Serum interferon alpha receptor 2 mRNA may predict efficacy of interferon alpha with/without low-dose sorafenib for metastatic clear cell renal cell carcinoma.

BACKGROUND: Interferon (IFN) alpha is one of the central agents in immunotherapy for renal cell carcinoma (RCC). It acts by binding to the IFN-alpha receptor (IFNAR). We previously reported that increased tumor expression of IFNAR2 mRNA was associated with the metastatic potential and progression of RCC, as well as with a poor response of metastatic RCC to IFN-alpha therapy. This study investigated the influence of serum IFNAR2 in RCC patients. METHODS: We measured serum IFNAR2 mRNA levels and quantified IFNAR mRNA expression in paired tumor and non-tumor tissues from the surgical specimens of 66 consecutive RCC patients by the real-time reverse transcription polymerase chain reaction (RT-PCR). We also measured phosphorylated Akt (Ser-473) and phosphorylated-S6 ribosomal protein (Ser-235/236) proteins levels in paired tumor and non-tumor tissues of patients with metastatic RCC by Western blotting. RESULTS: The serum level of IFNAR2 mRNA was not associated with its tumor tissue level. Serum IFNAR2 mRNA was positively correlated with tumor size (P < 0.05), but not with tumor grade, pT stage, metastasis, microscopic vascular invasion, or serum C-reactive protein. Serum levels of IFNAR2 mRNA were significantly higher in patients with a good response to IFN-alpha ± sorafenib than in those with a poor response (P < 0.0001). Tumor tissue IFNAR2 mRNA levels and phosphorylated-S6 ribosomal protein (Ser-235/236) levels were associated with metastatic potential (P < 0.001 and P < 0.01, respectively), and patients with a low IFNAR2 mRNA level and low phosphorylated Akt (Ser-473) protein level in the primary tumor showed a good response to IFN-α ± sorafenib (IFN-α ± Sor: CR-PR) (P < 0.01 and P < 0.05, respectively). Kaplan-Meier survival analysis showed that a higher serum IFNAR2 mRNA level was associated with longer overall survival of treated patients (P < 0.05), while a higher tumor tissue IFNAR2 mRNA level was related to shorter overall survival (P < 0.01). CONCLUSIONS: Our findings suggest that a high serum level of IFNAR2 mRNA may be a useful marker for predicting the response of metastatic RCC to IFN-alpha ± sorafenib therapy.

Increased Rac1 activity and Pak1 overexpression are associated with lymphovascular invasion and lymph node metastasis of upper urinary tract cancer.

BACKGROUND: Lymphovascular invasion (LVI) and lymph node metastasis are conventional pathological factors associated with an unfavorable prognosis of urothelial carcinoma of the upper urinary tract (UC-UUT), but little is known about the molecular mechanisms underlying LVI and nodal metastasis in this disease. Rac1 small GTPase (Rac1) is essential for tumor metastasis. Activated GTP-bound Rac1 (Rac1 activity) plays a key role in activating downstream effectors known as Pak (21-activated kinase), which are key regulators of cytoskeletal remolding, cell motility, and cell proliferation, and thus have a role in both carcinogenesis and tumor invasion. METHODS: We analyzed Rac1 activity and Pak1 protein expression in matched sets of tumor tissue, non-tumor tissue, and metastatic lymph node tissue obtained from the surgical specimens of 108 Japanese patients with UC-UUT. RESULTS: Rac1 activity and Pak1 protein levels were higher in tumor tissue and metastatic lymph node tissue than in non-tumor tissue (both P < 0.0001). A high level of Rac1 activity and Pak1 protein expression in the primary tumor was related to poor differentiation (P < 0.05), muscle invasion (P < 0.01), LVI (P < 0.0001), and lymph node metastasis (P < 0.0001). Kaplan-Meier survival analysis showed that an increase of Rac1 activity and Pak1 protein was associated with a shorter disease-free survival time (P < 0.01) and shorter overall survival (P < 0.001). Cox proportional hazards analysis revealed that high Rac1 activity, Pak1 protein expression and LVI were independent prognostic factors for shorter overall and disease-free survival times (P < 0.01) on univariate analysis, although only Pak1 and LVI had an influence (P < 0.05) according to multivariate analysis. CONCLUSIONS: These findings suggest that Rac1 activity and Pak1 are involved in LVI and lymph node metastasis of UC-UUT, and may be prognostic markers for this disease.

Expression of RhoA mRNA and activated RhoA in urothelium and smooth muscle, and effects of a Rho-kinase inhibitor on contraction of the porcine urinary bladder.

AIMS: To investigate the concentration and activity of RhoA in detrusor and urothelium, as well as the effects of a Rho-kinase inhibitor, Y-27632 [(+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride], on contraction of the pig urinary bladder. METHODS: The concentration of RhoA mRNA was studied by the real-time RT-PCR and activated RhoA enzyme was studied by activation assay and Western blotting. In functional studies, the response to Y-27632 was examined in bladder strips with or without urothelium. RESULTS: The concentration of RhoA mRNA (n = 38) and activated RhoA enzyme (n = 19) were greater in urothelium than in detrusor. Tension decrease after administration of Y-27632 (1 nM to 100 microM) was significantly greater in tissues with urothelium than in tissues without urothelium, after pre-contraction with KCl (decrease by 52.0 +/- 4.6% vs. 28.0 +/- 6.8%, respectively; P = 0.0088) or with carbachol (decrease by 53.1 +/- 7.2% vs. 30.6 +/- 5.8%, respectively; P = 0.0035). Maximum contraction on CRC to carbachol was reduced significantly after administration of 3, 10, and 30 microM Y-27632 (to 72.2 +/- 6.8%, 43.9 +/- 7.1%, and 25.0 +/- 5.5%, respectively, of the control value) in strips with intact urothelium (n = 36), but was reduced only at 10 and 30 microM (to 66.7 +/- 8.3% and 85.6 +/- 2.6%, respectively) in tissues without urothelium (n = 20). Inhibitory effect of Y-27632 (3-30 microM) on the response to electrical field stimulation at 20 and 50 Hz was also greater in tissues with intact urothelium than in tissues without urothelium. CONCLUSIONS: The concentration of RhoA mRNA and activated RhoA enzyme were greater in urothelium than in detrusor. Y-27632 showed a stronger inhibitory effect in detrusor with intact urothelium than in dose without urothelium.

[Retroperitoneal ganglioneuroma: a case report].

A 67-year-old male presented for examination of a retroperitoneal tumor, incidentally found by abdominal computed tomography (CT). CT and magnetic resonance imaging (MRI) revealed a round heterogeneous tumor, 10 cm in diameter, at the left renal hilus and involving the left renal vein. The tumor was low-intensity on T1-weighted MRI imaging, and high-intensity on T2-weight MRI imaging. The tumor was easily resected via a transabdominal approach. The pathological diagnosis was ganglioneuroma.