Dynamic changes of quality of life in muscle-invasive bladder cancer survivors.

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.

Prothymosin-α enhances phosphatase and tensin homolog expression and binds with tripartite motif-containing protein 21 to regulate Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 signaling in human bladder cancer.

Prothymosin-α (PTMA) is a small, acidic protein that is usually transported into the nucleus and involves many cellular and immunological functions. Previous studies demonstrated that aberrant location of PTMA expression exists in human bladder cancer, but the role of PTMA protein expression remains elusive. In this study, we created ectopic nuclear or cytoplasmic PTMA expression in human bladder cancer cells by infecting lentiviruses carrying wild type or deleted nuclear localization signal of the PTMA gene. The in vivo tumorigenesis assay showed PTMA protein with deleted nuclear localization signal promotes J82 xenograft tumor growth in mice and shortens their survival more so than the wild type. Chromatin immunoprecipitation showed that wild-type PTMA protein binds to the PTEN promoter and enhances phosphatase and tensin homolog (PTEN) expression. Through immunoblot proteomics and in vivo ubiquitination studies, PTMA protein can bind with tripartite motif-containing protein 21 (TRIM21) and block its ubiquitination. Also, TRIM21 can downregulate both forms of PTMA protein. In human bladder tumors, loss of nuclear PTMA expression was an unfavorable prognostic indicator for shorter disease-free survival (hazard ratio, 1.54; P = 0.009). Our data support that nuclear PTMA protein serves as a tumor suppressor in bladder cancer through upregulating PTEN and orchestrating TRIM21 for the regulation of Nrf2 signaling.

The role of Lutheran/basal cell adhesion molecule in human bladder carcinogenesis.

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.

Association of Prostate Blood Flow with Male Lower Urinary Tract Symptoms.

PURPOSE: To investigate the association of prostate blood flow (PBF) with lower urinary tract symptoms (LUTS) in aged males using Doppler spectral waveform (DSW) analysis. PATIENTS AND METHODS: We performed a prospective analysis involving 133 aged males with clinical diagnosis of LUTS. DSW parameters (peak-systolic velocity (PSV), end-diastolic velocity (EDV), and resistive index (RI)) were measured at bilateral neurovascular bundles (NVB), periurethral, and capsular branches by Doppler transrectal ultrasound with the patient in the right lateral decubitus position. The associations of PBF parameters and the International Prostate Symptom Score (IPSS) were analyzed. RESULTS: Overall, total IPSS scores were significantly correlated with the RI of bilateral NVB vessels (r2 = 0.03, 0.04; p = 0.04, 0.02, respectively), and PSV of left NVB vessels. PSV of bilateral NVB vessels were associated with the storage score (p = 0.022 and p = 0.016), but not with the voiding score. The sum of the frequency and urgency score was also associated with EDV of both capsular and urethral branches (p = 0.043 and p = 0.009, respectively), and PSV of NVB vessels on both sides (p = 0.045 and p = 0.019, respectively). CONCLUSIONS: There is an association between PBF and LUTS, especially with storage symptoms. The findings may provide some insights in understanding the underlying pathophysiology of lower urinary tract dysfunction.

Antiangiogenesis as the novel mechanism for justicidin A in the anticancer effect on human bladder cancer.

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.

Validation and simplification of Fournier's gangrene severity index.

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.

Risk of secondary primary malignancies in survivors of upper tract urothelial carcinoma: A nationwide population-based analysis.

BACKGROUND: To investigate the cancer types and risk factors of secondary primary malignancy (SPM) in patients with upper tract urothelial carcinoma (UTUC) in Taiwan. METHODS: Using National Health Insurance Research Dataset and catastrophic illness registry, we enrolled newly diagnosed UTUC patients from 2000 to 2013. Those without catastrophic illness registration were excluded from the study. The cancer types and hazard ratios (HRs) of subsequent SPMs were calculated according to the antecedent malignancy. We analyzed the risk factors for developing SPMs using multivariate Cox proportional hazard models. RESULTS: A total of 9050 UTUC patients were registered and 2187 (24.2%) patients developed SPMs during the study period. As compared with primary UTUC, the relative risk ratios of SPM was 2.5 folds and 18% higher in those with antecedent non-UC malignancy and with bladder cancer history, respectively. Totally, 387 (37.8%) of 1022 UTUC patients with antecedent non-UC malignancy developed subsequent SPM after UTUC diagnosis. The antecedent and subsequent cancer types are similar and kidney cancer is most common, followed by hepatoma. Multivariate analysis showed that a history of antecedent non-UC malignancy is the most unfavorable factor for SPM development (HR, 2.50; 95% CI, 2.23-2.81), followed by liver disease, male gender, antecedent bladder cancer history, age ≥ 75 years, and chronic kidney disease. CONCLUSIONS: Our study, conducted in Taiwan and involving 9050 UTUC patients, meticulously examined the types of SPM and the associated risk factors. Our research unearthed several pivotal discoveries: a preceding history of non-UC malignancies emerged as the single most influential factor contributing to the occurrence of subsequent cancers, followed by liver disease, male gender, antecedent bladder cancer history, age ≥75 years, and chronic kidney disease. Futhermore, kidney cancer emerged as the predominant subsequent malignancy, closely trailed by hepatoma..

TGF-ß1 conjugated to gold nanoparticles results in protein conformational changes and attenuates the biological function.

Gold nanoparticles (AuNPs) are widely used as carriers or therapeutic agents due to their great biocompatibility and unique physical properties. Transforming growth factor-beta 1 (TGF-ß1), a member of the cysteine-knot structural superfamily, plays a pivotal role in many diseases and is known as an immunosuppressive agent that attenuates immune response resulting in tumor growth. The results reported herein reflect strong interactions between TGF-ß1 and the surface of AuNPs when incubated with serum-containing medium, and demonstrate a time- and dose-dependent pattern. Compared with other serum proteins that can also bind to the AuNP surface, AuNP-TGFß1 conjugate is a thermodynamically favored compound. Epithelial cells undergo epithelial-mesenchymal transition (EMT) upon treatment with TGF-ß1; however, treatment with AuNPs reverses this effect, as detected by cell morphology and expression levels of EMT markers. TGF-ß1 is found to bind to AuNPs through S-Au bonds by X-ray photoelectron spectroscopy. Fourier transform infrared spectroscopy is employed to analyze the conformational changes of TGF-ß1 on the surface of AuNPs. The results indicate that TGF-ß1 undergoes significant conformational changes at both secondary and tertiary structural levels after conjugation to the AuNP surface, which results in the deactivation of TGF-ß1 protein. An in vivo experiment also shows that addition of AuNPs attenuates the growth of TGF-ß1-secreting murine bladder tumor 2 cells in syngeneic C3H/HeN mice, but not in immunocompromised NOD-SCID mice, and this is associated with an increase in the number of tumor-infiltrating CD4⁺ and CD8⁺ T lymphocytes and a decrease in the number of intrasplenic Foxp3(+) lymphocytes. The findings demonstrate that AuNPs may be a promising agent for modulating tumor immunity through inhibiting immunosuppressive TGF-ß1 signaling.

WWOX protein expression varies among RCC histotypes and downregulation of WWOX protein correlates with less-favorable prognosis in clear RCC.

BACKGROUND: WWOX has been shown to be a candidate tumor suppressor gene in numerous human cancers. The objective of this study is to determine the expression of WWOX in human renal cell carcinoma tumor cells and its possible correlation with clinical outcome. METHODS: The WWOX protein expressions of human renal cell carcinoma (RCC) tumor and of matched normal renal parenchyma were examined, and its correlation with clinical cancer-specific survival was investigated. RESULTS: Downregulation of WWOX only in clear cell type RCC was demonstrated in our results including immunohistochemistry, Western blot, and RT-PCR assay. For the remnant cell types of RCC, sample sizes were insufficient to draw any conclusion of WWOX protein expression. The decreased expression of WWOX in clear cell RCC tumor compared with matched normal renal parenchyma was also correlated with clinical cancer-specific survival (Kaplan-Meier, p=0.0482). CONCLUSIONS: We proved that the expression level of WWOX is downregulated in human clear cell RCC. Moreover, the decreased expression of WWOX in clear cell RCC tumor compared with matched normal renal parenchyma was also correlated with clinical cancer-specific survival. Since clear cell RCC is a special human cancer using unique molecular pathogenesis, further investigation will provide more linking intracellular signaling of WWOX and novel therapeutic targets of human renal cell carcinoma.

Outcome of Non-Muscle Invasive Upper Tract Urothelial Carcinoma Receiving Endoscopic Ablation: An Inverse Probability of Treatment Weighting Analysis.

We compared the outcomes in early-stage upper tract urothelial carcinoma (UTUC) patients receiving endoscopic ablation (EA) with radical nephroureterectomy (RNU). From 2004 to 2018, cTa/T1N0M0 UTUC patients undergoing EA and RNU were enrolled. For reducing observational bias, propensity scores based on inverse probability of treatment weighting (IPTW) were utilized for comparing the oncologic outcomes and renal function changes. In total, 65 of 184 cTa/T1 UTUC patients were analyzed after exclusion of 119 patients with end-stage renal disease, and lack of previous ureteroscopic biopsy. The studied patients included 23 who received EA and 42 RNU, and both groups were well balanced after adjusting with IPTW. The median follow-up period was 43.6 months. There was no statistical difference between the two groups in terms of oncological outcome. The EA group exhibited less estimated glomerular filtration rate (eGFR) decline one year later (0.0% vs. 20.2%, p < 0.001) and less worsening of chronic kidney status (13.2% vs. 46.5%, p = 0.026). Among patients receiving EA, high-grade tumors exhibited higher subsequent recurrence in the residual urinary tract than did the low-grade ones. (p = 0.037). In summary, endoscopic ablation preserves renal function without compromising oncological outcome in selected UTUC patients. High-grade tumors should be strictly followed up following endoscopic ablation.

Determinants and Dynamic Changes of Generic Quality of Life in Human Bladder Cancer Patients.

We measured and determined the factors associated with long-term generic quality-of-life (QOL) changes in human bladder cancer patients. We utilized the World Health Organization QOL-Brief questionnaire to assess consecutive patients' QOL at outpatient clinics of our hospital. A mixed-effects model was constructed to investigate the determinants of QOL changes according to each domain and individual item after controlling for demographic and clinical factors, as well as the effect of radical cystectomy. We also applied a kernel smoothing method to describe the long-term dynamic changes after the first definite treatment. In total, 1185 repeated measurements were collected from 343 bladder cancer patients. The mixed-effects models demonstrated that marital status, monthly income, and comorbidity with heart disease and diabetes were significant determinants among all the study participants. Regardless of the urinary diversion type, radical cystectomy contributed to lower scores for all four domains, mainly from 4-5 years after cystectomy, which declined significantly in patients who were older than 60 years. As for non-muscle-invasive bladder cancer (NMIBC) patients with preserved bladders, tumor recurrence was a major predictor for lower scores for sexual activity in the social domain. In summary, generic QOL can be independently influenced by many factors, not only cystectomy and tumor recurrence, which should be discussed with patients before treatment.

Additive Effects of Arsenic and Aristolochic Acid in Chemical Carcinogenesis of Upper Urinary Tract Urothelium.

BACKGROUND: Aristolochic acids (AA) and arsenic are chemical carcinogens associated with urothelial carcinogenesis. Here we investigate the combined effects of AA and arsenic toward the risk of developing upper tract urothelial carcinoma (UTUC). METHODS: Hospital-based (n = 89) and population-based (2,921 cases and 11,684 controls) Taiwanese UTUC cohorts were used to investigate the association between exposure to AA and/or arsenic and the risk of developing UTUC. In the hospital cohort, AA exposure was evaluated by measuring aristolactam-DNA adducts in the renal cortex and by identifying A>T TP53 mutations in tumors. In the population cohort, AA exposure was determined from prescription health insurance records. Arsenic levels were graded from 0 to 3 based on concentrations in well water and the presence of arseniasis-related diseases. RESULTS: In the hospital cohort, 43, 26, and 20 patients resided in grade 0, 1+2, and 3 arseniasis-endemic areas, respectively. Aristolactam-DNA adducts were present in >90% of these patients, indicating widespread AA exposure. A>T mutations in TP53 were detected in 28%, 44%, and 22% of patients residing in grade 0, 1+2, and 3 arseniasis-endemic areas, respectively. Population studies revealed that individuals who consumed more AA-containing herbs had a higher risk of developing UTUC in both arseniasis-endemic and nonendemic areas. Logistic regression showed an additive effect of AA and arsenic exposure on the risk of developing UTUC. CONCLUSIONS: Exposure to both AA and arsenic acts additively to increase the UTUC risk in Taiwan. IMPACT: This is the first study to investigate the combined effect of AA and arsenic exposure on UTUC.

An unusual function of RON receptor tyrosine kinase as a transcriptional regulator in cooperation with EGFR in human cancer cells.

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.

History of Urinary Retention Is a Risk Factor for Infection after Prostate Biopsy: A Nationwide, Population-Based Cohort Study.

BACKGROUND AND AIM: Infection or bleeding after transrectal prostate biopsy remains a concern of both patients and urologists. We explored the risk of association of certain co-morbidities with both complications. PATIENTS AND METHODS: Using the Taiwan National Health Insurance Research Database, we identified patients undergoing prostate biopsy from 2000 to 2013. We used logistic multivariable regression to search for associations between post-biopsy hospitalization and the two co-morbidities within a year after biopsy. RESULTS: Among 3,601 prostate biopsies, 100 infections (3.77%) and 52 (1.44%) bleeding-related emergency room visits and hospitalizations were recorded within 30 days after biopsy. The group having the biopsy as an inpatient exhibited older age (p < 0.0001) and a higher percentage of having diabetes mellitus (p = 0.015) than patients without either complication. The logistic multivariable regression analysis showed that urinary retention, freedom from diabetes, and performance as an outpatient procedure were independent risk factors for infection-related hospitalization (odds ratios 1.81, 1.96, and 1.72; p values 0.031, 0.037, and 0.010, respectively). CONCLUSION: Patients with a recent history of urinary retention have a higher probability of infection-related hospitalization after prostate biopsy.

Indoleamine-2,3-dioxygenase-1 expression predicts poorer survival and up-regulates ZEB2 expression in human early stage bladder cancer.

PURPOSES: Indoleamine-2,3-dioxygenase-1 (IDO1) is a key enzyme of tryptophan metabolism which regulates T cell function in immune cells and little is known about the role of IDO1 expression in bladder cancer cells. The study is aimed to evaluate the clinical relevance of IDO1 expression in human bladder urothelial carcinoma (UC). MATERIALS AND METHODS: One hundred and sixty paraffin-embedded UC tissues (130 bladder, 30 upper urinary tract) and 47 adjacent normal tissues were retrieved for IDO1 immunostaining. Urine samples from UC and non-UC patients were collected before surgery for measuring the concentration of tryptophan and its metabolites. Clinicopathological correlates of IDO1 expression and the prognostic values in human bladder cancer were explored. External validation was performed with 4 published bladder cancer datasets, as well as in vitro studies. RESULTS: As compared with normal adjacent tissues, UC exhibited a higher frequency of IDO1 expression (chi-square, P = 0.0005). IDO1 expression is an independent poor prognostic factor for disease progression [hazard ratio and 95% confidence interval, 3.80 (1.46-9.86), P = 0.006], which is associated with decreased number of intratumoral infiltrating CD8+ lymphocyte (unpaired t test, P = 0.026). External validation showed that patients with higher IDO1 expression exhibit decreased disease-specific survival than those with lower IDO1 expression. Furthermore, IDO1 expression correlated positively with the expression of several EMT markers, including ZEB2, fibronectin and vimentin. The in vitro T24 cell subline demonstrated that IDO1 expression can up-regulate ZEB2 expression probably through miR-200c signaling. CONCLUSION: IDO1 expression predicts poorer survival and up-regulates ZEB2 expression in human bladder cancer.

The molecular signature for urothelial carcinoma of the upper 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.

Immunohistochemical detection of prostate-specific antigen expression in primary urothelial carcinoma of the urinary bladder.

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.

Low-dose etoposide enhances telomerase-dependent adenovirus-mediated cytosine deaminase gene therapy through augmentation of adenoviral infection and transgene expression in a syngeneic bladder tumor model.

The human telomerase reverse transcriptase (hTERT) promoter can selectively drive transgene expression in many telomerase-positive human cancer cells. Here we evaluated combination therapy of adenoviral vector Ad-hTERT-CD encoding E. coli cytosine deaminase (CD) driven by the hTERT promoter and low-dose etoposide (0.1 microg/mL) for treating bladder cancer. Ad-hTERT-CD conferred sensitivity to 5-fluorocytosine (5-FC) in bladder cancer cells, which could be enhanced by etoposide treatment, but not in normal cells. Such effect was correlated with up-regulation of hypoxia-inducible factor (HIF)-1alpha expression. By contrast, etoposide activated p53 and down-regulated hTERT promoter activity in normal cells. Etoposide also increased adenoviral infection via enhancement of coxsackie-adenovirus receptor expression on bladder cancer and normal cells. Combination index analysis revealed that combined therapy of Ad-hTERT-CD (10(9) plaque-forming units)/5-FC (200 mg/kg) with etoposide (2 mg/kg) synergistically suppressed tumor growth and prolonged survival in mice bearing syngeneic MBT-2 bladder tumors. This combination therapy regimen induced complete tumor regression and generated antitumor immunity in 75% of tumor-bearing mice. Furthermore, increased infiltrating CD4(+) and CD8(+) T cells and necrosis within tumors were found in mice receiving combination therapy of Ad-hTERT-CD and etoposide compared with those treated with either treatment alone. Thus, the potential high therapeutic index of the combination therapy may be an appealing therapeutic intervention for bladder cancer. Furthermore, because a majority of human tumors exhibit high telomerase activity, adenovirus-mediated CD gene therapy driven by the hTERT promoter in combination with low-dose etoposide may be applicable to a broad spectrum of cancers.

Effects of branded versus generic terazosin hydrochloride in adults with benign prostatic hyperplasia: a randomized, open-label, crossover study in Taiwan.

BACKGROUND: Terazosin is an alpha1-selective adrenoceptor blocking agent that has been reported in many clinical trials to be an effective choice for the treatment of benign prostatic hyperplasia (BPH). To improve cost-effectiveness, the development of an effective and well-tolerated generic formulation is needed. OBJECTIVE: The aim of this study was to compare the efficacy and tolerability of branded versus generic terazosin hydrochloride in adult patients with symptomatic BPH in Taiwan. METHODS: This randomized, open-label, 2-sequence, 2-period crossover study was conducted at the Urological Clinic, National Cheng Kung University Medical Center, Taman, Taiwan. Men newly diagnosed with symptomatic BPH who had not previously received treatment for BPH were recruited between August 2002 and April 2006. Patients were randomly assigned to 1 of 2 treatment sequences. Group A received generic terazosin during period 1 (6 weeks) and branded terazosin in period 2 (6 weeks); group B received the branded drug during period 1 and the generic during period 2. The 2 study periods were separated by a 1-week washout period. All treatments were given by mouth once daily (bedtime) at an initial dosage of 2 mg/d for the first 2 weeks. At the week-2 study visit in each treatment period, the dosage could be increased to 4 mg/d or decreased to 1 mg/d based on each patient's response and experience of adverse effects (AEs), based on the opinion of the investigator. Efficacy variables included the total score on the International Prostate Symptom Scale (IPSS), a 7-item instrument used to assess objective lower urinary tract symptoms, including quality of life. IPSS was measured at baseline and weeks 2 and 6 of each treatment period, and maximal and mean uroflow rates, measured at baseline and week 6. Tolerability was assessed at each time point using physical examination, including vital signs; laboratory analysis; and spontaneous reporting. RESULTS: Fifty-three patients were randomized; 43 were included in the efficacy analysis (mean [SD] age, group A, 64.5 [7.7] years and group B, 62.9 [8.2] years; mean [SD] weight, group A, 66.4 [7.2] kg and group B, 67.1 [8.9] kg; all patients were Taiwanese). At 2 and 6 weeks, no significant between-product differences were found in mean (SD) decreases from baseline in IPSS total score (generic, 2.46 [0.84] and 2.46 [1.00], respectively; branded, 1.56 [0.60] and 2.87 [0.71]). At week 6, the between-product difference in mean increase from baseline in maximal uroflow rate was nonsignificant (generic, 2.36 [0.90] mL/s; branded, 2.03 [0.62] mL/s). A total of 86 treatment-emergent AEs were reported (45 with the generic drug; 41 with the branded drug), all of which were considered by the investigator as nonserious except for 1 case of acute epididymitis, which occurred with the generic drug. The most common AEs reported with the generic and branded formulations were dizziness (7/48 [14.6%] and 10/50 [20.0%], respectively) and peripheral edema (1/48 [2.1%] and 3/50 [6.0%]). No significant differences in the prevalences of AEs were found between the 2 treatments. CONCLUSION: In this group of Taiwanese patients with symptomatic BPH, the efficacy and tolerability of generic terazosin were similar to those of branded terazosin.

Does HER2 immunoreactivity provide prognostic information in locally advanced urothelial carcinoma patients receiving adjuvant M-VEC chemotherapy?

INTRODUCTION: To evaluate the impact of HER2 immunoreactivity on clinical outcome in locally advanced urothelial carcinoma patients who received surgery alone, or methotrexate, vinblastine, epirubicin, and cisplatin (M-VEC) as adjuvant chemotherapy. MATERIALS AND METHODS: We studied 114 formalin-fixed paraffin-embedded specimens obtained from locally advanced urothelial carcinoma patients receiving surgery alone or adjuvant M-VEC. The authors evaluated HER2 immunoreactivity using immunohistochemical staining and explored the influence of pathological parameters and HER2 immunoreactivity on progression-free survival (PFS) and disease-specific overall survival (OS) using univariate and multivariate Cox's analyses. RESULTS: Urothelial carcinoma of the bladder had a significantly higher frequency of HER2 immunoreactivity than that of the upper urinary tract (60.7 vs. 20.7%, p < 0.0001). Overall, nodal status was a strong and independent prognostic indicator for clinical outcome. The HER2 immunoreactivity was significantly associated with PFS (p = 0.02) and disease-specific OS (p = 0.005) in advanced urothelial carcinoma patients. As for patients with adjuvant M-VEC, HER2 immunoreactivity was a significant prognostic factor for PFS (p = 0.03) and disease-specific OS (p = 0.02) using univariate analysis, but not multivariate analysis, and not for patients receiving watchful waiting. CONCLUSIONS: HER2 immunoreactivity might have a limited prognostic value for advanced urothelial carcinoma patients with adjuvant M-VEC.