Preoperative systemic inflammation response index indicates poor prognosis in patients treated with resection of renal cell carcinoma with inferior vena cava tumor thrombus.

OBJECTIVES: To evaluate the prognostic value of systemic Inflammation Response Index (SIRI) in patients with renal cell carcinoma and inferior vena cava tumor thrombus (RCC-IVCTT) treated with radical nephrectomy and IVCTT thrombectomy. METHODS: We retrospectively reviewed the clinical data of 144 consecutive patients with RCC-IVCTT who received radical nephrectomy and IVCTT thrombectomy at our center from January 2008 to August 2018. Receiver operating characteristic curve analysis was performed to calculate the optimal cutoff value of preoperative SIRI. Kaplan-Meier analysis was used to compare progression-free survival (PFS) and overall survival (OS). Univariable and multivariable Cox proportional hazard models were constructed to identify the independent prognostic factor for OS and PFS. The Harrell concordance index (C-index) was used to assess whether preoperative SIRI could improve the predictive accuracy of the existent prognostic models including Tumor, Node, Metastasis (TNM) stage model, University of California at Los Angeles Integrated Staging System (UISS) model and Stage, Size, Grade and Necrosis (SSIGN) model. RESULTS: Elevated preoperative SIRI was significantly correlated with clinicopathologic features that are associated with tumor progression. Patients were divided into a high or low SIRI group by the optimal cutoff value of SIRI. Patients in the high SIRI group had longer postoperative hospital stays and lost more blood during surgery. Kaplan Meier curve showed that high SIRI was correlated with decreased OS (P = 0.036) and PFS (P = 0.039) for patients with RCC-IVCTT after surgery. Increased preoperative SIRI was an independently risk factor for decreased OS (P = 0.038) and PFS (P = 0.021). To evaluate PFS, integrating SIRI to each model led to an increased predictive accuracy of 13.2% for TNM staging model (P = 0.007), 14.4% for UISS model (P = 0.000), 12.9% for SSIGN model (P = 0.003). To evaluate OS, integrating SIRI to each model led to an increased predictive accuracy of 13.2% for TNM staging model (P = 0.006), 12.8% for UISS model (P = 0.004), 12.4% for SSIGN model (P = 0.008). CONCLUSIONS: Preoperative SIRI serves as an independent predictor of prognosis for patients with RCC-IVCTT after surgery. Adding preoperative SIRI to the established prognostic models enhance their predictive accuracy.

CD146 as a Prognostic-Related Biomarker in ccRCC Correlating With Immune Infiltrates.

BACKGROUNDS: CD146 is highly expressed in various malignant tumors and associated with the poor prognosis. However, the role of CD146 in clear cell renal cell carcinoma (ccRCC) is still unknown. This study aimed to identify the role of CD146 in ccRCC by integrated bioinformatics analysis. METHODS: CD146 mRNA expression and methylation data in ccRCC was examined using the TIMER, UALCAN, and MethSurv databases. CD146 expression in paraffin-embedded tissues (140 cancer samples and 140 paracancer tissues) from our cohort were examined by immunohistochemistry assay. The LinkedOmics database was used to study the signaling pathways related to CD146 expression. TIMER and TISIDB were used to analyze the correlations among CD146, CD146-coexpressed genes, tumor-infiltrating immune cells, and immunomodulators. The relationship between CD146 and drug response in renal cancer cell lines was analyzed by the CTRP and CCLE databases. RESULTS: The mRNA and protein levels of CD146 were elevated in ccRCC tissues than that in paracancer tissues. The DNA methylation of CD146 in ccRCC tissues were lower than that in normal tissues. Importantly, high CD146 expression was associated with poor prognosis in patients with ccRCC. Furthermore, multivariate Cox regression analysis showed that CD146 was an independent prognostic factor in ccRCC. GO and KEGG pathway analyses indicated the co-expressed genes of CD146 were mainly related to a variety of immune-related pathways, including Th1 and Th2 cell differentiation, Th17 cell differentiation, and leukocyte transendothelial migration. Our data demonstrated that the expression and methylation status of CD146 were strongly correlated with immune infiltration levels, immunomodulators, and chemokines. Further, the sensitivity and resistance of renal cancer cell lines to some drugs were related to CD146 expression. CONCLUSIONS: Our study highlights the clinical significance of CD146 in ccRCC and provides novel insights into the immune function of CD146 in the tumor microenvironment.

FGL1 as a Novel Mediator and Biomarker of Malignant Progression in Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC), which is the most prevalent renal cell carcinoma subtype, has a poor prognosis. Emerging strategies for enhancing the immune response in ccRCC therapy are currently being investigated. Fibrinogen-like Protein 1(FGL1) is a novel mechanism that tumors may use to evade the immune system by binding LAG-3 and negatively regulating T cells. In this study, we aimed at investigating the underlying mechanism of FGL1 in ccRCC, and its expression and prognostic value. We found that FGL1 was upregulated in tumor tissues and plasma specimens of ccRCC patients. High FGL1 expression predicted a poor prognosis for ccRCC patients. We also discovered that overexpression of FGL1 enhances RCC cell migration, invasion, and metastasis by activating the epithelial-to-mesenchymal transition (EMT). Consistent with these results, we identified a significant positive correlation between expression of FGL1 and EMT-related genes through tissue microarray analysis. Gene-expression analysis revealed that FGL1-deficient ccRCC cell lines had altered transcriptional output in inflammatory response, cell-cell signaling, negative regulation of T cell activation, and intracellular signal transduction. Depletion of FGL1 significantly inhibited tumor growth and lung metastasis in orthotopic xenograft mouse model. Infiltration of myeloid-derived CD11b+ and Ly6G+ immune cells in tumor microenvironment (TME) was strikingly decreased when FGL1 expression reduced. Therefore, increased FGL1 expression in ccRCC is positively correlated with poor prognosis. Mechanistically, FGL1 facilitates the EMT process and modulates TME, which promotes ccRCC progression and metastasis. Consequently, targeting FGL1 can potentially improve clinical outcome of ccRCC patients.