCC have identified several susceptibility loci, additional variants might be missed due to the highly conservative selection.Methods: We conducted a multiphase study utilizing three independent genome-wide scans at MD Anderson Cancer Center (MDA RCC GWAS and MDA RCC OncoArray) and National Cancer Institute (NCI RCC GWAS), which consisted of a total of 3,530 cases and 5,714 controls, to investigate genetic variations in obesity-related genes and RCC risk.Results: In the discovery phase, 32,946 SNPs located at ±10 kb of 2,001 obesity-related genes were extracted from MDA RCC GWAS and analyzed using multivariable logistic regression. Proxies (R2 > 0.8) were searched or imputation was performed if SNPs were not directly genotyped in the validation sets. Twenty-one SNPs with P < 0.05 in both MDA RCC GWAS and NCI RCC GWAS were subsequently evaluated in MDA RCC OncoArray. In the overall meta-analysis, significant (P < 0.05) associations with RCC risk were observed for SNP mapping to IL1RAPL2 [rs10521506-G: ORmeta = 0.87 (0.81-0.93), Pmeta = 2.33 × 10-5], PLIN2 [rs2229536-A: ORmeta = 0.87 (0.81-0.93), Pmeta = 2.33 × 10-5], SMAD3 [rs4601989-A: ORmeta = 0.86 (0.80-0.93), Pmeta = 2.71 × 10-4], MED13L [rs10850596-A: ORmeta = 1.14 (1.07-1.23), Pmeta = 1.50 × 10-4], and TSC1 [rs3761840-G: ORmeta = 0.90 (0.85-0.97), Pmeta = 2.47 × 10-3]. We did not observe any significant cis-expression quantitative trait loci effect for these SNPs in the TCGA KIRC data.Conclusions: Taken together, we found that genetic variation of obesity-related genes could influence RCC susceptibility.Impact: The five identified loci may provide new insights into disease etiology that reveal importance of obesity-related genes in RCC development. Cancer Epidemiol Biomarkers Prev; 26(9); 1436-42. ©2017 AACR.

Obesity as defined by waist circumference but not body mass index is associated with higher renal mass complexity

ObjectivesObesity, typically defined as a body mass index (BMI)≥30kg/m2, is an established risk factor for renal cell carcinoma (RCC) but is paradoxically linked to less advanced disease at diagnosis and improved outcomes. However, BMI has inherent flaws, and alternate obesity-defining metrics that emphasize abdominal fat are available. We investigated 3 obesity-defining metrics, to better examine the associations of abdominal fat vs. generalized obesity with renal tumor stage, grade, or R.E.N.A.L. nephrometry score. Methods and materialsIn a prospective cohort of 99 subjects with renal masses undergoing resection and no evidence of metastatic disease, obesity was assessed using 3 metrics: body mass index (BMI), radiographic waist circumference (WC), and retrorenal fat (RRF) pad distance. R.E.N.A.L. nephrometry scores were calculated based on preoperative CT or MRI. Univariate and multivariate analyses were performed to identify associations between obesity metrics and nephrometry score, tumor grade, and tumor stage. ResultsIn the 99 subjects, surgery was partial nephrectomy in 51 and radical nephrectomy in 48. Pathology showed benign masses in 11 and RCC in 88 (of which 20 had stage T3 disease). WC was positively correlated with nephrometry score, even after controlling for age, sex, race, and diabetes status (P = 0.02), whereas BMI and RRF were not (P = 0.13, and P = 0.57, respectively). WC in stage T2/T3 subjects was higher than in subjects with benign masses (P = 0.03). In contrast, subjects with Fuhrman grade 1 and 2 tumors had higher BMI (P<0.01) and WC (P = 0.04) than subjects with grade 3 and 4 tumors. ConclusionsOur data suggest that obesity measured by WC, but not BMI or RRF, is associated with increased renal mass complexity. Tumor Fuhrman grade exhibited a different trend, with both high WC and BMI associated with lower-grade tumors. Our findings indicate that WC and BMI are not interchangeable obesity metrics. Further evaluation of RCC-specific outcomes using WC vs. BMI is warranted to better understand the complex relationship between general vs. abdominal obesity and RCC characteristics.

Evaluation of COX-2 expression in renal cell carcinoma and its correlation with clinicopathological factors: a tissue microarray study

AbstractObjectives: This study, aimed to evaluate the expression of COX-2 in renal cell carcinoma, and correlate it with different patient clinicopathological data, emphasizing on the role of COX-2 as a prognostic factor for renal cell carcinoma and to decide which cases more likely benefit from the targeted therapy later on. Patients and Methods: The present series consisted of tissue samples obtained from 47 patients (30 patients were males and 17 were females). All the tumor samples were collected from the Pathology Department, Faculty of Medicine, Alexandria University during the period from July 2009 to November 2010. Archival paraffin-embedded renal cell carcinoma tissue samples were used to prepare tissue microarray blocks for immunohistochemical staining with COX-2 antibody. Marker expression was categorized for statistical analysis then correlated to clinicopathological variables. Results: The histological types was significantly associated with COX-2 expression, with higher expression being more common in papillary and chromophobe renal cell carcinoma, the majority of these two types were in score 1 and 2 while majority of clear cell renal cell carcinoma had score 0 and 1. Conclusion: The association of COX-2 marker was related to the histologic type of tumor; COX-2 expression study might provide prognostic information regarding tumor aggressiveness. These findings suggested a potential impact of COX-2 targeted therapy in the treatment of renal cell carcinoma with overexpressed COX-2 that needs further investigation.

Preoperative serum cystatin-C as a potential biomarker for prognosis of renal cell carcinoma.

PurposeThe prognostic value of serum cystatin-C (Cys-C) in renal cell carcinoma (RCC) remains unknown. The purpose of this study is to explore the prognostic value of Cys-C for RCC patients.Patients and methodsThe levels of preoperative Cys-C, creatinine (CRE) and estimated glomerular filtration rate (e-GFR) were retrospectively collected in 325 RCC patients undergoing surgery. The cutoff values of Cys-C, CRE and e-GFR were determined by the standardized Cutoff Finder algorithm. The receiver operating characteristic (ROC) curve and pairwise comparison were performed to compare the three variables. Univariate and multivariate Cox regression analyses were performed to investigate the prognostic value of serum Cys-C in RCC.ResultsBased on the analysis of Cutoff Finder algorithm, ROC curve and pairwise comparison, the preoperative Cys-C was superior to CRE and e-GFR as a predictive factor in RCC. Multivariate Cox regression analyses showed that high preoperative Cys-C (>1.09 mg/L) was significantly associated with shorter overall survival (OS) in all RCC patients (hazard ratio [HR], 1.59; P = 0.012), patients at pT1-2 (P<0.001), pN0 (P<0.001) and pM0 stages (P<0.001). Moreover, Multivariate Cox regression analyses also showed that in the 306 patients without metastasis, high preoperative Cys-C was also associated with shorter disease-free survival (DFS) (HR, 3.50; P = 0.013).ConclusionsAn elevated preoperative Cys-C level was demonstrated to be related with worse survival in patients with RCC. Measuring preoperative serum Cys-C might be a simple way for finding poor prognostic patients and patients with elevated preoperative Cys-C level should be more closely followed up.

Antibiotics prescription to decrease progression-free survival (PFS) and overall survival (OS) in patients with advanced cancers treated with PD1/PDL1 immune checkpoint inhibitors.

3015 Background: Use of antibiotics (ATB) alters the gut microbiota composition and decreases bacterial diversity. Pre-clinical evidences demonstrated the impact of the microbiota in the efficacy of immune checkpoint blockades (ICB) in cancer. Interaction between ATB and ICB has not been extensively investigated in cancer patients (pts). Our study evaluated the effect of ATB in cancer pts treated with PD-1/PD-L1 inhibitors. Methods: We conducted a retrospective analysis of pts treated with PD-1/PD-L1 inhibitors for advanced Renal Cell Carcinoma (RCC), Urothelial Cancer (UC) and Non-Small Cell Lung Cancer (NSCLC) and data on ATB use were collected. ATB(+)/(-) groups were defined as pts treated or not with ATB before (2 months period) or within the first month of ICB. PFS and OS were compared between both groups among all pts and then according to tumor site. Statistical analyses were performed using the Kaplan-Meier method. Cox regression analyses were performed separately for each cancer type adjusting for its specific risk factors. Results: Among 175 pts included, 51 (29%) received ATB (mostly beta-lactamases and fluoroquinolones). ATB(+) group had shorter PFS and OS when compared to ATB(-) group: 3.4 vs. 5.2 months, p &lt; 0.013, and 12.2 vs. 20.8 months, p &lt; 0.001, respectively. According to tumor type, ATB(+) group translated into decrease OS (7.0 vs. 13.8 months, p &lt; 0.038) in NSCLC. In RCC and UC pts, ATB (+) group had shorter PFS when compared to ATB(-) group (4.3 vs. 7.4 months, p &lt; 0.013 and 1.8 vs. 4.3 months, p = 0.048, respectively). The negative impact of ATB was maintained after multivariate analyses adjusting for risk factors in each tumor type. Conclusions: ATB prescription preceding or concomitant to the first injection of PD-1/PD-L1 inhibitors impaired the outcome in patients with advanced cancers. This reduction in efficacy seems to be independent of classical prognostic factors in RCC, UC and NSCLC. These data should be validated in larger cohort. In addition, the role of gut composition to explain this interaction is ongoing, as well as novel diagnosis tools based on microbiota to predict response/resistance to ICB.

Association between Polymorphisms in MicroRNAs and Risk of Urological Cancer: A Meta-Analysis Based on 17,019 Subjects.

Accumulating evidence has demonstrated that some single nucleotide polymorphisms (SNPs) existing in miRNAs correlate with the susceptibility to urological cancers. However, a clear consensus still not reached due to the limited statistical power in individual study. Thus, we concluded a meta-analysis to systematically evaluate the association between microRNA SNPs and urological cancer risk. Eligible studies were collected from PubMed, Embase, Web of Science, and CNKI databases. Pooled odds ratio (OR) and corresponding 95% confidence interval (95% CI) were calculated to assess the strength of the relationships between three SNPs (miR-196a2, C>T rs11614913; miR-146a, G>C rs2910164; and miR-499, A>G rs3746444) and the risk of urological cancers. In addition, the stability of our analysis was evaluated by publication bias, sensitivity and heterogeneity analysis. Overall, a total of 17,019 subjects from 14 studies were included in this meta-analysis. We found that CT (miR-196a2, C>T rs11614913) was a risk factor for renal cell carcinoma (CT vs. CC: OR = 1.72, 95%CI = 1.05–2.80, P = 0.03, I2 = 66%), especially in Asian population (CT vs. CC: OR = 1.17, 95%CI = 1.04–1.32, P < 0.01, I2 = 0%). miR-146a G>C rs2910164 was a protective factor of urological cancers (C vs. G: OR = 0.87, 95%CI = 0.81–0.93, P < 0.01, I2 = 0%), especially for bladder cancer. miR-499 A>G rs3746444 was correlated with an increased risk of urological cancers, specifically in Asian population. In conclusion, our meta-analysis suggests that polymorphisms in microRNAs, miR-196a2, C>T rs11614913, miR-146a G>C rs2910164 and miR-499 A>G rs3746444, may be associated with the development of urological cancers and the risks mainly exist in Asian populations.

Circulating levels of obesity-related markers and risk of renal cell carcinoma in the PLCO cancer screening trial

Obesity is an established risk factor for renal cell carcinoma (RCC). It is unclear what biologic mechanisms underlie this association, although recent evidence suggests that the effects of circulating hormones such as insulin-like growth factors (IGF) and adipokines may play a role. To address this question, we conducted a nested case-control study of RCC (252 cases, 252 controls) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial investigating associations with pre-diagnostic serum levels of total adiponectin, high-molecular-weight (HMW) adiponectin, IGF-1, IGF-binding protein-3 (IGFBP-3), and C-peptide. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated using conditional logistic regression. After adjustment for potential confounders, non-significant associations with RCC were observed for total adiponectin (OR for highest vs. lowest quartile=0.65, 95% CI 0.37-1.14; p trend=0.35), HMW adiponectin (0.67, 0.38-1.17; p trend=0.36), IGF-1 (1.35, 0.77-2.39; p trend=0.17), IGFBP-3 (1.47, 0.83-2.62; p trend=0.53), and C-peptide (1.52, 0.86-2.70; p trend=0.15). In a joint analysis with body mass index (BMI, kg/m2), obese individuals (BMI≥30) with above-median levels of IGFBP-3 had a significantly higher risk versus those with BMI<25 and below-median IGFBP-3 (OR 2.42, 1.11-5.26), whereas obese individuals with low IGFBP-3 did not (1.18,0.53-2.64) (p interaction=0.35). The results of this study, while not clearly supporting associations with these obesity-related hormones, suggest that the association between obesity and RCC may be partially modified through mechanisms related to elevated IGFBP-3.

SPARCL1 suppresses cell migration and invasion in renal cell carcinoma.

Previous studies have shown that the human SPARC‑like 1 (SPARCL1) is crucial for human cancer migration and invasion. In the present study, the expression, biological function and possible molecular regulatory mechanisms of SPARCL1 were investigated in human renal cell carcinoma (RCC). The protein expression of SPARCL1 in cells was evaluated using western blot analysis and immunohistochemical staining in the tissue microarray. The effects of SPARCL1 on the biological behaviors of RCC cells were assessed using invitro assays. The present study also provisionally investigated the role of SPARCL1 on the mitogen‑activated protein kinase (MAPK) signaling pathway. The results revealed that the expression of SPARCL1 was decreased in the RCC cell lines examined and in the tissue microarray. The overexpression of SPARCL1 significantly inhibited cell migration and invasion, and this may have been due to the inactivation of p38/c‑Jun N‑terminal kinase (JNK)/extracellular signal‑regulated kinase (ERK) MAPKs. The results showed that high expression levels of SPARCL1 offered potential as a useful prognostic factor in RCC. Taken together, the present study demonstrated that the expression of SPARCL1 was downregulated in RCC cells and tissues, however, the overexpression of SPARCL1 inhibited RCC cell migration and invasion. SPARCL1 also reduced the expression of phosphorylated p38/JNK/ERK MAPKs. These data suggested that increasing the protein expression level of SPARCL1 may be novel strategy for treating RCC.

Distinct immunophenotypes and prognostic factors in renal cell carcinoma with sarcomatoid differentiation: a systematic study of 19 immunohistochemical markers in 42 cases

BackgroundRenal cell carcinoma (RCC) with sarcomatoid differentiation is a relatively rare tumor containing both carcinoma and sarcomatoid components. However, there has not been a systemic study on immunophenotypes of renal cell carcinoma with sarcomatoid differentiation, especially using some renal specific immunohistochemical markers. In this study, we aimed to comprehensively investigate the distinct immunophenotypes of RCC with sarcomatoid differentiation to analyze the pathogenesis of sarcomatoid differentiation and identify new prognostic factors in RCC with sarcomatoid differentiation.MethodsA total of 42 cases of RCCs with sarcomatoid differentiation were enrolled into the study. Immunohistochemistry study was performed on tissue microarrays to evaluate the expressions of 19 immunohistochemical markers including a series of epithelial, mesenchymal markers and RCC specific markers. Kaplan-Meier method was applied to assess the prognostic values of CD10, CAIX, p53 and Bcl-2.ResultsHistologically, 42 cases of RCCs with sarcomatoid differentiation presented with different proportions of carcinoma and sarcomatoid components. The cohort contained 35 cases of clear cell renal cell carcinoma (CCRCC) and 7 cases of chromophobe renal cell carcinoma (ChRCC) based on the carcinoma components. Immunohistochemically, all cases were positive for vimentin, and 80% of cases showed immunostaining for at least one epithelial marker, such as CK, EMA, CK7 and CK18. Notably, the expression rates of CAIX, CD10 and PAX8 in sarcomatoid cells were 76%, 76% and 64%, respectively. The carcinoma component of the tumors showed differentient labeling for CAIX, CD10, vimentin, CK7 and CD117 in CCRCC vs ChRCC, but the sarcomatoid component lost the specificity for these markers (p < 0.05). Patients with positive expressions of CAIX, p53 and Bcl-2 had a poor prognosis.ConclusionsThe sarcomatoid cells in RCC with sarcomatoid differentiation express both epithelial and mesenchymal markers, supporting their epithelial origin. PAX8, CAIX and CD10 could be used as the reliable and useful markers to determine the renal origin of sarcomatoid cells such as in fine needle aspiration cases and metastatic RCC with sarcomatoid differentiation. CAIX, p53 and Bcl-2 might play important roles in the transformation from renal cell carcinoma to high malignant sarcomatoid differentiation, and these three immunohistochemical markers are adverse prognostic factors for the survival of patients with RCC with sarcomatoid differentiation.

Predictive value of the modified Glasgow Prognostic Score for the therapeutic effects of molecular-targeted drugs on advanced renal cell carcinoma.

Inflammation is considered to be a prognostic factor for renal cell carcinoma (RCC). An inflammation-based prognostic score (modified Glasgow Prognostic Score; mGPS) is widely used for preoperative patients; however, little information is available regarding its prognostic value in patients with RCC treated with molecular-targeted drugs. A total of 32 advanced and recurrent RCC patients initially treated with molecular-targeted drugs from October, 2009 to August, 2015 were retrospectively investigated. Information on patient characteristics prior to treatment initiation and the clinical course were retrieved from clinical records. The correlation between survival and patient variables was analyzed. Survival was compared among patient groups according to the mGPS score. The median patient age was 66 years. The percentage of patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 was 87.5, and 65.6% of the RCCs were clear cell carcinomas. A Memorial Sloan-Kettering Cancer Center index of good or intermediate was determined for 75% of the patients. Sunitinib, pazopanib or sorafenib was administered to 56, 22 and 13% of the cases, respectively. An mGPS score of 0, 1 and 2 was calculated for 66, 9 and 25% of the cases, respectively. Patients in the mGPS low group (score 0) exhibited significantly better progression-free survival (PFS) and overall survival (OS) compared with patients in the mGPS high group (score 1 or 2) (median PFS, 307 vs. 70 days and median OS, 1,081 vs. 140 days, respectively). In conclusion, inflammatory status as assessed by the mGPS score was closely associated with the prognosis of RCC patients treated with molecular-targeted therapy.

Prognostic effect of serum C-reactive protein kinetics on advanced renal cell carcinoma treated with sunitinib.

C-reactive protein (CRP) is an independent prognostic factor for renal cell carcinoma (RCC). The aim of the present study was to investigate the prognostic effect of pretreatment serum CRP level and CRP kinetics on patients with advanced RCC treated with sunitinib. A total of 56 consecutive patients with advanced RCC treated with sunitinib between December, 2008 and December, 2012 were enrolled in the present study. The patients were retrospectively divided into 3 cohorts according to pretreatment serum CRP level and CRP kinetics: i) Normal CRP cohort (pretreatment CRP ≤0.30 mg/dl); ii) normalized CRP cohort (pretreatment CRP >0.30 mg/dl that normalized within 2 cycles of treatment); and iii) non-normalized CRP cohort (pretreatment CRP >0.30 mg/dl that did not normalize after sunitinib initiation). Disease control rate, progression-free survival and overall survival times were compared for the 3 cohorts. The normal (n=17, 30.4%) and the normalized (n=8, 14.3%) CRP cohorts exhibited significantly better disease control rates compared with the non-normalized CRP cohort (n=31, 55.4%; P<0.0001 and P=0.0445, respectively). The normal CRP cohort exhibited significantly longer progression-free survival compared with the non-normalized CRP cohort (P=0.0050). The normal and normalized CRP cohorts exhibited significantly longer overall survival compared with the non-normalized CRP cohort (P=0.0005 and 0.0466, respectively). Therefore, CRP kinetics and normal pretreatment CRP level are prognostic indicators in patients with advanced RCC treated with sunitinib.

IJU this issue

Have you ever noticed morphological variations in inferior vena cava thrombus associated with renal cell carcinoma (RCC)? Do you feel any difficulty in determining the T factor of RCC (T3a or T3b) because the invasion of the inferior vena cava wall by the cancer cannot be precisely evaluated in the preoperative computed tomography or magnetic resonance imaging (MRI)? Choi et al. (Seoul, Korea) have shown challenging data connecting morphological features and the prognosis of non-metastatic RCC with inferior vena cava thrombus. They classified two types, namely, spherical (type 1) and speculated (type 2). A total of 29 patients had type 1 (18.6%), and 127 patients had type 2 (81.4%). Type 1 had a better prognosis than type 2 in overall survival and cancer-specific survival. Here arises a fundamental question. What is the biological background that makes these differences? Conceivably, well-marginated, firm cancer with abundant connective tissues makes type 1, whereas friable and disintegrating cancer makes type 2. However, abundant connective tissue is occasionally observed in sarcomatoid RCC showing a poor prognosis.1 If consistency can be evaluated by imaging, that helps precise preoperative staging. Clinical implications are that this helps the indication of an umbrella stent that blocks pulmonary embolism. A preoperative umbrella stent should be considered in type 2, because friable cancer tissue is likely to break off. Concordantly, in this cohort, perioperative mortality was higher in type 2. Do you think that aged patients with testicular germ cell tumors have a poor prognosis in comparison with young patients? Our feelings are “yes,” because aged patients cannot tolerate the standard chemotherapeutic regimen because of morbidities. Kawai et al. (Tokyo, Japan) described a Japanese cohort of patients aged 50 years and older. Of the 1119 cases, 123 (11.0%) were diagnosed at age ≥50 years. They were frequently seminomas, and more frequently diagnosed in clinical stage 1 than younger patients. Regarding metastatic cases, aged patients are classified more as the better prognosis group; however, cancer-specific survival was not superior to younger patients. This is due to the fact that not enough chemotherapy was given to the aged patients. They suggested alternative regimens without bleomicin for aged patients with comorbidities. Adenocarcinoma (ADK) of the bladder is rare. We vaguely believe that ADK has a poorer prognosis than urothelial carcinoma of the bladder. Is it really so? Using the SEER database of 10 024 patients with non-metastatic bladder cancer, Zaffuto et al. (Milan, Italy) have shown that 215 (2.1%) had ADK. Interestingly, cancer-specific mortality rates did not defer from urothelial carcinoma. A higher cancer-specific mortality applies to the signet ring cell variant. Among ADK patients, 30.7% harbored the signet ring cell variant. The signet ring cell variant should be paid attention to when ADK is pathologically diagnosed. Classical 12-core transrectal ultrasound-guided biopsy is limited to detecting clinically significant prostate cancer. Multiparametric MRI (mpMRI) has been widely used to facilitate the accurate diagnosis of clinically significant cancer. Tsivian et al. (Durham, USA) analyzed the accuracy of mpMRI in a repeat biopsy cohort of 50 cases using comprehensive transperitoneal mapping biopsy as the reference. mpMRI had high specificity and a high negative predictive value for detecting clinically significant prostate cancer. However, in our daily practice, target biopsy is the standard procedure, which might miss a relevant number of clinically significant prostate cancers, as mentioned by Kesch et al. (Heidelberg, Germany). We published a paper evaluating the prognostic marker of mpMRI for predicting biological recurrence after radical prostatectomy.2 We took Prostate Imaging Reporting and Data System 4/5 as positive, and showed that mpMRI was an independent biomarker for biological recurrence. We believe mpMRI is an effective index for determining the therapeutic strategy, as well as a the follow-up strategy.

Obesity, Diabetes Mellitus, Hypertension and other Risk Factors for Renal Cell Carcinoma in Japan: A Mini-Review

Background: The incidence of kidney cancer is high in Western Europe, Northern Europe and North America, while it is low in Asia. Although the incidence of kidney cancer in Japan is lower than the rates in the other industrialized countries, there is no doubt that it is increasing. In this paper, we would like to introduce the result of epidemiological studies, which evaluate the non-genetic risk factors for kidney cancer in the Japanese population. Methods: Relevant studies were identified in the PubMed database using the combination of “Japan”, “kidney cancer”, “renal cell cancer” and “risk”, and the ICHUSHI database (Japanese database) using a combination of “kidney cancer /renal cell cancer”, and “risk factor”. In addition, we selected one cohort study from the references of these reports. Results and Discussion: Several studies were identified in the database. In these studies, obesity, diabetes mellitus, hypertension, kidney diseases, chronic renal disease with dialysis, tobacco smoke, fondness for fatty food, milk, and black tea are associated with an increased risk of kidney cancer. On the other hand, an inverse association with the kidney cancer risk is found for an intake of starchy roots (i.e., taro, sweet potato and potato), physical activity and educational level. In Japan, however, drinking black tea and milk may be surrogates for a westernized dietary habit while eating starchy roots may be a surrogate for a traditional Japanese dietary habit. Additional studies are needed to confirm the risk factors for kidney cancer in the Japanese population.

Preoperative Albumin to Globulin Ratio (AGR) as Prognostic Factor in Renal Cell Carcinoma.

Background: Malnutrition and systemic inflammatory response are frequently associated with prognosis in patients with several types of cancer, including renal cell carcinoma (RCC). The study is aimed to investigate the ability of preoperative serum albumin to globulin ratio (AGR) to predict the long-term mortality of RCC patients.Methods: The study is a retrospective study of an unselected cohort of 895 RCC patients who underwent a curative radical or partial nephrectomy at the Department of Urology in the Sun Yat-Sen University Cancer Center between January 2000 and December 2012 and had documented preoperative serum total protein and albumin (ALB) levels. The preoperative AGR was calculated as the ratio of ALB to (total protein-ALB) and its association with other clinical indices was assessed using survival analysis.Results: Low preoperative AGR was associated with older population, lower hemoglobin, higher total protein, lower ALB, lower body mass index and advanced stage. The univariate and multivariate Cox analyses demonstrated that preoperative AGR was an independent prognostic indicator of overall survival (OS) (hazard ratio (HR): 0.63, 95% confidence interval (CI): 0.43 to 0.93, P=0.022). In addition, patients with low preoperative AGR at pT1-2, pT3-4, pN0, pN1, pM0 and pM1 stages had significantly shorter OS than patients with high preoperative AGR.Conclusion: Preoperative AGR is a proven objective, reproducible, inexpensive survival predictor of RCC patients following surgical resection and should be considered for routine clinical use.

Overall prognostic impact of C-reactive protein level in patients with metastatic renal cell carcinoma treated with sorafenib.

C-reactive protein (CRP) is an independent prognostic factor for renal cell carcinoma (RCC). The aim of the present study was to investigate the overall prognostic impact of CRP in patients with metastatic RCC treated with sorafenib. Between April 2008 and December 2014, 40 consecutive patients with metastatic RCC were treated with sorafenib at our institution. The patients were divided into two cohorts according to the pretreatment CRP level: (i) a normal CRP cohort (≤0.30 mg/dl) and (ii) an elevated CRP cohort (>0.30 mg/dl). Kaplan-Meier overall survival analysis was carried out. The effects of selected variables on survival were assessed by multivariate regression using the Cox proportional hazards model. The normal CRP cohort included 16 patients (40.0%) and the elevated CRP cohort included 24 patients (60.0%). The normal CRP cohort showed significantly longer overall survival than the elevated CRP cohort (median, 52.0 vs. 17.0 months; P=0.0072). On multivariate analysis, normal CRP predicted longer overall survival (hazard ratio, 0.367; 95% confidence interval, 0.147-0.914; P=0.0313). Pretreatment normal CRP predicted better overall survival in patients with metastatic RCC treated with sorafenib and CRP level may be a useful biomarker for predicting overall survival of patients treated with sorafenib.