第一届中日泌尿外科会议抄录

IMPACT AND IMPLICATION OF RENAL ARTERY NUMBER ON OUTCOMES OF RENAL DONORS AND RECIPIENTS IN RETROPERITONEOSCOPIC LIVE DONOR NEPHRECTOMY

Kazuya Omoto, Naoshi Miyamoto, Hideki Ishida, Tadahiko Tokumoto, Hiroyuki Amano, Hayato Nishida, Hiroki Shirakawa, Shouichi Iida, and Kazunari Tanabe

Department of Urology, Tokyo Women’s Medical University

BACKGROUND AND OBJECTIVE : Since the initial reports in 1995, laparoscopic donor nephrectomy has evolved as an acceptable, safe alternative to open donor nephrectomy. However, recent report has suggested that renal artery number is important in selecting the appropriate kidney for laparoscopic procurement. We have tried to establish the technique of retroperitoneoscopic live donor nephrectomy (RPLDN) since 2001. In order to assess the effect of renal artery multiplicity on donor and recipient outcomes after RPLDN, we reviewed our experience of RPLDN.
METHODS : During a 5-year periods, 275 patients underwent live donor renal transplants with allograft procured by RPLDN at our institute. Of these, 206 (74.9%), 54 (19.6%) and 15 (5.5%) patients had one, two and three renal arteries, respectively. Surgical renovascular reconstructions were performed in patients with multiple renal arteries. Study variables included operative time, blood loss, warm ischemia time (WIT), hospital stay, graft function and complications.
RESULTS : No significant differences were found between the one and two renal arteries group regarding operative time (305±70 vs. 327±75 min), blood loss (45 vs. 50 ml), hospital stay (3.9±1.5 vs. 4.4±1.8 days), WIT (4.8±1.6 vs. 5.2±1.7), slow graft function (0/206 vs. 1/54), and ureteral complications (2/206 vs. 1/54). In contrast, kidneys with three renal arteries had longer operative time (305±70 vs. 362±82 min, p=0.003), hospital stay (3.9±1.5 vs. 5.5±2.4 days, p=0.0003), WIT (4.8±1.6 vs. 6.8±3.0, p=0.0001), and more slow graft function (0/206 vs. 2/15, p=0.0012) than that with one renal artery. However, no significant differences were observed among the three groups in the serum creatinine level at 7 (1.40±0.9 vs. 1.54± 1.6 vs. 1.58±0.9 mg/dl, respectively) and 14 post-operative days  (1.42±0.8 vs. 1.40±0.7 vs. 1.62±0.9 mg/dl, respectively). There was no patient with multiple renal arteries required hemodialysis after transplantation due to acute tubular necrosis.
CONCLUSIONS : Kidneys with multiple renal arteries provided similar outcomes as to postoperative graft function and complications compared with those of one renal artery. These results indicate that laparoscopic procurement of kidneys with multiple renal arteries could be an option for RPLDN.

Eight-Year Biochemical Disease-Free Survival after High-Intensity Focused Ultrasound (HIFU) for Localized Prostate Cancer

T. Uchida¹, A. Murota¹, Y. Nagata¹, S. Shoji², M. Hoshi², Y. Usui², T. Terachi².

1. Tokai University Hachioji Hospital, Hachioji; 2.Tokai University, Isehara, Japan

INTRODUCTION : Prostate cancer is the most common malignancy in men and the second leading cause of death in the USA. In Japan, although the incidence of prostate cancer has been much less than in American and European countries, it has been sharply increasing during the last two decades. Recently, a number of alternative less invasive treatments has been developed for patients with localized prostate cancer such as laparoscopic radical prostatectomy, three-dimensional conformal radiotherapy (3D-CRT), intensity-modulated external beam radiotherapy (IMRT), brachytherapy and cryosurgical ablation of the prostate have been applied to treat this group of patients. High-intensity focused ultrasound (HIFU) induces intense ultrasound energy with consequent heat destruction of the prostate at a specific focal distance from the transrectal probe without damage to the intervening tissue. The purpose of the study was to assess the prostate-specific antigen (PSA) level with a long-term follow-up after HIFU for prostate cancer, and to identify the predictors for an improved disease-fee survival.
METHODS : Between 1999 and 2007, 517 patients who underwent treatment with the Sonablate® HIFU device (Focus surgery, Indianapolis, USA) for T1-3 N0M0 prostate cancer, with at least 1 year of follow-up, were studied. Three generation HIFU devices were employed such as Sonablate® 200 in 31 (6%), Sonablate® 500 in 385 (74%) and Sonablate 500® version 4 in 101 (20%) patients, respectively. Among them, 86 (17%) patients were treated twice, 14 (3%) with 3 times and 2 (0.4%) with 4 times. During the follow-up evaluation, PSA measurement and prostate biopsy were performed. Biochemical failure was defined according to the criteria recommended by the American Society for Therapeutic Radiology and Oncology (strict ASTRO), i.e., a rise by 2 ng/ml or more above the nadir PSA be considered for biochemical failure, consensus panel. None of the patients had received androgen deprivation with or without other anticancer therapy prior to documenting a biochemical failure. The median follow-up was of 24 months duration. Both Kaplan-Meier curves and multivariate data analyses were employed.
RESULTS : The median age and PSA were 68 years and 9.2 ng/ml,  respectively. The median operation time and hospitalization were 142 min and 4.0 days. The stage was determined to be as follows: T1c in 294 (57%), T2a in 22 (4%), T2b in 82 (16%), T2c in 87 (17%) and T3 in 32 (6%) patients. The Gleason scores were 2 to 4, 5 to 7 and 8 to 10 in 37 (7%), 413 (80%) and 67 (13%), respectively. The patients’ risk of progression was assessed according to the criteria of D’Amico et al., i.e. preoperative total PSA level, clinical stage and Gleason score. Patients considered to be at low-risk had a PSA ≤ 10 ng/ml, Gleason score ≤ 6 and clinical stage T1c-2a. Patients with a clinical stage of ≥ T2c, Gleason score of 8-10 or total PSA level > 20ng/ml were identified as the high-risk group, and remaining are classified at intermediate–risk. The actual 5-year biochemical disease-free rate (bDFR) with the low, intermediate and high–risk groups were 84%, 64% and 44%, respectively (p<0.0001). Negative prostate biopsy findings were obtained in 83% of the patients. A multivariate analysis identified the pretreatment PSA level (p<0.0001), neoadjuvant hormonal therapy (p<0.0001) and the disease stage (p=0.0324) to be associated with the bDFR. Urethral stricture and epididymitis were observed in 16% and 4% of the patients. The majority of men (81%) who had erections prior to therapy managed to preserve their erectile function.
CONCLUSION : HIFU appears to be both an effective and well tolerated procedure for men with localized prostate cancer, especially those with low-risk.

The present and future of gene therapy for prostate cancer in Okayama University

Department of Urology Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences

Haruki Kaku, Masami Watanabe, Peng Huang, Jie Chen, Ryuta Tanimoto, Fernando Abarzua, Takashi Saika, Yasutomo Nasu, Hiromi Kumon

In situ gene therapy for prostate cancer is an on-going project in Okayama University. We started the clinical protocol of prostate cancer gene therapy in 2001 with adenovirus vector-mediated herpes simplex virus-thymidine kinase gene transduction and ganciclovir. We completed the initial phase I/II study successfully, demonstrating the safety and clinical efficacy of this suicide gene therapy against patients with hormone refractory prostate cancer (Mol Ther.15:834, 2007).
Our second clinical protocol of in situ gene therapy with a recombinant adenoviral vector of interleukin-12 has been reviewed by the Japanese National Committee and will be initiated soon.  We are expecting this immunogene to be effective against local and metastatic tumors as detected in the preclinical study (Gene Therapy, 6 : 338, 1999).
In 2003, the Center for Gene and Cell Therapy with GMP facility was founded as a ministerial ordinace institution at Okayama University Hospital. Since then, a number of basic researches to create novel gene therapy for prostate cancer have been conducted in the institution. As the results, we identified and characterized a novel tumor suppressor gene, REIC (reduced expression in immortalized cells), and demonstrated its greate potential for prostate cancer gene therapy. Adenovirus vector-mediated REIC gene transfer efficiently induced apoptosis in human prostate cancer cell lines but not in normal cells including prostate epithelial and stromal cells (Cancer Res. 65:9617,2005). In addition, we  constructed a new viral agent, Telomelysin (a tumor- and telomerase-specific replication-competent adenovirus) for cancer gene therapy. Telomelysin showed strong anticancer effects on a xenotransplnated human prostate cancer of LNCaP. Interestingly, the ipsilateral treatment significantly suppressed contralateraltumor growth in both sides of tumor model (Caner Gene Ther. 2007 in press).
We here report our present and future strategies of in situ gene therapy for prostate cancer.

IRIDIUM-192 HIGH-DOSE-RATE BRACHYTHERAPY FOR T1c-T3bN0M0 PROSTATE CANCER.

Yoshimasa Jo, Ryoei Hara, Norio Kondo, Tomohiro Fujii, Teruhiko Yokoyama, Yoshiyuki Miyaji and Atsushi Nagai

Department of Urology , Kawasaki Medical School, Kurashiki, Okayama, Japan

PURPOSE : To determine the efficacy of radiotherapy for T1c-T3bN0M0 prostate cancer in a prospective clinical trial of concurrent external beam radiotherapy (EBRT) and fractionated irridium-192 (Ir-192) high-dose rate brachytherapy (HDR-BT).
Materials and Methods: 312 patients with T1c-T3bN0M0 prostate cancer diagnosed between October 1997 and August 2005 underwent HDR-BT with external radiotherapy. Treatment consisted of external irradiation (4-port irradiation) of the prostate at 36.8-39.0 Gy (13-16fraction) and HDR-BT at 18-24 Gy (2-4 fraction). No patient received adjuvant hormonal therapy after radiotherapy.
RESULTS : The most recent PSA level was 0.01 to 5.5ng/mL (median, 0.31ng/mL). 25 patients (6.5%) suffered recurrence and were considered failures (bone metastasis in 7 and biochemical failure in 18). The overall biochemical disease-free survival (BDFS) rate was 92 % at 5 years. The BDFS rate by risk category was 98% at 5 years for low risk, 95% for intermediate risk, and 84% for high risk. The BDFS was better in patients when initial PSA level was<20 ng/mL compared with≧20 ng/mL ( 93% and 79%, respectively, P<0.001). All patients tolerated the treatment well, with no grade 4 (RTOG) acute complications. However 49 patients (15.7%) developed urethral stricture.
CONCLUSIONS : With a low complication rate and satisfactory BDFS rates, this combination therapy is considered to be an alternative method for clinically T1c-T3b prostate cancer and is expected to improve the QOL of patients. Further long-term follow-up will be needed to confirm this treatment.

Effects of BH4 and statins on erectile function in diabetic rats.

Hiroaki Nishimatsu, Tadaichi Kitamura

Dept. of Urology and Andrology, Unoversity of Tokyo, Japan

Tetrahydrobiopterin is not only known as the rescue cofactor of as the co-factor of Hyperphenylalaninemia, also nitiric oxide synthase, like calmodulin. The statin drugs are essentially the HMG-CoA reductase inhibitors, which were introduced to lower serum lipid levels, ostensibly to prevent coronary heart disease (CVD). Statins improve endothelial function by upregulating endothelial nitric oxide (NO) production that is mediated by inhibiting the isoprenylation of rho GTPase. Withdrawal of statin treatment could suppress endothelial NO production and may impair vascular function. We have reported that adrenomedullin (AM)-induced vasodilation is at least in part nitric oxide (NO)-cGMP-dependent in the rat. Although it is well known that NO is much involved in the erectile function, it is controversial as to whether AM influences the erectile function. Thus, we examined the effects of BH4 and statins on intracavernous pressure (ICP) during penile erection. The left carotid artery of rats was cannulated to monitor of mean arterial pressure (MAP). Bipolar electrodes were positioned on the cavernous nerve. The right cavernous body was cannulated with a needle connected to a pressure transducer to monitor ICP. Electrical stimulation (ES) increased ICP in a voltage-dependent manner. Elevation of ICP continued during ES. The administarion of BH4 and statins by gavage significantly potentiated ES-induced increases in both maximal developed ICP/MAP and area under the curve (ICP trace; AUC). Since BH4 slightly lowered MAP, ICP was normalized by MAP. i.v. administration of N(omega)-nitro-L-arginine, a NO synthase inhibitor, markedly decreased BH4 or statin/AM/ES-induced ICP elevation. However, in the presence of E-4021, a cGMP-specific phosphodiesterase inhibitor, Statins further increased both ICP/MAP and AUC. These results suggest that a NO-cGMP pathway is involved in the regulation of these NOS activating drug-induced rat cavernous vasorelaxation.
KEY WORDS : Tetrahydrobiopterin, statins, NOS
REFERENCES : Nishimatsu H, Hirata Y, Kitamura T:  Peptides. Volume 22(11) 1913-8, 2001
Effects of intracavernous administration of adrenomedullin on erectile function in rats.

Sensitization of human renal cell carcinoma cells to TRAIL-R2-mediated apoptosis and cytotoxicity by low concentrations of doxorubicin

Xiu-Xian Wu, Ahmed Mamdouh Abd El Hamed, Mohammed Ahmed Abdel-Muneem Nouh, Masashi Inui, Mikio Sugimoto, and Yoshiyuki Kakehi

Department of Urology, Faculty of Medicine, Kagawa University

BACKGROUND : Tumor necrosis factor-related apoptosis-inducing ligand receptor-2 (TRAIL-R2) is a novel molecular target of cancer therapy. Here, we investigated the effect of chemotherapeutic agents on TRAIL-R2-mediated apoptosis in renal cell carcinoma (RCC) cells.
METHODS : Cytotoxicity and synergy was assessed by MTT and isobolograpic analyses, respectively. TRAIL-R2 expression was detected by real-time RT-PCR, flow cytometry, and Western blotting. Apoptosis was assessed by DNA Ladder and caspase assays.
RESULTS : Treatment of ACHN human RCC cell line with agonistic TRAIL-R2 antibody (HGS-ETR2) in combination with 5-fluorouracil, vinblastine, paclitaxel or docetaxel did not overcome resistance to these agents. However, treatment with HGS-ETR2 in combination with doxorubicin had a synergistic cytotoxicity. Synergy was also achieved in two other human RCC cell lines and in primary RCC cells derived from eight patients. Sequential treatment with doxorubicin followed by HGS-ETR2 induced significantly more cytotoxicity than reverse treatment or simultaneous treatment (P < 0.05). Low concentrations of doxorubicin (0.1 and 1 µg/ml) significantly increased TRAIL-R2 expression at both mRNA and protein levels. Furthermore, doxorubicin and HGS-ETR2 combination significantly enhanced caspase 8 activity, Bid cleavage, Bcl-xL decrease, releasing cytochrome c, caspase 9 and caspase 3 activities, and induced synergistic apoptosis. The activation of caspases and apoptosis induced with HGS-ETR2 and doxorubicin was blocked by human recombinant DR5:Fc chimera protein.
CONCLUSIONS : These findings suggest that doxorubicin sensitizes RCC cells to TRAIL-R2-mediated apoptosis by inducing TRAIL-R2 expression, and that the combination treatment with HGS-ETR2 and doxorubicin might be a promising targeted therapy for RCC.

Replication competent oncolytic adenovirus for the treatment of prostate cancer

Hua Wang¹, Makoto Satoh², Hirofumi Hamada³, Yoichi Arai⁴

1. Department of Urology, Zhejiang Cancer Hospital
2. Department of Urology, Sen-en General Hospital
3. Biomedical Research Center Laboratory of Molecular Medicine, Sapporo Medical University

OBJECTIVE : Replication-restricted oncolytic adenovirus has been reported as a novel strategy for the treatment cancer. Here, we demonstrate a double mutated oncolytic adenovirus AxdAdB-3 with mutation of E1A in the CR-2 pRB-binding site and deletion of E1B 55KD for the treatment of prostate cancer. Methods: Cytopathic effects of AxdAdB-3 were examined in human prostate carcinoma cell lines (DU145, PC3 and LNCaP) and human normal prostate derived cell lines (PrEC and PrSC) with AxE1AdB and dl922-947 by crystal violet staining and MTT assay. The therapeutic efficacy of AxdAdB-3 for the treatment of prostate cancer was investigated in an orthotopic prostate cancer model established with DU145 in SCID mice. Results: AxdAdB-3 induced potent cytopathic effects in prostate cancer cell lines tested. AxdAdB-3 showed no cytotoxic on normal prostate derived cell lines PrEC and PrSC. In vivo, AxdAdB-3 showed apparent antitumor effect in orthotopic prostate cancer model and significantly improved survival. Conclusions. These results suggest that AxdAdB-3 could be a promising tool for viral therapy of prostate cancer in patients with disease resistant to hormone therapy.