Published papers

Purpose: To investigate the site-specific pattern of disease recurrence and/or metastasis and the associated patient outcomes after radical nephroureterectomy (RNU) in upper tract urothelial carcinoma (UTUC). Methods: A total of 733 patients with UTUC from a retrospective multi-institutional cohort were included, with a median follow-up of 34 months. Associated patient outcomes were analyzed by multivariate analysis. To evaluate the influence of primary tumor location, we divided it into four areas: renal pelvis, and upper, middle, and lower ureter. Results: A total of 218 patients experienced disease recurrence, with the majority of relapses occurring within the first 3 years. Cumulative incidence rates of first disease recurrence at 1 and 3 years were 18.9 and 29.8 %, respectively. Of these patients, 38.5 % developed distant recurrence; 17.4 % experienced both local and distant recurrences; and 44.0 % developed isolated local recurrence. The predominant sites of distant metastasis were lung, liver, and bone. Multivariate analysis revealed that the prevalence of local recurrence and lung metastasis was significantly associated, with primary tumor location being independent of other clinicopathological variables. Lower/middle ureter tumors had a higher rate of local recurrence in the pelvic cavity, and renal pelvic tumors had a higher prevalence of distant relapse in the lungs. Similar results were obtained when rerunning the data set by excluding patients who received adjuvant chemotherapy (n = 131). Conclusions: This multi-institutional study provided a detailed picture of metastatic behavior after RNU, and primary tumor locations were associated with unique patterns of metastatic spread in UTUC patients.

Purpose: Teneligliptin is a novel DPP-4 inhibitor in development for treating type 2 diabetes mellitus that does not require dose adjustment for diabetic patients with end-stage renal disease; however, it had not been known whether or not teneligliptin is safe or potent in dialysis patients. We conducted a prospective study to assess the utility of teneligliptin for diabetic patients undergoing hemodialysis. Methods: Blood glucose, glycated albumin, and HbA1c were measured every 4 weeks, at 4, 12, 20, and 28 weeks, and every 8 weeks, respectively, for patients treated with teneligliptin (n = 14; 7 patients newly started and 7 that switched from other medications) and patients of a control group who continued ongoing antidiabetic therapy (n = 29). Results: Blood glucose level showed a 36.7 mg/dl decrease from 4 weeks in the teneligliptin group (p < 0.05). The differences in glycated albumin (at 28 w) and HbA1c (at 24 w) between the teneligliptin group and the control group were -3.1 % (p < 0.05) and -0.57 % (p = 0.057), respectively. These parameters also decreased in patients who switched from voglibose 0.2 mg t.i.d. or vildagliptin 50 mg qd after teneligliptin administration. No case with hypoglycemia was identified. One patient had the dose of a laxative administered for constipation increased; however, no patient ceased teneligliptin due to side effects. Conclusion: Teneligliptin 20 mg is well tolerated, safe, and significantly improves glycemic control in diabetic patients with end-stage renal disease. Teneligliptin 20 mg once daily was considered to be more potent than voglibose 0.2 mg t.i.d. or vildagliptin 50 mg qd.

Background and objective: Few studies have addressed the predictive value of positive urine cytology for prognosis in patients with upper tract urothelial carcinoma (UTUC). We investigated whether the status of preoperative urine cytology could provide additional prognostic information following radical nephroureterectomy (RNU). Materials and methods: The study included 474 patients with primary nonmetastatic UTUC (pTa-4N0M0) from a retrospective multi-institutional cohort. The median follow-up period was 35 months. Associations between the status of urine cytologic evaluation and outcomes were analyzed using multivariate Cox regression models. Urine cytology was evaluated preoperatively using voided samples. Disease recurrence was defined as any relapse in nonbladder lesions and was coded separately from intravesical recurrence. Results: Positive urine cytology was detected in 184 patients (38.8%) preoperatively. Disease recurrence occurred in 127 patients, while intravesical recurrence occurred in 219 patients; 83 patients died of UTUC during follow-up. Kaplan-Meier analysis revealed that only the incidence of intravesical recurrence was significantly associated with the status of urine cytologic evaluation (P = 0.024); the intravesical recurrence-free survival rates at 1 and 3 years following RNU were 61.4% and 46.2% in patients with positive urine cytology and 71.1% and 51.6% in their counterparts, respectively. Multivariate analysis showed that gender (hazard ratio [HR] = 1.74, 95% confidence interval [CI]; 1.28-2.43), tumor multifocality in RNU specimens (HR = 1.64, 95% CI; 1.09-2.47), and positive urine cytology (HR = 1.41, 95% CI; 1.08-1.85) were independent risk factors for subsequent intravesical recurrence. Conclusions: The results showed the prognostic value of positive urine cytology in patients with primary UTUC, and preoperative positive urine cytology may be associated with a significant increase in the prevalence of intravesical recurrence following RNU.

Background: Few studies have discussed the prognostic impact of serum C-reactive protein (CRP) level in upper tract urothelial carcinoma (UTUC). Objective: To investigate whether the perioperative level of CRP provides additional prognostic information following radical nephroureterectomy (RNU). Design, setting, and participants: A total of 564 patients with UTUC from a retrospective multi-institutional cohort were included. The median follow-up was 32 mo. Intervention: All patients underwent RNU without neoadjuvant chemotherapy, while 106 patients (18.8%) received adjuvant chemotherapy. Outcome measurements and statistical analysis: Associations between perioperative CRP level and outcome were assessed using multivariate analysis. A serum CRP level >0.50 mg/dl was defined as elevated. Results and limitations: Preoperative CRP (pre-CRP) level was elevated in 136 patients (24.1%). Multivariate analysis showed that pre-CRP elevation was an independent predictor of subsequent disease recurrence (hazard ratio [HR]: 1.47 for CRP 0.51-2.00; HR: 1.89 for CRP >2.00). Five-year recurrence-free survival rates were 69.2% in patients with pre-CRP levels ≤0.50 mg/dl, 54.3% in patients with pre-CRP levels between 0.51 and 2.00 mg/dl, and 35.4% in patients with pre-CRP levels >2.00 mg/dl (p < 0.001). Similar results were found in cancer-specific mortality, showing that pre-CRP elevation was an independent predictor of worse outcome (HR: 1.74 for CRP 0.51-2.00; HR: 2.31 for CRP >2.00). In a subgroup analysis of the elevated pre-CRP group, postoperative normalisation of CRP level was an independent predictor of better outcome. This study is limited by its retrospective nature as well as its heterogeneous group of patients and variable follow-up protocols resulting from the multi-institution design. Conclusions: Serum CRP may become a possible biomarker in UTUC, suggesting that patients with an elevated pre-CRP level could be predicted to have subsequent disease recurrence and cancer-specific mortality, while postoperative normalisation of CRP level was an independent predictor for prognosis.

Purpose: Effective therapeutic strategies that can achieve long-term improvement in patients with castration resistant prostate cancer are urgently needed. We recently reported that the activated PI3K/Akt/mTOR signaling pathway induced by docetaxel explains resistance to docetaxel in castration resistant prostate cancer. In this study we explored the efficacy of NVP-BEZ235, a dual PI3K and mTORC1/2 inhibitor, for docetaxel resistant castration resistant prostate cancer. Materials and Methods: We used the 2 human castration resistant prostate cancer cell lines C4-2 and C4-2AT6. At our laboratory C4-2AT6 cells were established from C4-2 under androgen ablated treatment for 6 months. We investigated the efficacy of NVP-BEZ235 monotherapy and NVP-BEZ235 combined with docetaxel in vitro and in vivo. Results: Increased phosphorylated Akt in C4-2AT6 cells was significantly inhibited by NVP-BEZ235 in a dose and time dependent manner. WST cell proliferation assay results in C4-2AT6 cells revealed that combined administration of NVP-BEZ235 and docetaxel had significant, synergistically greater cytotoxicity than NVP-BEZ235 or docetaxel monotherapy. Combined NVP-BEZ235 (40 mg/kg) and docetaxel (4 mg/kg) in vivo in a castrated mouse xenograft model inhibited C4-2AT6 tumor growth to a greater degree than in the monotherapy groups. Also, NVP-BEZ235 showed significant efficacy with docetaxel at a low concentration in vivo, suggesting that NVP-BEZ235 effectively decreased resistance to docetaxel. Conclusions: Results suggest that inhibition of the PI3K/Akt/mTOR signaling pathway by NVP-BEZ235 can overcome docetaxel resistance in human castration resistant prostate cancer. Our findings provide a molecular basis for the clinical use of combined administration of NVP-BEZ235 and docetaxel in patients with castration resistant prostate cancer.

Physiologically relevant steroid 5α-reductase (SRD5A) activity that is essential for dihydrotestosterone (DHT) biosynthesis in human castration-resistant prostate cancer (CRPC) has not been fully characterized yet. In this study to ascertain the potential SRD5A activity, we cultured two human CRPC cell lines, C4-2 and C4-2AT6, with the steroid precursor: 13C-[2,3,4]-androstenedione (13C-Adione), and analyzed the sequential biosynthesis of 13C-[2,3,4]-testosterone ( 13C-T) and 13C-[2,3,4]-DHT (13C-DHT) by liquid chromatography/mass spectrometry (LC/MS/MS). The 13C-DHT/ 13C-T concentration ratio detected by LC/MS/MS in C4-2AT6 cells appeared to reflect the SRD5A activity. The ratio in C4-2AT6 was significantly lower than that in C4-2. An increased concentration of DHT did not have a positive effect on cell proliferation, rather it exhibited inhibitory effects. 5α-reductase inhibitors did not have any inhibitory effect at clinically achievable concentrations. These results indicate that CRPC cells may have an unknown regulation system to protect themselves from an androgenic suppressive effect mediated by SRD5A activity.

Mucosa-associated lymphoid tissue (MALT) lymphoma occurs in various sites, but rarely in the urinary tract. Imaging studies of a 69-year-old male revealed a left hydronephrosis and diffuse thickening of the renal pelvic and upper ureteral wall. Retrograde pyelography revealed a narrowing in this region, and brush cytology specimens contained atypical cells. As the lesion was considered to be malignant, surgical excision was performed. Histological analysis revealed an intense lymphoid infiltrate mainly consisting of B cells. The immunohistochemistry results demonstrated that the lesion was positive for CD20 and CD79a and negative for CD5 and cyclin D1. These findings led to a diagnosis of MALT lymphoma. Pathological exploration disclosed a focally dense invasion of lymphoma cells into not only the renal pelvis, but the whole ureteral wall and surrounding tissue; therefore, the patient underwent eight courses of rituximab treatment. Diffuse invasion of lymphoma cells into the whole ureter was rarely observed. Since the surgery, the patient has survived for 78 months without evidence of a recurrence of lymphoma.

Objectives To investigate oncological outcomes and prognostic factors in patients with upper tract urothelial carcinoma (UTUC) who experienced disease recurrence after radical nephroureterectomy (RNU). Few studies have focused on the clinical courses of patients who experienced disease recurrence after RNU. Patients and Methods A total of 204 UTUC patients who experienced disease recurrence from a retrospective multi-institutional cohort were included in the present study. Associated patient outcomes were analyzed using multivariate analysis. Results The mean time from RNU to first disease recurrence was 15.0 months and ≈90% of patients experienced disease recurrence within the first 3 years after RNU. During a median follow-up of 8.1 month after disease recurrence, 165 patients died from UTUC and five patients died from other causes. In the 204 cohorts, 1- and 3-year cancer-specific survival rates were 40.2% and 9.7%, respectively, and 1- and 3-year overall survival rates were 39.5% and 9.4%, respectively. After disease recurrence, 132 patients underwent systemic chemotherapy, and a subgroup analysis of patients who underwent systemic chemotherapy multivariate analysis showed that performance status, the presence of liver metastasis and the number of recurrence sites were independently prognostic of cancer-specific and overall survival after relapsing. According to three significant variables, 1- and 3-year cancer-specific survival rates were 72.7% and 20.8% in patients with no risk factors, 46.5% and 7.5% in patients with one risk factor, and 26.4% and 4.4% in patients with two or three risk factors, respectively (P < 0.001). Conclusions Most patients died from UTUC within 3 years, even though systemic chemotherapies were administered after relapsing. Multivariate analysis showed that performance status, the presence of liver metastasis and the number of recurrence sites were independently related to poor survival after systemic chemotherapy.

Background: Bcl-xL has an important role in the control of cell death through its inhibition of apoptosis. The aim of this study was to investigate the clinicopathological significance of Bcl-xL in upper urinary tract urothelial carcinoma (UTUC) and the therapeutic effect of targeting Bcl-xL protein in urothelial carcinoma (UC) cells. Methods: We evaluated the immunohistochemical expression of Bcl-xL in 175 UTUC patients to determine the clinical role of BclxL expression in clinical outcome. We used bafilomycin A1 (BMA) as a specific inhibitor of Bcl-xL to examine the biological effects in UC cells in vitro and in vivo. Results: Immunohistochemical analysis of Bcl-xL expression revealed that patients with a high Bcl-xL score had a significantly lower 5-year cancer-specific survival (CSS) rate (53.2%) than those with a low Bcl-xL score (77.2%) (P = 0.0011). Multivariate analysis indicated that a high Bcl-xL score was an independent prognostic factor of CSS (P = 0.023). BMA inhibited UMUC-3 cell proliferation in vitro by induction of apoptosis. Treatment with BMA significantly inhibited tumour growth in UMUC-3 tumours in this mouse xenograft model accompanied by an elevated apoptosis induction. Conclusion: Bcl-xL appears to be a significant molecular marker for the prognosis of UTUCs. Targeting Bcl-xL may be a promising therapeutic strategy for patients with UC.

Background:We recently isolated vasohibin-1 (VASH1), a novel angiogenic molecule that is specifically expressed in activated vascular endothelial cells (ECs), and the status of VASH1 expression has been documented in various cancer angiogenesis. The aim of this study was to assess the prognostic value of VASH1 expression in prostate cancer (PCa).Methods:In this study, we retrospectively analysed the clinical records and evaluated the VASH1 expression of tumour microvessels in 167 patients with PCa who underwent radical prostatectomy. We immunohistochemically examined the microvessels positive for anti-CD34 as microvessel density (MVD) and the microvessels with activated ECs positive for VASH1 density.Results:We found that the VASH1 expression was restricted to ECs in the tumour stroma. VASH1 density was significantly associated with pathological T stage, Gleason score and MVD. The 5-year PSA recurrence-free survival rate was 58.8% in patients with higher VASH1 density (≧12 per mm 2) and 89.1% in patients with lower VASH1 density (<12 per mm 2), respectively (P<0.001). Microvessel density was not an independent predictor of PSA recurrence. Multivariate analysis revealed that high VASH1 density was an independent prognostic indicator of PSA recurrence (P=0.007, HR=2.950).Conclusion:VASH1 density represents a clinically relevant predictor of patient prognosis and can be a new biomarker that would provide additional prognostic information in PCa.

Purpose: The current study was done to determine whether atorvastatin, the HMGCoA (3-hydroxy-3-methylglutaryl CoA) reductase inhibitor, could decrease renal transforming growth factor-β (TGF-β) levels in unilateral ureteral obstruction (UUO) and concomitantly affect renal tissue damage in UUO. Materials and Methods: Atorvastatin (20 mg/kg) was administered to rats 1 day prior to UUO and every day thereafter. Kidneys were harvested at day 14 after UUO. Tissue TGF-β was measured by bioassay using mink lung epithelial cells. Renal tubular proliferation and apoptosis were detected by immunostaining proliferating cell nuclear antigen and polyclonal antisingle strand DNA antibody, respectively. Fibrosis was assessed by measuring collagen deposition with trichrome stained slides. Interstitial leukocyte was detected by immunostaining CD45. Results: TGF-β bioassay showed that the obstructed kidney in the control group contained significantly higher TGF-β than the unobstructed kidney in the control group (mean ± SD 79.1 ± 48.5 vs 28.7 ± 13.7 pg/mg tissue) and atorvastatin significantly decrease tissue TGF-β in the obstructed kidney (53.4 ± 37.0 pg/mg tissue). Immunostaining polyclonal antisingle strand DNA antibody demonstrated that the obstructed kidney in the control group has significantly more tubular apoptosis than the unobstructed counterpart (4.8 ± 2.8 vs 2.1 ± 1.2 nuclei per high power field) and atorvastatin significantly decreased renal tubular apoptosis in the obstructed kidney (1.1 ± 0.7 nuclei per high power field). In addition, immunostaining proliferating cell nuclear antigen showed that the obstructed kidney in the atorvastatin group had significantly more renal tubular proliferation than the obstructed kidney in the control group (48.7 ± 20.8 vs 17.3 ± 10.6 per high power field). Control obstructed kidney showed significantly more fibrosis, which was also blunted by atorvastatin. Conclusions: Atorvastatin significantly decreases tissue TGF-β, resulting in a decrease in tubular damage and interstitial fibrosis. This suggests that atorvastatin is a promising agent for preventing renal tubular damage in UUO.

Purpose: We determined whether the novel nuclear factor κB activation inhibitor dehydroxymethylepoxyquinomicin (DHMEQ), which is derived from epoxyquinomicin C, affects renal inflammatory responses in unilateral ureteral obstruction. Materials and Methods: DHMEQ (8 mg./kg.) was administered to rats 1 day after unilateral ureteral obstruction and every day thereafter. Kidneys were harvested at day 7 after unilateral ureteral obstruction. Tissue nuclear factor κB activity and transforming growth factor-β were determined by electrophoretic mobility shift assay and bioassay using mink lung epithelial cells, respectively. Renal tubular proliferation and apoptosis were detected by immunostaining proliferating cellular nuclear antigen and the TUNEL (Intergen, Purchase, New York) assay, respectively. Leukocyte infiltration was detected by immunostaining for CD45. Fibrosis was assessed by measuring tissue hydroxyproline content. Results: Unilateral ureteral obstruction for 7 days significantly activated nuclear factor κB, induced tubular apoptosis, proliferation and interstitial fibrosis in the obstructed kidney of the control group compared with their unobstructed counterparts (30.3 ± 4.5 nuclei per high power field versus 1.7 ± 0.4, 25.7 ± 3.3 nuclei per high power field versus 3.2 ± 0.4 and 6.2 ± 0.3 μmol. hydroxyproline per gm. tissue versus 3.4 ± 0.1, respectively). Conversely daily administration of DHMEQ (8 mg./kg.) significantly inhibited nuclear factor κB activation and decreased mean tubular apoptosis (9.5 ± 2.1 nuclei per high power field), proliferation (10.2 ± 2.4 nuclei per high power field) and interstitial fibrosis (4.9 ± 0.4 μmol. hydroxyproline per gm. tissue) in the obstructed kidney. Conclusions: Specific inhibition of nuclear factor κB can prevent inflammatory renal responses, suggesting that targeting nuclear factor κB activation may be feasible for preventing inflammatory kidney diseases.