Atsushi Kyan

Prospective Randomized Phase II Trial of a Single Early Intravesical Instillation of Pirarubicin (THP) in the Prevention of Bladder Recurrence After Nephroureterectomy for Upper Urinary Tract Urothelial Carcinoma: The THP Monotherapy Study Group Trial

PURPOSE We evaluated the efficacy of a single early intravesical instillation of pirarubicin (THP) in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma (UUT-UC). PATIENTS AND METHODS From December 2005 to November 2008, 77 patients clinically diagnosed with UUT-UC from 11 institutions participating in the Tohoku Urological Evidence-Based Medicine Study Group were preoperatively enrolled in this study. Patients were randomly assigned to receive or not receive a single instillation of THP (30 mg in 30 mL of saline) into the bladder within 48 hours after nephroureterectomy. Cystoscopy and urinary cytology were repeated every 3 months for 2 years or until the occurrence of first bladder recurrence. RESULTS Seventy-two patients were evaluable for efficacy analysis, 21 of whom had a subsequent bladder recurrence. Significantly fewer patients who received THP had a recurrence compared with the control group (16.9% at 1 year and 16.9% at 2 years in the THP group v 31.8% at 1 year and 42.2% at 2 years in the control group; log-rank P = .025). No remarkable adverse events were observed in the THP-treated group. Based on multivariate analysis, THP instillation (hazard rate [HR], 0.26; 95% CI, 0.07 to 0.91; P = .035) and open surgery (HR, 0.28; 95% CI, 0.09 to 0.84; P = .024) were independently predictive of a reduced incidence of bladder recurrence. CONCLUSION In this prospective randomized phase II study, a single intravesical instillation of THP seemed to reduce bladder recurrence after nephroureterectomy. A phase III, large-scale, multicenter study is needed to confirm these observations.

N-Acetylglucosaminyltransferase V and β1-6 Branching N-Linked Oligosaccharides Are Associated with Good Prognosis of Patients with Bladder Cancer

Purpose:N-acetylglucosaminyltransferase V (GnT-V) is an enzyme that catalyzes β1-6 branching of N-acetylglucosamine on asparagine (N)-linked oligosaccharides (N-glycan) of cell proteins. We examined the relationship between GnT-V expression and clinicopathologic features of the patients with bladder cancer. Experimental Design: We immunohistochemically examined GnT-V expression in paraffin-embedded bladder cancer specimen using anti-GnT-V monoclonal antibody. We compared GnT-V expression with cause-specific survival of the patients with bladder cancer treated by radical cystectomy. Kaplan-Meier survival curves were generated to show the cause-specific survival. Univariate and multivariate analyses were carried out to compare GnT-V expression with other clinical and pathologic variables. We also evaluated mRNA expression of GnT-V and N-linked oligosaccharide structure in bladder cancer specimens. Results: Immunohistochemistry revealed that GnT-V expression inversely correlated with tumor grade and stage. The incidence of positive GnT-V expression in bladder cancer was significantly higher in low-grade/superficial cancer than in high-grade/invasive cancer. The patients whose tumor was positive for GnT-V survived significantly longer than those whose tumor was negative for GnT-V. Univariate and multivariate analyses revealed that GnT-V expression was an independent predictor of prognosis of the patient. The expression of GnT-V mRNA determined by reverse transcription-PCR was consistent with the results with immunohistochemistry for tumor samples. Carbohydrate structural analysis revealed that superficial bladder cancer is rich in branched N-linked oligosaccharides, for which biosynthesis GnT-V is responsible. Conclusions: GnT-V and its resultant β1-6 branching N-linked oligosaccharides are closely related to low malignant potential and good prognosis of the patients with bladder cancer.

Core 2 N-acetylglucosaminyltransferase-1 expression induces aggressive potential of testicular germ cell tumor.

We studied orchiectomy specimens from 130 patients immuhistochemically with testicular germ cell tumor (TGCT) using anti‐core 2 N‐acetylglucosaminyltransferase‐1 (C2GnT‐1) antibody. The incidence of C2GnT‐1 positivity in stage I disease (29.5%, 21/71) was significantly lower than that in higher stages (84.7%, 50/59) (P < 0.001, χ2 test). This significant difference was also found when the cases were divided into seminoma and NSGCT according to histopathological classification. Kaplan‐Meier plots and the log rank test showed that in the patients with stage I seminoma, C2GnT‐1‐positive cases had a higher risk for recurrence (P < 0.001). This was also the case with the patients with stage I NSGCT (P < 0.001). To determine whether C2GnT‐1 promotes aggressive behavior of cancer cells, a C2GnT‐1‐negative human TGCT cell line, JKT‐1, was stably transfected with a mammalian expression vector containing C2GnT‐1 cDNA. In vitro assays revealed that JKT‐1‐C2 cells are more invasive than mock transfectants, although there are no differences in proliferation activity. When orthotopically inoculated into athymic nude mice, JKT‐1‐C2 cells produced larger testicular tumors extending to the retroperitoneum with mesenteric metastasis, while mock transfectants produced small tumors without metastasis (P < 0.01, Mann‐Whitneys U‐test). When injected via the tail vein, JKT‐1‐C2 cells produced a number of metastatic lung foci. In contrast, mock transfectants produced a small number of nodules (p < 0.01, Mann‐Whitneys U‐test). These results strongly suggest that C2GnT‐1 enhances the metastatic potential of TGCT and may be a reliable biomarker for aggressive potential of TGCT.

Functional Correlation of Trophinin Expression with the Malignancy of Testicular Germ Cell Tumor

Trophinin is a membrane protein that is potentially involved in human embryo implantation by mediating homophillic cell adhesion between trophoblastic cells and endometrial cells. Trophinin expression by maternal cells may be induced by the embryo that secretes human chorionic gonadotropin (hCG). Because the process of tumor metastasis resembles that of trophoblast invasion and proliferation during embryo implantation, we hypothesized that testicular cancers that synthesize hCG express trophinin thus becoming aggressive trophoblast-like cells. We screened paraffin-embedded orchiectomy specimens of 158 patients with testicular germ cell tumor by immunohistochemistry using antitrophinin antibody. This screening identified trophinin-positive specimens with the frequencies 39 of 91 (43%) in stage I, 14 of 24 (58%) in stage II, and 41 of 43 (95%) in stage III (P < 0.001). Thus, trophinin expression positively correlates with clinical stage. Remarkably, trophinin was found in all of the cases (33 of 33) with lung metastasis. The levels of serum hCG-β were significantly higher in the patients with trophinin-positive tumors than those with trophinin-negative tumors (P = 0.004). To determine whether trophinin promotes aggressiveness of the cell, trophinin-negative human seminona cell line JKT-1 was stably transfected with a mammalian expression vector containing trophinin cDNA. In vitro assays revealed that trophinin-expressing JKT-1-Tro cells are more invasive than JKT-1-mock cells, whereas there are no differences between JKT-1-Tro and JKT-1-mock in their proliferation activity. Upon orthotopic inoculation to athymic nude mice, JKT-1-Tro cells exhibited i.p. metastases in all of the mice (n = 5), whereas JKT-1-mock produced no metastases (n = 5). These results suggest strongly that trophinin enhances invasiveness of the cells and promotes metastasis of testicular germ cell tumor.

Intravesical Seeding of Upper Urinary Tract Urothelial Carcinoma Cells During Nephroureterectomy: An Exploratory Analysis from the THPMG Trial

OBJECTIVE The Pirarubicin Monotherapy Study Group trial was a randomized Phase II study that evaluated the efficacy of intravesical instillation of pirarubicin in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma. This study conducted further analysis of the Pirarubicin Monotherapy Study Group cohort, focusing on intravesical seeding of cancer cells. METHODS Using the data from the Pirarubicin Monotherapy Study Group trial, bladder recurrence-free survival rates and factors associated with bladder recurrence in the control group were analyzed. RESULTS Of 36 patients in the control group, 14 with positive urine cytology had more frequent recurrence when compared with the 22 patients with negative cytology (P = 0.004). Based on the multivariate analysis in the control group, voided urine cytology was an independent predictive factor of bladder recurrence (hazard ratio, 5.54; 95% confidence interval 1.12-27.5; P = 0.036). Of 72 patients in the Pirarubicin Monotherapy Study Group trial, 31 had positive urine cytology. Among the 31 patients, 17 patients who received pirarubicin instillation had fewer recurrences when compared with 14 patients who received control treatment (P = 0.0001). On multivariate analysis, pirarubicin instillation was an independent predictor of better recurrence-free survival rates in the patients with positive urine cytology (hazard ratio, 0.02; 95% confidence interval, 0.00-0.53; P = 0.018). Of 21 patients with bladder recurrence, 17 had recurrent tumor around cystotomy or in the bladder neck compromised by the urethral catheter, supporting the notion that tumor cells seeded in the injured urothelium. CONCLUSIONS Intravesical instillation of pirarubicin immediately after nephroureterectomy significantly reduced the bladder recurrence rate in patients with positive voided urine cytology. The results suggest that intravesical seeding of upper urinary tract urothelial carcinoma occurs during nephroureterectomy.

Influence of 1 year of androgen deprivation therapy on lipid and glucose metabolism and fat accumulation in Japanese patients with prostate cancer

Background:We prospectively examined influence of androgen deprivation therapy (ADT) on lipid and glucose metabolisms in Japanese patients with prostate cancer.Methods:Patients with prostate cancer who were hormone-naive and scheduled to receive long-term ADT were recruited between 2011 and 2013. Body weight, abdominal circumference and blood testing associated with lipid and glucose metabolism were recorded every 3 months during 1 year of ADT. Computed tomography (CT) was performed to measure areas of subcutaneous and visceral fat before and after 1 year of ADT. ADT was limited to a luteinizing hormone-releasing hormone (LHRH) agonist with or without bicalutamide.Results:Of 218 patients registered, data were available from 177 patients who completed 1 year of ADT. Of these, CT was performed before and after 1 year of ADT in 88 patients. Median age was 75 years (range, 49–85 years). Median PSA before ADT was 16.7 ng ml−1 (range, 0.3–3316). Clinical stage was B (54.2%), C (23.2%) and D (20.9%). Mean increases in body weight and abdominal circumference after 1 year of ADT were 2.9 and 3.0%, respectively. Mean increases in total, low-density lipoprotein and high-density lipoprotein cholesterol and triglycerides were 10.6, 14.3, 7.8 and 16.2%, respectively. Mean increases in fasting blood sugar and hemoglobin A1c (HbA1c) were 3.9 and 2.7%, respectively. Lipid alterations were noted in patients without comorbidities, whereas changes in HbA1c were noted in patients with diabetes mellitus at baseline. These lipid and glucose alterations were prominent in the early ADT period. Both visceral and subcutaneous fat, as measured by CT, increased by >20%. The increase in subcutaneous fat was significantly greater than that in visceral fat (P=0.028).Conclusions:One year of ADT significantly changed lipid and glucose metabolism in Japanese patients with prostate cancer. Patient characteristics or comorbidities at baseline may be associated with ADT-induced metabolic changes.

Clinical predictors of the estimated glomerular filtration rate 1 year after radical nephrectomy in Japanese patients

Purpose To evaluate renal function 1 year after radical nephrectomy (RN) for renal cell carcinoma, the preoperative predictors of postnephrectomy renal function were investigated by sex, and equations to predict the estimated glomerular filtration rate (eGFR) 1 year after RN were developed. Materials and Methods A total of 525 patients who underwent RN between May 2007 and August 2011 at Tohoku University Hospital and its affiliated hospitals were prospectively evaluated. Overall, 422 patients were analyzed in this study. Results Independent preoperative factors associated with postnephrectomy renal function were different in males and females. Preoperative eGFR, age, tumor size, and body mass index (BMI) were independent factors in males, while tumor size and BMI were not independent factors in females. The equations developed to predict eGFR 1 year after RN were: Predicted eGFR in males (mL/min/1.73 m2)=27.99−(0.196×age)+(0.497×eGFR)+(0.744×tumor size)−(0.339×BMI); and predicted eGFR in females=44.57−(0.275×age)+(0.298×eGFR). The equations were validated in the validation dataset (R2=0.63, p<0.0001 and R2=0.31, p<0.0001, respectively). Conclusions The developed equations by sex enable better prediction of eGFR 1 year after RN. The equations will be useful for preoperative patient counseling and selection of the type of surgical procedure in elective partial or RN cases.

Penile blood pressure is useful to identify candidates for tadalafil treatment in patients with lower urinary tract symptoms

To determine whether penile blood pressure (PBP) can be used to identify patients who can benefit from tadalafil treatment, the correlation between PBP at baseline and changes in lower urinary tract symptoms (LUTS) induced by tadalafil treatment was studied prospectively.

MP78-04 EFFICACY OF EARLY URETERAL LIGATION ON PREVENTION OF INTRAVESICAL RECURRENCE AFTER RADICAL NEPHROURETERECTOMY FOR UPPER URINARY TRACT UROTHELIAL CARCINOMA: A PROSPECTIVE SINGLE-ARM MULTICENTER CLINICAL TRIAL

Shinichi Yamashita*, Akihiro Ito, Koji Mitsuzuka, Masataka Aizawa, Naomasa Ioritani, Sendai, Japan; Shigeto Ishidoya, Sendai, Japan; Yoshihiro Ikeda, Osaki, Japan; Kenji Numahata, Yamagata, Japan; Kazuhiko Orikasa, Kesennuma, Japan; Tatsuo Tochigi, Natori, Japan; Fumihiko Soma, Hachinohe, Japan; Takashige Namima, Hideo Saito, Sendai, Japan; Makoto Sato, Rifu, Japan; Shinnosuke Katoh, Yuzawa, Japan; Shozo Ota, Sendai, Japan; Atsushi Kyan, Shirakawa, Japan; Atsushi Takeda, Ichinoseki, Japan; Yasuhiro Kaiho, Yoichi Arai, Sendai, Japan

MP09-07 EVALUATION OF EFFICACY OF PDE5 INHIBITER BY PENILE BLOOD PRESSURE FOR BENIGN PROSTATIC HYPERPLASIA PATIENTS WITH LOWER URINARY TRACT SYMPTOMS

INTRODUCTION AND OBJECTIVES: Tadalafil is a phosphodiesterase 5 inhibitor that affects cyclic guanosine monophosphate (cGMP). It is known to improve not only smooth muscle relaxation of the prostatic urethra and bladder, but also pelvic ischemia. In the daily clinic, tadalafil is usually prescribed for patients with lower urinary tract symptoms (LUTS), but not all patients respond to tadalafil treatment. The purpose of this study was to identify those who would be good candidates for tadalafil. This evaluation used penile blood pressure (PBP) as a feasible and reproducible method related to pelvic blood perfusion. METHODS: A prospective study was performed in our hospital between September 2014 and October 2016. Patients showing poor response to a1 blockers for benign prostate hyperplasia (BPH) were eligible for this study. Tadalafil was administered in exchange of the a1 blocker. Demographic data, I-PSS, I-PSS QOL, IIEF-5, uroflowmetry (UFM), post-voiding residue (PVR), prostate volume (by transabdominal ultrasound), PBP, and axial brachial index (ABI) were evaluated before and at 4 and 12 weeks after switching to tadalafil. The relationship between I-PSS scores and PBP was examined in these patients. To measure PBP, a cuff for the big toe was wrapped around the penis. This study was approved by the institutional review board. RESULTS: A total of 55 patients were eligible. Within 4 weeks after switching to tadalafil, 3 patients dropped out of the study because of adverse events and another three dropped out because of worsening LUTS. Overall, 49 patients tolerated tadalafil for the entire 12 weeks and were investigated. Median age was 74 years. 25 patients with PBP less than 110 mmHg at baseline responded better to tadalafil, with improvement of I-PSS at 12 weeks compared to those with higher PBP (p1⁄4 0.006, Figure). Lower PBP at baseline was significantly associated with improved I-PSS by tadalafil at 12 weeks on uniand multivariate analyses (p<0.001 and p1⁄40.001, respectively). On multivariate analysis, improved I-PSS was also related to previous anticholinergic drug use (p1⁄40.021). CONCLUSIONS: This study demonstrated that PBP could reliably identify BPH patients who could benefit from tadalafil treatment. Especially in cases with PBP <110 mmHg, we can consider changing administration to tadalafil.