Springer Science and Business Media LLC Acta Medica Okayama 0946-2716 101 4 2023 Novel extracellular role of REIC/Dkk-3 protein in PD-L1 regulation in cancer cells 431 447 EN Yuma Gohara Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Nahoko Tomonobu Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Rie Kinoshita Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Junichiro Futami Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University Léna Audebert Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Youyi Chen Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Ni Luh Gede Yoni Komalasari Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Fan Jiang Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Chikako Yoshizawa Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Hitoshi Murata Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Ken-ichi Yamamoto Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Masami Watanabe Department of Urology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Hiromi Kumon Innovation Center Okayama for Nanobio-Targeted Therapy, Okayama University Masakiyo Sakaguchi Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine The adenovirus-REIC/Dkk-3 expression vector (Ad-REIC) has been the focus of numerous clinical studies due to its potential for the quenching of cancers. The cancer-suppressing mechanisms of the REIC/DKK-3 gene depend on multiple pathways that exert both direct and indirect effects on cancers. The direct effect is triggered by REIC/Dkk-3-mediated ER stress that causes cancer-selective apoptosis, and the indirect effect can be classified in two ways: (i) induction, by Ad-REIC-mis-infected cancer-associated fibroblasts, of the production of IL-7, an important activator of T cells and NK cells, and (ii) promotion, by the secretory REIC/Dkk-3 protein, of dendritic cell polarization from monocytes. These unique features allow Ad-REIC to exert effective and selective cancer-preventative effects in the manner of an anticancer vaccine. However, the question of how the REIC/Dkk-3 protein leverages anticancer immunity has remained to be answered. We herein report a novel function of the extracellular REIC/Dkk-3—namely, regulation of an immune checkpoint via modulation of PD-L1 on the cancer-cell surface. First, we identified novel interactions of REIC/Dkk-3 with the membrane proteins C5aR, CXCR2, CXCR6, and CMTM6. These proteins all functioned to stabilize PD-L1 on the cell surface. Due to the dominant expression of CMTM6 among the proteins in cancer cells, we next focused on CMTM6 and observed that REIC/Dkk-3 competed with CMTM6 for PD-L1, thereby liberating PD-L1 from its complexation with CMTM6. The released PD-L1 immediately underwent endocytosis-mediated degradation. These results will enhance our understanding of not only the physiological nature of the extracellular REIC/Dkk-3 protein but also the Ad-REIC-mediated anticancer effects. No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 0169-5002 178 2023 PD-1 blockade augments CD8+ T cell dependent antitumor immunity triggered by Ad-SGE-REIC in Egfr-mutant lung cancer 1 10 EN Takamasa Nakasuka Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kadoaki Ohashi Department of Respiratory Medicine, Okayama University Hospital Kazuya Nishii Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Atsuko Hirabae Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Sachi Okawa Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Nahoko Tomonobu Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kenji Takada Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Chihiro Ando Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiromi Watanabe Department of Respiratory Medicine, Okayama University Hospital Go Makimoto Department of Respiratory Medicine, Okayama University Hospital Kiichiro Ninomiya Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine Masanori Fujii Department of Respiratory Medicine, Okayama University Hospital Toshio Kubo Center for Clinical Oncology, Okayama University Hospital Eiki Ichihara Department of Respiratory Medicine, Okayama University Hospital Katsuyuki Hotta Center for Innovative Clinical Medicine, Okayama University Hospital Masahiro Tabata Center for Clinical Oncology, Okayama University Hospital Hiromi Kumon Innovation Center Okayama for Nanobio-targeted Therapy, Okayama University Yoshinobu Maeda Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Katsuyuki Kiura Department of Respiratory Medicine, Okayama University Hospital Objectives: No immunotherapeutic protocol has yet been established in never-smoking patients with lung cancer harboring driver oncogenic mutations, such as epidermal growth factor receptor (EGFR) mutations. The immunostimulatory effect of Ad-REIC, a genetically engineered adenovirus vector expressing a tumor suppressor gene, reduced expression in immortalized cells (REIC), has been investigated in clinical trials for various solid tumors. However, the immunostimulatory effect of the Ad-REIC in EGFR-mutant lung cancer with a non-inflamed tumor microenvironment (TME) has not been explored. Materials and methods: We used a syngeneic mouse model developed by transplanting Egfr-mutant lung cancer cells into single or double flanks of C57BL/6J mice. Ad-SGE-REIC, a 2nd-generation vector with an enhancer sequence, was injected only into the tumors from one flank, and its antitumor effects were assessed. Tumor-infiltrating cells were evaluated using immunohistochemistry or flow cytometry. The synergistic effects of Ad-SGE-REIC and PD-1 blockade were also examined. Results: Injection of Ad-SGE-REIC into one side of the tumor induced not only a local antitumor effect but also a bystander abscopal effect in the non-injected tumor, located on the other flank. The number of PD-1+CD8+ T cells increased in both injected and non-injected tumors. PD-1 blockade augmented the local and abscopal antitumor effects of Ad-SGE-REIC by increasing the number of CD8+ T cells in the TME of Egfr-mutant tumors. Depletion of CD8+ cells reverted the antitumor effect, suggesting they contribute to antitumor immunity. Conclusion: Ad-SGE-REIC induced systemic antitumor immunity by modifying the TME status from non-inflamed to inflamed, with infiltration of CD8+ T cells. Additionally, in Egfr-mutant lung cancer, this effect was enhanced by PD-1 blockade. These findings pave the way to establish a novel combined immunotherapy strategy with Ad-SGE-REIC and anti-PD-1 antibody for lung cancer with a non-inflamed TME. No potential conflict of interest relevant to this article was reported.

FRONTIERS MEDIA SA Acta Medica Okayama 2234-943X 12 2022 Engineering Cancer/Testis Antigens With Reversible S-Cationization to Evaluate Antigen Spreading 869393 EN Ai Miyamoto Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University Tomoko Honjo Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University Mirei Masui Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University Rie Kinoshita Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiromi Kumon Innovation Center Okayama for Nanobio-targeted Therapy, Okayama University Kazuhiro Kakimi Department of Immunotherapeutics, The University of Tokyo Hospital Junichiro Futami Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University Serum autoantibody to cancer/testis antigens (CTAs) is a critical biomarker that reflects the antitumor immune response. Quantitative and multiplexed anti-CTA detection arrays can assess the immune status in tumors and monitor therapy-induced antitumor immune reactions. Most full-length recombinant CTA proteins tend to aggregate. Cysteine residue-specific S-cationization techniques facilitate the preparation of water-soluble and full-length CTAs. Combined with Luminex technology, we designed a multiple S-cationized antigen-immobilized bead array (MUSCAT) assay system to evaluate multiple serum antibodies to CTAs. Reducible S-alkyl-disulfide-cationized antigens in cytosolic conditions were employed to develop rabbit polyclonal antibodies as positive controls. These control antibodies sensitively detected immobilized antigens on beads and endogenous antigens in human lung cancer-derived cell lines. Rabbit polyclonal antibodies successfully confirmed the dynamic ranges and quantitative MUSCAT assay results. An immune monitoring study was conducted using the serum samples on an adenovirus-mediated REIC/Dkk-3 gene therapy clinical trial that showed a successful clinical response in metastatic castration-resistant prostate cancer. Autoantibody responses were closely related to clinical outcomes. Notably, upregulation of anti-CTA responses was monitored before tumor regression. Thus, quantitative monitoring of anti-CTA antibody biomarkers can be used to evaluate the cancer-immunity cycle. A quality-certified serum autoantibody monitoring system is a powerful tool for developing and evaluating cancer immunotherapy. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 2073-4425 13 2 2022 Dkk3/REIC Deficiency Impairs Spermiation, Sperm Fibrous Sheath Integrity and the Sperm Motility of Mice 285 EN Ruizhi Xue Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Wenfeng Lin Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hirofumi Fujita Department of Cytology and Histology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Jingkai Sun Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Rie Kinoshita Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhiko Ochiai Laboratory of Veterinary Hygiene, Nippon Veterinary and Life Science University Junichiro Futami Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University Masami Watanabe Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hideyo Ohuchi Department of Cytology and Histology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Masakiyo Sakaguchi Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Zhengyan Tang Department of Urology, Xiangya Hospital, Central South University Peng Huang Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasutomo Nasu Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiromi Kumon Innovation Center Okayama for Nanobio-Targeted Therapy, Okayama University The role of Dickkopf-3 (Dkk3)/REIC (The Reduced Expression in Immortalized Cells), a Wnt-signaling inhibitor, in male reproductive physiology remains unknown thus far. To explore the functional details of Dkk3/REIC in the male reproductive process, we studied the Dkk3/REIC knock-out (KO) mouse model. By examining testicular sections and investigating the sperm characteristics (count, vitality and motility) and ultrastructure, we compared the reproductive features between Dkk3/REIC-KO and wild-type (WT) male mice. To further explore the underlying molecular mechanism, we performed RNA sequencing (RNA-seq) analysis of testicular tissues. Our results showed that spermiation failure existed in seminiferous tubules of Dkk3/REIC-KO mice, and sperm from Dkk3/REIC-KO mice exhibited inferior motility (44.09 +/- 8.12% vs. 23.26 +/- 10.02%, p < 0.01). The Ultrastructure examination revealed defects in the sperm fibrous sheath of KO mice. Although the average count of Dkk3/REIC-KO epididymal sperm was less than that of the wild-types (9.30 +/- 0.69 vs. 8.27 +/- 0.87, x10(6)), neither the gap (p > 0.05) nor the difference in the sperm vitality rate (72.83 +/- 1.55% vs. 72.50 +/- 0.71%, p > 0.05) were statistically significant. The RNA-seq and GO (Gene Oncology) enrichment results indicated that the differential genes were significantly enriched in the GO terms of cytoskeleton function, cAMP signaling and calcium ion binding. Collectively, our research demonstrates that Dkk3/REIC is involved in the process of spermiation, fibrous sheath integrity maintenance and sperm motility of mice. No potential conflict of interest relevant to this article was reported.

Oxford University Press Acta Medica Okayama 0368-2811 51 1 2020 Long-term ureteroscopic management of upper tract urothelial carcinoma: 28-year single-centre experience 130 137 EN Yuki Maruyama Department of Urology, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Science Motoo Araki Department of Urology, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Science Koichiro Wada Department of Urology, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Science Kasumi Yoshinaga Department of Urology, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Science Yosuke Mitsui Department of Urology, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Science Takuya Sadahira Department of Urology, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Science Shingo Nishimura Department of Urology, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Science Kohei Edamura Department of Urology, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Science Yasuyuki Kobayashi Department of Urology, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Science Masami Watanabe Department of Urology, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Science Toyohiko Watanabe Department of Urology, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Science Manoj Monga Department of Urology, The Cleveland Clinic Yasutomo Nasu Department of Urology, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Science Hiromi Kumon Innovation Center Okayama for Nanobio-Targeted Therapy, Okayama University Background Long-term survival outcomes of patients who undergo endoscopic management of non-invasive upper tract urothelial carcinoma remain uncertain. The longest mean follow-up period in previous studies was 6.1 years. This study reports the long-term outcomes of patients with upper tract urothelial carcinoma who underwent ureteroscopic ablation at a single institution over a 28-year period. Methods We identified all patients who underwent ureteroscopic management of upper tract urothelial carcinoma as their primary treatment at our institution between January 1991 and April 2011. Survival outcomes, including overall survival, cancer-specific survival, upper-tract recurrence-free survival and renal unit survival, were estimated using Kaplan−Meier methodology. Results A total of 15 patients underwent endoscopic management, with a mean age at diagnosis of 66 years. All patients underwent ureteroscopy, and biopsy-confirmed pathology was obtained. Median (range; mean) follow-up was 11.7 (2.3–20.9, 11.9) years. Upper tract recurrence occurred in 87% (n = 13) of patients. Twenty percent (n = 3) of patients proceeded to nephroureterectomy. The estimated cancer-specific survival rate was 93% at 5, 10, 15 and 20 years. Estimated overall survival rates were 86, 80, 54 and 20% at 5, 10, 15 and 20 years. Only one patient experienced cancer-specific mortality. The estimated mean and median overall survival times were 14.5 and 16.6 years, respectively. The estimated mean cancer-specific survival time was not reached. Conclusions Although upper tract recurrence is common, endoscopic management of non-invasive upper tract urothelial carcinoma provides a 90% cancer-specific survival rate at 20 years in selected patients. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 0815-9319 29 5 2014 Potential of adenovirus-mediated REIC/Dkk-3 gene therapy for use in the treatment of pancreatic cancer 973 983 EN Daisuke Uchida Hidenori Shiraha Hironari Kato Teruya Nagahara Masaya Iwamuro Junro Kataoka Shigeru Horiguchi Masami Watanabe Akinobu Takaki Kazuhiro Nouso Yasutomo Nasu Takahito Yagi Hiromi Kumon Kazuhide Yamamoto Background and AimThe reduced expression in immortalized cells REIC/the dickkopf 3 (Dkk-3) gene, tumor suppressor gene, is downregulated in various malignant tumors. In a prostate cancer study, an adenovirus vector carrying the REIC/Dkk-3 gene (Ad-REIC) induces apoptosis. In the current study, we examined the effects of REIC/Dkk-3 gene therapy in pancreatic cancer. MethodsREIC/Dkk-3 expression was assessed by immunoblotting and immunohistochemistry in the pancreatic cancer cell lines (ASPC1, MIAPaCa2, Panc1, BxPC3, SUIT-2, KLM1, and T3M4) and pancreatic cancer tissues. The Ad-REIC agent was used to investigate the apoptotic effect in vitro and antitumor effects in vivo. We also assessed the therapeutic effects of Ad-REIC therapy with gemcitabine. ResultsThe REIC/Dkk-3 expression was lost in the pancreatic cancer cell lines and decreased in pancreatic cancer tissues. Ad-REIC induced apoptosis and inhibited cell growth in the ASPC1 and MIAPaCa2 lines in vitro, and Ad-REIC inhibited tumor growth in the mouse xenograft model using ASPC1 cells. The antitumor effect was further enhanced in combination with gemcitabine. This synergistic effect may be caused by the suppression of autophagy via the enhancement of mammalian target of rapamycin signaling. ConclusionsAd-REIC induces apoptosis and inhibits tumor growth in pancreatic cancer cell lines. REIC/Dkk-3 gene therapy is an attractive therapeutic tool for pancreatic cancer. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 0918-8959 60 12 2013 Testosterone replacement elevates the serum uric acid levels in patients with female to male gender identity disorder 1321 1327 EN Hiroaki Kurahashi Masami Watanabe Morito Sugimoto Yuichi Ariyoshi Sabina Mahmood Motoo Araki Kazushi Ishii Yasutomo Nasu Atsushi Nagai Hiromi Kumon Gender identity disorder (GID) results from a disagreement between a person's biological sex and the gender to which he or she identifies. With respect to the treatment of female to male GID, testosterone replacement therapy (TRT) is available. The uric acid (UA) level can be influenced by testosterone; however, the early effects and dose-dependency of TRT on the serum UA concentration have not been evaluated in this population. We herein conducted a dose-response analysis of TRT in 160 patients with female to male GID. The TRT consisted of three treatment groups who received intramuscular injections of testosterone enanthate: 125 mg every two weeks, 250 mg every three weeks and 250 mg every two weeks. Consequently, serum UA elevation was observed after three months of TRT and there was a tendency toward testosterone dose-dependency. The onset of hyperuricemia was more prevalent in the group who received the higher dose. We also demonstrated a positive correlation between increased levels of serum UA and serum creatinine. Since the level of serum creatinine represents an individual's muscle volume and the muscle is a major source of purine, which induces UA upregulation, the serum UA elevation observed during TRT is at least partially attributed to an increase in muscle mass. This is the first study showing an association between serum UA elevation and a TRT-induced increase in muscle mass. The current study provides important information regarding TRT for the follow-up and management of the serum UA levels in GID patients. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 68 2 2014 Molecular Epidemiology and Clinical Implications of Metallo-β-Lactamase-Producing Pseudomonas aeruginosa Isolated from Urine 89 99 EN Shinichi Sako Reiko Kariyama Ritsuko Mitsuhata Masumi Yamamoto Koichiro Wada Ayano Ishii Shinya Uehara Susumu Kokeguchi Nobuchika Kusano Hiromi Kumon Original Article 10.18926/AMO/52405 We conducted a study on molecular epidemiology and clinical implications of metallo-β-lactamase (MBL)-producing Pseudomonas aeruginosa isolated from urine. Over a 10-year period from 2001 through 2010, a total of 92 MBL-producing P. aeruginosa urine isolates were collected from patients (one isolate per patient) who were admitted to 5 hospitals in Okayama Prefecture, Japan. When cross-infection was suspected in the hospital, pulsed-field gel electrophoresis was performed. In the resulting dendrogram of 79 MBL-producing P. aeruginosa urine isolates, no identical isolates and 7 pairs of isolates with ≥80% similarity were found. The biofilm-forming capabilities of 92 MBL-producing P. aeruginosa urine isolates were significantly greater than those of 92 non-MBL-producing urine isolates in a medium of modified artificial urine. The imipenem resistance transferred in 16 of 18 isolates tested, and these frequencies were in the range of 10－3 to 10－9. All of 18 isolates tested belonged to internationally spread sequence type 235 and had 3 gene cassettes of antimicrobial resistance genes in the class 1 integron. The strong biofilm-forming capabilities of MBL-producing P. aeruginosa urine isolates could be seriously implicated in nosocomial infections. To prevent spread of the organism and transferable genes, effective strategies to inhibit biofilm formation in medical settings are needed. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 68 2 2014 Molecular Simulation Analysis of the Structure Complex of C2 Domains of DKK Family Members and β-propeller Domains of LRP5/6:Explaining Why DKK3 Does Not Bind to LRP5/6 63 78 EN Yasuyuki Fujii Tyuji Hoshino Hiromi Kumon Original Article 10.18926/AMO/52403 Dickkopf (DKK) proteins interact with low-density lipoprotein receptor-related protein 5/6 (LRP5/6) to modulate WNT signaling. The interaction is mediated by a cysteine-rich domain (C2) in the DKK protein and β-propeller domains (PD) of LRP5/6. However, the third member of the DKK family (DKK3) does not bind to LRP5/6. To determine why DKK3 does not bind to the receptor domains, we performed a molecular modeling simulation study including homology modeling, protein-protein docking and molecular dynamics (MD). The computed affinities (ΔGbinding) between the C2 and PD models were consistent with the previously reported experimental results. The C2 model of DKK3 showed the lowest affinity for PD models. Multiple sequence alignment of C2 domains revealed that the DKK3 genes have a unique 7-amino-acid insertion (L249-E255 in human DKK3) and P258 in a finger loop 1 (FL1). Interestingly, the insertion sequence is evolutionally conserved. MD simulations of high-affinity complex models of C2 and PD showed that FL1 directly interacts with the PD models and stabilizes the complex models. We also built a 7-amino-acid-deletion/P258G mutant model of DKK3C2 and estimated its affinities for the PD models. The affinity for human LRP5PD2 was increased by the substitution (ΔGbinding＝－48.9kcal/mol) and the affinity was compatible with that of high-affinity ligands. The results suggested that the lack of affinity between human DKK3 and human LRP5/6 results from: i) insertion of the 7 amino acids, and ii) P258 in human DKK3. The sequence differences thus suggest an explanation for this unique property of DKK3. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 68 1 2014 A Rare Complication:Misdirection of an Indwelling Urethral Catheter into the Ureter 47 51 EN Tsutomu Ishikawa Motoo Araki Takeshi Hirata Masami Watanabe Shin Ebara Toyohiko Watanabe Yasutomo Nasu Hiromi Kumon Case Report 10.18926/AMO/52144 We report 3 patients with the rare complication of an indwelling urethral catheter misdirected into the ureter. This is the largest series to date. Patients were referred to us for a variety of reasons following exchange of their chronic indwelling urinary catheters. CT in all cases demonstrated the urinary catheters residing in the left ureter. The ages of the patients were 37, 67 and 81 years old. All patients suffered from neurogenic bladder. Two patients were female, one was male, and 2 of the 3 had a sensory disorder inhibiting their pain response. The catheters were replaced with open-end Foley catheters. Extensive follow-up CT scans were obtained in one case, demonstrating improvement of hydronephrosis and no evidence of ureteral stenosis. Cystoscopy in this patient demonstrated normally positioned and functioning ureteral orifices. Although the placement of an indwelling urethral catheter is a comparatively safe procedure, one must keep in mind that this complication can occur, particularly in female patients with neurogenic bladder. CT without contrast is a noninvasive, definitive diagnostic tool. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 68 1 2014 Robot-Assisted Radical Prostatectomy:Modified Ultradissection Reduces pT2 Positive Surgical Margins on the Bladder Neck 35 41 EN Motoo Araki Wooju Jeong Sung Yul Park Young Hoon Lee Yasutomo Nasu Hiromi Kumon Sung Joon Hong Koon Ho Rha Original Article 10.18926/AMO/52142 The purpose of this study was to compare the positive surgical margin (PSM) rates of 2 techniques of robot-assisted radical prostatectomy (RARP) for pT2 (localized) prostate cancer. A retrospective analysis was conducted of 361 RARP cases, performed from May 2005 to September 2008 by a single surgeon (KHR) at our institution (Yonsei University College of Medicine). In the conventional technique, the bladder neck was transected first. In the modified ultradissection, the lateral border of the bladder neck was dissected and then the bladder neck was transected while the detrusor muscle of the bladder was well visualized. Perioperative characteristics and outcomes and PSM rates were analyzed retrospectively for pT2 patients (n＝217), focusing on a comparison of those undergoing conventional (n＝113) and modified ultradissection (n＝104) techniques. There was no difference between the conventional and modified ultradissection group in mean age, BMI, PSA, prostate volume, biopsy Gleason score, and DʼAmico prognostic criteria distributions. The mean operative time was shorter (p＜0.001) and the estimated blood loss was less (p＜0.01) in the modified ultradissection group. The PSM rate for the bladder neck was significantly reduced by modified ultradissection, from 6.2% to 0% (p＜0.05). In conclusion, modified ultradissection reduces the PSM rate for the bladder neck. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 125 2 2013 おかやまメディカルイノベーションセンター（OMIC） ―近未来のライフイノベーションの実現に向けて― 173 175 EN Hiromi Kumon No potential conflict of interest relevant to this article was reported.

Springer Japan KK Acta Medica Okayama 1341-9625 18 1 2013 Could salvage surgery after chemotherapy have clinical impact on cancer survival of patients with metastatic urothelial carcinoma? 110 115 EN Kensuke Bekku Takashi Saika Yasuyuki Kobayashi Ryo Kioshimoto Taiki Kanbara Yasutomo Nasu Hiromi Kumon The clinical impact of salvage surgery after chemotherapy on cancer survival of patients with metastatic urothelial carcinoma is controversial. We aimed to verify the clinical role of salvage surgery by analyzing the long-term outcome in patients with urothelial carcinoma treated by chemotherapy. Between 2003 and 2010 at a single institution, 31 of 47 patients (66%) with metastatic urothelial carcinoma showed objective responses (CR in 4, PR in 27) after multiple courses of cisplatin/gemcitabine/paclitaxel-based chemotherapy, and a cohort of patients with partial response (PR) were retrospectively enrolled. Twelve (10 male and 2 female, median age 64.0 years) of 27 patients with PR underwent salvage surgeries after the chemotherapy: metastatectomy of residual lesions (10 retroperitoneal lymph nodes, 2 lung), and 6 radical surgeries for primary lesions as well. Progression-free survival and overall patient survival rates were analyzed retrospectively and compared with those of patients without salvage surgery. All 12 patients achieved surgical CR. Pathological findings of metastatic lesions showed viable cancer cells in 3 patients. In univariate analysis, sole salvage surgery affected overall survival in 27 patients with PR to the chemotherapy (P = 0.0037). Progression-free survival and overall survival rates in patients with salvage surgery were better than those in 15 PR patients without the surgery (39.8 vs. 0%, and 71.6 vs. 12.1% at 3 years, P = 0.01032 and 0.01048; log-rank test). Salvage surgery for patients with residual tumor who achieve partial response to chemotherapy could have a possible impact on cancer survival. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 0020-7136 126 7 2010 Down-regulation of BiP/GRP78 sensitizes resistant prostate cancer cells to gene-therapeutic overexpression of REIC/Dkk-3 1562 1569 EN Ryuta Tanimoto Masakiyo Sakaguchi Fernando Abarzua Ken Kataoka Kaoru Kurose Hitoshi Murata Yasutomo Nasu Hiromi Kumon Nam-Ho Huh We have recently shown that an adenovirus carrying REIC/Dkk-3 (Ad-REIC) exhibits a potent tumor-specific cell-killing function for various human cancers. It has also become evident that some human cancers are resistant to Ad-REIC-induced apoptosis. The aim of the present study was to determine the molecular mechanisms of resistance to Ad-REIC. First, we isolated resistant clones from a human prostate cancer cell line, PC3, after repeated exposure to Ad-REIC. Infection efficiency of the adenovirus vector and expression level of REIC/Dkk-3 in the resistant clones were similar to those in the parental PC3 cells. By screening for alteration in levels and functional status of proteins involved in Ad-REIC-induced apoptosis, we found that BiP/GRP78, an ER-residing chaperone protein, was expressed at higher levels consistently among resistant cells. Expression levels of BiP and rates of apoptosis induced by Ad-REIC were inversely correlated. Down-regulation of BiP with siRNA sensitized the resistant cells to Ad-REIC in vivo as well as in culture. These results indicate that BiP is a major determinant of resistance to Ad-REIC-induced apoptosis. Thus BiP is useful for diagnosis of inherent and acquired resistance of cancers and also as a target molecule to overcome resistance to the gene therapeutic Ad-REIC. No potential conflict of interest relevant to this article was reported.

Nature Publishing Group Acta Medica Okayama 0929-1903 17 7 2010 Potent antitumor effects of combined therapy with a telomerase-specific, replication-competent adenovirus (OBP-301) and IL-2 in a mouse model of renal cell carcinoma 484 491 EN P Huang H Kaku J Chen Y Kashiwakura T Saika Y Nasu Y Urata T Fujiwara M Watanabe H Kumon OBP-301 (a telomerase-specific, replication-competent adenovirus with hTERT promoter) was constructed in a previous study and it showed a strong anticancer effect by inducing cell lysis in human lung and prostate cancer cells. This study investigated the effectiveness of a combination therapy of OBP-301 and interleukin-2 (IL-2) in a mouse model of renal cell carcinoma (RCC). The cell-killing effect of OBP-301 was confirmed in vitro in the RENCA cancer cells. In in vivo experiment, luciferase-expressing RENCA cells were implanted in the left kidney and lung of BALB/c mice to prepare the RCC metastatic model. The animals were randomly divided into four treatment groups: PBS, IL-2 alone, OBP-301 alone and the combination. The analyses of orthotopic tumor weight, lung metastasis and luciferin-stained tumor images 14 days after each treatment showed significant tumor growth inhibition in the combination group in comparison with that in the OBP-301- or IL-2-treated groups. In addition, the percentage of regulatory T-cells (Tregs) in the combination group was significantly suppressed in comparison with that in the PBS and single-agent treatment groups. The outcomes of this study suggest that tumor-specific oncolytic immunovirotherapy may become an attractive strategy for the treatment of human RCC. No potential conflict of interest relevant to this article was reported.

The American Society for Biochemistry and Molecular Biology, Inc. Acta Medica Okayama 0021-9258 284 21 2009 Overexpression of REIC/Dkk-3 in Normal Fibroblasts Suppresses Tumor Growth via Induction of Interleukin-7 14236 14244 EN Masakiyo Sakaguchi Ken Kataoka Fernando Abarzua Ryuta Tanimoto Masami Watanabe Hitoshi Murata Swe Swe Than Kaoru Kurose Yuji Kashiwakura Kazuhiko Ochiai Yasutomo Nasu Hiromi Kumon Nam-ho Huh We previously showed that the tumor suppressor gene REIC/Dkk-3, when overexpressed by an adenovirus (Ad-REIC), exhibited a dramatic therapeutic effect on human cancers through a mechanism triggered by endoplasmic reticulum stress. Adenovirus vectors show no target cell specificity and thus may elicit unfavorable side effects through infection of normal cells even upon intra-tumoral injection. In this study, we examined possible effects of Ad-REIC on normal cells. We found that infection of normal human fibroblasts (NHF) did not cause apoptosis but induced production of interleukin (IL)-7. The induction was triggered by endoplasmic reticulum stress and mediated through IRE1 alpha, ASK1, p38, and IRF-1. When Ad-REIC-infected NHF were transplanted in a mixture with untreated human prostate cancer cells, the growth of the cancer cells was significantly suppressed. Injection of an IL-7 antibody partially abrogated the suppressive effect of Ad-REIC-infected NHF. These results indicate that Ad-REIC has another arm against human cancer, an indirect host-mediated effect because of overproduction of IL-7 by mis-targeted NHF, in addition to its direct effect on cancer cells. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 66 1 2012 Laparoscopic-Assisted Tension-free Vaginal Mesh: An Innovative Approach to Placing Synthetic Mesh Transvaginally for Surgical Correction of Pelvic Organ Prolapse 23 29 EN Toyohiko Watanabe Miyabi Inoue Ayano Ishii Toyoko Yamato Masumi Yamamoto Katsumi Sasaki Yasuyuki Kobayashi Motoo Araki Shinya Uehara Takashi Saika Hiromi Kumon Original Article 10.18926/AMO/48078 Polypropylene mesh implants for the correction of pelvic organ prolapse (POP) are now available in Japan. We developed an innovative approach for correcting POP by placing polypropylene mesh transvaginally with laparoscopic assistance. From June 2007 through March 2010, sixteen consecutive patients with symptomatic stage 2 or 3 pelvic organ prolapse underwent the laparoscopic-assisted tension-free vaginal mesh procedure at Okayama University Hospital. All patients were evaluated before and at 1, 3, 6, and 12 months after surgery. Female sexual function was also evaluated with the Female Sexual Function Index (FSFI). The procedure was performed successfully without significant complications. Fifteen of 16 patients were considered anatomically cured (93.8%) at 12 months postoperatively. One patient with a recurrent stage 3 vaginal vault prolapse required sacral colpopexy six months postoperatively. Total FSFI scores improved significantly from 10.3±1.3 at baseline to 18.0±1.2 at 12 months after surgery. The laparoscopic-assisted trans-vaginal mesh is a safe, effective, and simple procedure for POP repairs. The procedure not only restores anatomic relationships but also improves sexual function. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 66 1 2012 Preclinical Safety and Efficacy of in Situ REIC/Dkk-3 Gene Therapy for Prostate Cancer 7 16 EN Keiichiro Kawauchi Masami Watanabe Haruki Kaku Peng Huang Kasumi Sasaki Masakiyo Sakaguchi Kazuhiko Ochiai Nam-ho Huh Yasutomo Nasu Hiromi Kumon Original Article 10.18926/AMO/48076 The preclinical safety and therapeutic efficacy of adenoviral vectors that express the REIC/Dkk-3 tumor suppressor gene (Ad-REIC) was examined for use in prostate cancer gene therapy. The Ad-human (h) and mouse (m) REIC were previously demonstrated to induce strong anti-cancer effects in vitro and in vivo, and we herein report the results of two in vivo studies. First, intra-tumor Ad-hREIC administration was examined for toxicity and therapeutic effects in a subcutaneous tumor model using the PC3 prostate cancer cell line. Second, intra-prostatic Ad-mREIC administration was tested for toxicity in normal mice. The whole-body and spleen weights, hematological and serum chemistry parameters, and histological evaluation of tissues from throughout the body were analyzed. Both experiments indicated that there was no significant difference in the examined parameters between the Ad-REIC-treated group and the control (PBS- or Ad-LacZ-treated) group. In the in vitro analysis using PC3 cells, a significant apoptotic effect was observed after Ad-hREIC treatment. Confirming this observation, the robust anti-tumor efficacy of Ad-hREIC was demonstrated in the in vivo subcutaneous prostate cancer model. Based on the results of these preclinical experiments, we consider the adenovirus-mediated REIC/Dkk-3 in situ gene therapy to be safe and useful for the clinical treatment of prostate cancer. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 65 5 2011 Single Nucleotide Polymorphism WRN Leu1074Phe Is Associated with Prostate Cancer Susceptibility in Chinese Subjects 315 323 EN Lei Wang Haruki Kaku Peng Huang Kexin Xu Kai Yang Jiheng Zhang Ming Li Liping Xie Xiaofeng Wang Akiko Sakai Masami Watanabe Yasutomo Nasu Kenji Shimizu Hiromi Kumon Yanqun Na Original Article 10.18926/AMO/47013 Deficiencies in the human DNA repair gene WRN are the cause of Werner syndrome, a rare autosomal recessive disorder characterized by premature aging and a predisposition to cancer. This study evaluated the association of WRN Leu1074Phe (rs1801195), a common missense single nucleotide polymorphism in WRN, with prostate cancer susceptibility in Chinese subjects. One hundred and forty-seven prostate cancer patients and 111 male cancer-free control subjects from 3 university hospitals in China were included. Blood samples were obtained from each subject, and the single nucleotide polymorphism WRN Leu1074Phe was genotyped by using a Snapshot assay. The results showed that WRN Leu1074Phe was associated with the risk of prostate cancer in Chinese men and that the TG/GG genotype displayed a decreased prevalence of prostate cancer compared with the TT genotype (OR＝0.58, 95%CI:0.35-0.97, p＝0.039). Through stratified analysis, more significant associations were revealed for the TG/GG genotype in the subgroup with diagnosis age <_ 72 yr (OR＝0.27, 95%CI:0.12-0.61, p＝0.002) and in patients with localized diseases (OR＝0.36, 95%CI:0.19-0.70, p＝0.003). However, no statistically significant difference was found in the subgroup with age ＞72 yr or in patients with advanced diseases. We concluded that the genetic variant Leu1074Phe in the DNA repair gene WRN might play a role in the risk of prostate cancer in Chinese subjects. No potential conflict of interest relevant to this article was reported.

Academic Press Inc Elsevier Science Acta Medica Okayama 0006-291X 412 2 2011 Tumor suppressor REIC/Dkk-3 interacts with the dynein light chain, Tctex-1 391 395 EN Kazuhiko Ochiai Masami Watanabe Hideo Ueki Peng Huang Yasuyuki Fujii Yasutomo Nasu Hirofumi Noguchi Takeshi Hirata Masakiyo Sakaguchi Nam-ho Huh Yuji Kashiwakura Haruki Kaku Hiromi Kumon Persistent hepatitis C virus (HCV) infection causes chronic liver diseases and is a global health problem. HuH-7 hepatoma-derived cells are widely used as the only cell-based HCV replication system for HCV research, including drug assays. Recently, using different hepatoma Li23-derived cells, we developed an HCV drug assay system (ORL8), in which the genome-length HCV RNA (O strain of genotype 1b) encoding renilla luciferase replicates efficiently. In this study, using the HuH-7-derived OR6 assay system that we developed previously and the ORL8 assay system, we evaluated 26 anti-HCV reagents, which other groups had reported as anti-HCV candidates using HuH-7-derived assay systems other than ORB. The results revealed that more than half of the reagents showed different anti-HCV activities from those in the previous studies, and that anti-HCV activities evaluated by the ORB and ORL8 assays were also frequently different. In further evaluation using the HuH-7-derived AH1R assay system, which was developed using the AH1 strain of genotype 1b, several reagents showed different anti-HCV activities in comparison with those evaluated by the OR6 and ORL8 assays. These results suggest that the different activities of anti-HCV reagents are caused by the differences in cell lines or HCV strains used for the development of assay systems. Therefore, we conclude that plural HCV assay systems developed using different cell lines or HCV strains are required for the objective evaluation of anti-HCV reagents. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 65 2 2011 For Vol. 64, No. 1 pp 27-31 Prognostic Factors Influencing Survival after ephroureterectomy for Transitional Cell Carcinoma of the Upper Urinary Tract 143 149 EN Yasuyuki Kobayashi Takashi Saika Daisuke Manabe Yasutomo Nasu Hiromi Kumon Corrected and Republished Article 10.18926/AMO/45274 We analyzed the prognostic factors influencing survival after surgeries for upper urinary tract urothelial carcinoma (UUT-UC) with longer follow-up periods than in previous studies. Between January 2000 and December 2004, 386 patients underwent nephroureterectomy for UUT-UC. The data for the 221 patients with UUT-UC were retrospectively reviewed. Nine variables were evaluated for association with the survival outcomes of cause-specific survival. The prognostic significance was tested univariately with the log-rank test. The simultaneous effects of multiple prognostic factors were estimated by multiple regression analysis using the Cox proportional hazards model. The median follow-up was 38.4 months. The 5-year over all survival was 62.3%. Significant prognostic factors for disease-specific survival rate on univariate analysis were pathological stage (p0.0001), tumor grade (p0.0324), and venous invasion (p0.0001). Multivariate analysis revealed that only venous invasion was significant for disease-specific survival rate (p0.0205). Venous invasion was the only independent prognostic factor in pathologically localized UUT-UC. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 66 6 2005 Detrusor overactivity induced by intravesical application of adenosine 5 '-triphosphate under different delivery conditions in rats 1332 1337 EN Jun Nishiguchi Yukio Hayashi Michael B Chancellor Fernando de Miguel William C de Groat Hiromi Kumon Naoki Yoshimura Objectives. We investigate the effects of intravesical application of adenosine 5'-triphosphate (ATP) on bladder activity to elucidate the role of urothelial barrier function and ecto-ATPase activity in the ATP-mediated mechanism inducing detrusor overactivity. Methods. Continuous cystometry by an intravesical catheter inserted from the bladder dome was performed in conscious female rats. Results. ATP solutions adjusted to pH 6.0 did not elicit significant detrusor overactivity at a concentration of 60 mM. However, in bladders pretreated with protamine sulfate (10 mg/mL) to increase urothelial permeability, ATP solution (pH 6.0) induced detrusor overactivity by decreasing the intercontraction intervals. These irritant effects of ATIP after protamine treatment were antagonized by P2X receptor antagonists, such as pyridoxal-5-phosphate-6-azophenyl-2',4-disulfonic acid (70 mu mol/kg) and 2',3'-O-(2,4,6, trinitrophenyl) ATP (30 mu mol/kg). These were also suppressed in rats pretreated with systemic capsaicin (125 mg/kg subcutaneously). Alpha,beta-methylene ATP (5 mM, pH 6.0) or ATP (60 mM, pH6) after intravesical infusion of 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (5 mM, pH 6.0), an ecto-ATPase inhibitor, induced detrusor overactivity without protamine pretreatment, but the reduction in intercontraction intervals was smaller compared with that with ATP after protamine treatment. Conclusions. Low permeability of bladder epithelium and ecto-ATPase activity can prevent ATP activation of subepithelial P2X receptors to induce bladder overactivity. Thus, enhanced penetration of endogenous ATIP owing to urothelial damage may contribute to urinary frequency and bladder pain in hypersensitive bladder disorders such as interstitial cystitis. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 14 7 2007 Natural course of lower urinary tract symptoms following discontinuation of alpha-1-adrenergic blockers in patients with benign prostatic hyperplasia 598 601 EN Teruhiko Yokoyama Toyohiko Watanabe Takashi Saika Yasutomo Nasu Hiromi Kumon Yoshiyuki Miyaji Atsushi Nagai alpha 1-adrenergic blockers (alpha b) remain the first-line therapy in men with lower urinary tract symptoms (LUTS). The current published work advocates continued use of alpha b for their effect to be maintained. However, some patients decide to discontinue use of the medication after their symptoms are relieved and can keep good conditions. In this study, we investigated the natural course of LUTS after the discontinuation of successful treatment of alpha b. Methods: Among 75 patients with LUTS who stopped alpha b medication once their symptoms improved, 60 patients (age, 50-87 years; median, 70) who could be followed for at least 12 months after discontinuation of alpha b were analyzed in this study. Evaluations included a clinical determination of the International Prostate Symptom Score (IPSS), peak flow rate (Qmax) and postvoid residual urine volume (PVR). Upon patient request or in cases of PVR more than 100 mL, administration of alpha b was resumed. Results: Eighteen out of the 60 patients (30%) asked for re-treatment within 12 months after discontinuation (re-treatment group). The other 42 patents were able to maintain good condition without medication (discontinuation group). The IPSS was 15.9, 8.7, 10.1, 10.2, 9.7, 8.8 and 9.0, on the first visit, just before discontinuation, and 1, 3, 6, 9 and 12 months after stopping treatment among the discontinuation group, respectively. Similarly, Qmax was 10.6, 14.8, 14.2, 14.3, 14.7, 13.2 and 13.6 mL/ s, respectively. Treatment periods, prostatic volume and peak flow rates just before discontinuation of medication differed significantly between the re-treatment and discontinuation group. Conclusions: In spite of the short follow-up periods, these results suggest that selected patients with relatively small prostatic volume and good flow rates after therapy can discontinue alpha b medication after their symptoms improve. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 61 6 2007 Routine Transurethral Biopsy of the Bladder is not Necessary to Evaluate the Response to Bacillus Calmette-guerin Therapy 341 344 EN Takanori Murakami Shin Ebara Takashi Saika Shin Irie Katsuji Takeda Yoshio Maki Sadayuki Miyaji Daisuke Manabe Haruki Kaku Yasutomo Nasu Tomoyasu Tsushima Hiromi Kumon Original Article 10.18926/AMO/32881 We evaluated the need for transurethral biopsy at first follow-up after intravesical bacillus Calmette-Guerin (BCG) therapy for superficial bladder cancer. The records of 84 patients with superficial bladder cancer who received a 6- or 8-week course of BCG were reviewed. Pathological results before BCG, cystoscopic findings, urinary cytology, and biopsy results for evaluation of BCG therapy were reviewed. All 19 patients with positive urinary cytology had evidence of positive bladder biopsy results. Fifty-three of 54 patients (98.1%) with no visible recurrent tumor and negative urinary cytology demonstrated negative pathological results on bladder biopsy. When not found in conjunction with positive urinary cytology, erythematous mucosa on cystoscopy was not an indicator of tumor recurrence or residual cancer. In conclusion, routine transurethral biopsy of the bladder for evaluating the response to BCG intravesical therapy is not necessary in patients who have no visible tumor on cystoscopy and negative urinary cytology./ No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 61 6 2007 The Efficacy of Neoadjuvant Androgen Deprivation Therapy as a Prostate Volume Reduction before Brachytherapy for Clinically Localized Prostate Cancer 335 340 EN Shin Ebara Daisuke Manabe Yasuyuki Kobayashi Ryuta Tanimoto Takashi Saika Yasutomo Nasu Shirou Saito Takefumi Satoh Kenta Miki Katsuyoshi Hashine Hiromi Kumon Original Article 10.18926/AMO/32878 From September 2003 to December 2005, 188 patients who visited our hospital and allied institutions for the purpose of prostate brachytherapy were administrated hormonal therapy for volume reductions before brachytherapy. The pretreatment and posttreatment of prostate volume using a transrectal ultrasound volumetric study and the types and duration of hormonal therapy were analyzed. We administered 91 patients with Luteinizing hormone-releasing hormone (LH-RH) agonist, 49 patients with anti-androgen (bicaltamide/flutamide), and 48 patients with maximum androgen blockade (MAB). The duration of the hormonal therapy was 1-3 months for 49 patients, 4-6 months for 59 patients, 7-9 months for 40 patients, 10-12 months for 32 patients, and over 13 months for 8 patients. Before the initiation of hormonal therapy, the mean prostate volume was 35.12 ml (11.04-78.71 ml), and the average of prostate volume before and after hormonal therapy was 36.79 ml and 24.79 ml, respectively (a 32.4% reduction). The prostate volume reduction rate was 32.0% for the LH-RH agonist only, 18.1% for the anti-androgen only and 41.2% for the MAB. No statistically significant difference was observed for the duration of hormonal therapy between 3 groups. A three-month course of the neoadjuvant LH-RH agonist indicated a sufficient volume reduction effectiveness for a large prostate volume. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 61 4 2007 Orthotopic ileal neobladder versus sigmoidal neobladder: a "quality of life" (QOL) survey 229 234 EN Ryoji Arata Takashi Saika Tomoyasu Tsushima Fernando Abarzua Yasutomo Nasu Hiromi Kumon Original Article 10.18926/AMO/32868 To compare the quality of life (QOL) in patients with ileal neobladder and sigmoidal neobladder, a retrospective survey was conducted using a formulated questionnaire. Between January and March 1999, a QOL survey was conducted using self-administered questionnaires (EORTC QLQ-C30, IPSS, supplemented with detailed questionnaires about continence, sexual function, and patient’s satisfaction with the selected urinary diversion method) for 78 patients with orthotopic urinary reservoir (OUR) who were followed-up for more than 3 months after cystectomy. Among 78 patients, 63 had OUR using an ileal segment (male/female＝59/4, median age: 70.8 years old, median follow-up: 1.7 years). Fifteen patients had OUR using a sigmoidal segment (male/female＝13/2, median age: 71.9, median follow-up: 3.9). The QLQ-C30 functional evaluation and the items in relation to sexual function showed no diff erences between the 2 groups. Concerning the voiding condition, bladder emptying, frequency, and urgency, scores in the sigmoidal OUR group were signifi cantly higher. The QOL score concerning voiding conditions, daytime, and nighttime continence and quantity of pad showed a better score in the ileal OUR group. Concerning the satisfaction with methods of urinary diversion, patients in the sigmoidal OUR group expressed less satisfaction than their preoperative expectations. Considering several postoperative voiding conditions, ileal OUR seems superior to sigmoidal OUR. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 64 1 2010 Epidemiology of Chlamydophila caviae-like Chlamydia Isolated from Urethra and Uterine Cervix 1 9 EN Wataru Murao Koichiro Wada Akira Matsumoto Michihisa Fujiwara Hideto Fukushi Toshio Kishimoto Koichi Monden Reiko Kariyama Hiromi Kumon Original Article 10.18926/AMO/32863 In 2000, chlamydial strains OK133 and OK135 were isolated from 2 female patients with cervicitis. These strains were unresponsive to commercially available PCR and LCR test kits for the diagnosis of Chlamydia trachomatis infection, and their phenotypic characteristics were very similar. The OK135 nucleotide sequence in MOMP-VD2 gene closely resembled that of Chlamydophila caviae GPIC. A similar strain was isolated in 2003 from a male patient OKM2 with urethritis, from which the strain SC10-6 was cloned by the plaque purification method. The nucleotide sequence of the entire MOMP gene of SC10-6 was exactly the same as that of OK135. Thus, the strains OK135 and SC10-6, together with OK133, have been called C. caviae-like Chlamydia. We designed primers for nested PCR assay, the product of which showed a single-band 311-bp fragment, to detect C. caviae-like Chlamydia. Of swab specimens obtained from 202 patients from 2003 to 2006 (119 male and 83 female patients), 18 specimens (8.9%) from 14 male and 4 female patients were positive, suggesting that C. caviae-like Chlamydia infection is rather common. Thus far, it has not been determined whether C. caviae-like Chlamydia is pathogenic for humans. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 64 1 2010 Prognostic Factors Influencing Survival after ephroureterectomy for Transitional Cell Carcinoma of the Upper Urinary Tract 27 31 EN Yasuyuki Kobayashi Takashi Saika Daisuke Manabe Yasutomo Nasu Hiromi Kumon Original Article 10.18926/AMO/32862 We analyzed the prognostic factors influencing survival after surgeries for upper urinary tract urothelial carcinoma (UUT-UC) with longer follow-up periods than in previous studies. Between January 2000 and December 2004, 386 patients underwent nephroureterectomy for UUT-UC. The data for the 221 patients with UUT-UC were retrospectively reviewed. Nine variables were evaluated for association with the survival outcomes of cause-specific survival. The prognostic significance was tested univariately with the log-rank test. The simultaneous effects of multiple prognostic factors were estimated by multiple regression analysis using the Cox proportional hazards model. The median follow-up was 38.4 months. The 5-year over all survival was 62.3%. Significant prognostic factors for disease-specific survival rate on univariate analysis were pathological stage (p0.0001), tumor grade (p0.0324), and venous invasion (p0.0001). Multivariate analysis revealed that only venous invasion was significant for disease-specific survival rate (p0.0205). Venous invasion was the only independent prognostic factor in pathologically localized UUT-UC. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 57 6 2003 Anterior urethral recurrence of superficial bladder cancer: its clinical significance. 293 297 EN Takashi Saika Tomoyasu Tsushima Yasutomo Nasu Ryoji Arata Haruki Kaku Naoki Akebi Nobuyuki Kusaka Hiromi Kumon Article 10.18926/AMO/32815 The aim of this study was to reveal the clinical features of anterior urethral recurrence in patients with superficial bladder cancer, and to determine the appropriate treatment. Three hundred and three patients with superficial bladder cancer, who were newly diagnosed and initially treated conservatively in our hospital between 1965 and 1990, were followed for at least 5 years and their clinical outcomes were analyzed. Clinical factors, including anterior urethral recurrence, were evaluated statistically regarding tumor progression. Eight patients (2.6%) had anterior urethral recurrence following superficial bladder cancer. Twenty-four patients (7.9%) had tumor progression and 149 (49.2%) had tumor recurrence. In a multivariate analysis using a logistic model, anterior urethral recurrence was the most important factor, followed by histological grade. Four of 5 patients who were treated for anterior urethral recurrent tumors by transurethral resection showed progression and died of the cancer within one year. Two of the remaining three patients who underwent radical cysto-urethrectomy at the time of anterior urethral recurrence survived. Anterior urethral recurrence following superficial bladder cancer is a predictor for rapid subsequent malignant progression. Once there is anterior urethral recurrence, radical intensive therapy, including radical cysto-urethrectomy, should be carried out immediately. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 37 3 1983 Human urinary cytology using a "direct mapping" technique: a combined light and scanning electron microscopic investigation. 233 250 EN Hiromi Kumon Hiroyuki Ohmori Toshio Tanaka Article 10.18926/AMO/32431 A total of 252 bladder-washing and voided specimens from normal, and inflammatory and malignant lesions were examined by a direct mapping technique, i.e., a combined use of light (LM) and scanning electron microscopy (SEM). A newly-designed mesh, which consists of a piece of gelatine-covered, osmium-impregnated and polylysine-coated glass-slip with 42 compartments/25 mm2, was used in this study. This mesh permitted us to directly correlate LM and SEM images, which resulted in a shortening of the observation time. Malignancy of exfoliated urothelial cells has been determined on the basis of the presence or absence of pleomorphic microvilli as observed by SEM. Subsequently, a new "SEM grading" system for human urinary cytology was proposed. The direct mapping technique has enhanced the accuracy of the diagnosis over conventional methods, especially in cases of noninvasive, low-grade malignant tumors of the urinary bladder. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 37 6 1983 Prostatic malacoplakia: a case report with a review of 49 cases of malacoplakia of various sites in Japan. 493 501 EN Hiromi Kumon Masato Furukawa Masaya Tsugawa Yosuke Matsumura Hiroyuki Ohmori Toshio Tanaka Article 10.18926/AMO/32408 We reported a 62-year-old man with malacoplakia of the prostate, and reviewed 49 cases of malacoplakia hitherto observed in Japan in which the lesions originated from the urogenital tract, except for one gastric case. E. Coli was emphasized as a possible causative agent for malacoplakia especially in the urogenital tract. The possible histiocytic origin of von Hansemann cells was stressed by demonstrating cytoplasmic processes and desmosomes in our prostatic case. An adjuvant use of cholinergic agents and ascorbic acid with chemotherapeutic agents was recommended for treating malacoplakia. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 58 1 2004 Effectiveness of a nonsteroidal anti-inflammatory drug for nocturia on patients with benign prostatic hyperplasia: a prospective non-randomized study of loxoprofen sodium 60 mg once daily before sleeping. 45 49 EN Tohru Araki Teruhiko Yokoyama Hiromi Kumon Article 10.18926/AMO/32115 We explored the effectiveness of loxoprofen sodium (loxoprofen), which is the most common non-steroidal anti-inflammatory drug (NSAID) in Japan, for patients with benign prostatic hyperplasia (BPH) complaining of nocturia. A total of 93 BPH patients aged 49-84 years were enrolled in the study. These patients had received standard drug therapy with alpha1-blocker for BPH, followed by anticholinergic drugs, hypnotics, tricyclic antidepressants, and/or antiduretic hormone, but they still complained about 2 or more episodes of nocturia. They each took a single 60-mg tablet of loxoprofen prior to sleeping at night for 14 days in addition to their BPH treatments. The effects were assessed by questionnaire before and after treatment as excellent (nocturia disappeared or decreased by 2 or more voids/night), improved (nocturia decreased by 1 void/night), unchanged, or worsened (nocturia increased). Nocturia improved or disappeared in 74.2% of patients: excellent, improved, unchanged, and worsened results were obtained in 37.6%, 36.6%, 21.5%, and 4.3% of patients, respectively. The effects were better in patients whose baseline nocturia was > 2 times than in those with a lesser frequency at enrollment (P = 0.04). Loxoprofen can be an effective and useful treatment option for patients with BPH complaining of refractory nocturia. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 58 3 2004 High-energy transurethral microwave thermotherapy in patients with benign prostatic hyperplasia: comparative study between 30-and 60-minute single treatments. 151 156 EN Teruhiko Yokoyama Masaya Tsugawa Atsushi Nagai Hiromi Kumon Article 10.18926/AMO/32106 We retrospectively evaluated the subjective and objective treatment results of transurethral microwave thermotherapy (TUMT) for benign prostatic hyperplasia (BPH) and explored the difference in effectiveness between 30- and 60-min single treatments. From June 1997 through March 2003, 58 men with BPH underwent TUMT using the Targis device. Twenty-seven and 31 patients each received a single treatment of 60 or 30 min, respectively. Evaluations after treatment included a clinical determination of the International Prostate Symptom Score, urodynamic assessments by peak flow rate, and magnetic resonance imaging (MRI). In the 60-min treatment, the symptom score improved significantly, from 17.9 to 9.5 after 2 months. Similarly, there was a significant improvement in peak flow rate, from 6.7 to 11.2 ml/sec after 2 months. In the 30-min treatment, the symptom score also improved significantly, from 18.4 to 13.4 after 2 weeks. Similarly, there was a significant improvement in the peak flow rate, from 6.4 to 11.7 ml/sec after 1 month. MRI imaging showed necrosis of the prostate gland 2 weeks after either treatment. These results demonstrated that both the 60-min and the 30-min treatments were effective for patients with BPH. Moreover, the 30-min treatment led to quicker improvement than the 60-min treatment. Thus, a 30-min TUMT protocol is considered recommendable for this treatment. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 58 4 2004 Biofilm formation among methicillin-resistant Staphylococcus aureus isolates from patients with urinary tract infection. 207 214 EN Eiichi Ando Koichi Monden Ritsuko Mitsuhata Reiko Kariyama Hiromi Kumon Article 10.18926/AMO/32090 Staphylococci have been confirmed to form biofilms on various biomaterials. The purpose of this study was to investigate biofilm formation among methicillin-resistant Staphylococcus aureus (MRSA) isolates from patients with urinary tract infection (UTI) and to assess the relationship between biofilm-forming capacities and virulence determinants/clinical background. Over a 12-year period from 1990 through 2001, a total of 109 MRSA isolates were collected from patients (one isolate per patient) with UTI at the urology ward of Okayama University Hospital. We used the in vitro microtiter plate assay to quantify biofilm formation. We then investigated the presence of several virulence determinants by polymerase chain reaction assay and found eight determinants (tst, sec, hla, hlb, fnbA, clfA, icaA, and agrII) to be predominant among these isolates. Enhanced biofilm formation was confirmed in hla-, hlb-, and fnbA-positive MRSA isolates, both individually and in combination. Upon review of the associated medical records, we concluded that the biofilm-forming capacities of MRSA isolates from catheter-related cases were significantly greater than those from catheter-unrelated cases. The percentage of hla-, hlb-, and fnbA-positive isolates was higher among MRSA isolates from catheter-related cases than those from catheter-unrelated cases. Our studies suggest that MRSA colonization and infection of the urinary tract may be promoted by hla, hlb, and fnbA gene products. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 58 4 2004 Ureteroscopy using a detachable access sheath. 215 216 EN Fernando Abarzua Koichi Monden Atsushi Nagai Yasutomo Nasu Hiromi Kumon Article 10.18926/AMO/32084 Ureteroscopy has evolved in many aspects, particularly in the flexibility and size of ureteroscopes. We have developed a new detachable access sheath to make ureteroscopic procedures more straight-forward and to reduce possible damage to delicate instruments used in the procedure. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 33 6 1979 Malacoplakia of probable retroperitoneal origin. 455 462 EN Hiromi Kumon Masaaki Morioka Tohru Araki Yosuke Matsumura Hiroyuki Ohmori Toshio Tanaka Article 10.18926/AMO/32050 A case of extravesical malacoplakia, the first case in Japan, is described in detail. The patient was a 61-year-old woman with a right flank mass. Radiologically, the mass was thought to be of the renal origin. Surgically, however, the tumor was found attached not only to the cortical surface but extended to the retroperitoneum and psoas muscle. Pathological examination confirmed the lesion to be malacoplakia characterized by the presence of von Hansemann cells and Michaelis-Gutmann bodies. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 59 3 2005 Clinical implications of biofilm formation by Enterococcus faecalis in the urinary tract. 79 87 EN Yuko Seno Reiko Kariyama Ritsuko Mitsuhata Koichi Monden Hiromi Kumon Article 10.18926/AMO/31979 The potential relationships between biofilm formation and pathogenicity of Enterococcus faecalis in urinary tract infections (UTI) were investigated. Over a 12-year period from 1991 through 2002, a total of 352 E.faecalis isolates were collected from patients with complicated UTI (one isolate per patient) at the urology ward of Okayama University Hospital. We analyzed the prevalence and transferability of genes encoding virulence factors(asa1, esp, cylA, gelE /sprE )and antimicrobial resistance(aac(6') /aph(2'')). The production of biofilm, hemolysin and gelatinase by these isolates was also examined and the associated medical records of patients were retrospectively reviewed. Of 352 E. faecalis isolates, 315 possessed and/or genes. Of the 63 hemolysin- and 167 gelatinase-producing isolates, 59 and 94 isolates, respectively, possessed both asa1 and esp genes. E. faecalis isolates with both asa1 and esp genes formed biofilms at significantly higher rates than those with neither gene (P=0.038). The genes encoding asa1, cylA , and aac(6') /(aph(2'') were transferable and appeared to have accumulated in these isolates. The E. faecalis isolates possessing asa1 and/or esp genes were found from both catheter-related or -unrelated UTI. Our study indicates that E. faecalis isolates that have accumulated virulence genes are apt to form persistent biofilms in the urinary tracts. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 59 3 2005 Retroperitoneoscopic pyelolithotomy as initial treatment for upper urinary tract large stone. 109 112 EN Hideo Ozawa Atsushi Nagai Katsutoshi Uematsu Hiroyuki Ohmori Hiromi Kumon Article 10.18926/AMO/31978 We report a case in which retroperitoneoscopic pyelolithotomy was the procedure selected to treat a large stone in the upper urinary tract. A 71-year-old woman who had multiple cerebral infarction and dementia was admitted with a persistent high fever unresponsive to antibiotics. The diagnosis was pyelonephritis and urosepsis associated with ureteral calculus. A large calculus(3.0 x 2.0 cm)was found in the left ureter at the L3 level. She underwent nephrostomy of the left side. After the patient's general condition had improved, surgery was performed successfully with an uneventful recovery. The findings in this case confirm that retroperitoneoscopic surgery allows removal of a large stone in a single, minimally invasive procedures. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 59 5 2005 Synergistic effect of fosfomycin and fluoroquinolones against Pseudomonas aeruginosa growing in a biofilm. 209 216 EN Takeshi Mikuniya Yoshihisa Kato Reiko Kariyama Koichi Monden Muneo Hikida Hiromi Kumon Article 10.18926/AMO/31977 Ulifloxacin is the active form of the prodrug prulifloxacin and shows a highly potent antipseudomonal activity. In this study, we examined the combined effect of fosfomycin and ulifloxacin against Pseudomonas aeruginosa (P. aeruginosa) growing in a biofilm using a modified Robbins device with artificial urine, and compared it to that of the combination of fosfomycin and ciprofloxacin or levofloxacin. An ATP bioluminescence assay was used to evaluate the antibacterial activity of the agents against sessile cells in a mature biofilm developed on a silicon disk. The total bioactivity of P. aeruginosa growing in a biofilm that had not been fully eradicated by fosfomycin or any of the fluoroquinolones alone at 10 times the MIC decreased after combination treatment with fosfomycin and fluoroquinolones. Morphological changes occurred in a time-dependent fashion; namely, swollen and/or rounding cells emerged within a couple of hours after combination treatment, marking the initial stage in the process leading to the destruction of the biofilms. We could not find any difference among the 3 fluoroquinolones with regard to their synergistic effects when administered with fosfomycin. The combination treatment of fosfomycin and fluoroquinolones with highly potent antipseudomonal activities was effective in eradicating sessile cells of P. aeruginosa in the biofilm and promises to be beneficial against biofilm-associated infectious diseases. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 59 5 2005 Sex reassignment surgery for male to female transsexuals: initial experience in Okayama university hospital. 231 233 EN Atsushi Nagai Eijirou Tokuyama Yuzaburo Nanba Tetsuya Tsutsui Yoshihiro Kimata Mikiya Nakatsuka Isao Koshima Takashi Saika Yasutomo Nasu Hiromi Kumon Article 10.18926/AMO/31976 The first case of sex reassignment surgery (SRS) in our hospital was performed in January 2001; as of February, 2005, 4 cases of MTF-SRS had been performed. In the 2 most recent cases, we used penile and scrotal skin flaps to avoid complications. The depth and width of the new vagina was made to be adequate for sexual intercourse. Future attention should be focused on devising a surgical technique that will help prevent the complications of partial necrosis of the epidermal skin and wound dehiscence. Although ours is only an initial experience, we describe our surgical technique herein. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 59 5 2005 Long-term clinical outcomes of 420 consecutive prostate cancer patients in a single institute. 195 199 EN Kohei Edamura Takashi Saika Takashi Senoh Fumihito Koizumi Daisuke Manabe Shin Ebara Haruki Kaku Teruhiko Yokoyama Fernando Abarzua Atsushi Nagai Yasutomo Nasu Tomoyasu Tsushima Hiromi Kumon Article 10.18926/AMO/31973 This study was undertaken to reveal the trends of prostate cancer and the outcome of treatment modalities for each disease stage in patients in a single institute over a 10-year period. From January 1994 through December 2003, 420 consecutive patients with previously untreated and histologically confirmed prostate cancer were analyzed for annual distributions of disease stages and treatment modalities and for long-term clinical progression-free survival, prostate cancer-specific survival, and prostate-specific antigen (PSA) failure-free survival rates for each stage and treatment modality. Annual trends showed that the number of patients, especially those with clinically localized cancer, increased dramatically. The 5-year disease-specific survival rates for patients with clinically localized disease were 100 percent for all treatment modalities, including hormonal therapy alone. Patients with PSA levels less than 10 ng/ml showed an 81 percent 5-year PSA failure-free survival rate with radical prostatectomy. Stage C patients treated by surgery or radiation-based therapy with concomitant hormonal therapy obtained 93 percent and 100 percent cause-specific survival rates, respectively, and those treated by hormonal therapy alone showed a 79 percent rate. The number of patients with localized prostate cancer was increasing in this decade. While long-term hormonal therapy alone was highly efficient in controlling localized prostate cancer, radical therapies in conjunction with neo-adjuvant hormonal therapy produced better survival rates in cases of locally advanced disease. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 59 2 2005 Clinical results of one-stage urethroplasty with parameatal foreskin flap for hypospadias. 45 48 EN Atsushi Nagai Yasutomo Nasu Masami Watanabe Norihiro Kusumi Hiromu Tsuboi Hiromi Kumon Article 10.18926/AMO/31964 We investigated the usefulness of one-stage urethroplasty by the parameatal foreskin flap method (OUPF procedure), which is useful for repairing all types of hypospadias. Between June 1992 and March 2001, the OUPF procedure was performed on 18 patients with hypospadias: 10 patients with distal and 8 with proximal hypospadias. The follow-up periods ranged from 33-75 months, with an average of 52 months. The duration of surgery, the catheter indwelling period, and the postoperative complications of each patient were analyzed. The median age of the patients at the time of surgery was 3 years and 8 months. The length of surgery for OUPF II ranged from 150-230 min (average 186 min), and from 190-365 min (average 267 min) for OUPF IV. Postoperative complications were confirmed in 3 of the 18 patients (16.6%). Two patients had fistulas, and one had a meatal regression. The fistulas were successfully closed by the simple multilayered closure method. After adopting DuoDerm dressings instead of elastic bandages for protection of the wound, no fistulization occurred. DuoDerm dressings are useful in the healing of wounds without complications. To date, the longest follow-up period has been 75 months, and during that time there have been no late complications such as urethral stenosis or penile curvature. OUPF is a useful method in the treatment of hypospadias with a low incidence of early and late complications. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 59 6 2005 Intracavernous injection of prostaglandin E1 is effective in patients with erectile dysfunction not responding to phosphodiseterase 5 inhibitors. 279 280 EN Atsushi Nagai Norihiro Kusumi Hiromu Tsuboi Kazushi Ishii Takashi Saika Yasutomo Nasu Hiromi Kumon Short Communication 10.18926/AMO/31956 We report on 64 patients who did not achieve erections adequate for satisfactory sexual intercourse from among a total of 243 patients who were prescribed PDE5 inhibitors for erectile dysfunction (ED). Intracavernous injection (ICI) of PGE was performed in this non-responder group. An ICI of 20 or 40 mcg of PGE1 in 1 ml saline was performed and the responses evaluated. Forty-nine out of 64 (77 percent ) cases responded to 20 mcg of PGE1. Forty mcg of PGE was injected into the 15 non-responding cases, and 9 patients responded favorably. The overall effective rate was 58/64 (91 percent ). No major adverse effects were observed. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 63 3 2009 Prospective longitudinal comparative study of health-related quality of life in patients treated with radical prostatectomy or permanent brachytherapy for prostate cancer 129 135 EN Makoto Kobuke Takashi Saika Yoshiko Nakanishi Shin Ebara Daisuke Manabe Tatsuya Uesugi Hiroyuki Nose Ryoji Arata Tomoyasu Tsushima Yasutomo Nasu Hiromi Kumon Original Article 10.18926/AMO/31847 To determine health-related quality of life (HRQOL) after radical retropubic prostatectomy (RRP) or permanent prostate brachytherapy (BT), third party-conducted QOL surveys were prospectively compared. Between 2004 and 2005, 37 patients underwent RRP and 36 were treated with BT. A QOL survey consisting of the Medical Outcomes Study 36-Item Short Form (SF-36), the University of California, Los Angeles, Prostate Cancer Index (UCLA-PCI) and the International Prostate Symptoms Score (IPSS) was completed prospectively by a research coordinator at baseline, and at 1, 3, 6 and 12 months after treatment. The RRP patients scored well in general QOL except at 1 month after surgery, with their mental health better than at baseline by 6 months after surgery. Disease-specific QOL in RRP patients received a low score at 1 month for both urinary and sexual function, though urinary function rapidly recovered to baseline levels. BT patient QOL was not affected by the therapy except in the IPSS score. However, general and mental health scores in BT patients were inferior to those in RRP patients. This prospective study revealed differences in QOL after RRP and BT. These results will be helpful in making treatment decisions. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 63 5 2009 Experimental and Clinical Studies on Fluoroquinolone-insusceptible Escherichia coli Isolated from Patients with Urinary Tract Infections from 1994 to 2007 263 272 EN Koichiro Wada Reiko Kariyama Ritsuko Mitsuhata Shinya Uehara Toyohiko Watanabe Koichi Monden Hiromi Kumon Original Article 10.18926/AMO/31836 Urinary tract infections (UTIs) due to fluoroquinolone-insusceptible Escherichia coli have become increasingly common in recent years. We investigated the potential relationships between clinical measures to combat fluoroquinolone-insusceptible E. coli and experimental analyses on E. coli isolates. Over a 14-year period from 1994 through 2007, a total of 828 E. coli isolates were collected from patients (one isolate per patient) with UTI at the urology ward of Okayama University Hospital. We analyzed the mutations in quinolone resistance-determining regions of DNA gyrase (gyrA) and topoisomerase IV (parC). The production of biofilm by these isolates was also examined and the associated medical records were retrospectively reviewed. Seven of 189 (3.7%) strains from uncomplicated UTIs and 82 of 639 (12.8%) strains from complicated UTIs were insusceptible to fluoroquinolones. Amino acid replacements of type II topoisomerases were frequently observed at positions 83 and 87 in GyrA and at positions 80 and 84 in ParC. No significant difference in the biofilm-forming capabilities was observed between fluoroquinolone-susceptible and -insusceptible E. coli. Our study suggests that biofilm formation of fluoroquinolone-insusceptible E. coli isolates is not a major mechanism of resistance in patients with UTI. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 56 1 2002 Laparoscopic radical prostatectomy: initial cases at Okayama University Hospital. 51 52 EN Atsushi Nagai Yasutomo Nasu Yoshinori Shirasaki Hiroki Iguchi Ryouji Arata Masaya Tsugawa Tomoyasu Tsushima Hiromi Kumon Article 10.18926/AMO/31722 We performed laparoscopic prostatectomy in seven cases with organ-confined prostate cancer. In 6 cases, the surgery was completed successfully and the mean operative time was 424 min. Volume of blood loss was 200 to 3,200 ml and catheterization lasted 6 to 37 days. No major complications were observed in 6 of the cases. In one case, open surgical conversion was necessary mainly due to a bladder injury. Although these were the first cases of laparoscopic prostatectomy in our institution, the technical difficulty and complexity of the surgery were moderate. We believe that laparoscopic radical prostatectomy will become a standard option for the treatment of organ-confined prostate cancer. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 56 6 2002 Botulinum toxin treatment of urethral and bladder dysfunction. 271 277 EN Teruhiko Yokoyama Hiromi Kumon Christopher P Smith George T Somogyi Michael B Chancellor Article 10.18926/AMO/31693 Tremendous excitement has been generated by the use of botulinum toxin for the treatment of various types of urethral and bladder dysfunction over the past several years. Botulinum toxin is the most lethal naturally occurring toxin known to mankind. Why, then, would an urologist want to use this agent to poison the bladder or urethral sphincter? In this review article we will examine the mechanisms underlying the effects of botulinum toxin treatment. We will discuss the current use of this agent within the urologic community and will provide perspectives on future targets of botulinum toxin. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 56 4 2002 Localization of dynamin 2 in rat seminiferous tubules during the spermatogenic cycle. 205 209 EN Hiroki Iguchi Masami Watanabe Akihiro Kamitani Atsushi Nagai Osamu Hosoya Kimiko Tsutsui Hiromi Kumon Article 10.18926/AMO/31681 Dynamin is a protein essential to endocytosis. Dynamin 2, a dynamin isoform, is expressed most intensely in testicular tissue; however, precise localization has never been studied. Therefore, we investigated the expression of dynamin 2 in rat testicular tissue using immunohistochemical methods, and discuss here the physiological function of this protein. Testicular tissues were obtained from Wistar rats at 10, 21 and 63 days of age. Immunohistochemistrical examination and Western blot analysis were conducted using dynamin 2 specific antibody. Western blot analysis showed that expression in 21- and 63-day-old rats was more intense than that in 10-day-old rats. Dynamin 2 expression was observed using immunohistochemical method in the seminiferous tubules of all rats. In the 63-day-old rats, the expression was intense, especially in spermatids in the earlier maturation stages and in spermatocytes, and was observed in Sertoli cells. However, in spermatids, the expression gradually declined as spermatids matured to spermatozoa. In the 21-day-old rats, the expression was evident in spermatocytes and Sertoli cells, but that in the 10-day-old rats was weak. Intense expression of dynamin 2 during spermatogenesis suggests that this protein plays an important role in this process. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 62 1 2008 Iodine-125 Seed Implantation (Permanent Brachytherapy) for Clinically Localized Prostate Cancer 9 13 EN Shin Ebara Yoshihisa Katayama Ryuta Tanimoto Kohei Edamura Hiroyuki Nose Daisuke Manabe Tomoko Kobayashi Yasuyuki Kobayashi Makoto Kobuke Mitsuhiro Takemoto Takeshi Saika Yasutomo Nasu Susumu Kanazawa Hiromi Kumon Original Article 10.18926/AMO/30986 From January 2004 to March 2007, 308 patients with clinically localized prostate cancer were treated using iodine-125 (125I) seed implantation (permanent brachytherapy) at Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences. We evaluated the treatment’s effi cacy and morbidity in 300 prostate cancer patients who were followed up for more than 1 month after brachytherapy. Based on the National Comprehensive Cancer Network (NCCN) guidelines, patients with a prostate volume of less than 40 ml in transrectal ultrasound imaging were classifi ed as low or intermediate risk. The median patient age was 67 years (range 50 to 79 years), the median prostate-specific antigen (PSA) value before biopsy was 6.95 ng/ml (range 1.13 to 24.7 ng/ml), and the median prostate volume was 24.33 ml (range 9.3 to 41.76 ml). The median follow-up was 18 months (range 1 to 36 months) and the PSA levels decreased in almost all patients after brachytherapy. Although 194 of 300 patients (64.7%) complained of diffi culty in urination, pollakisuria/urgency, miction pain, and/or urinary incontinence, all of which might be associated with radiation prostatitis during the fi rst month after brachytherapy, these symptoms gradually improved. 125I seed implantation brachytherapy is safe and eff ective for localized prostate cancer within short-term follow up. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 62 6 2008 Initial Report of Hybrid Radical Prostatectomy for Prostate Cancer:Reduced Bleeding, Clear Vision, and Secure Surgical Margins 379 384 EN Takashi Saika Yasuyuki Kobayashi Toyohiko Watanabe Daisuke Manabe Shin Ebara Shinya Uehara Yasutomo Nasu Hiromi Kumon Original Article 10.18926/AMO/30950 To evaluate morbidity in Hybrid Radical Prostatectomy (HRP, hybridized laparoscopic and open retropubic radical prostatectomy). The operative and pathological outcomes obtained in 25 consecutive patients who underwent HRP were reviewed. The median operating time was 220min, median blood loss was 550ml, and no patient required an allogenic blood transfusion. No severe postoperative complications were observed. The surgical margin was positive in 12% of all patients, and in 1 patient with pT2 or less (4.5%). These results indicate that HRP is safe and may be able to combine the benefits of both laparoscopic and open procedures. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 62 6 2008 Mechanistic Analysis of Resistance to REIC/Dkk-3-induced Apoptosis in Human Bladder Cancer Cells 393 401 EN Tomoko Kobayashi Masakiyo Sakaguchi Ryuta Tanimoto Fernando Abarzua Mikiro Takaishi Haruki Kaku Ken Kataoka Takashi Saika Yasutomo Nasu Masahiro Miyazaki Hiromi Kumon Nam-ho Huh Original Article 10.18926/AMO/30945 We have recently shown that a new therapeutic modality using the REIC/Dkk-3 gene (Ad-REIC) is effective against various human cancers, including those of prostate, testis and breast origins. The aim of the present study was to examine the sensitivity of bladder cancers to Ad-REIC and to clarify the molecular mechanisms that determine sensitivity/resistance. We found that 2 human bladder cancer cell lines, T24 and J82, are resistant to Ad-REIC. In T24 and J82 cells, the ER stress response and activation of JNK were observed in a manner similar to that in the sensitive PC3 cells. Translocation of Bax to mitochondria occurred in PC3 cells but not in T24 and J82 cells. Bcl-2 was remarkably overexpressed in T24 and J82 compared with the expression levels in sensitive cell lines. Treatment of T24 and J82 cells with a Bcl-2 inhibitor sensitized the cells to Ad-REIC-induced apoptosis. The results indicate that some human bladder cancers are resistant to apoptosis induced by overexpression of REIC/Dkk-3, which is at least in part due to up-regulation of Bcl-2. These results provide a basis for possible use of Bcl-2 as a marker of sensitive cancers and to try to sensitize resistant cancers to Ad-REIC by down-regulation of Bcl-2. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 62 4 2008 The Benefits of Clamping the Renal Artery in Laparoscopic Partial Nephrectomy 269 273 EN Yasuyuki Kobayashi Takashi Saika Daisuke Manabe Yasutomo Nasu Hiromi Kumon Original Article 10.18926/AMO/30939 The purpose of this study is to compare the performance of laparoscopic partial nephrectomy (LPN) with and without clamping of the renal artery and to evaluate the impact of clamping on postoperative renal function. A total of 20 patients underwent LPN, 13 without and 7 with clamping of the renal artery. The 2 groups were compared with respect to complications, blood loss, operative time, mean tumor size, and incidence of positive margins. Renal function was evaluated by pre- and postoperative renal scintigraphy using 99mTechnetium-mercaptoacetyltriglycine (99mTc-MAG3). Intraoperative blood loss was significantly higher in the group without clamping than in the group with clamping (p0.04). In the group with clamping, the median warm ischemic time was 35min (range 25-40min). The serum creatinine values and the renal scintigraphy showed no influence on postoperative renal function with or without clamping. In the group without clamping, 2 cases were showed positive surgical margins. The procedure performed with clamping of the renal artery is superior to the procedure performed without clamping as it provides the advantages of controlling hemorrhaging without injury to renal function and prolonging the surgical time and allowing for more accurate resection of renal tumors. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 60 1 2006 Combination chemotherapy with estramustine phosphate, ifosfamide and cisplatin for hormone-refractory prostate cancer. 43 49 EN Haruki Kaku Takashi Saika Tomoyasu Tsushima Atsushi Nagai Teruhiko Yokoyama Fernando Abarzua Shin Ebara Daisuke Manabe Yasutomo Nasu Hiromi Kumon Article 10.18926/AMO/30759 We evaluated the efficiency and toxicity of estramustine phosphate (ECT), ifosfamide (IFM) and cisplatin (CDDP) combination chemotherapy in twenty-one patients with hormone-refractory prostate cancer (HRPC), for which there is currently no effective treatment. Patients received a daily dose of 560 mg ECT in combination with 1.2 g/m2 IFM on days 1 to 5 and 70 mg/m2 CDDP on day 1. This combination therapy was given every 3 to 4 weeks. An objective response of more than 50% reduction in prostate-specific antigen was observed in 9 of 18 patients (50%), and a more than 50% reduction in bi-dimensionally measurable soft-tissue lesions was observed in 2 of 7 patients (29%). The median duration of response among the cases showing partial response was 40 weeks, while the median duration of response of overall partial-response plus stable cases was 30 weeks. The median survival duration of all cases was 47 weeks. Toxicity was modest and acceptable. In conclusion, the ECT, IFM and CDDP combination chemotherapy regimen is a viable treatment option for HRPC. However, in comparison with our previous chemotherapy regimen of IFM and CDDP, no additional long-lasting effects resulting from the inclusion of ECT could be affirmed. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 60 2 2006 Effects of radiofrequency ablation on individual renal function: assessment by technetium-99m mercaptoacetyltriglycine renal scintigraphy. 85 91 EN Takashi Mukai Shuhei Sato Toshihiro Iguchi Hidefumi Mimura Kotaro Yasui Hideo Gobara Takashi Saika Yasutomo Nasu Hiromi Kumon Susumu Kanazawa Article 10.18926/AMO/30731 We quantitatively evaluated total and individual renal function by technetium-99m mercaptoacetyltriglycine (Tc-99m MAG3) renal scintigraphy before and after radiofrequency ablation (RFA) of renal tumors. Eleven patients who underwent Tc-99m MAG3 renal scintigraphy 1 week before and after RFA were evaluated (7 men and 4 women ; age range : 23-83 years ; mean age : 60.6 years). Five patients had solitary kidneys, and five had normally or minimally functioning contralateral kidneys. One patient had a renal cell carcinoma in the contralateral kidney. One patient with a solitary kidney underwent RFA a second time for a residual tumor. In patients with a solitary kidney, MAG3 clearance decreased after 5 of 6 RFAs, and in patients with a normally functioning contralateral kidney, MAG3 clearance decreased after 4 of 5 RFAs, but no significant differences were observed between before and after treatments. In addition to the total MAG3 clearance, the split MAG3 clearance was evaluated in patients with a normally functioning contralateral kidney. MAG3 clearance decreased in 4 of 5 treated kidneys, while it adversely increased in the contralateral kidneys after 4 of 5 RFAs. No significant differences, however, were observed between before and after treatments. The results of our study revealed no significant differences in sCr, BUN, CCr, or MAG3 clearance between pre- and post-RFA values. These results support data regarding the functional impact and safety of renal RFA in published reports. We evaluated total and individual renal function quantitatively using Tc-99m MAG3 renal scintigraphy before and after treatment. This scintigraphy was very useful in assessing the effects of RFA on renal function. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 60 6 2006 Involvement of STAT3 in Bladder Smooth Muscle Hypertrophy Following Bladder Outlet Obstruction 299 309 EN Osamu Fujita Masato Asanuma Teruhiko Yokoyama Ikuko Miyazaki Norio Ogawa Hiromi Kumon Original Article 10.18926/AMO/30724 We examined the involvement of the signal transducer and activator of transcription 3 (STAT3) in bladder outlet obstruction (BOO)-induced bladder smooth muscle hypertrophy using a rat in vivo and in vitro study. BOO induced increases in bladder weight and bladder smooth muscle thickness 1 week after the operation. By using antibody microarrays, 64 of 389 proteins blotted on the array met our selection criteria of an INR value between > or = 2.0 and < or = 0.5. This result revealed up-regulation of transcription factors, cell cycle regulatory proteins, apoptosis-associated proteins and so on. On the other hand, down-regulation (INR value < or = 0.5) of proteins was not found. In a profiling study, we found an increase in the expression of STAT3. A significant increase in nuclear phosphorylated STAT3 expression was confirmed in bladder smooth muscle tissue by immunohistochemistry and Western blot analysis. Cyclical stretch-relaxation (1 Hz) at 120% elongation significantly increased the expression of STAT3 and of alpha-smooth muscle actin in primary cultured bladder smooth muscle cells. Furthermore, the blockade of STAT3 expression by the transfection of STAT3 small interfering RNA (siRNA) significantly prevented the stretch-induced increase in alpha-smooth muscle actin expression. These results suggest that STAT3 has an important role in the induction of bladder smooth muscle hypertrophy. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 96 9-10 1984 尿路結石症に関する臨床統計的考察その2 尿路感染症との関連性について 1029 1035 EN Hiromi Kumon Toshihiko Asahi Masaya Tsugawa Masataka Furukawa Nobuyuki Akazawa Hiroyuki Ohmori The relationship of urinary tract infection (UTI) to urolithiasis was studied in 1069 patients who were treated in the Department of Urology, Okayama University Hospital. Of 211 cases with known causative factors, 58 (27.5%) had UTI. The incidence of cloudy urine became higher with increasing age and was significantly higher in females with renal calculi than in males with renal calculi. The main organisms isolated from the urine were Pseudomonas, Staphylococcus, E. coli and Proteus. UTI, caluculi containing struvite, and proteus in the urine were fonud significantly more often in cases of stghorn caluculi than in cases of other renal calculi. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 96 9-10 1984 尿路結石症に関する臨床統計的考察その1 岡山大学泌尿器科における最近9年間の症例について 1019 1027 EN Hiromi Kumon Toshihiko Asahi Masaya Tsugawa Masaaki Okimune Kazutoyo Miyata Hiroyuki Ohmori During the 9-year period from 1972 to 1980, 1069 cases of urolithiasis were seen in the Department of Urology, Okayama University Hospital. The ratio of males to females was 2.1 to 1. The maximum incidence of urolithiasis occurred from the third to fifth decade. The overall recurrence rate was 26.7% , and most recurrence (62.1%) occurred 1-3 years following the removal of initial calculi. Concerning renal calculi, the incidence of residual calculi and postoperative recurrence was dependent on the shape and number of calculi rather than operative methods. Mixed calcium oxalate and phosphate calculi were found most frequently, and calculi containing struvite also were found frequently in females. The components of recurrent calculi were identical to those of initial calculi in most cases (72.8%). No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 103 11-12 1991 超音波パルスドップラ法による腎機能評価に関する検討―Dynamic CT 及び Ccr との比較を中心として― 1177 1181 EN Shuhei Satoh Takahiro Kitagawa Nobuo Satoh Izumi Togami Shin Kimoto Yoshio Hiraki Satoru Uno Hiromi Kumon Hiroyuki Ohmori To evaluate the clinical application of the ultrasonic Doppler technique, renal arterial blood flow was measured in 7 normal subjects and 3 patients with renal dysfunction. For the purpose of correction of blood flow measured by the Doppler technique, some basic studies were performed. The ratio of peak diastolic to peak systolic velocity (D/S ratio) correlated well with both the creatinine clearance and the CA ratio calculated from the results of Dynamic CT. There was no correlation between the corrected velocity of the arterial blood flow and the creatinine clearance. The D/S ratio obtained by the ultrasonic Doppler technique is thought to be a useful parameter in the evaluation of the renal function. However, the Dynamic CT is thought to be superior in objectiveness to the ultrasonic Doppler technique. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 114 2 2002 前立腺癌遺伝子治療の現状と展望 173 177 EN No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 114 1 2002 第250回　日本泌尿器科学会岡山地方会 101 116 EN 特別シンポジウム「泌尿器科学：過去・現在・未来」 No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 113 3 2001 慢性精巣痛とその治療：Microsurgical Denervation の有用性 285 287 EN No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 113 3 2001 泌尿器科から見た性同一性障害 267 271 EN No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 116 3 2005 泌尿器科における難治性感染症「尿路バイオフィルム感染症」 273 279 EN No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 00301558 120 2 2008 XIII 泌尿器科がんにおける標準的治療 207 213 EN Makoto Kobuke Yasutomo Nasu Hiromi Kumon No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 00301558 119 3 2008 <会員紹介>志賀潔・秦佐八郎記念賞を受賞して 331 333 EN Hiromi Kumon No potential conflict of interest relevant to this article was reported.