Qi Bai

Prognostic significance of ST3GAL-1 expression in patients with clear cell renal cell carcinoma

BackgroundAberrant sialylated carbohydrate synthesis is frequently noted in various cancers. Sialyltransferase ST3GAL-1, which adds a sialic acid in an α-2,3 linkage to Gal β1,3 GalNAc, preforms an important role in modulating cellular behaviors. However, little is known about prognostic significance of ST3GAL-1 in clear cell renal cell carcinoma (ccRCC). In this study, we aimed to investigate the prognostic significance of sialyltransferase ST3GAL-1 and its correlation with clinical outcomes in patients with ccRCC.MethodsA total of 286 patients who underwent nephrectomy between 2005 and 2007 in a single academic center were recruited. Immunohistochemical staining was performed on tissue microarrays to assess the expression level. Kaplan-Meier method and Cox proportional hazard model were applied to assess the prognostic value of ST3GAL-1. Nomograms were generated as prediction model for overall survival and disease free survival at 5 and 8 years after nephrectomy.ResultsThe present results show high expression of ST3GAL-1 is associated with reduced overall survival (p = 0.013) and disease free survival (p = 0.004). In multivariate cox analyses, ST3GAL-1 was defined as an independent prognostic factor for overall survival (p = 0.006) and disease free survival (p = 0.001). After incorporation into the University of California Integrated Staging System (UISS) intermediate/high risk group for non-metastatic ccRCC, ST3GAL-1 could further distinguish patient with dismal prognosis (p = 0.015 and 0.002 for OS and DFS respectively). The nomograms revealed better predictive accuracy in predicting 5- and 8- year overall survival and disease free survival than the TNM stage alone.ConclusionsST3GAL-1 is an independent adverse prognostic factor for recurrence and survival of patients with ccRCC.

High Level of Anaphylatoxin C5a Predicts Poor Clinical Outcome in Patients with Clear Cell Renal Cell Carcinoma

Anaphylatoxin C5a, a potent pro-inflammatory peptide produced in the process of complement activation, was proved to have a vital role in tumor initiation and progession by previous investigations. However whether it could act as a prognostic marker remains unknown. Here we retrospectively enrolled 272 ccRCC patients undergoing nephrectomy in Zhongshan Hospital, Shanghai between 2005 and 2007. C5a level was assessed by immunohistochemistry and its association with clinicopathologic features and prognosis were evaluated. Our results indicated that high tumoral C5a level was associated with poor overall survival (OS) (hazard ratio = 1.753, 95% CI 1.068–2.878, P = 0.026). In addition, tumoral C5a could significantly stratify patients’ prognosis both in advanced stage (TNM III + IV) and intermediate/high risk group (SSIGN score ≥4) (P < 0.001 and = 0.008, respectively). Furthermore, incorporating tumoral C5a with other parameters could improve the predicting accuracy, compared with TNM and SSIGN system (c-index = 0.789, 0.713 and 0.727, respectively). In conclusion, tumoral C5a is an independent adverse prognostic biomarker for clinical outcome of ccRCC patients after nephectomy.

Enrichment of C5a-C5aR axis predicts poor postoperative prognosis of patients with clear cell renal cell carcinoma

Anaphylatoxin C5a and its receptor C5aR on cancer cells constitute a vital axis to cancer progression. In this study, we measured C5aR level by immunohistochemistry in the same cohort of our previous C5a research, and C5a-C5aR axis status was determined by synthesizing C5a and C5aR data. C5aR was an adverse independent prognostic factor for ccRCC patients. Kaplan-Meier analyses revealed the unique position of both C5a and C5aR high population in postoperative survival, based on which patients were then shunted into C5a-C5aR enriched and non-enriched groups. Obviously, C5a-C5aR enriched patients significantly had a poorer overall survival (OS) and recurrence free survival (RFS) compared with non-enriched ones, and the independence of C5a-C5aR axis was verified by multivariable analyses (HR 2.118, P = 0.001 for OS, HR 1.715, P = 0.035 for RFS). Established nomograms based on our findings reflected much better predicting accuracy in contrast with most common used TNM and Fuhrman systems. Meanwhile, consistent with HR, C5a-C5aR axis in this study held its advantages over C5a and C5aR for OS prediction by c-index analyses, rather than RFS prediction.

Tumor infiltrating CD19+ B lymphocytes predict prognostic and therapeutic benefits in metastatic renal cell carcinoma patients treated with tyrosine kinase inhibitors

ABSTRACT The objective response rate (ORR) of tyrosine kinase inhibitors (TKIs) therapy in metastatic renal cell cancer (mRCC) patients was not satisfactory. Effective indicator of mRCC patient selection for TKI therapy is urgently needed. The function of tumor infiltrating B lymphocytes (TIBs) in tumor immune elimination is still unclear. We aim to investigate the prognostic and predictive value of TIBs for TKI therapy in mRCC patients in this study. 108 eligible patients treated with TKI were enrolled in this study. TIBs was estimated by immunohistochemical staining of CD19 in the resected tumor, and its relationship with clinicopathological features, clinical outcomes and CD8+ tumor infiltrating T lymphocytes (CD8+ TILs) were evaluated. Associations between the expression level of CD19 and CD8+ TILs associated cytotoxic effectors were also assessed in public databases. Results showed TIBs positive infiltration predicted better therapeutic response to sunitinib (p = 0.006), longer overall survival (OS) (p < 0.001) and progression-free survival (PFS) (p = 0.028) in mRCC patients. Combining TIBs and International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) model showed a better predict value of OS in TKI-treated mRCC patients than IMDC model alone. We also found a positive correlation between TIBs and CD8+ TILs (p < 0.001). Patients with both cells high infiltration showed markedly better OS compared with those infiltrated by CD8+ T cells alone (p = 0.015). To conclude, TIBs density was not only an independent prognostic factor for mRCC patients, but also a predictive marker for TKI therapy response. It may potently enhance the antitumor effect by recruiting and activating CD8+ TILs in mRCC.

Decreased expression of JMJD3 predicts poor prognosis of patients with clear cell renal cell carcinoma

Previous studies have demonstrated abnormal H3K27 methylation status during clear cell renal cell carcinoma (ccRCC) carcinogenesis, and have suggested that the histone H3K27 demethylases, jumonji domain-containing protein 3 (JMJD3) and ubiquitously-transcribed TPR gene on the X chromosome, are important regulatory factors that alter H3K27 methylation status. The present study aimed to explore the prognostic value of JMJD3 in patients with ccRCC. A total of 331 ccRCC samples were stained for JMJD3 by immunohistochemistry. Stage, Size, Grade and Necrosis (SSIGN) and University of California Los Angeles Integrated Staging System (UISS) scores were applied to stratify risks. Survival analyses were performed through the Kaplan-Meier estimator method and Cox proportional hazard model. The results revealed that JMJD3 expression in ccRCC was significantly increased compared with that in the peritumoral tissue (P<0.001) and negatively associated with a number of other clinicopathological characteristics. Kaplan-Meier estimator and multivariate analyses revealed that decreased tumoral JMJD3 expression was associated with OS (hazard ratio, 2.141; P=0.003), and DFS prediction (hazard ratio, 1.737; P=0.033). In addition, following stratification of patients into three risk levels using the SSIGN and UISS scores, decreased tumoral JMJD3 expression was associated with shorter OS (P=0.003 for SSIGN and UISS scores) and DFS (P=0.007 for SSIGN and P=0.041 for UISS score) in the intermediate risk groups. The results from the present study suggest that JMJD3 is a novel prognostic marker for patients with ccRCC and is of particular significance in patients with intermediate-risk disease.

Prognostic value of copper transporter 1 expression in patients with clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) features a Von Hippel-Lindau mutation, associated with a hypoxia-inducible factor (HIF) imbalance. Copper transporter 1 (CTR1) may also promote tumor progression through the modulation of the HIF pathway by copper. Therefore, the present study explored the prognostic effect of tumor CTR1 expression in patients with ccRCC. A total of 293 patients with ccRCC that underwent nephrectomy were retrospectively enrolled. CTR1 expression was assessed by immunohistochemistry, and its association with clinicopathological features and prognosis were evaluated. The present data indicated that high tumor CTR1 expression was independently associated with poor overall survival (OS) [hazard ratio, 2.291; 95% confidence interval (CI), 1.389–3.777; P<0.001] and disease-free survival (DFS) (hazard ratio, 2.210; 95% CI, 1.299–3.759; P=0.003) rates in patients with ccRCC. Furthermore, CTR1 expression was significantly higher for Mayo Clinic stage, size, grade and necrosis score risk groups, and could be incorporated into several existing prognostic models to improve performance. Nomograms incorporating tumor CTR1 expression with other parameters performed well in the 5- and 8-year OS and DFS rate predictions of patients (concordance index 0.805 and 0.787, respectively). In conclusion, the present study demonstrated that CTR1 expression is a potential independent biomarker for poor prognosis for the recurrence and survival prediction of patients with ccRCC following nephrectomy.

Low CCL17 expression associates with unfavorable postoperative prognosis of patients with clear cell renal cell carcinoma

BackgroundChemokine (C–C motif) ligand 17 (CCL17) is a chemokine mainly produced by myeloid dendritic cells. It is a ligand for CC chemokine receptor 4 (CCR4) and CC chemokine receptor 8 (CCR8). The aim of this study was to investigate prognostic values of CCL17 expression in patients with clear cell renal cell carcinoma (ccRCC).MethodsThe study included 286 patients with ccRCC. CCL17 expression was analyzed by immunohistochemistry on tissue microarrays. Prognostic values of CCL17 expression and patients’ clinical outcomes were evaluated.ResultsKaplan-Meier method showed that low CCL17 expression was associated with worse patient overall survival (OS) and recurrence-free survival (RFS) (OS, P = 0.002; RFS, P = 0.007). Low CCL17 expression was an adverse independent risk factor for OS and RFS in multivariate analyses (OS, P = 0.006, P = 0.011 for bootstrap; RFS, P = 0.002, P = 0.025 for bootstrap). We constructed two nomograms incorporating parameters derived from multivariate analyses to predict patients’ OS and RFS (OS, c-index 0.799; RFS, c-index 0.787) and they performed better than existed integrated models.ConclusionLow CCL17 expression is a potential independent adverse prognostic biomarker for recurrence and survival of patients with ccRCC after nephrectomy. Established nomograms based on this information could help predict ccRCC patients’ OS and RFS.

Prognostic value of CC-chemokine receptor seven expression in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitor

BackgroundCC-chemokine receptor seven (CCR7), a G-protein coupled receptor normally facilitating immune cells lymphatic homing, has recently been identified on several cancer cells in promoting invasion and lymphatic specific metastasis by mimicking normal leukocytes. As tyrosine kinase inhibitors for metastatic renal cell carcinoma (mRCC) mostly emphasized on vascular inhibition, whether the CCR7 expressing tumor cells with potential lymphatic invasion function could have an impact on mRCC patient’s drug response and survival, was unknown.MethodsIn this study, in a clinical aspect, we retrospectively investigated the prognostic and predictive impact of tumoral CCR7 expression in 110 mRCC patients treated with sunitinib and sorafenib, and its correlation with pre- or post-administration lymphatic involvement. Immunohistochemistry on tissue microarrays were conducted for CCR7 expression evaluation.ResultsKaplan-Meier and univariate analyses suggested high tumoral CCR7 expression as an adverse prognosticator for mRCC patients’ overall survival (OS), which was further confirmed in the multivariate analyses (P = 0.002, P = 0.003 for bootstrap). This molecule could be combined with Heng’s risk model for better patient OS prediction. High tumoral CCR7 expression was also an independent dismal predictor for patients’ progression free survival (PFS) (P = 0.010, P = 0.013 for bootstrap), and correlated with poorer best drug response. Moreover, a possible correlation of CCR7 high expression and patients’ baseline and post-administration lymph node metastasis was found.ConclusionsHigh tumoral CCR7 expression correlated with potential lymphatic involvement and poor prognosis of mRCC patients treated with tyrosine kinase inhibitors. Further external validations and basic researches were needed to confirm these results.

Dot1l expression predicts adverse postoperative prognosis of patients with clear-cell renal cell carcinoma

Background Disruptor of telomeric silencing 1-like (Dot1l), a histone methyltransferase that targets the histone H3 lysine 79 (H3K79), has been reported that its high expression is associated with various cancers, while the association between Dot1l expression and clear-cell renal cell carcinoma (ccRCC) is still unknown. Patients and Methods We retrospectively enrolled 282 patients with ccRCC undergoing nephrectomy from a single institution between 2005 and 2007, with a median follow-up of 99 months. Dot1l expression was evaluated by immunohistochemistry in clinical specimens. We compared the clinical outcomes by Kaplan-Meier survival analyses and assessed the prognostic value of Dot1l expression. Harrells concordance index (C-index) was used to assess the predictive accuracy of different prognostic models. Results Higher Dot1l expression indicated poorer OS (P<0.001) and RFS (P<0.001) in patients with ccRCC. Moreover, Dot1l expression could stratify ccRCC patients in pT stage, Fuhrman grade and SSIGN/ Leibovich subgroups, which might redefine individual risk stratification. Multivariate analyses further indicated that Dot1l expression was an independent prognostic factor for OS (P=0.007) and RFS (P=0.001). The prognostic accuracy of conventional prognostic models was notably improved with Dot1l integration. Two nomograms and calibration plots were built to predict OS and RFS for patients with ccRCC and performed better based on C-index value. Conclusion Dot1l expression is a promising independent prognostic indicator for postoperative recurrence and survival of patients with ccRCC.

High CLEC-2 expression associates with unfavorable postoperative prognosis of patients with clear cell renal cell carcinoma

Background Chemokine (C-C motif) ligand 21 (CCL21), a ligand of the chemokine (C-C motif) receptor 7, has recently been identified as an immuno-based anti-cancer molecule for its dendritic cells and T lymphocytes chemoattractant function. The aim of this study was to investigate prognostic values of CCL21 expression in metastatic renal cell carcinoma patients treated with targeted therapy. Methods This study included 111 patients with metastatic renal cell carcinoma receiving targeted therapy. CCL21 expression was analyzed by immunohistochemistry on tissue microarrays. Prognostic value of tumoral CCL21 expression and patients clinical outcomes were evaluated. RESULTS Kaplan-Meier method showed that low CCL21 expression was associated with shorter patient overall survival and progression-free survival (overall survival, P = 0.005; progression-free survival, P = 0.044). Further stratified analysis showed that low CCL21 expression was significantly associated with shorter overall survival in clear cell renal cell carcinoma patients (P = 0.017) and patients treated with sorafenib (P = 0.009). Low CCL21 expression was also an adverse independent risk factor for overall survival (hazard ratio, 2.106; 95% CI, 1.286-3.450; P = 0.003) and progression-free survival (hazard ratio 1.617; 95%CI 1.060-2.465; P = 0.026) in multivariate analyses. CCL21 expression was significantly associated with treatment best response to targeted therapy (P = 0.009). This molecule could also be combined with Heng risk model to increase its overall survival predictive accuracy. Conclusion Low CCL21 expression was a potential independent adverse prognostic biomarker for overall survival and progression-free survival for metastatic renal cell carcinoma patients treated with targeted therapy.