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Purpose: Vascular endothelial growth factor tyrosine kinase inhibitors (TKIs) have been the standard of care for advanced and metastatic clear cell renal cell carcinoma (ccRCC). However, the therapeutic effect of TKI monotherapy remains unsatisfactory given the high rates of acquired resistance to TKI therapy despite favorable initial tumor response. Materials and Methods: To define the TKI-resistance mechanism and identify new therapeutic target for TKI-resistant ccRCC, an integrative differential gene expression analysis was performed using acquired resistant cohort and a public dataset. Sunitinib-resistant RCC cell lines were established and used to test their malignant behaviors of TKI resistance through in vitro and in vivo studies. Immunohistochemistry was conducted to compare expression between the tumor and normal kidney and verify expression of pathway-related proteins. Results: Integrated differential gene expression analysis revealed increased interferon-induced transmembrane protein 3 (IFITM3) expression in post-TKI samples. IFITM3 expression was increased in ccRCC compared with the normal kidney. TKI-resistant RCC cells showed high expression of IFITM3 compared with TKI-sensitive cells and displayed aggressive biologic features such as higher proliferative ability, clonogenic survival, migration, and invasion while being treated with sunitinib. These aggressive features were suppressed by the inhibition of IFITM3 expression and promoted by IFITM3 overexpression, and these findings were confirmed in a xenograft model. IFITM3-mediated TKI resistance was associated with the activation of TRAF6 and MAPK/AP-1 pathways. Conclusions: These results demonstrate IFITM3-mediated activation of the TRAF6/MAPK/AP-1 pathways as a mechanism of acquired TKI resistance, and suggest IFITM3 as a new target for TKI-resistant ccRCC.

Thermal ablation has been established as an alternative treatment for renal cell carcinoma (RCC) in patients who are poor candidates for surgery. However, while American and European guidelines have been established for American and European patients, respectively, no ablation guidelines for Asian patients with RCCs have been established many years after the Asian Conference on Tumor Ablation (ACTA) had been held. Given that Western guidelines are difficult to apply to Asian patients due to differences in body habitus, economic status, and insurance systems, the current review sought to establish the first version of the ACTA guidelines for treating a RCC with thermal ablation.

Purpose: This study aimed to compare progression-free survival (PFS), overall survival (OS), and cancer-specific survival (CSS) in Heng intermediate-risk patients with metastatic renal cell carcinoma (mRCC) treated with first-line immunotherapy (IT) or targeted therapy (TT). Materials and Methods: From 2000 to 2017, a total of 186 intermediate-risk mRCC patients treated with first-line IT (n=64, 34.4%) or TT (n=122, 65.6%) were retrospectively evaluated for PFS, OS, and CSS using the Kaplan–Meier method with log-rank test and Cox proportional hazards models for their risk factors with a p-value for significance of

Purpose: Renal cell carcinoma is a heterogeneous kidney cancer, and over 403,000 cases were reported worldwide in 2018. Current methods for studying renal cell carcinoma are limited to two-dimensional (2D) culture of primary cell lines and patient-derived xenograft models. Numerous studies have suggested that 2D culture poorly represents the diversity, heterogeneity, and drug-resistance of primary tumors. The time and cost associated with patient-derived xenograft models poses a realistic barrier to their clinical utility. As a biomimetic model, patient-derived three-dimensional (3D) organoid culture can overcome these disadvantages and bridge the gap between in vitro cell culture and in vivo patient-derived xenograft models. Here, we establish a patient-derived 3D organoid culture system for clear cell renal cell carcinoma and demonstrate the biomimetic characteristics of our model with respect to both primary kidney cancer and conventional 2D culture. Materials and Methods: Normal renal tissues and tumor tissues were collected from patients with clear cell renal cell carcinoma. The dissociated cells were cultured as conventional 2D culture and 3D organoid culture. The biomimetic characteristic of the two cultures were compared. Results: Compared with 2D culture, the 3D organoid cultures retained the characteristic lipid-rich, clear cell morphology of clear cell renal cell carcinoma. Carbonic anhydrase 9 and vimentin were validated as biomarkers of renal cell carcinoma. Expression of the two validated biomarkers was more enhanced in 3D organoid culture. Conclusions: Patient-derived 3D organoid culture retains the characteristics of renal cell carcinoma with respect to morphology and biomarker expression.

Purpose: To evaluate the significance of preoperative and follow-up neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as prognostic factors for recurrence in patients with non-metastatic clear cell renal cell carcinoma (NMCCRCC). Materials and Methods: We retrospectively reviewed the medical records of 309 patients with NMCCRCC who underwent radical or partial nephrectomy. The prognostic significance of various clinicopathological variables, preoperative NLR (pNLR) and PLR (pPLR), and NLR and PLR at recurrence or quasi-recurrence (rNLR and rPLR) for recurrence-free survival (RFS) was analyzed. Results: At mean follow-up of 93 months, 44 patients (14.2%) developed recurrence. In the univariate analysis, clinical presentation, tumor size, pathologic tumor stage, Fuhrman grade, pNLR, pPLR and rNLR were significant prognostic factors for RFS. In the multivariate analysis using pNLR and pPLR as continuous variables, tumor size, pathologic tumor stage and pPLR were independent prognostic factors for RFS. In the multivariate analysis using pNLR and pPLR as dichotomous variables, tumor size, pathologic tumor stage, Fuhrman grade and pNLR ≥1.7 were independent prognostic factors for RFS. In multivariate analyses using rNLR and rPLR, only tumor size and pathologic tumor stage were independent prognostic factors for RFS. In a subset of patients with recurrence or at least 42 months follow-up without recurrence, rNLR ≥1.9 was significantly associated with worse RFS, albeit without independent significance. Conclusions: pNLR and pPLR are independent prognostic factors for RFS in patients with NMCCRCC. We propose that postoperative follow-up NLR of 1.9 and higher with one or more adverse clinicopathological factors should prompt radiologic evaluation for possible metastasis.