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Background: We aimed to evaluate the prognostic significance of hyponatremia in patients with metastatic clear cell renal cell carcinoma (RCC) treated with a tyrosine kinase inhibitor (TKI)., Methods: This study included a total of 209 consecutive Japanese patients undergoing radical nephrectomy who were subsequently treated with either sunitinib or sorafenib as a first-line therapy for metastatic clear cell RCC. In this series, normal natremia and hyponatremia prior to the introduction of TKI was defined as a serum sodium level >136 and ≤136 mEq/L, respectively., Results: Patients were classified into 165 (78.9 %) with normal natremia and 44 (21.1 %) with hyponatremia. Progression-free survival (PFS) in the hyponatremia group (median 10.0 months) was significantly poorer than that in the normal natremia group (median 28.4 months). Overall survival (OS) in the hyponatremia group (median 20.9 months) was significantly poorer than that in the normal natremia group (median 38.5 months). Multivariate analyses identified hyponatremia, in addition to the existence of sarcomatoid components in radical nephrectomy specimens, high serum C-reactive protein levels, and low serum albumin levels, as poor prognostic factors for both PFS and OS. There were significant differences in both PFS and OS according to the number of these 4 independent risk factors that were positive (negative for any risk factors vs positive for 1 or 2 risk factors vs positive for 3 or 4 risk factors)., Conclusions: Hyponatremia appears to be one of the most powerful prognostic predictors in Japanese patients treated with a TKI as a first-line agent against metastatic clear cell RCC.

Purpose: The objective of this study was to investigate the mechanism mediating the acquisition of a resistant phenotype to sorafenib in renal cell carcinoma (RCC)., Methods: A parental mouse RCC cell line, RenCa (RenCa/P), was continuously exposed to increasing doses of sorafenib, and a cell line resistant to sorafenib (RenCa/R), showing an approximately sixfold higher IC(50) than that of RenCa/P, was established. Changes in the expression of several molecules in these cell lines following sorafenib treatment were evaluated by western blotting, and the effects of sorafenib treatment on the in vivo growth patterns were compared., Results: There were no significant differences in sensitivities to potential agents against RCC between RenCa/P and RenCa/R. Among several apoptosis-related proteins, the expression of clusterin in RenCa/R was significantly greater than that in RenCa/P. Following treatment with sorafenib, the expression level of phosphorylated p44/42 mitogen-activated protein kinase (MAPK) in RenCa/P, but not that in RenCa/R, was significantly decreased. Furthermore, additional treatment with a specific inhibitor of the MAPK signaling pathway significantly increased the sensitivity of RenCa/R to sorafenib, but not that of RenCa/P. There was no significant difference between the in vivo growth patterns of RenCa/P and RenCa/R in mice without sorafenib treatment; however, the growth inhibitory effect of sorafenib on the RenCa/P tumor was significantly greater than that on the RenCa/R tumor., Conclusions: These findings suggest that the upregulation of clusterin and continuous activation of the MAPK pathway during sorafenib treatment may be involved in the acquisition of a resistance to sorafenib in RCC.

Background: The aim of this study was to evaluate the use of sunitinib as third-line therapy for metastatic renal cell carcinoma (mRCC)., Methods: This study included a total of 35 consecutive Japanese patients with mRCC who were treated with third-line sunitinib after sequential use of cytokine therapy (interferon-α and/or interleukin-2) and sorafenib between September 2008 and December 2010. The clinical outcomes of third-line sunitinib in these patients were retrospectively reviewed., Results: Of the 35 patients, 3 (8.6%), 28 (80.0%) and 4 (11.4%) were judged to have a partial response, stable disease and progressive disease, respectively, as the best response to sunitinib. The median progression-free survival (PFS) and overall survival (OS) of these patients following the introduction of sunitinib were 10.9 and 14.2 months, respectively. Of several factors examined, response to sorafenib and performance status appeared to be independently associated with PFS and OS, respectively, on multivariate analyses. The common grade 3-4 adverse events related to third-line sunitinib were thrombocytopenia (51.4%), neutropenia (42.9%) and hypertension (14.3%)., Conclusion: Despite the low response rate, third-line sunitinib is well tolerated and could provide comparatively favorable prognostic outcomes in Japanese patients with mRCC after first-line cytokine therapy and second-line sorafenib; therefore, treatment with sunitinib could be one on the therapeutic options for patients with mRCC even after the failure of sequentially performed systemic therapies, such as cytokine therapy and sorafenib.

Objectives: To investigate the expression levels of multiple molecular markers in radical nephrectomy specimens from patients with metastatic renal cell carcinoma (RCC) treated with sorafenib in order to identify factors predicting susceptibility to this agent., Materials and Methods: This study included 45 consecutive patients undergoing radical nephrectomy for clear cell RCC who were diagnosed as having metastatic diseases refractory to cytokine therapy and subsequently treated with sorafenib. Expression levels of 19 molecular markers involved in the regulation of apoptosis, cell cycle, signal transduction, and angiogenesis in primary RCC specimens were measured by immunohistochemical staining., Results: There was no molecular marker having significant impact on the prediction of response to sorafenib. However, progression-free survival (PFS) was significantly associated with the expression levels of Bcl-xL and platelet-derived growth factor receptor (PDGFR)-α in addition to the presence of bone metastasis and C-reactive protein level on univariate analysis. Of these significant factors, PDGFR-α expression and the presence of bone metastasis appeared to be independently related to PFS by multivariate analysis. Furthermore, there were significant differences in PFS according to positive numbers of these 2 independent risk factors; that is, disease progression occurred in 2 of 7 patients who were negative for risk factor, 19 of 34 positive for a single risk factor, and 6 of 6 positive for both risk factors., Conclusions: Collectively, these findings suggest that it would be useful to consider expression levels of potential molecular markers, particularly PDGFR-α, as well as clinical parameters to select metastatic RCC patients likely to benefit from treatment with sorafenib., (Copyright © 2013 Elsevier Inc. All rights reserved.)