Search

Tumor thrombus formation is a unique aspect of renal cell carcinoma with significant therapeutic and prognostic implications. The prognostic significance of cephalad extent of tumor thrombi to the right atrium remains controversial. Extended surgical removal, however, is the only way to expect survival. In 1989, a 40-year-old man was diagnosed with an advanced renal cell carcinoma (T(3C)N(2)M(0)) involving perinephric fat, hilar and para-aortic lymph nodes and a tumor thrombus extending to the right atrium. He was treated with extensive surgical resection of the tumor and its lymphatic and vascular extensions. Interferon-alpha injections were given for 2.5 years as an adjuvant immunotherapy. The patient was annually checked with abdominal ultrasound, chest X-ray and computed tomography, but has manifested no local or distant metastasis for 18 years. To our knowledge, this is the first reported case of extensive surgery on advanced renal cell carcinoma with no evidence of recurrence for 18 years.

Purpose: Interstitial cystitis remains a poorly understood urological condition characterized by chronic pelvic pain and increased urinary frequency in the absence of any known etiology. Urothelial dysfunction and other abnormalities are presumed to be involved in the disease. Uroplakins that are expressed by urothelial cells are thought to have an important role as major barrier proteins on the apical surface of the urothelium., Materials and Methods: Gene expression of uroplakin Ia, Ib, II, III and III-delta4 was quantitatively measured in bladder biopsy samples from 29 patients with interstitial cystitis and 16 control subjects using real-time reverse transcriptase-polymerase chain reaction., Results: The mRNA levels of the uroplakin Ia, Ib and II genes were relatively low and uroplakin III was relatively high in interstitial cystitis bladders compared to normal controls, although not significantly. Uroplakin III-delta4, a splicing variant of uroplakin III, was significantly up-regulated in interstitial cystitis samples (p <0.001). When patients with interstitial cystitis were divided into those with and without ulcerative changes, the uroplakin III and III-delta4 genes were significantly up-regulated only in patients with nonulcerative interstitial cystitis. Even more interesting was the finding that up-regulation of uroplakin III-delta4 was much more prominent than that of uroplakin III, that is 26.5 vs 5.6-fold compared to the median values of normal subjects., Conclusions: Although the clinical implications of the over expression of uroplakin III and III-delta4 in nonulcerative interstitial cystitis bladders remains to be clarified, from the diagnostic viewpoint uroplakin III-delta4 is a potential marker for identifying nonulcerative interstitial cystitis.

Purpose: We evaluated the correspondence between UCLA PCI and the Extended Prostate Cancer Index Composite for Japanese patients with localized prostate cancer., Materials and Methods: A total of 385 patients treated with retropubic radical prostatectomy, external beam radiation, hormonal therapy or select watchful waiting from 2002 to 2006 were enrolled. For this study we used equipercentile linking, a technique that identifies scores on the 2 measures that have the same percentile rank., Results: Urinary and sexual functions showed a strong correlation (r = 0.85 and 0.93, respectively, p <0.0001). In contrast, the correlation for bowel function was relatively weak (r = 0.47, p <0.0001). The correlations of each Extended Prostate Cancer Index Composite bother domain with UCLA PCI were 0.6 (p <0.0001). The linking between each scale of the Extended Prostate Cancer Index Composite and UCLA PCI domains showed that an Extended Prostate Cancer Index Composite urinary function score of 73 was equivalent to a UCLA PCI score of 60. With regard to urinary bother an Extended Prostate Cancer Index Composite score of 69 to 84 was equivalent to a UCLA PCI score of 75. A sexual function score of 18 on UCLA PCI corresponded to an Extended Prostate Cancer Index Composite score of 12 and a sexual bother score of 50 on UCLA PCI corresponded to an Extended Prostate Cancer Index Composite score of 56 to 88., Conclusions: The urinary and sexual domains of UCLA PCI and the Extended Prostate Cancer Index Composite showed strong correlations. In contrast, the correlation for the bowel domain was relatively weak. The results of the linking analysis between UCLA PCI and the Extended Prostate Cancer Index Composite may have implications useful for their interpretation.

Previous studies indicated that the anticancer agent adriamycin (ADR) could induce activation of cytotoxic T lymphocytes (CTL) and natural killer cells. In this study, we investigated the effect of ADR on the susceptibility of human renal cell carcinoma (RCC) cells to lysis by peripheral blood lymphocytes (PBL) and tumor infiltrating lymphocytes (TIL). Treatment of human RCC cell line ACHN and freshly derived RCC cells with ADR at 1 microg/ml or more for 3 h significantly enhanced their susceptibility to lysis by PBL (P<0.05). This ADR-induced enhancement of susceptibility of RCC cells to lysis by PBL was also observed when freshly derived TIL were used as effector cells (P<0.05). ADR up-regulated the expression of leukocyte function-associated antigen-3 (LFA-3) and intercellular adhesion molecule-1 (ICAM-1), which are critical in the binding and killing of CTL against cancer cells. Of the five fresh RCC cell cultures treated with ADR, LFA-3 was increased in all and ICAM-1 was increased in three of them, respectively (P<0.05). Up-regulation of LFA-3 and ICAM-1 was also observed in ACHN cells treated with two derivatives of ADR, epirubicin and pirarubicin. ADR further significantly increased the bindings of PBL to RCC cells (P<0.05). These findings suggest that treatment of RCC patients with low doses of ADR may sensitize the RCC cells to killing by PBL and TIL and may be a novel immunotherapeutic modality for the treatment of drug-resistant and/or immune-resistant RCC. The inducing of LFA-3 and ICAM-1 by ADR may be involved in the enhancement of susceptibility of PBL and TIL-mediated cytolysis in human RCC cells.

Aim: We prospectively investigated health-related quality of life (HR-QOL), including sexual function and sexual bother, in patients who underwent nerve grafting during a radical prostatectomy in comparison with those who underwent a non-nerve-sparing radical prostatectomy., Methods: Between August 2001 and May 2004, radical prostatectomies were performed on 69 patients with clinical T1-T2N0/M0 prostate cancer. Of these, 66 patients (22: nerve-grafting patients, 44: non-nerve-sparing and non-nerve-grafting patients) were enroled into this study. The observation periods ranged from 12-46 months (median: 29 months). The general HR-QOL was measured with the SF-36 General Health Survey and disease-specific HR-QOL was measured with the University of California Los Angeles-Prostate Cancer Index., Results: Penile tumescence was observed in 11 out of 15 (73.3%) prostate-specific antigen failure-free patients who underwent unilateral nerve grafting with contra-lateral nerve-sparing or bilateral nerve grafting. Vaginal penetration was observed in six out of 15 (40.0%) patients. The time for partial erection and for intercourse, respectively, ranged from 3-21 months (median = 6 months) and 6-36 months (median = 13.5 months). There were no significant differences in general HR-QOL changes over time between the nerve-grafting patients and the patients without any nerve-preserving procedures. The sexual function score was significantly better in the nerve-grafting (bilateral nerve graft or unilateral nerve graft with contra-lateral nerve-sparing) patients than in the non-nerve-sparing/non-nerve-grafting patients. The sexual bother score, however, was more serious for the patients who underwent nerve-grafting surgery than for the non-nerve-sparing/non-nerve-grafting patients., Conclusion: Sexual bother is serious for patients who attempt to maintain sexual function after special surgical procedures, such as nerve-grafting surgery. We should be aware that careful counseling is needed to avoid impatient and excessive hope for the recovery of sexual function.

Purpose: Health related quality of life in Japanese men with localized prostate cancer treated with current multidisciplinary treatment modalities was assessed using a newly developed Japanese version of the Extended Prostate Cancer Index Composite. We evaluated psychometric properties of the Japanese version of the Extended Prostate Cancer Index Composite., Materials and Methods: A cross-sectional analysis of health related quality of life was done in 460 patients treated with radical prostatectomy, external beam radiation therapy, permanent (125)I seed implantation androgen deprivation therapy or watchful waiting. Patients were enrolled in January to July 2005. Serum testosterone was measured in all participants., Results: Missing values ranged from 0.4% to 16.3% with 10% or greater observed for 15 of 50 items (30%). A missing value of 10% or greater correlated with higher age and lower educational background (p<0.05). Internal consistency reliability was 0.7 or higher for almost all subscales except the bowel function and hormonal function subscales. Test-retest reliability and factor validity were successfully verified. Known groups validity revealed significant improvement in urinary domain scores with time in patients treated with radical prostatectomy plus permanent (125)I seed implantation. Bowel domain scores were worse in patients treated with external beam radiation therapy compared to the other modalities. Decreased hormonal domain scores correlated with low serum testosterone (p<0.001). Salvage androgen deprivation therapy after radical prostatectomy negatively influenced sexual function but not sexual bother., Conclusions: Reliability and validity of the Japanese version of the Extended Prostate Cancer Index Composite were verified, although revision is needed for it to be more comprehensible for elderly patients and those with low education. It can be used for cross-cultural assessment of health related quality of life in patients with localized prostate cancer treated with current multidisciplinary treatment modalities.

Purpose: TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) triggers apoptosis in various tumor cells by engaging death receptors 4 and 5. We investigated the effect of chemotherapeutic agents on death receptor 4 mediated apoptosis in human renal cell carcinoma cells using HGS-ETR1, which is a human monoclonal agonistic antibody specific for death receptor 4., Materials and Methods: Cytotoxicity was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Synergy was assessed by isobolographic analysis., Results: Treatment of the ACHN human renal cell carcinoma cell line with HGS-ETR1 combined with 5-fluorouracil, vinblastine or gemcitabine did not overcome resistance to these agents. However, treatment with HGS-ETR1 combined with doxorubicin had a synergistic cytotoxic effect. Synergy was also achieved in another human renal cell carcinoma cell line, Caki-1, and in 5 freshly derived renal cell carcinoma cell cultures. A synergistic effect was also observed with HGS-ETR1 combined with the doxorubicin derivatives epirubicin, pirarubicin or amrubicin. The synergy achieved in cytotoxicity with HGS-ETR1 and doxorubicin was also achieved in apoptosis. Sequential treatment with doxorubicin followed by HGS-ETR1 induced significantly more cytotoxicity than reverse treatment or simultaneous treatment (p<0.05). Doxorubicin remarkably increased the cell surface expression of death receptor 4 in renal cell carcinoma cells. The combination of doxorubicin and HGS-ETR1 significantly activated the caspase cascade, including caspase-8, 9, 6 and 3, which are the downstream molecules of death receptors., Conclusions: These findings indicate that doxorubicin sensitizes renal cell carcinoma cells to death receptor 4 mediated apoptosis through the induction of death receptor 4 and the activation of caspases, suggesting that combination therapy of doxorubicin and HGS-ETR1 might be effective as renal cell carcinoma therapy.

Objectives: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a variety of tumor cells through two of its receptors: TRAIL-R1 and TRAIL-R2. In this study, we investigated the susceptibility of human prostate cancer and bladder cancer cells to HGS-ETR2, a human monoclonal agonistic antibody specific for TRAIL-R2., Methods: The cell surface expression of TRAIL-R1 and TRAIL-R2 on prostate cancer and bladder cancer cells was determined using flow cytometry. Cytotoxicity was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and caspase activities were measured by a quantitative colorimetric assay., Results: HGS-ETR2 effectively induced apoptotic cell death in DU145, PC3, and LNCaP human prostate cancer cells and J82 and T24 human bladder cancer cells. The increased effectiveness of HGS-ETR2 for inducing cell death might have been affected by differences in the cell surface expression of the two TRAIL receptors, in that TRAIL-R2, but not TRAIL-R1, was frequently expressed in the prostate cancer and bladder cancer cells. HGS-ETR2 significantly activated the caspase cascade, including caspase-3, -6, -8, and -9, which were the downstream molecules of the death receptors in prostate cancer cells. Caspase-3, -6, and -9 were also significantly activated with HGS-ETR2-induced apoptosis in the bladder cancer cells., Conclusions: These findings suggest the potential utility of TRAIL-R2 antibody as a novel therapeutic agent against prostate cancer and bladder cancer.

The introduction of PSA screening has led to confirming a shift towards an earlier pathological stage in the diagnosis of prostate cancer. Consequently, the proportion of detecting early stage prostate cancer has clearly been increasing. On the other hand, progressive cancers in the form of distant metastases and locally advanced ones that have been confirmed at the initial diagnosis exhibit a constant rate. In addition, there have been a lot of cases where hormonal resistance was acquired during hormonal therapy which resulted in advanced metastases of the prostate. Prostate cancer has a tendency to be metastatic to bones. Combining the fact that the survival period of patients undergoing treatment is prolonged after metastases, the length of suffering caused by complications, such as ostealgia, pathological fracture and myelopathy, becomes an issue in which QOL and ADL of the patient are sacrificed for a long time. As for treatment of prostate cancer with metastases, a palliative treatment is common in the clinical scene. However, we can extend a life prognosis with use of radiotherapy and surgical treatment in addition to the palliative treatment at an appropriate time. It appears that a combination of new chemotherapy and hormonal therapy will be promising. In the future, we believe that the appearance of new anticancer drugs, endocrine therapies, bisphosphonates and strontium treatment could be used as a part of the treatment strategy for prostate cancer with bone metastases.

A temporary inferior vena cava (IVC) filter was placed in 4 patients. Patient 1 had an advanced testicular germ cell tumor with IVC tumor thrombosis, patient 2 presented with a large adrenal tumor with IVC tumor thrombosis, patient 3 was found to have deep vein thrombosis following grade 3b renal injury, and patient 4 was suffering severe SLE with renal vein thrombosis. The temporary inferior vena cava filter prevented pulmonary thromboembolism in all cases, and no adverse reaction was observed. Temporary inferior vena cava filter is safe and useful to prevent pulmonary thromboembolism associated with urological disorders.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptosis in a variety of tumor cells through two of its receptors: TRAIL-R1 and TRAIL-R2. We investigate the susceptibility of human renal cell carcinoma (RCC) cells to TRM-1 and HGS-ETR2, 2 human monoclonal agonistic antibodies specific for TRAIL-R1 and TRAIL-R2, respectively. HGS-ETR2 effectively induced apoptotic cell death in 10 of 11 cell cultures, including 2 human RCC cell lines and 9 human primary RCC cell cultures, with a more pronounced effect after preincubation with anti-human IgG Fc. In contrast, TRM-1 was effective in only 1 primary RCC cell culture. The increased effectiveness of HGS-ETR2 for inducing cell death might have been affected by differences in the cell-surface expression of the 2 TRAIL receptors, namely that TRAIL-R2 but not TRAIL-R1 was frequently expressed in most of the RCC cells tested. The activities of caspase-9, -8, -6, and -3 were increased with HGS-ETR2-induced apoptosis, and cell death could be blocked by specific caspase inhibitors for caspase-9, -8, and -3, and the general caspase inhibitor. In vivo administration of HGS-ETR2 with or without cross-linker significantly suppressed tumor growth of subcutaneously inoculated human RCC xenografts in immunodeficient mice. These results suggest the potential utility of TRAIL-R2 antibody as a novel therapeutic agent in RCC.

Purpose: Current methods used to determine pathological examination of the lymphatics after radical cystectomy are tedious and costly. We performed a systemic study of uroplakin II (UP II) and cytokeratin 20 (CK 20) expression in pelvic lymph nodes on multiple sides in patients with bladder cancer., Materials and Methods: A total of 82 pelvic lymph node and 19 bladder tumor samples were obtained from 21 patients with bladder cancer by radical cystectomy with pelvic lymphadenectomy for reverse transcriptase-polymerase chain reaction assay., Results: Of the 19 bladder tumor tissue specimens 19 (100%) and 13 (68.4%) were positive for UP II and CK 20 mRNA expression, respectively. UP II mRNA was detected in 15 of 16 pelvic lymph node samples (93.8%) with pathologically proven metastases, whereas 9 (56.6%) were positive for CK 20 mRNA. The reverse transcriptase-polymerase chain reaction assay for UP II was statistically more sensitive than that for CK 20 in detecting not only primary tumors, but also metastatic pelvic lymph nodes (p = 0.0179 and 0.0373, respectively). Of 66 pelvic lymph node samples without metastasis UP II was detected in 6 (10%), while CK 20 was not. In addition, UP II and CK 20 mRNA could be detected in at least 50 and 500 bladder cancer HT1197 cells, respectively., Conclusions: These results indicate that UP II might be a more useful marker than CK 20 for detecting micrometastases of bladder cancer in the pelvic lymph nodes, although a greater number of patients and longer followup are needed to come to a definitive conclusion.

The authors performed cavernous nerve reconstruction by nerve grafting in 22 patients (unilateral-16, bilateral-6) between August 2001 and June 2004. Harvesting of the sural nerve was unexpectedly more difficult than nerve grafting in the extremities or the head and neck, because a knee and lumbar bending position was impossible due to the pelvic surgical field. Suture of the grafted nerve on the distal side required great effort, because there was only sufficient space for one hand at the maximum in a deep region of the pelvic cavity, and the nerve ends easily become invisible by inflow of even a small amount of urine or blood. The mean time of the nerve harvesting and grafting was 1 hr 50 min for unilateral grafting and 2 hr 40 min for bilateral grafting. Recovery of erectile function was observed in about half the patients who had undergone surgery nearly 1 year before. Since harvesting of the sural nerve and nerve grafting were more difficult than expected, modification and improvement of many surgical elements, such as improvement of surgical devices and application of endoscopic techniques, are necessary.

Purpose: To develop a Japanese version of the Expanded Prostate Cancer Index Composite (EPIC): originally designed to measure the Quality of Life of localized prostate cancer patients, after careful assessments of cross-cultural equivalence, face validity and practically., Methods: We translated the original version that consisted of 50 items into a preliminary Japanese version. This multi-stage procedure included a forward-translation, back-translation and discussion with the original developer. Additionally, we tested the preliminary Japanese version on 11 localized prostate cancer patients and identified problems with its cross-cultural equivalence, practicality. Based on the findings of this pretest, we revised the Japanese version. Consensus by discussion among all researchers was obtained through out this process., Results: The original developer reviewed the back-translation of the preliminary Japanese version: some wording was revised. In the pretest, the average age of patients was 68.8 years old. Four of the sexual subscale showed over 10 percent missing data. In five items, all patients chose identical answers. We conducted an in-depth qualitative investigation of these items. The average response time was 11.7 minutes. We revised the Japanese to reflect patients' opinions as much as possible. Items which were showed problems in terms of cross-cultural adaptation included questions measuring 'bother' and two items of the sexual subscale. The wordings of these items were revised so that Japanese patients could easier understand them. We ensured that the original developer's intentions remained the same. The original developed approved all revisions., Conclusion: We translated and adapted the original EPIC to the Japanese culture. The Japanese version of EPIC was found to be functional in the pretest.

The 12 th Oncology Forum discussed the progress and future strategy of cancer prevention in Japan. The National Cancer Center has established a research center for screening focusing on the most common six cancer, stomach, lung, liver, colon, breast and uterus cancer. The program so far had a cumulative detection rate of 3.3%, which is high,and may reflect the selection of subjects. Screening and chemoprevention is also being investigated in prostate cancer, but the issues centre on how to make this widely available. High risk subjects can also be identified for breast cancer. Obesity and family history are especially important. In colorectal cancer studies are evaluating different diets, but general application is not yet possible and the infrastructure to implement any general screening and prevention does not exist. Development of pharmaceutical treatments for prevention is difficult because of the need for very safe treatments, and also because of the length of time needed to carry out studies. Overall, cancer prevention is still in evolution. New approaches are needed, and new infrastructure will be needed at a government level to implement this.

Purpose: EPCA, a nuclear matrix protein, has been identified as a novel prostate cancer marker through protein profiling analyses comparing prostate cancer and its normal counterpart. A recent study of prostate biopsy specimens revealed that EPCA stained positive in the cancer negative biopsy cores of individuals with cancer at later biopsy. We clarified the relationship between EPCA expression and clinicopathological parameters, including grade and stage. Morphological characteristics of EPCA positive cells in noncancerous tissues were also analyzed., Materials and Methods: Prostate tissue specimens were obtained from 50 patients with localized prostate cancer and 10 with invasive bladder cancer. EPCA expression was analyzed with a polyclonal antibody. Anti-P504S/anti-p63/anti-34betaE12 monoclonal antibodies were used for adjunct diagnosis for prostatic intraepithelial neoplasia. A monoclonal antibody, CD45RO, was used to confirm inflammatory infiltrates surrounding focal atrophic glands., Results: EPCA staining was positive in the prostate samples of 94% of patients with prostate cancer but it was completely negative in samples from patients with bladder cancer. There was no correlation of EPCA staining intensity with Gleason grade or pT stage. In noncancerous tissues adjacent to major cancer foci EPCA was positive in 86% of prostate cancers. Most EPCA positive glands adjacent to cancer consisted of prostatic intraepithelial neoplasia and proliferative inflammatory atrophy., Conclusions: EPCA seems to reflect nuclear matrix alterations that occur in the earlier stage of prostate carcinogenesis. Individuals in whom the prostate is influenced by this field effect may be detected with this new biomarker.

Nucleotide pyrophosphatases/phosphodiesterases (NPPs) are ubiquitous membrane-associated or secreted ectoenzymes that release nucleoside 5'-monophosphate from a variety of nucleotides and nucleotide derivatives. The mammalian NPP family comprises seven members, but only three of these (NPP1-3) have been studied in some detail. Previously we showed that lysophospholipase D, which hydrolyzes lysophosphatidylcholine (LPC) to produce lysophosphatidic acid, is identical to NPP2. More recently an uncharacterized novel NPP member (NPP7) was shown to have alkaline sphingomyelinase activity. These findings raised the possibility that other members of the NPP family act on phospholipids. Here we show that the sixth member of the NPP family, NPP6, is a choline-specific glycerophosphodiester phosphodiesterase. The sequence of NPP6 encodes a transmembrane protein containing an NPP domain with significant homology to NPP4, NPP5, and NPP7/alkaline sphingomyelinase. When expressed in HeLa cells, NPP6 was detected in both the cells and the cell culture medium as judged by Western blotting and by enzymatic activity. Recombinant NPP6 efficiently hydrolyzed the classical substrate for phospholipase C, p-nitrophenyl phosphorylcholine, but not the classical nucleotide phosphodiesterase substrate, p-nitrophenyl thymidine 5'-monophosphate. In addition, NPP6 hydrolyzed LPC to form monoacylglycerol and phosphorylcholine but not lysophosphatidic acid, showing it has a lysophospholipase C activity. NPP6 showed a preference for LPC with short (12:0 and 14:0) or polyunsaturated (18:2 and 20:4) fatty acids. It also hydrolyzed glycerophosphorylcholine and sphingosylphosphorylcholine efficiently. In mice, NPP6 mRNA was predominantly detected in kidney with a lesser expression in brain and heart, and in human it was detected in kidney and brain. The present results suggest that NPP6 has a specific role through the hydrolysis of polyunsaturated LPC, glycerophosphorylcholine, or sphingosylphosphorylcholine in these organs.

The chemopreventive efficacies of raloxifene and nimesulide, an anti-estrogen but with anti-androgen action and a cyclooxygenase-2 (COX-2) selective inhibitor, respectively, were evaluated in probasin/SV40 T antigen (Tag) transgenic (TG) rats. The treatment groups were placebo, nimesulide (400 p.p.m. in basal diet p.o.), raloxifene (slow-release pellets implanted s.c., 5 mg/kg/day), raloxifene (5 mg/kg/day) plus nimesulide (400 p.p.m.), and raloxifene (10 mg/kg/day) plus nimesulide (400 p.p.m.). Animals were killed at 17 weeks of age, and prostate tissues were harvested and weighed by lobes. Tissues were evaluated by histology, immunohistochemistry, and western blot analyses and blood was collected to measure the testosterone levels. All the animals in the placebo group had tumors in each lobe compared with only 43% each in the dorsolateral (DLP) and anterior prostate (AP) of the animals treated with raloxifene (10 mg/kg/day) plus nimesulide. The total prostate weights and adenocarcinoma portions were significantly reduced in the three raloxifene-treated groups, whereas atrophic glands were increased. There were no significant differences between the nimesulide alone and placebo groups or between the raloxifene (5 mg/kg/day) alone and raloxifene (5 mg/kg/day) plus nimesulide group, suggesting a lack of cancer preventive effects of the COX-2 inhibitor in this animal model. PCNA positive rates in ventral prostate (VP) and DLP, and androgen receptor (AR) levels in VP were significantly reduced in the three raloxifene-treated groups. Furthermore, circulating testosterone was decreased after raloxifene (10 mg/kg/day) plus nimesulide treatment. These results demonstrate that raloxifene, but not nimesulide, inhibits prostate carcinogenesis in SV40 Tag TG rats associated with a decline in circulating testosterone levels and a loss of AR expression, as well as an inhibition of cell proliferation.

Background: To report short-term clinical outcomes of endoscopic correction of congenital urethral stricture in 10 boys who suffer from enuresis resistant to conservative therapy., Methods: Fifteen boys ranging between 5 and 15 years old consulted our clinics for nocturnal and diurnal enuresis which had not been improved by medication and behavioral therapy. Among them, voiding cystography revealed bulbar narrowing (Cobb's Collar) in 10 cases and vesico-ureteral reflux was found in four cases (seven ureters). Endoscopically, this lesion was recognized as a ring-form stenosis just distal to the urethral sphincter. It was incised with infantile urethrotome., Results: Vesico-ureteral reflux was resolved in four ureters and improved in one. In all cases, daytime enuresis resolved dramatically and night enuresis became controllable., Conclusions: Boys who suffer from diurnal enuresis should immediately be explored for the existence of congenital urethral stenosis. Early resolution may bring about better urinary behavior.

The E-cadherin gene has been identified as having a physiological role in cellular attachment, and is hypothesized to participate in carcinogenesis. A polymorphism (an A to C substitution) in the 5'-untranslated region has a direct effect on E-cadherin gene transcriptional regulation. We explored the association between E-cadherin gene polymorphism and the risk of prostate cancer in a Japanese population. The subjects consisted of 236 patients with prostate cancer, 209 benign prostatic hyperplasia (BPH) patients and 139 male controls. A marginally significant difference was found between prostate cancer patients and male controls (P = 0.053). No significant difference was observed between prostate cancer and BPH patients. When patients with prostate cancer were divided into two groups, stage A+B and stage C+D, a significant difference was observed between progressive cancer patients (stage C+D) and male controls (odds ratio = 1.93, P = 0.016). It is possible that the presence of one A allele resulted in an increased risk of cancer progression.

Prostate cancer is increasingly detected at early stages and patients can choose various forms of treatment which have favorable survival outcomes. Radical prostatectomy is a major procedure for treating early stage prostate cancer curatively. The instruments of measuring health related QOL (HRQOL) accurately for early prostate cancer treatment were developed. Some of the instruments were useful in Japan after translating into Japanese and pilot testing. Many authors have reported QOL data after radical prostatectomy. These data suggested that general and urinary domains of HRQOL recovered rapidly after radical prostatectomy, but recovery of sexual domains of HRQOL took longer. Recently several authors have reported that HRQOL were affected with ethnic and cultural differences. These results strongly suggested a need for longitudinal surveys in Japanese patients.

A randomized controlled trial has started in Japan to evaluate radiotherapy and endocrine therapy for prostate-specific antigen (PSA) failure after radical prostatectomy. Patients who have PSA failure after radical prostatectomy for localized prostate cancer (T1-2N0M0) are randomized into treatment groups of either radiotherapy +/- endocrine therapy or endocrine therapy alone. The Urologic Oncology Study Group (UOSG) in the Japan Clinical Oncology Group (JCOG) composed of 36 specialized institutions will recruit 200 patients. The primary end-point is time to treatment failure (TTF) of bicalutamide, and secondary end-points are TTF of protocol treatment, progression-free survival, overall survival, adverse events and quality of life (QOL). The Clinical Trial Review Committee of the JCOG approved the protocol on April 13, 2004, and the study was activated on May 17, 2004.

Background: CYR61 is an extracellular matrix-associated protein that promotes adhesion, migration, and proliferation of endothelial cells and fibroblasts. Prostate enlargement, which frequently causes the urethral compression, is often histologically observed as stromal and epithelial hyperplasia in an enlarged gland. To determine whether or not CYR61 has relevance to the progression of benign prostatic hyperplasia (BPH), we investigated the induction of CYR61, and also examined its function in both prostatic stromal and epithelial cells., Methods: Recombinant CYR61 protein was used for the examination of the activity of CYR61 as to cell adhesion and proliferation. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was utilized to screen for inducers of the CYR61 gene in prostatic cells. Finally, the effects of an anti-sense oligonucleotide, which could reduce the production of CYR61, on the morphology and growth of prostatic cells were also examined., Results: Recombinant CYR61 protein promotes prostatic cell adhesion and proliferation. The mRNA for CYR61, a growth factor-inducible immediate early gene, was markedly induced by fetal bovine serum (FBS) within 1 hr, and strongly induced by transforming growth factor-beta1 (TGF-beta) for at least 19 hr following stimulation. The suppression of CYR61 production with an anti-sense oligonucleotide causes obvious morphological changes of prostatic cells. Furthermore, we have shown that CYR61 is necessary, at least in part, for FBS-induced prostatic cell proliferation, because dramatic inhibition of cellular growth was caused by the suppression of CYR61 production with the addition of the anti-sense oligonucleotide before FBS stimulation., Conclusions: In this study, we demonstrate that serum growth factors induce the CYR61 gene in both stromal and epithelial cells, and that CYR61 plays functional roles in cell adhesion, morphology, and proliferation, supporting its involvement in benign prostatic enlargement. These results strongly suggest that CYR61 is a key molecule, and therefore could be a potential therapeutic target in prostatic hyperplastic growth., (2004 Wiley-Liss, Inc.)

Three dimensional conformal radiotherapy (3D-CRT) for localized prostate cancer under field adjustment with gold marker implantation was performed according to the treatment strategy based on the clinical risk factors to the patients who chose external beam radiotherapy. The treatment strategy contains indications for laparoscopic staging lymphadenectomy and neoadjuvant combined androgen blockade (CAB). This protocol was applied to 19 patients at Kagawa University Hospital from July 2001 to December 2003. The patients were divided into high-risk group (n=14): T3-4N0M0 or PSA > or = 20 ng/ml or Gleason sum > or = 8 or suspicious node, and low-risk group (n=5): T1c-2bN0M0 and PSA < 20 ng/ml and Gleason sum < or = 7 and no suspicious nodes. Basically, high-risk patients underwent laparoscopic staging lymphadenectomy prior to radiotherapy. One of the 14 patients had a positive node and underwent endocrine therapy. The high-risk group received neoadjuvant CAB for 3 to 4 months, followed by gold marker implantation. One patient chose endocrine therapy at this point. Low-risk patients underwent marker implantation without endocrine therapy. Every patient successfully completed planned irradiation. The changes of prostate volume and serum PSA after neoadjuvant CAB were significant [28.7 ml to 15.7 ml (p=0.004) and 53.9 ng/ml to 1.4 ng/ml (p=0.023), respectively]. Only one patient in the high-risk group had biochemical failure. No grade 3 or 4 adverse events occurred in NCI-CTC grading. The analysis of gravity center migration of the implanted gold markers in the first 8 patients showed that the planned safety margin might not be wide enough to avoid neighboring organ irradiation. These results suggested that 3D-CRT under field adjustment with implanted gold markers contributes to both higher efficacy and lower morbidity.

Lysophosphatidic acid (LPA) is a lipid mediator with multiple biological activities and is detected in various biological fluids, including human seminal plasma. Due to its cell proliferation stimulatory and anti-apoptotic activities, LPA has been implicated in the progression of some cancers such as ovarian cancer and prostate cancer. Here, we show that prostatic acid phosphatase, which is a non-specific phosphatase and which has been implicated in the progression of prostate cancer, inactivates LPA in human seminal plasma. Human seminal plasma contains both an LPA-synthetic enzyme, lysoPLD, which converts lysophospholipids to LPA and is responsible for LPA production in serum, and its major substrate, lysophosphatidylcholine. In serum, LPA accumulated during incubation at 37 degrees C. However, in seminal plasma, LPA did not accumulate. This discrepancy is explained by the presence of a strong LPA-degrading activity. Incubation of LPA with seminal plasma resulted in the disappearance of LPA and an accompanying accumulation of monoglyceride showing that LPA is degraded by phosphatase activity present in the seminal plasma. When seminal plasma was incubated in the presence of a phosphatase inhibitor, sodium orthovanadate, LPA accumulated, indicating that LPA is produced and degraded in the fluid. Biochemical characterization of the LPA-phosphatase activity identified two phosphatase activities in human seminal plasma. By Western blotting analysis in combination with several column chromatographies, the major activity was revealed to be identical to prostatic acid phosphatase. The present study demonstrates active LPA metabolism in seminal plasma and indicates the possible role of LPA signaling in male sexual organs including prostate cancer.

Clinical application of anticancer agents has been often hampered by toxicity against normal cells, so the achievement of their cancer-specific action is still one of the major challenges to be addressed. Previously, we reported that arsenic trioxide (As2O3) could be a promising new drug against not only leukemia but also solid tumors. The cytotoxicity of As2O3 occurred through the generation of reactive oxygen species (ROS), thus inhibiting radical scavenging systems would enhance the therapeutic efficacy of As2O3 provided that normal cells were relatively resistant to such a measure. Here, we report that the combination therapy of As2O3 with L-buthionine-sulfoximine (BSO), which inhibits a critical step in glutathione synthesis, effectively enhanced in vitro growth inhibition effect of As2O3 on all 11 investigated cell lines arising from prostate, breast, lung, colon, cervix, bladder, and kidney cancers, compared with As2O3 treatment alone. Furthermore, this combination enhanced cytotoxicity to cell lines from prostate cancer with less toxicity to those from normal prostate. In vitro cytotoxic assay using ROS-related compounds demonstrated that hydrogen peroxide (H2O2) is a major cytotoxic mediator among ROS molecules. Biochemical analysis showed that combined use of As2O3 and BSO blocked H2O2-scavenging systems including glutathione, catalase, and glutathione peroxidase, and that the degree of this blockade was well correlated with intracellular ROS levels and sensitivity to this treatment. Finally, the effectiveness of the combination therapy of As2O3 with BSO was demonstrated with an orthotopic model of prostate cancer metastasis. We propose that the combination therapy of As2O3 with BSO is a valid means of blockade of H2O2-scavenging system, and that the combination of a ROS-generating agent with an inhibitor of major scavenging systems is effective in terms of both efficacy and selectivity. Furthermore, because the effective doses of both compounds are within clinically achievable range, this report will lead to immediate benefit for the development of a new cancer therapy.

Background: Macrophage inhibitory cytokine-1 (MIC-1) is a member of transforming growth factor-beta/bone morphogenetic protein (BMP) superfamily. Despite its potential role in prostatic regulation, little is known about its biological activity., Methods: Expression profiling using 42K Affymetrix HuGeneFL array was conducted to compare symptomatic benign prostatatic hyperplasia (BPH), histological BPH without symptoms, and normal prostate samples from donors. MIC-1 gene expression was analyzed by RT-PCR in pure culture of prostate epithelial and stromal cells, and prostate cancer cells, LNCaP, PC-3, DU-145. Influence of androgens on MIC-1 expression in LNCaP cells was analyzed by Northern blot. Enhancement of promoter activity of MIC-1 by androgens was examined using reporter assays., Results: In contrast to normal prostates, MIC-1 gene was down-regulated in BPH samples with symptoms and histological BPH obtained from cystoprostatectomy specimens (P < 0.005 and P < 0.01, respectively). Expression level of MIC-1 in androgen-sensitive LNCaP cells was high and enhanced by androgens, whereas in the androgen-insensitive PC-3 and DU-145 cells the expression level was low. An 11 kb promoter region of MIC-1 gene was identified to be 6- to 12-fold activated by androgens., Conclusions: Down-regulation of MIC-1 may play a role in the development of BPH. MIC-1 is positively regulated by androgens, but other regulatory factors remain unclear., (Copyright 2004 Wileey-Liss, Inc.)

Purpose: Our previous DNA microarray analyses revealed that the macrophage inhibitory cytokine-1 (MIC-1) gene was significantly down-regulated in symptomatic benign prostatic hyperplasia (BPH) samples. We compared the histopathological features of inflammatory changes in prostate adenoma tissues from individuals with symptomatic and asymptomatic (histological only) BPH using MIC-1 mRNA levels., Materials and Methods: Prostate adenoma tissues were obtained from 25 patients who underwent transurethral prostatectomy to relieve lower urinary tract symptoms due to BPH and 6 patients with bladder cancer who underwent cystoprostatectomy due to bladder cancer. Inflammatory changes in the prostate were examined histopathologically and immunohistochemically, and classified according to the consensus classification system of the Chronic Prostatitis Collaborative Research Network and International Prostatitis Collaborative Network advocated in 2001 with some modification. MIC-1 mRNA was assessed quantitatively by real-time reverse transcriptase-polymerase chain reaction., Results: MIC-1 gene down-regulation was observed in 16 of 25 symptomatic BPH samples (64.0%), whereas MIC-1 mRNA was high in 6 of 6 prostate adenoma samples from patients with bladder cancer (p = 0.0006). MIC-1 gene down-regulation correlated with the grade of glandular/ periglandular inflammatory changes with statistical significance (p = 0.0387). MIC-1 gene down-regulation was found in only 1 of 7 BPH samples with a glandular predominant pattern, whereas it was found in 15 of 24 BPH samples with a mixed type or stromal predominant pattern (p = 0.0373)., Conclusions: Gland destruction by inflammatory infiltrates, followed by replacement of the stromal component in symptomatic BPH may be induced by the down-regulation of the MIC-1 gene.

Arsenic trioxide (As2O3) induces clinical remission in acute promyelocytic leukemic patients and apoptosis in various tumor cells in vitro. To develop As2O3-based combination chemotherapy for renal cell carcinoma (RCC), we investigated the cytotoxic effects of As2O3 in combination with chemotherapeutic agents or L-buthionine sulfoximine (BSO), a glutathione (GSH) synthesis inhibitor. Cytotoxicity and synergy were assessed by the MTT assay and isobolographic analysis, respectively. Apoptosis was monitored by Hoechst 33342 staining, flow cytometrical analysis, and DNA fragmentation assay. Treatment of ACHN cells with As2O3 in combination with adriamycin, vinblastine, or 5-fluorouracil induced an antagonistic effect. However, combination treatment with As2O3 and BSO resulted in a synergistic cytotoxic effect. Synergy was also obtained in Caki-1, Caki-2, NC65 cells and freshly derived RCC cells from 6 patients. Simultaneous treatment of ACHN cells with As2O3 and BSO caused significantly more cytotoxicity than the As2O3 first BSO second or the reverse treatment. We further explored the mechanisms underlying this synergistic effect and found that the synergistic cytotoxicity of As2O3 and BSO was realized by inducing apoptosis. This combination markedly decreased intracellular GSH content and GSH-S-transferase (GST) activity. However, neither the intracellular GSH nor GST was decreased by As2O3 with adriamycin, vinblastine, or 5-fluorouracil. Furthermore, the GSH-increasing agents N-acetylcysteine and lipoic acid significantly inhibited the combined cytotoxicity of As2O3 and BSO. These findings indicate that BSO sensitizes RCC cells to As2O3-induced apoptosis through the down-regulation of the intracellular GSH redox system, suggesting the potential application of a combination of As2O3 and BSO for the treatment of RCC.

Lysophosphatidic acid (LPA) is an endogenous lipid growth factor that is thought to play important roles in cell proliferation and antiapoptosis and therefore may have roles in the development and progression of benign prostatic hyperplasia (BPH). CYR61 (CCN1), on the other hand, is a growth factor-inducible immediate early gene that functions in cell proliferation, differentiation, and extracellular matrix synthesis. Here we show the close relationship between LPA-induced expression of CYR61 and prostate enlargement. CYR61 mRNA and protein were dramatically up-regulated by 18:1 LPA (oleoyl-LPA) within 1 and 2 h, respectively, in both stromal and epithelial prostatic cells. G protein-coupled receptors, i.e. Edg-2, Edg-4, and Edg-7, for LPA were also expressed in both stromal and epithelial prostatic cells. Furthermore, on DNA microarray analysis for normal and BPH patients, CYR61 was found to be related to the development and progression of BPH, regardless of symptoms. Although CYR61 mRNA was synthesized in hyperplastic epithelial cells, in many cases of BPH, CYR61 protein was detected in both the epithelial and stromal regions of BPH patient tissues. The functional contribution of CYR61 to prostatic cell growth was demonstrated by recombinant CYR61 protein and anti-CYR61 neutralizing antibodies, which inhibited CYR61-dependent cell spreading and significantly diminished cell proliferation, respectively. In conclusion, these data support the hypothesis that LPAs induce the expression of CYR61 by activating G proteincoupled receptors and that CYR61 acts as a secreted autocrine and/or paracrine mediator in stromal and epithelial hyperplasia, demonstrating the potential importance of this signaling mechanism in the disease.

Objectives: To assess the clinical benefit of the methods of detection of p53 mutations in human urothelial carcinoma., Methods: A total of 75 surgical specimens of urothelial carcinoma were analyzed using a yeast functional assay (FASAY) and immunohistochemistry (IHC), in combination with sequencing analysis., Results: Of the 75 specimens, 24 (32.0%) were positive (mutant) by FASAY and 23 (30.7%) were positive by IHC. The sequencing analysis confirmed that all 24 FASAY-positive tumors harbored mutations, and no mutations were detected in any FASAY-negative tumors. In contrast, nuclear accumulation of p53 protein was detected in 9 (17.6%) of 51 tumors with no mutation, and 10 (41.7%) of 24 tumors with mutation showed no positive staining on IHC. The mutations detected by FASAY and IHC were both associated with stage and grade, but null mutations of p53 were not associated with stage. Concerning chemosensitivity, 6 (85.7%) of 7 responders harbored p53 missense mutations in at least one allele (P = 0.01), and only 4 (57.1%) were judged positive by IHC (P = 0.13)., Conclusions: FASAY is more accurate than IHC in detecting the various types of p53 mutations, suggesting that a comprehensive approach for the detection of p53 mutations may be essential to elucidate their clinical significance.

Background: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a new member of the tumor necrosis factor family. The present study investigated whether anthracyclines enhance TRAIL-induced apoptosis and cytotoxicity in renal cell carcinoma (RCC) cells., Methods: Cytotoxicity was measured using the microtiter assay. Apoptosis was monitored using DNA ladder analysis. Caspase activity was determined using a quantitative colorimetric assay., Results: Treatment of ACHN and Caki-1 human RCC lines with TRAIL, in combination with subtoxic concentrations of epirubicin (EPI) or pirarubicin (THP), enhanced induction of apoptosis and cytotoxicity. Sequential treatment with EPI followed by TRAIL induced significantly more cytotoxicity than the inverse treatment. The combined cytotoxicity of TRAIL and EPI was significantly inhibited by the TRAIL-neutralizing fusion protein DR5:Fc, although EPI did not affect the mRNA expression of DR4, DR5, DcR1 or DcR2. The combination treatment with TRAIL and EPI activated caspase-6 and -3, which were downstream molecules of the death receptor. Furthermore, the combined cytotoxicity of TRAIL and EPI was almost completely inhibited by Z-VAD-FMK, and partly inhibited by Ac-DMQD-CHO., Conclusion: These findings indicate that anthracyclines sensitize RCC cells to TRAIL-induced apoptosis and cytotoxicity through activation of caspases, suggesting that TRAIL, in combination with anthracyclines, has a therapeutic potential in the treatment of RCC.

Background: We report the outcome of radical cystectomy for patients with invasive bladder cancer, who did not have regional lymph node or distant metastases, at 21 hospitals., Methods: Retrospective, non-randomized, multi-institutional pooled data were analyzed to evaluate outcomes of patients who received radical cystectomy. Between 1991 and 1995, 518 patients with invasive bladder cancer were treated with radical cystectomy at 21 hospitals. Of these, 250 patients (48.3%) received some type of neoadjuvant and/or adjuvant therapy depending on the treatment policy of each hospital., Results: The median follow-up period was 4.4 years, ranging from 0.1 to 11.4 years. The 5-year overall survival rate was 58% for all 518 patients. The 5-year overall survival rates for patients with clinical T2N0M0, T3N0M0 and T4N0M0 were 67%, 52% and 38%, respectively. The patients with pT1 or lower stage, pT2, pT3 and pT4 disease without lymph node metastasis had 5-year overall survivals of 81%, 74%, 47% and 38%, respectively. The patients who were node positive had the worst prognosis, with a 30% overall survival rate at 5 years. Neoadjuvant or adjuvant chemotherapy did not provide a significant survival advantage, although adjuvant chemotherapy improved the 5-year overall survival in patients with pathologically proven lymph node metastasis., Conclusions: The current retrospective study showed that radical cystectomy provided an overall survival equivalent to studies reported previously, but surgery alone had no more potential to prolong survival of patients with invasive cancer. Therefore, a large-scale randomized study on adjuvant treatment as well as development of new strategies will be needed to improve the outcome for patients with invasive bladder cancer.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/Apo2L) is a recently identified member of the TNF ligand family that selectively induces apoptosis in tumor cells in vitro and in vivo but not in most normal cells. Chemotherapeutic drugs induce apoptosis and the upregulation of death receptors or activation of intracellular signaling pathways of TRAIL. Numerous chemotherapeutic drugs have been shown to sensitize tumor cells to TRAIL-mediated apoptosis. Studies from our laboratory have also shown that TRAIL-resistant renal cell carcinoma, prostate gland cancer, and bladder cancer cells are sensitized by subtoxic concentrations of chemotherapeutic drugs including doxorubicin, epirubicin, pirarubicin, and cisplatin. TRAIL, particularly in combination with chemotherapeutic agents, is thus potentially promising in the treatment of cancer. This review addresses the putative role of TRAIL in cancer treatment and discusses the molecular basis of the synergistic effect of TRAIL and chemotherapeutic drugs.

Among urological diseases, benign prostatic hyperplasia (BPH) exhibits a high morbidity rate, afflicting approximately 50% of men older than age 50 years. Despite intense research efforts over the past decades, the etiology and mechanisms of BPH progression are only poorly understood. Employing oligonucleotide microarrays, the authors analyzed the gene expression profiles in normal and BPH prostate samples and found that CYR61, an immediate early gene, is markedly overexpressed in BPH. To quantify cellular CYR61 mRNA expression directly, the authors developed an assay using branched-chain DNA (bDNA) technology. A human prostatic epithelial cell line, BRF-55T, derived from a BPH patient, was treated with fetal bovine serum to stimulate gene expression, and then the induction profile of the CYR61 mRNA in these serum-stimulated cells was quantitated using both bDNA and quantitative reverse transcriptase-PCR (RT-PCR). The results obtained with the 2 detection systems were found to be very similar. The bDNA assay was also found to be sensitive and highly reproducible. To the authors' knowledge, this is the first time that identifying CYR61 as a novel marker for BPH and its quantitation has been reported. These detection methods not only may be useful for diagnostic purposes but may also be used to identify suppressors of CYR61 expression for BPH therapy employing high-throughput screening assays.

Objectives: To evaluate, in a retrospective analysis of the outcome of 393 consecutive patients undergoing radical nephrectomy, the advantages and disadvantages of concomitant ipsilateral adrenalectomy with this operation., Methods: The medical records, pathologic specimens, and preoperative and postoperative computed tomography scans of 165 patients with, and 228 patients without, concomitant adrenalectomy were reviewed. The incidence of adrenal involvement in the former patients and ipsilateral adrenal recurrence in the latter patients was evaluated. The influence of adrenalectomy on the disease-specific survival was also assessed by both univariate and multivariate analyses., Results: Of the 165 patients, only 5 (3.0%) had adrenal involvement. All of these cases were diagnosed as cT3 or greater preoperatively, and preoperative computed tomography detected 4 of these 5 cases. Of the 228 patients without adrenalectomy, no ipsilateral adrenal recurrence was observed at a mean follow-up of 65.2 months. Ipsilateral adrenalectomy did not confer a favorable prognosis on the patients., Conclusions: Our results indicate that the advantages of ipsilateral adrenalectomy in patients with normal findings on preoperative computed tomography are limited. Concomitant ipsilateral adrenalectomy is indicated in cases such as locally advanced tumors with uncertain preoperative imaging studies or those with apparent adhesion or inflammation around the adrenal gland at surgery, thus suggesting perinephric tumor involvement.

Renal cell carcinoma (RCC) is one of the most drug-resistant malignancies in humans. We show that adriamycin (ADR) and TNF-related apoptosis-inducing ligand (TRAIL)/Apo2L have a synergistic cytotoxic effect against RCC cells. This synergistic cytotoxicity was obtained in ACHN, A704, Caki-1 and Caki-2 human RCC cell lines and freshly derived RCC cells from 6 patients. This synergistic effect, however, was not achieved in 5 samples of freshly isolated normal kidney cells. We further explored the mechanisms underlying this synergistic effect and found that the synergistic cytotoxicity of TRAIL/Apo2L and ADR was realized by inducing apoptosis. Sequential treatment with ADR followed by TRAIL/Apo2L induced significantly more cytotoxicity than the reverse treatment. ADR increased the expression of DR4 and DR5 in RCC cells, but not in the normal kidney cells. Furthermore, the synergistic cytotoxicity was significantly inhibited by DR4:Fc and DR5:Fc fusion proteins, which inhibit TRAIL/Apo2L-mediated apoptosis. In addition, caspase activity assays and treatment of caspase inhibitors demonstrated that the combination treatment with ADR and TRAIL/Apo2L activated caspase cascade, including caspase-9, -8, -6 and -3, which were the downstream molecules of death receptors. These findings indicate that ADR sensitizes RCC cells to TRAIL/Apo2L-mediated apoptosis through induction of DR4 and DR5, suggesting that the combination therapy of TRAIL/Apo2L and ADR might be effective for RCC therapy., (Copyright 2003 Wiley-Liss, Inc.)

We report three cases of congenital urethral stricture in boys. They were 8, 7 and 5 years old. They complained of enuresis both day and night. Voiding cystography revealed bulbar narrowing (Cobb's Collar) in all cases, and vesico-ureteral reflux (VUR) occurred in two cases (three ureters). Endoscopically this lesion showed ring-form stenosis just distal to the urethral sphincter, and incised by using an infantile urethrotome. After the operation, VUR resolved in two ureters and improved in one. In all cases, daytime enuresis resolved dramatically, and night enuresis became controllable. Congenital urethral stenosis in boys is an important clinical entity in pediatric urology, and is not such a rare disease.

The C-half of cisplatin resistance-associated overexpressed protein (CROP), an SR-related protein, comprises domains rich in arginine and glutamate residues (RE domain), and is rich in arginine and serine residues (RS domain). We analyzed the role of the individual domains of CROP in cellular localization, subnuclear localization, and protein-protein interaction. CROP fused with green fluorescent protein, GFP-CROP, localized exclusively to the nucleus and showed a speckled intranuclear distribution. The yeast two-hybrid system revealed that CROP interacted with SF2/ASF, an SR protein involved in RNA splicing, as well as CROP itself. The RE and RS domains were necessary for both the intranuclear speckled distribution and the protein-protein interaction. CROP was phosphorylated by mSRPK1, mSRPK2, and Clk1 in vitro, and when cells were treated with cisplatin the subnuclear distribution of GFP-CROP was changed. These results suggest that cisplatin affects RNA splicing by changing the subnuclear distribution of SR proteins including CROP.

Objectives: To determine the percent area density of epithelial and stromal components in the development of prostatic hyperplasia in spontaneously hypertensive (SH) rats., Methods: The ventral lobes of prostates obtained from male SH rats and their normotensive counterparts, Wistar Kyoto (WKY) rats, were examined histopathologically at 15, 29, 40, and 54 weeks of age (5 SH and WKY rats each at each age group). The degree of prostatic hyperplasia was evaluated with a score-chart protocol, histoscore. The percent area density of epithelium and stroma of the ventral prostate were determined using a computerized image analysis system., Results: Definite lesions of hyperplastic changes were demonstrated in the ventral prostate of SH rats from 15 to 54 weeks. In comparison with WKY rats, SH rats showed a significantly increased degree of prostatic hyperplasia as reflected by the histoscore values. Furthermore, the histoscore of the ventral prostate of SH rats increased with age (from 21.7 +/- 0.7 at 15 weeks to 26.1 +/- 0.4 at 54 weeks). The percent area density of epithelium and stroma were significantly increased in SH rats, and the ratio of stroma to epithelium ranged from 1:2.94 to 1:3.50 in SH rats but was maintained at 1:1.15 to 1:1.19 in WKY rats during the observation period., Conclusions: The hyperplastic changes of the ventral prostate may develop with advancing age in SH rats. The development of prostatic hyperplasia may result from both epithelial and stromal proliferation and may be predominantly expressed as a glandular type in SH rats.

The incidence rate of early-stage prostate cancer has dramatically increased since the introduction of the widespread use of PSA testing in developed countries, including Japan. With the downward stage migration there has been much interest in the concept of watchful waiting not only for elderly patients with a life expectancy of less than 10 years but also in younger patients with good social and sexual activity. The results of a recent randomized comparison between radical prostatectomy and watchful waiting for localized disease indicated comparable overall survival but superiority of surgery in disease-specific survival. The predictive value of clinico-pathological parameters including biopsy features and serum PSA seems insufficient to predict tumor growth potential. Our ongoing prospective study is aimed at clarifying whether PSA doubling time assessment for 6 months in patients with favorable biopsy features can be a good indicator for further watchful waiting or immediate aggressive treatment without any survival disadvantage.

Prostate specific antigen (PSA) failure occurs in 20% to 50% of patients who undergo radical prostatectomy. There is no consensus on how PSA failure should be managed. Recently, salvage radiotherapy is reported to be an effective treatment for PSA failure, and 20%-70% of cases are recurrence-free. The aim of salvage radiotherapy is a cure and this is quite different from other options, for example, endocrine therapy. Salvage radiotherapy is likely to become more important as a treatment for PSA failure after radical prostatectomy.

Methods: The Japanese version (version 1.2) of the UCLA PCI was developed through a process of translation, back-translation, and refinement after interviewing patients. Reliability and validity were examined for 125 Japanese patients with localized prostate cancer. The patients simultaneously responded to the Japanese version of the RAND 36-Item Health Survey (SF-36) and five representative questions from the International Index of Erectile Function (IIEF)., Results: Internal consistency reliability was very high for both urinary and sexual function scales, and lower for bowel function. The test-retest reliability of the urinary and sexual function scales and the urinary bother scales was stable, while that of the bowel function and bother scales was relatively unstable. Sexual function scores did not correlate highly with sexual bother scores. Furthermore, poor sexual function and bother had little association with the SF-36 scores. Missing data as to urinary and bowel function/bother scales were minimal (0.8%-2.4%), while those for sexual function and bother were relatively high (4.8%-11.2%)., Conclusions: The results of this pilot study, together with the previous American study, suggest ethnic or cultural difference in how impaired sexual function is integrated into overall QOL. A future cross-cultural comparative study using the UCLA PCI and SF-36 will provide useful information about the influence of cultural or ethnic differences on health-related QOL in prostate cancer patients.

Purpose: To translate the UCLA Prostate Cancer Index (UCLA PCI), which is designed to measure Quality of Life (QOL) of patients with prostate cancer, and to adapt it as needed for use in Japan., Methods: We translated the original English version into a preliminary Japanese version in a multi-stage procedure according to established guidelines. Then, we tested the preliminary Japanese version on 6 patients with prostate cancer, and we revised the Japanese version based on the findings of the pilot test., Results: The back-translation of the preliminary Japanese version was reviewed by its original developer, and some wordings were revised. In the pilot testing, the average time required to complete the questionnaire was 5.5 minutes. Four of the 20 items frequently had missing data (> 15%). This is believed to have been due to inappropriate wording of the response choices, which were revised accordingly., Conclusion: We conducted translation and cross-cultural adaptation of the Japanese version of UCLA PCI. Pilot testing proved to be useful in refining items and response choices.

Purpose: To investigate the short-term effects of TNP-470 in combination with cisplatin in a rat model of bladder cancer., Materials and Methods: Following treatment of TNP-470 with or without cisplatin for 7 days, the states of angiogenesis, apoptosis and cell proliferation were evaluated in rat bladder cancer induced by N-butyl-N-(4-hydroxybutyl) nitrosamine., Results: In comparison with untreated tumors, we noted a significantly decreased microvessel density (MVD) in the rat bladder cancer treated by TNP-470, and a significantly increased apoptotic index (AI) when treated by cisplatin. In TNP-470 plus cisplatin-treated tumors, both significantly decreased MVD and increased AI were observed in non-invasive and invasive rat bladder cancers in addition to a significantly decreased proliferation index (PI) in invasive cancer., Conclusion: The combination therapy of TNP-470 with cisplatin may act through both the inhibition of angiogenesis and induction of apoptosis, and invasive tumor cells may be much more sensitive to this combined therapy in rat bladder cancer.