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Background: To explore the dynamic changes and effects of radical cystectomy on quality of life in muscle-invasive bladder cancer survivors., Methods: Patients with muscle-invasive bladder cancer were randomly recruited in this study. We used the World Health Organization Quality of Life-Brief questionnaire to assess consecutive patients' quality of life. We applied kernel smoothing to illustrate the dynamic changes of the domain and item scores after treatment. Mixed-effects models were constructed to determine the effects of radical cystectomy on the scores of each item and domain of the World Health Organization Quality of Life-Brief questionnaire after controlling demographic and clinical factors., Results: We collected 397 repeated measurements of the World Health Organization Quality of Life-Brief questionnaire from 109 muscle-invasive bladder cancer patients. Forty-two of them received radical cystectomy. Patients with radical cystectomy exhibited higher levels of education, less co-morbidities (i.e., diabetes and heart diseases), but were associated with more malignancies. Construction of mixed-effects models showed patients with radical cystectomy and those with bladder sparing had similar scores in the three main domains and their items, except that of certain items of physical domain. By applying kernel smoothing method, we found that stage III-IV patients consistently showed higher scores on sleep and rest after radical cystectomy for more than 5 years. In contrast, stage II patients receiving radical cystectomy did not show a higher score on the "sleep and rest" item compared with those with bladder sparing operation., Conclusions: Radical cystectomy may result in sound sleep and rest, especially in those with stage III-IV bladder cancer., (© 2022. The Author(s).)

Bladder cancer is a common tumour of the urinary system, and more than 90% is urothelial carcinoma. Therefore, it is important for discovering the key target genes and molecules of bladder tumour cell metastasis and invasion. Our research initially explored the regulation of deltaN p63 on the progression and metastasis of bladder cancer and found that deltaN p63 can influence the occurrence of EMT through PTEN and ultimately regulate the growth and metastasis of bladder cancer. In summary, this study identified a new EMT regulator, deltaN p63, further revealed the mechanism of the invasion and metastasis of bladder cancer cells, and provided a theoretical basis for finding new target molecules and drugs to treat bladder cancer. In conclusion, this study will further reveal the mechanism of tumour cell invasion and metastasis and provide a theoretical basis for cancer treatment to find new target molecules and drugs., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Yong-Hua Tian et al.)

Objectives: To determine the optimal surgical timing in high-risk patients with Fournier's gangrene by the Simplified Fournier's Gangrene Severity Index., Methods: From 1989 to 2018, 118 male patients diagnosed with Fournier's gangrene with complete medical records were retrospectively reviewed. Patients' demographics, laboratory parameters at initial diagnosis, Fournier's Gangrene Severity Index and Simplified Fournier's Gangrene Severity Index, and the time interval from emergency room arrival to surgical intervention were collected. The Fournier's gangrene patients were categorized into low-risk (Simplified Fournier's Gangrene Severity Index ≤2) and high-risk groups (Simplified Fournier's Gangrene Severity Index >2). Differences between the variables within the two groups were analyzed. The optimal surgical timing was analyzed with the receiver operating characteristic curve in high-risk Fournier's gangrene patients., Results: The overall mortality of 118 Fournier's gangrene patients was 14.4%. After risk stratification with the Simplified Fournier's Gangrene Severity Index scoring system, the mortality of low-risk and high-risk Fournier's gangrene patients was 1.3% and 41.0%, respectively. In the high-risk group, the time interval from emergency room arrival to surgical intervention was the only variable with a significant difference between survivors and non-survivors (P = 0.039). The optimal surgical timing was determined at 14.35 h, which allowed the highest sensitivity (0.688) and specificity (0.762) to affect mortality. The mortality was significantly lower in high-risk Fournier's gangrene patients with early surgical intervention compared with late intervention (23.8% vs 68.8%, P = 0.007)., Conclusions: The Simplified Fournier's Gangrene Severity Index is a quick and reliable screening tool for first-line physicians to identify high-risk patients with Fournier's gangrene (Simplified Fournier's Gangrene Severity Index >2) who have poor survival outcomes. We recommended early surgical intervention within 14.35 h to maximize the survival of high-risk Fournier's gangrene patients., (© 2019 The Japanese Urological Association.)

Nocturnal enuresis causes significant psychological distress to affected children and their family and requires appropriate management. A 12-member expert committee of pediatric urologists and pediatric nephrologists in Taiwan with extensive experience in treating enuresis was established to develop consensus statements and a recommended treatment algorithm for the management of patients with nocturnal enuresis in Taiwan after careful consideration of current evidence, existing guidelines, and expert opinion as well as local practice and culture. The finalized consensus statements were reviewed by and have received endorsement from the Taiwan Urological Association and the Taiwan Pediatric Association. Patients with suspected enuresis should undergo a thorough initial assessment to fully evaluate urinary signs and symptoms and to rule out underlying causes of diurnal and nocturnal incontinence. Behavioral therapy is recommended throughout the course of management. Desmopressin in the fast-melting formulation is the recommended first-line pharmacological treatment. Combination therapy may be effective in patients who have failed first-line treatment. These consensus statements and a recommended treatment algorithm were created by the expert committee to provide practical support for clinical decision making by physicians in Taiwan., (Copyright © 2018. Published by Elsevier B.V.)

The failure of androgen deprivation therapy in prostate cancer treatment mainly results from drug resistance to androgen receptor antagonists. Although an aberrant caveolin‑1 (Cav‑1) expression has been reported in multiple tumor cell lines, it is unknown whether it is responsible for the progression of castration‑resistant prostate cancer (CRPC). Thus, the aim of the present study was to determine whether Cav‑1 can be used as a key molecule for the prevention and treatment of CRPC, and to explore its mechanism of action in CRPC. For this purpose, tissue and serum samples from patients with primary prostate cancer and CRPC were analyzed using immunohistochemistry and enzyme‑linked immunosorbent assay, which revealed that Cav‑1 was overexpressed in CRPC. Furthermore, Kaplan‑Meier survival analysis and univariate Cox proportional hazards regression analysis demonstrated that Cav‑1 expression in tumors was an independent risk factor for the occurrence of CRPC and was associated with a shorter recurrence‑free survival time in patients with CRPC. Receiver operating characteristic curves suggested that serum Cav‑1 could be used as a diagnostic biomarker for CRPC (area under the curve, 0.876) using a cut‑off value of 0.68 ng/ml (with a sensitivity of 82.1% and specificity of 80%). In addition, it was determined that Cav‑1 induced the invasion and migration of CRPC cells by the activation of the H‑Ras/phosphoinositide‑specific phospholipase Cε signaling cascade in the cell membrane caveolae. Importantly, simvastatin was able to augment the anticancer effects of androgen receptor antagonists by downregulating the expression of Cav‑1. Collectively, the findings of this study provide evidence that Cav‑1 is a promising predictive biomarker for CRPC and that lowering cholesterol levels with simvastatin or interfering with the expression of Cav‑1 may prove to be a useful strategy with which to prevent and/or treat CRPC.

According to World Health Organization reports, cardiovascular diseases (CVDs) are amongst the major causes of death globally and are responsible for over 18 million deaths every year. Traditional detection methods for CVDs include cardiac computerized tomography scans, electrocardiography, and myocardial perfusion imaging scans. Although diagnosis of CVDs through such bio-imaging techniques is common, these methods are relatively costly and cannot detect CVDs in their earliest stages. In contrast, the levels of certain micro RNA (miRNA) biomarkers extracted from extracellular vesicles (EVs) in the bloodstream have been recognized as promising indicators for early CVD detection. However, detection and quantification of miRNA using existing methods are relatively labor-intensive and time-consuming. In this study, a new integrated microfluidic system equipped with highly sensitive field-effect transistors (FETs) was capable of performing EV extraction, EV lysis, target miRNA isolation and miRNA detection within 5 h. The limit of detection was within the physiological range (femtomolar) for two targeted miRNAs, miR-21 and miR-126, meaning that this integrated microfluidic system has the potential to be used as a tool for early detection of CVDs.

Background: To explore the feasibility and long-term outcomes of renal preservation in a retrospective cohort of patients with ureteral urothelial carcinoma undergoing total ureterectomy with ileal-ureteral substitution., Methods: A retrospective review of the data from patients treated with total ureterectomy with ileal-ureteral substitution from 1988 to 2016 was performed. The pre-operative oncological status, long-term oncological outcome, long-term renal functional outcome, early and late complications were analyzed., Results: A total of eight patients with a median age of 70 years were included. The median follow-up time was 109 months. Six patients had multi-focal tumor involvement over the target ureter, and six patients had bilateral upper tract involvement. Only one patient encountered the upper-tract recurrence. The 2 and 5-year cancer-specific survival rates were 87.5 and 75.0%, respectively. The renal function was well-preserved in most patients, with only one patient needed life-long postoperative hemodialysis. Five patients experienced early complications and four patients experienced late complications. No perioperative mortality happened., Conclusions: A total ureterectomy with an ileal-ureteral substitution is feasible for treating ureteral urothelial carcinoma when a renal-sparing procedure is indicated. It provides good long-term oncological outcomes over the upper tract, and it also preserves the renal function.

Arsenic may affect the function of proximal convoluted tubules and glomeruli, but epidemiological data on the association between arsenic ingestion and end-stage renal disease (ESRD) are limited. Therefore, we conducted a nationwide population-based study in Taiwan, where the incidence of ESRD is the highest in the world, to study the potential association. Using the National Health Insurance Database in Taiwan, we constructed a cohort of 362,505 members with age≥40years in 1998. We identified patients of ESRD newly diagnosed between January 1, 1998 and December 31, 2010 and performed Cox proportional hazard regressions to identify risk factors for ESRD and evaluate their effects. Arsenic levels in drinking water were assessed on the basis of a nationwide census survey conducted by the government, of which measurement reports were available for 311 townships. We identified 5442 new patient of ESRD during the study period and found that residents of areas with arsenic levels≥50μg/L in the drinking water had a hazard ratio (HR) of 1.14 (95% confidence interval [CI]: 1.08-1.21) for ESRD. After adjusting for sex, age, income, and comorbidities, we found an adjusted HR of 1.12 (95% CI: 1.06-1.19), which was still statistically significant. Furthermore, the effect was modified by comorbidities, with more prominent effects on patients with less than three comorbidities (adjusted HR=1.51; 95% CI: 1.22-1.86 for low comorbidity score). In conclusion, a high arsenic level in drinking water was a risk factor for ESRD, independent of other documented risk factors. Reducing high-risk comorbidities in patients with early-stage renal dysfunction is important for slowing the progression of the disease to ESRD, even in the endemic area of arsenic exposure., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Lutheran/basal cell adhesion molecule (Lu/BCAM) is a membrane bound glycoprotein. This study was performed to investigate the role and downstream signaling pathway of Lu/BCAM in human bladder tumorigenesis., Methods: Five human bladder cancer (E6, RT4, TSGH8301, TCCSUP and J82), one stable mouse fibroblast cell line (NIH-Lu) expressing Lu/BCAM transgene and sixty human uroepithelial carcinoma specimens were analyzed by real-time PCR, immunohistochemistry (IHC), immunofluorescence (IFA) staining, Western blotting and promoter luciferase assay for Lu/BCAM, respectively. The tumorigenicity of Lu/BCAM was demonstrated by focus formation, colony-forming ability, tumour formation, cell adhesion and migration., Results: H-ras V12 was revealed to up-regulate Lu/BCAM at both transcriptional and translation levels. Lu/BCAM expression was detected on the membrane of primary human bladder cancer cells. Over-expression of Lu/BCAM in NIH-Lu stable cells increased focus number, colony formation and cell adhesion accompanied with F-actin rearrangement and decreased cell migration compared with parental NIH3T3 fibroblasts. In the presence of laminin ligand, Lu/BCAM overexpression further suppressed cell migration accompanied with increased cell adhesion. We further revealed that laminin-Lu/BCAM-induced cell adhesion and F-actin rearrangement were through increased Erk phosphorylation with an increase of RhoA and a decrease of Rac1 activity. Similarly, high Lu/BCAM expression was detected in the tumors of human renal pelvis, ureter and bladder, and was significantly associated with advanced tumor stage (p = 0.02). Patients with high Lu/BCAM expression showed a trend toward larger tumor size (p = 0.07) and lower disease-specific survival (p = 0.08), although not reaching statistical significance., Conclusion: This is the first report showing that Lu/BCAM, in the presence of its ligand laminin, is oncogenic in human urothelial cancers and may have potential as a novel therapeutic target.

Justicidin A (JA) is one of the methanol extracts of Justicia procumbens and was reported to induce apoptosis and inhibit the proliferation of human colon cancer cells. Using bladder cancer as a paradigm, this study was designed to identify the novel molecular basis underlying the antiangiogenic activities of JA and its potential in cancer therapy. Human bladder cancer cell lines (TSGH8301 and RT4) and immortalized uroepithelial cell lines (E6 and E7) were chosen to investigate the efficacy of JA in cell proliferation, apoptosis, and angiogenesis in vitro. The biological effects of JA treatment in vivo were examined using a xenograft tumor model in SCID mice. JA showed a dose-dependent and time-dependent inhibition of cell proliferation on TSGH8301 cancer cells, with IC50 values determined to be 0.44 μmol/l. Of interest, TSGH8301 cancer cells were more sensitive to JA than E7 immortalized uroepithelial cells, especially at lower concentrations. We further showed that JA inhibited the autocrine production of angiogenic factors and matrix-degrading enzymes in vitro and microvessel density in SCID mice in vivo (P< 0.01). Both differential cytotoxicity and angiogenesis inhibition of JA were confirmed by SCID mice experiments. Together, JA showed antiangiogenesis in vitro and in vivo through pleiotropic positive and negative regulators of angiogenesis molecules. The current investigation supports the potential of JA as an alternative chemoprevention agent for human bladder cancer.

Objectives: To validate the predictive value of Fournier's Gangrene Severity Index in patients with Fournier gangrene and to facilitate patient mortality risk-stratification by simplifying the Fournier's Gangrene Severity Index., Methods: From January 1989 to December 2011, 85 male patients with clinically-documented Fournier's gangrene undergoing intensive treatment and with complete medical records were recruited. The demographic information and nine parameters of Fournier's Gangrene Severity Index were compared between survivors and non-survivors. The parameters that showed a significant difference between the two groups were selected to generate a simplified scoring index., Results: Of the 85 patients recruited, 16 patients died of the disease with mortality rate of 18.8%. The Fournier's Gangrene Severity Index score at initial diagnosis was significantly higher in non-survivors than in survivors. Of the nine parameters of Fournier's Gangrene Severity Index, the scores of serum creatinine level, hematocrit level and serum potassium level were significantly different between the two groups. However, the mean body temperatures, heart rate, respiration rate, white blood cell count, serum sodium and bicarbonate levels were non-significantly different. Of the 12 patients with chronic kidney disease or end-stage renal disease, 10 died of severe sepsis. A simplified scoring index including parameters of creatinine, hematocrit and potassium was generated, which provided sensitivity and specificity of 87% and 77% in predicting patient mortality, respectively. The predictive values of this simplified Fournier's Gangrene Severity Index were shown to be non-inferior to Fournier's Gangrene Severity Index in our patients., Conclusions: The simplified Fournier's Gangrene Severity Index is easy to use at initial diagnosis, and offers a way to compare outcomes in different clinical populations., (© 2014 The Japanese Urological Association.)

Upper urinary tract urothelial carcinoma is a relatively uncommon disease and is diagnosed more frequently at advanced stages. The prognosis of these patients mainly has been related to tumor stage and grade. As a result, the definition of prognostic indicators enabling precise patient selection is mandatory for neoadjuvant or adjuvant therapies. The epithelial membrane protein (EMP2) was identified as one of the up-regulated genes by isoflavones. EMP2 overexpression suppressed foci formation, anchorage-independent growth in vitro, and tumorigenicity in severe combined immunodeficiency mice (all P < 0.05). In addition, a cross-talk between EMP2 and integrins αV and β3 was shown in the regulation of cell adhesion and migration. Higher EMP2 expression was associated with a better progression-free survival (P = 0.008) and cancer-related death (P < 0.001). EMP2 was identified as a tumor-suppressor gene in urinary tract urothelial carcinoma and may be an innovative co-targeting candidate for designing integrin-based cancer therapy., (Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: The aim was to identify the risk factors for renal scarring and deteriorating renal function in children with primary vesico-ureteral reflux (VUR)., Materials and Methods: Patients with primary VUR admitted to the National Cheng Kung University Hospital were retrospectively analyzed. The outcomes were renal scarring, assessed by technetium-99 m dimercaptosuccinic acid scanning, and renal function, assessed by estimated glomerular filtration rate. Univariate and multivariate models were applied to identify the corresponding independent predictors., Results: A total of 173 patients with primary VUR were recruited. The median age of VUR diagnosis was 10.0 months (IQR: 4.0-43.0 months). After adjusting for confounding factors, it was found that older age of VUR diagnosis (≥5 years vs. <1 year, adjusted OR = 2.78, 95% CI = 1.00-7.70, p = 0.049), higher grade of VUR (high grade [IV-V] vs. none, adjusted OR = 15.17, 95% CI = 5.33-43.19, p<0.0001; low grade [I-III] vs. none, adjusted OR = 5.72, 95% CI = 2.43-13.45, p<0.0001), and higher number of UTI (≥2 vs. 0, adjusted OR = 3.21, 95% CI = 1.06-9.76, p = 0.039) were risk factors for renal scarring, whereas a younger age of VUR diagnosis (≥5 years vs. <1 year, adjusted HR = 0.16, 95% CI: 0.05-0.51, p = 0.002), renal scarring (yes vs. no, adjusted HR = 3.66, 95% CI: 1.32-10.16, p = 0.013), and APN (yes vs. no, adjusted HR = 3.10, 95% CI: 1.05-9.14, p = 0.041) were risk factors for developing chronic kidney disease stage 2 or higher., Conclusions: Our findings expand on the current knowledge of risk factors for renal scarring and deteriorating renal function, and this information can be used to modify the management and treatment of VUR.

The prognostic importance of examining ErbB receptor family expression in human bladder cancer remains uncertain. Using published evidence, we examined the clinical value and the updated results of clinical trials targeting ErbB receptor family members. Twenty-seven articles from 65 references related to ErbB receptor expression assessment in bladder cancer were reviewed. The estimates included the association significance, hazard ratios, and 95% confidence intervals (CIs) from actuarial curves and survival analyses. A meta-analysis was done on those reports using univariate log-rank tests or a Cox-regression model. The methods of analysis and study subjects chosen varied widely among studies. The overall risks of disease progression for patients with EGFR or ErbB2 overexpression were 4.5 (95% CI: 2.5-8.4) and 1.1 (95% CI: 0.6-1.9), and the risks of mortality were 3.0 (95% CI: 1.6-5.9) and 1.1 (95% CI: 1.0-1.2), respectively. However, the significance of coexpression patterns of the ErbB receptor family remains controversial. None of six clinical trials yielded convincing results for blockading ErbB receptor signaling in urothelial carcinoma. The results of this analysis suggest that assessing co-expression patterns of the ErbB family may provide better prognostic information for bladder cancer patients.

Unlabelled: What's known on the subject? and What does the study add? Silodosin administered by 4 mg twice daily is as effective as tamsulosin 0.2 mg daily in treating patients with LUTS associated with BPH. Relative to tamsulosin, silodosin has less cardiovascular side effects as judged by the minimal changes of blood pressure and pulse rats after treatment., Objective: • To test the hypothesis that the efficacy of silodosin would not be inferior to tamsulosin in treating patients with lower urinary tract symptoms associated with benign prostate hyperplasia (BPH)., Patients and Methods: • At nine medical centres, 209 patients with an International Prostate Symptom Score (IPSS) of ≥13 were randomized to silodosin (4 mg twice daily) or tamsulosin (0.2 mg once daily) for 12 weeks. • The primary efficacy measure was the mean change from baseline to endpoint in IPSS. • The non-inferiority margin of the IPSS change was set at 1.0. • Secondary efficacy measures included change in maximal urinary flow rate (Q(max)) and health-related quality of life (HRQL) score., Results: • Of the 170 (81.3%) patients who completed the study, 86.2% in the silodosin group vs 81.9% in the tamsulosin group achieved a ≥25% decrease in IPSS (P= 0.53). • The mean difference (silodosin minus tamsulosin) in IPSS change from baseline was -0.60 (95% confidence interval -2.15, 0.95), inferring the non-inferiority of silodosin to tamsulosin. • The mean changes in the Q(max) and HRQL score from baseline were comparable between the groups (both, P > 0.05). Although patients receiving silodosin had a significantly higher incidence of abnormal ejaculation (9.7% vs tamsulosin 1.0%, P= 0.009), only 1.9% discontinued treatment. • Tamsulosin treatment resulted in a significant reduction in mean systolic blood pressure (-4.2 mmHg, within-group P= 0.004) relative to the negligible change of silodosin (-0.1 mmHg, within-group P= 0.96), Conclusion: • The trial shows the non-inferiority of silodosin 4 mg twice daily to tamsulosin 0.2 mg once daily in patients with symptoms of BPH., (© 2011 THE AUTHORS. BJU INTERNATIONAL © 2011 BJU INTERNATIONAL.)

Purpose: Quest for specific urinary biomarkers for benign prostatic hyperplasia (BPH)., Experimental Design: Proteomics studies were conducted with urines of the training set to discovering marker candidates that could differentiate BPH from normal subjects by matching results deduced from MALDI-TOF of individual samples and results deduced from nanoLC-ESI-MS/MS-based stable isotope dimethyl labeling of two pooled samples (BPH and normal). Samples were digested before analysis and such an approach takes into account the subject-to-subject variation and differential amount, as well as protein identification. Selected markers were validated by ELISA conducted on the training set and the test set as well as another set of urines collected from prostate cancer patients., Results: Nine marker candidates were identified from proteomics studies; CD14, prostate-specific antigen and pancreatic α-amylase precursor were further selected for ELISA validation. Urinary CD14 is among the best match with high specificity (>81%) for both training and test sets. In addition, from the study of prostate cancer patients, CD14 also allows the distinction of BPH from cancer with high specificity (84-100%) when combined with urinary prostate-specific antigen., Conclusions and Clinical Relevance: Urinary CD14 is suggested to have a high specificity in the diagnosis of BPH in distinction from normal as well as cancer subjects., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Homodimerization of RON (MST1R), a receptor tyrosine kinase, usually occurs in cells stimulated by a ligand and leads to the downstream activation of signaling pathways. Here we report that bladder cancer cells, in response to physiological stress, use an alternative mechanism for signaling activation. Time-course studies indicated that RON migrated directly from the membrane to the nucleus of bladder cancer cells in response to serum starvation. Biochemical and genetic studies implied that this nuclear internalization was complexed with epidermal growth factor receptor (EGFR) and required the docking of importins. In vivo analysis confirmed that nuclear RON was present in 38.4% (28/73) of primary bladder tumors. Chromatin immunoprecipitation (ChIP) on microarray analysis further revealed that this internalized complex bound to at least 134 target genes known to participate in three stress-responsive networks: p53, stress-activated protein kinase/c-jun N-terminal kinase and phosphatidylinositol 3-kinase/Akt. These findings suggest that RON, in a complex with EGFR, acts as a transcriptional regulator in response to acute disturbances (e.g. serum starvation) imposed on cancer cells. In an attempt to re-establish homeostasis, these cells bypass regular mechanisms required by ligand stimulation and trigger the RON-directed transcriptional response, which confers a survival advantage.

Objective: To investigate the effects of shRNA-transforming growth factor (TGF)-beta1 plasmid upon epithelial-myofibroblast transdifferentiation of renal allograft in rats., Methods: Divided the Wistar rats into 4 groups: Group J (sham-operated group), T (plasmid group), H (vacant plasmid group) and Y (simply transplantation group). The SD to Wistar rat transplant kidney-sclerosis accelerated model was constructed and transfected with the plasmid based on hydromechanics. Transplanted kidneys were collected at Months 1, 2 and 3 post-transplantation. The gene transcriptional levels of TGF-beta1 and E-cadherin were detected by RT-PCR and the protein variation of E-cadherin was examined by Western blotting. The pathological changes and infiltrated inflammatory cells were assessed by HE staining and the immunohistochemical staining of E-cadherin and alpha-SMA used to label epithelial cells and fibroblast in order to exhibit cell transdifferentiation., Results: Compared with Group H and Y, the mRNA transcription of TGF-beta1 was obviously inhibited in the Group T: at Month 3, the TGF-beta1 mRNA of Group T is 0.73 +/- 0.08, significantly lower than Group H and Y (0.92 +/- 0.07 and 0.95 +/- 0.04, both P < 0.01); the expression of E-cadherin was maintained at a high level: at the Month 3, the E-cadherin mRNA of Group T is 0.39 +/- 0.11, significantly higher than Group H and Y (0.15 +/- 0.07, and 0.17 +/- 0.06, both P < 0.01); the E-cadherin protein of Group T is 0.38 +/- 0.08, significantly higher than group H and Y (0.15 +/- 0.07 and 0.15 +/- 0.07, both P < 0.01); epithelial cells were much more and fibroblast was much less than that of Group H and Y; there were also less infiltrated chronic inflammatory cells and extracellular matrix deposition in the Group T., Conclusion: The shRNA-TGF-beta1 plasmid can inhibit the epithelial-myofibroblast transdifferentiation of renal allograft in rats. The mechanisms may be associated with its effects of down-regulating TGF-beta1 and up-regulating E-cadherin.

Background: Prostate-specific antigen (PSA) is a 33-kDa serine protease that is secreted by prostatic epithelium and non-prostate tissues. Ectopic expression of PSA has also been reported in a variety of non-prostatic epithelial tumors., Patients and Methods: Expression of PSA and its clinical implication were examined in a total of 422 cases of primary urothelial carcinoma of the bladder., Results: Cytoplasmic reactivity to PSA was observed in 6 cases (1.4%), with the staining being to a low degree in 3 and a high degree in the remaining 3 cases. Expression of PSA was positively related to multiplicity, large tumors (> or = 3 cm) and muscle invasion (> or = pT2) (p = 0.0008, 0.004 and 0.03, respectively). Patients with tumors of low PSA expression had a better survival than those with tumors of high PSA expression (p = 0.03)., Conclusion: Focal expression of PSA can occasionally be detected in some large, invasive urothelial cancer cells. This phenotypic change should be considered in the differential diagnosis of poorly differentiated carcinoma of the lower urinary tract.

Purpose: Frequent loss of heterozygosity of microsatellites on a specific chromosomal region has been reported in various types of human cancer. The same loss of heterozygosity has also been identified in matched serum or urine DNA. We determined a urine microsatellite marker profile specific to urothelial carcinoma of the upper urinary tract., Materials and Methods: We analyzed the loss of heterozygosity of primary tumors and their matched urine DNA samples from 30 patients with urothelial carcinoma of the upper urinary tract. We investigated a total of 77 markers from 25 chromosomal regions and a total of 53 from 23 chromosomal regions for their preferential loss in urothelial carcinoma and renal cell carcinoma of the kidney, respectively. Specificity was then confirmed in a cohort of 22 renal cell carcinoma cases., Results: Of 30 patients with urothelial carcinoma 25 (83.3%) were detected using the molecular urine test. Of 48 markers detected as loss of heterozygosity in urine 20 (41.7%) were localized at the chromosomal loci reported for renal cell carcinoma. The diagnostic specificity of the remaining 31 markers was cross-validated in a renal cell carcinoma cohort. With the cutoff set at 100% specificity urothelial carcinoma was accurately diagnosed in 24 of 30 patients (80.0%) using 13 markers, including D9S195, D18S67, GSN, D1S162, D8S261, D3S1300, D21S1436, D16S310, D3S1307, FABP2, D11S907, D15S1007 and D13S133., Conclusions: The marker panel may permit a high throughput differential diagnosis of urothelial carcinoma of the upper urinary tract from that of renal cell carcinoma at an early stage of disease. The accurate diagnosis of renal cancer may help determine appropriate treatment planning and minimizing intraoperative frozen consultation.

Purpose: Collaboration of heterologous receptor tyrosine kinases has emerged as an important paradigm in tumor progression. We recently proved that RON has an important role in human bladder carcinogenesis. Since epidermal growth factor receptor has been suggested to cross-talk with RON, we examined the significance of epidermal growth factor receptor in modulating RON associated tumorigenesis., Materials and Methods: The biological significance of collaboration between RON and epidermal growth factor receptor was examined in the TSGH8301, J82 and JR bladder cancer cell lines with different expression status. Immunoprecipitation and immunoblotting assays were done to investigate the interaction of RON with epidermal growth factor receptor in relation to epidermal growth factor receptor kinase inhibitor treatment. Time lapse wound healing monitoring and Transwelltrade mark assay were used for cell migration analysis and the effect on cell transformation was analyzed with foci formation assay. Finally, a bladder cancer cohort of 78 patients was studied for clinical significance by immunohistochemistry., Results: Epidermal growth factor receptor was directly associated with RON, irrespective of ligand stimulation. The siRNA experiment and epidermal growth factor receptor kinase inhibitors efficiently inhibited RON related biological effects, including mitogenesis, migration, anti-apoptosis and neoplastic transformation. Co-expression of RON/epidermal growth factor receptor was found in 26 of 78 patients (33.3%) with bladder cancer. It was significantly associated with tumor invasion (p < 0.05), the risk of local recurrence (p = 0.0003) and decreased patient survival (p = 0.04). Important indicators for patient survival were co-expression of RON and epidermal growth factor receptor (p = 0.001) and tumor staging (p = 0.05)., Conclusions: Cross-talk between epidermal growth factor receptor and RON exists in vivo. Thus, it should be considered in treatment planning for patients with bladder cancer.

Inflammatory pseudotumor (IP) is generally considered to be a non-neoplastic, inflammatory response despite its gross and microscopic features of spindle cell neoplasm. Reported herein is a case arising from the muscularis propria of the urinary bladder in a 14-year-old girl who presented with gross hematuria and impending hypovolemic shock. The tumor consisted of proliferating myofibroblastic cells and various types of inflammatory cells. The immunoregulatory responses and reactions were investigated with regard to infiltration of inflammatory mononuclear cells being a documented finding in IP. Immunhistochemical and in situ hybridization studies for cytokines showed that the myofibroblastic cells were positive for interleukin (IL)-4, IL-5 and negative for interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha expression. The patient has been free of disease since excision of the tumor 34 months ago. Thus, cytokine production in IP suggests that it is reactive in nature and myofibroblasts may be the source of cytokines in the pathogenic process.

Background: The cytokine-producing ability of urothelium, a urinary tract barrier between urine and underlying connective tissue, may exacerbate the pathogenesis of congenital ureteropelvic junction obstruction (UPJ-O) disease. A role for urothelium in human urinary tract obstruction has rarely been described. In this study, we investigated the immunopathologic characteristics of, and cytokine production by, urothelium in children with congenital UPJ-O., Methods: Twenty-four children with congenital UPJ-O who had received pyeloplasty were enrolled. Morphologic abnormalities and pathologic and inflammatory changes of UPJ-O segments were studied. Expression of cytokines and chemokines in urothelium was investigated and compared with control tissue by immunohistochemistry (IHC), in situ hybridization (ISH), and urinary enzyme-linked immunosorbent assay (ELISA)., Results: Atypical or simple hyperplasia of the urothelium with evidence of Ki67 over-expression was found frequently in UPJ-O. There were variable degrees of inflammatory cell and eosinophil infiltration. Augmented expression of IL-5 and eotaxin detected by IHC and ISH, and enhanced degranulation of tissue mast cells were observed in the urothelium of UPJ-O segments. IL-4, IFN-gamma, and TNF-alpha were undetectable. Significantly higher levels of urinary IL-5, IFN-gamma, and eotaxin were detected in urine collected from the obstructed kidney. Among these, high urinary IL5 and/or IFN-gamma levels were associated with more severe obstructive uropathy (P < 0.05)., Conclusion: Urothelium, like intestinal and respiratory epithelia, plays an active role in immunoregulation and may contribute to exacerbation of the pathogenesis of congenital UPJ-O. Many eosinophil-associated disease cytokines, which can lead to the degranulation of mast cells, are predominant regulators in UPJ-O urothelium.

Genistein has been reported to be a natural chemopreventive in several types of human cancer. In our prior study, soy isoflavones were shown to induce cell cycle arrest and apoptosis of bladder cancer cells in the range of human urine excretion. This study was designed to identify the novel molecular basis underlying anti-angiogenic activities of soy isoflavones. An immortalized E6 and five human bladder cancer cell lines were studied by immunoassay, flow cytometry, functional activity, reverse transcription-polymerase chain reaction, immunoblotting, and transwell co-culture in vitro. The efficacy of soy isoflavones on angiogenesis inhibition in vivo was examined by nude mice xenograft and chick chorioallantoic membrane bioassay. Factors analyzed included angiogenic factors, matrix-degrading enzymes, and angiogenesis inhibitors. Genistein was the most potent inhibitor of angiogenesis in vitro and in vivo among the isoflavone compounds tested. It may also account for most of the reduced microvessel density of xenografts observed and the suppressed endothelial migration by soy isoflavones. Genistein exhibited a dose-dependent inhibition of expression/excretion of vascular endothelial growth factor165, platelet-derived growth factor, tissue factor, urokinase plasminogen activator, and matrix metalloprotease-2 and 9, respectively. On the other hand, there was an up-regulation of angiogenesis inhibitors-plasminogen activator inhibitor-1, endostatin, angiostatin, and thrombospondin-1. In addition, a differential inhibitory effect between immortalized uroepithelial cells and most cancer cell lines was also observed. Altogether, we discovered that tissue factor, endostatin, and angiostatin are novel molecular targets of genistein. The current investigation provides further evidence in support of soy-based foods as natural dietary inhibitors of tumor angiogenesis.

Hematuria is one of the most common disorders in children. Bladder tumors are rare in children, and inflammatory pseudotumor (IP) is especially rare. We report a case of inflammatory pseudotumor of the bladder in a 13-year-old girl manifested as acute onset of non-traumatic and painless gross hematuria with impending hypovolemic shock. A huge intravesicular mass (6.5 x 3.8 cm) was noted on renal-bladder ultrasound, cystoscopy, and computed tomography. Partial cystectomy was performed to remove the mass. Pathology led to a diagnosis of leiomyoma and subsequent confirmation as an IP. To our knowledge, our case is the first presentation of bladder IP in Taiwan among the reported pediatric cases.

Purpose: Children with congenital unilateral ureteropelvic junction obstruction were evaluated with 99mtechnetium-labeled diethylenetriaminepentaacetic acid furosemide renal scans (DTPA) to determine the correlation of tubular function tests, growth factors and renal function., Materials and Methods: A total of 38 children diagnosed with congenital unilateral ureteropelvic junction obstruction and recipients of dismembered pyeloplasty were prospectively studied. Before pyeloplasty split renal tubular function, creatinine clearance, urinary growth factors and a marker for apoptosis of each kidney were examined. Renal function of the obstructed kidney was evaluated by DTPA before and after pyeloplasty. Initially patients with DTPA greater than 40% were designated group 1 and those with DTPA 40% or less were assigned to group 2. After surgery followup patients with DTPA greater than 40% were designated the well preserved group and those with DTPA 40% or less were assigned to the poorly preserved group. Statistical analyses were performed to determine the best predictive variable for treatment., Results: Mean initial DTPA split renal function values of groups 1 and 2 were 47.3% and 28.8%, respectively and subsequently, they were 48.4% and 35.3%. Initial DTPA on the obstructed side of less than 35% had a 100% sensitivity and 100% positive predictive rate for a poorly preserved renal outcome. Among the various tubular functions, only percent fractional excretion of sodium and percent fractional excretion of chloride correlated with post-pyeloplasty DTPA. Urinary epidermal growth factor/creatinine correlated with preservation of renal function on postoperative DTPA renal scans. Although urinary transforming growth factor/creatinine levels and apoptosis ratios were higher on the obstructed side, they were not significantly different between the groups., Conclusions: Proximal tubular dysfunction, such as increased percent fractional excretion of sodium and chloride, and initial DTPA 35% or less, suggest a high possibility of poorly preserved renal outcome. Urinary transforming growth factor-beta1 and apoptosis are not correlated with renal outcome. A high urinary level of epidermal growth factor might be a potential indicator of preservation of renal growth.

Background: We examined the efficiency and cost effectiveness of a temperature feedback diode-laser system in the treatment of benign prostatic hypertrophy (BPH)., Methods: One hundred twenty patients with symptomatic BPH were included in this study between October 1997 and January 1998. Sixty of them were treated by transurethral resection of the prostate (TUR-P), and 60 patients were treated by temperature feedback interstitial laser coagulation (ILC). Direct and indirect cost parameters, such as operative time, operation-related consumables, duration of hospitalization, and amount of medication used were compared between the 2 groups., Results: All subjective and objective urinary parameters exhibited significant improvement 12 months after ILC. A reduction of 26.8% (46.6 to 34.1 ml) of the pretreatment prostate volume was observed at 12 months following ILC. The duration of hospital stay, operative time, and postoperative medications were significantly lower for those receiving ILC (5.9 to 2.5 days, p < 0.001) than for those who underwent TUR-P. The variety of laboratory tests needed for preoperative evaluation was no less when ILC was chosen for treating BPH (p = 0.849). Indirect costs, such as investment in laser equipment and laser accessories were higher in the ILC group (p < 0.001)., Conclusion: The low morbidity profile, particularly the absence of retrograde ejaculation, makes ILC a valuable and attractive option for treatment of BPH patients who wish to retain their ejaculation ability, who have serious underlying diseases, or who have surgical risks for TUR-P or other invasive modalities.

Objectives: To perform a global loss of heterozygosity (LOH) analysis on a cohort of urothelial carcinoma to investigate the clinical implication of specific chromosomal loss. Allelic deletions detected as LOH have been used to study the markers for carcinogenesis., Methods: We examined the allelic loss on 14 chromosomal regions in a total of 71 cases of urothelial carcinoma. The results were analyzed in relation to biologic indicators of urothelial carcinoma and the clinical outcome with a mean follow-up of 101 months., Results: The incidence of LOH in order of frequency was 9p (54.9%), 9q (49.3%), 13q (40.8%), 14q (40.8%), 10q (39.4%), 17p (39.4%), 8p (38.0%), 21q (36.6%), 11p (31.0%), 18q (23.9%), 4q (21.1%), 3p (16.9%), 6q (14.1%), and 1q (8.5%). Positive association with one of the indicators was observed in 3p, 9p, 9q, 10q, 14q, and 18q. The chromosomes that correlated with two biologic indicators were 4q, 6q, 11p, 17p, and 21q. Univariate analysis found that patients having combined 9p and 14q deleted tumors had particularly poor long-term survival compared with those with other patterns of chromosomal alterations (P = 0.01). In the multivariate model, nonpapillary tumors had a greater risk of recurrence, and stage classification was the only important indicator in predicting patient survival (P = 0.04)., Conclusions: LOH assessment does not provide independent prognostic value compared with stage classification. However, chromosomes 4q, 6q, 9p, 11p, 14q, 17p, and 21q may harbor important tumor suppressor genes involved in the progression of urothelial carcinogenesis.

Purpose: Smooth muscle cells (SMC) of the bladder undergo hypertrophy and hyperplasia following exposure to sustained mechanical overload. Although superficial similarities in the response of the heart and bladder to hypertrophic stimuli suggest that similar molecular mechanisms may be involved, this remains to be demonstrated. In this study we compared signal transduction pathway activation in primary culture bladder SMC and cardiac myofibroblasts in response to cyclic stretch. The effects of growth factor stimulation on pathway activation in bladder SMC were also investigated., Materials and Methods: Primary culture rodent bladder SMC or cardiac myofibroblasts were subjected to cyclic stretch-relaxation in the absence or presence of pharmacologic inhibitors of the phosphoinositide-3-kinase, (PI3K)/Akt, extracellular signal-regulated kinase-mitogen activated protein kinase (Erk-MAPK) or the p38 stress-activated protein kinase-2 (SAPK2) pathways. In parallel experiments human bladder SMC were treated with platelet-derived growth factor-BB (PDGF-BB), heparin-binding EGF-like growth factor (HB-EGF) or fibroblast growth factor-2 (FGF-2). In each case the extent of DNA synthesis was determined by uptake of tritiated thymidine, and activation of specific signaling intermediates was determined by immunoblot analysis using antibodies to the non-phosphorylated and phosphorylated (activated) forms of Akt, p38 and Erk1/2., Results: Akt and p38 were rapidly phosphorylated in stretched bladder SMC and cardiac myofibroblasts, and stretch-induced DNA synthesis in these cells was ablated with inhibitors of PI3K or p38 but not Erk-MAPK. Similarly, PDGF-BB up-regulated DNA synthesis in bladder SMC in a p38 and Akt-dependent manner., Conclusions: We conclude that distinct stimuli, such as mechanical stretch and PDGF-BB, promote DNA synthesis in bladder SMC through shared downstream signaling pathways. Furthermore, phenotypically similar cells from the bladder and heart show comparable pathway activation in response to stretch. These findings suggest that similar molecular mechanisms underlie the altered growth responses of the bladder and heart to mechanical overload. This study also provides the first report of Akt activation in bladder SMC and suggests that Akt, consistent with its pivotal role in cardiac hypertrophy, may also be a key regulator of remodeling in the SMC compartment of the bladder exposed to hypertrophic/hyperplastic stimuli in vivo.

Objectives: To explore the clinical significance of p53 and HER-2/neu coexpression by immunohistochemistry in patients with invasive bladder cancer in Taiwan., Methods: Paraffin-embedded tumor blocks were obtained from 67 patients with invasive bladder cancer subjected to radical cystectomy, bilateral lymph node dissection, and urinary diversion with or without systemic chemotherapy. Two observers (N.H.C. and T.S.T.), blinded to clinical outcome, reviewed the immunohistochemical staining for p53 (PAb1801) and HER-2/neu (Ab-17). The results were analyzed for progression-free survival and patient survival., Results: Positive staining for p53 and HER-2/neu was found in 30 (44.8%) and 39 (58.2%) patients. In contrast to HER-2/neu, p53 expression was significantly associated with tumor grade and pathologic stage (p = 0.040 and 0.004, respectively), and tended to be related to the nodal status (p = 0.080). Most importantly, coexpression of p53 and HER-2/neu significantly correlated with nodal metastases (p = 0.020). Univariate and multivariate analysis revealed p53 and nodal status as two independent prognostic factors. Additionally, patients with p53 and HER-2/neu coexpression had the shortest time to relapse and overall survival, irrespective of whether adjuvant chemotherapy was given or not (p = 0.005 and 0.030)., Conclusions: In invasive bladder cancer, p53 was an important prognostic factor since its expression correlated with tumor grade and stage, even nodal status, whereas HER-2/neu did not show prognostic significance. Tumors with p53 and HER-2/neu coexpression were associated with nodal metastases, probably resulting in decreased progression-free survival. Although some basic studies provide some important supports, studies including larger patient cohorts would still be required to prove the hypothesis that p53 and HER-2/neu-coexpressing tumors have a worse prognosis and are more resistant to a cisplatin-based multidrug regimen., (Copyright 2003 S. Karger AG, Basel)

Spontaneous pyeloduodenal fistula is extremely rare. Most of the etiologies belong to chronic renal inflammatory disease, especially in patients with renal calculi. In published studies, only 2 cases have been reported in association with renal malignancy. We report a case of spontaneous pyeloduodenal fistula associated with transitional cell carcinoma, which has not been previously described in published reports.

Purpose: The c-met proto-oncogene encodes a receptor tyrosine kinase (Met) and has been shown to play a role in oncogenesis. Given that high titers of hepatocyte growth factor, the specific ligand for Met, are excreted in the urine and tend to reflect disease activity of bladder cancer, we performed this study to examine the clinical significance of Met in human bladder cancer., Materials and Methods: We studied the mRNA expression and genomic alteration of c-met in five bladder cancer cell lines. Significance of Met overexpression was then compared with p53 nuclear accumulation (TP53) in primary bladder cancer (n = 142 patients)., Results: Expression of c-met mRNA tended to positively correlate with differentiation of cancer cell lines in the absence of point mutation. High expression of Met was found in seven cases (4.9%), low expression in 32 cases (22.5%), and negative expression in 103 cases (72.5%). Expression of Met was positively associated with histologic grade, stage classification, tumor size, and nodular tumor growth (P <.05, respectively); however, it was not related to TP53 status. Factors that predicted disease progression were tumor stage, Met status, and TP53 accumulation (P <.05, respectively). Indicators for poor long-term survival were invasive cancer, multiple tumors, and Met overexpression (P =.0006,.01, and.04, respectively)., Conclusion: The c-met proto-oncogene plays a more important role in the progression of bladder carcinogenesis than p53. Evaluation of Met expression could identify a subset of bladder cancer patients who may require a more intensive treatment strategy.