Erectile Dysfunction: AUA Guideline.

PURPOSE: The purpose of this guideline is to provide a clinical strategy for the diagnosis and treatment of erectile dysfunction. MATERIALS AND METHODS: A systematic review of the literature using the Pubmed, Embase, and Cochrane databases (search dates 1/1/1965 to 7/29/17) was conducted to identify peer-reviewed publications relevant to the diagnosis and treatment of erectile dysfunction. Evidence-based statements were based on body of evidence strength Grade A, B, or C and were designated as Strong, Moderate, and Conditional Recommendations with additional statements presented in the form of Clinical Principles or Expert Opinions. RESULTS: The American Urological Association has developed an evidence-based guideline on the management of erectile dysfunction. This document is designed to be used in conjunction with the associated treatment algorithm. CONCLUSIONS: Using the shared decision-making process as a cornerstone for care, all patients should be informed of all treatment modalities that are not contraindicated, regardless of invasiveness or irreversibility, as potential first-line treatments. For each treatment, the clinician should ensure that the man and his partner have a full understanding of the benefits and risk/burdens associated with that choice.

Effect of Intravesical Instillation of Gemcitabine vs Saline Immediately Following Resection of Suspected Low-Grade Non-Muscle-Invasive Bladder Cancer on Tumor Recurrence: SWOG S0337 Randomized Clinical Trial.

Importance: Low-grade non-muscle-invasive urothelial cancer frequently recurs after excision by transurethral resection of bladder tumor (TURBT). Objective: To determine whether immediate post-TURBT intravesical instillation of gemcitabine reduces recurrence of suspected low-grade non-muscle-invasive urothelial cancer compared with saline. Design, Setting, and Participants: Randomized double-blind clinical trial conducted at 23 US centers. Patients with suspected low-grade non-muscle-invasive urothelial cancer based on cystoscopic appearance without any high-grade or without more than 2 low-grade urothelial cancer episodes within 18 months before index TURBT were enrolled between January 23, 2008, and August 14, 2012, and followed up every 3 months with cystoscopy and cytology for 2 years and then semiannually for 2 years. Patients were monitored for tumor recurrence, progression to muscle invasion, survival, and toxic effects. The final date of follow-up was August 14, 2016. Interventions: Participants were randomly assigned to receive intravesical instillation of gemcitabine (2 g in 100 mL of saline) (n = 201) or saline (100 mL) (n = 205) for 1 hour immediately following TURBT. Main Outcomes and Measures: The primary outcome was time to recurrence of cancer. Secondary end points were time to muscle invasion and death due to any cause. Results: Among 406 randomized eligible patients (median age, 66 years; 84.7% men), 383 completed the trial. In the intention-to-treat analysis, 67 of 201 patients (4-year estimate, 35%) in the gemcitabine group and 91 of 205 patients (4-year estimate, 47%) in the saline group had cancer recurrence within 4.0 years (hazard ratio, 0.66; 95% CI, 0.48-0.90; P<.001 by 1-sided log-rank test for time to recurrence). Among the 215 patients with low-grade non-muscle-invasive urothelial cancer who underwent TURBT and drug instillation, 34 of 102 patients (4-year estimate, 34%) in the gemcitabine group and 59 of 113 patients (4-year estimate, 54%) in the saline group had cancer recurrence (hazard ratio, 0.53; 95% CI, 0.35-0.81; P = .001 by 1-sided log-rank test for time to recurrence). Fifteen patients had tumors that progressed to muscle invasion (5 in the gemcitabine group and 10 in the saline group; P = .22 by 1-sided log-rank test) and 42 died of any cause (17 in the gemcitabine group and 25 in the saline group; P = .12 by 1-sided log-rank test). There were no grade 4 or 5 adverse events and no significant differences in adverse events of grade 3 or lower. Conclusions and Relevance: Among patients with suspected low-grade non-muscle-invasive urothelial cancer, immediate postresection intravesical instillation of gemcitabine, compared with instillation of saline, significantly reduced the risk of recurrence over a median of 4.0 years. These findings support using this therapy, but further research is needed to compare gemcitabine with other intravesical agents. Trial Registration: clinicaltrials.gov Identifier: NCT00445601.

A Contemporary Review of HPV and Penile Cancer.

Human papillomavirus (HPV) is a widespread sexually transmitted infection. In both men and women, HPV infection can result in a spectrum of genitourinary manifestations ranging from genital warts to cancer. Cervical cancer is nearly always associated with high-risk HPV infection. For men, penile cancer can develop following or independently of HPV infection. Basaloid and warty subtypes of penile squamous cell carcinoma are most frequently associated with HPV infection. Further research into the molecular alterations caused by HPV infection may provide prognostic markers and future treatment targets. Until an effective treatment for HPV infection is developed, prevention will remain the focus of disease control. For women, vaccination is increasingly utilized to prevent HPV infection and subsequent cervical cancer development. New recommendations for routine male vaccination may further reduce cancers for both men and women.

Peyronie's Disease: AUA Guideline.

PURPOSE: The purpose of this guideline is to provide a clinical framework for the diagnosis and treatment of Peyronie's disease. MATERIALS AND METHODS: A systematic review of the literature using the PubMed®, EMBASE® and Cochrane databases (search dates 1/1/1965 to 1/26/15) was conducted to identify peer-reviewed publications relevant to the diagnosis and treatment of PD. The review yielded an evidence base of 303 articles after application of inclusion/exclusion criteria. RESULTS: The systematic review was used to create guideline statements regarding treatment of PD. When sufficient evidence existed, the body of evidence for a particular treatment was assigned a strength rating of A (high quality evidence; high certainty), B (moderate quality evidence; moderate certainty), or C (low quality evidence; low certainty). Evidence-based statements of Strong, Moderate, or Conditional Recommendation were developed based on benefits and risks/burdens to patients. Additional consensus statements related to the diagnosis of PD are provided as Clinical Principles and Expert Opinions due to insufficient published evidence. CONCLUSIONS: There is a continually expanding literature on PD; the Panel notes that this document constitutes a clinical strategy and is not intended to be interpreted rigidly. The most effective approach for a particular patient is best determined by the individual clinician and patient in the context of that patient's history, values, and goals for treatment. As the science relevant to PD evolves and improves, the strategies presented here will be amended to remain consistent with the highest standards of clinical care.

Anticoagulation and antiplatelet therapy in urological practice: ICUD/AUA review paper.

PURPOSE: Given the lack of urology specific directives for the periprocedural management of anticoagulant and antiplatelet medications, the AUA (American Urological Association) and ICUD (International Consultation on Urological Disease) named an international multidisciplinary panel to develop consensus based recommendations. MATERIALS AND METHODS: A systematic literature review was queried by a methodologist for 3 questions. 1) When and in whom can anticoagulant/antiplatelet prophylaxis be stopped in preparation for surgery? 2) What procedures can be safely performed without discontinuing anticoagulant/antiplatelet prophylaxis? 3) What periprocedural strategies can adequately balance the risk of major surgical bleeding vs the risk of major thrombotic event? Hematology and cardiology guidelines, and 79 articles were selected for full review. RESULTS: Multidisciplinary management of anticoagulant/antiplatelet medications for patients with recent thromboembolic events, mechanical cardiac valves, atrial fibrillation and cardiac stents would reduce the high morbidity and mortality of inexpertly discontinuing or modifying these lifesaving therapies. No elective procedures requiring interruption of dual antiplatelet therapies should be performed with a recent bare metal or drug eluting stent. The risk of significant bleeding complications is low for patients who require continuation of aspirin for ureteroscopy, transrectal prostate biopsies, laser prostate outlet procedures and percutaneous renal biopsy. Open extirpative prostate and renal procedures can be performed with a low risk of significant hemorrhage for patients on aspirin and those requiring heparin based bridging strategies. The current literature does not give direction on the timing of the resumption of anticoagulant/antiplatelet prophylaxis other than that it be resumed as soon as the risk of bleeding has decreased. CONCLUSIONS: A total of 2,674 nonredundant article abstracts were obtained and assessed for relevance to key questions outlined by the panel. Overall 106 articles were selected for full text review and accepted or rejected based on the relation to the topic, quality of information and key questions. A total of 79 articles were accepted. Reasons for rejection (27 articles) included abstract only (12), insufficient information or unrelated to topic (13) and redundancy (2). We extracted study design, patient population, followup period and results from accepted articles, which serve as the evidence base.

Surgical management of urolithiasis in spinal cord injury patients.

Urolithiasis is a common condition in patients with spinal cord injury (SCI). Surgical management of stones in this population is more challenging and associated with lower clearance rates than the general population. The rate of complications - specifically infectious complications - is also high due to the chronic bacterial colonization. Shock wave lithotripsy (SWL) has a low clearance rate of 44-73 %. Percutaneous nephrolithotripsy is indicated for larger nephrolithiasis, but multiple procedures may be required to clear the stones. Ureteroscopy has been associated with low success rates because of difficulty in obtaining ureteral access. Historically, bladder stones were managed with open surgery or SWL. Recently, good results have been reported with the combination of endoscopic and laparoscopic techniques. Surgical management of urolithiasis in patients with SCI should be performed in high-volume centers in light of the technical challenges and higher rate of perioperative complications.

Ascertaining cause of death among men in the prostate cancer intervention versus observation trial.

BACKGROUND: The Prostate Cancer Intervention Versus Observation Trial (PIVOT) randomized 731 men with localized prostate cancer to radical prostatectomy or observation. PURPOSE: We describe the methods and results for cause-of-death assignments in PIVOT, and compare them to alternative strategies for ascertaining prostate cancer-specific mortality, as well as to the methods and results in the similar Scandinavian Prostate Cancer Group Study 4 (SPCG-4) trial. METHODS: Three PIVOT Endpoints Committee members, blinded to randomized treatment assignments, reviewed medical records and death certificates when available to assign a cause of death using a primary and a secondary adjudication question. Initial disagreements were resolved through discussion. The level of initial agreement among committee members was examined, as well as guesses at randomized treatment assignments for a convenience sample of cases. Final cause of death determinations were compared to death certificates. RESULTS: Complete agreement on cause of death by all three committee members before any discussion was achieved in 200/354 (56%) cases on the primary and 209/354 (59%) cases on the secondary. However, complete agreement on the primary rose to 306/354 (86%) when 'definite' and 'probably' categories were collapsed, as planned a priori. The three committee members' proportions of correct guesses of randomized treatment assignment were 82/121 (68%), 113/148 (76%), and 99/134 (74%). Using the committee's final adjudications as a gold standard, death certificates had suboptimal sensitivities, specificities, or predictive values depending on how they were used to determine cause of death. LIMITATIONS: There was no separate 'gold standard' by which to judge the accuracy of the final endpoints committee adjudications, and useful death certificates could not be obtained on about a third of PIVOT participants who died. CONCLUSIONS: The low level of initial agreement on cause of death among endpoint committee members and the potential for biased determinations due to partial unblinding to treatment assignment raise methodologic concerns about using prostate cancer mortality as an endpoint in clinical trials like PIVOT.

Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline.

PURPOSE: The purpose of this guideline is to provide a clinical framework for the diagnosis and treatment of non-neurogenic overactive bladder (OAB). MATERIALS AND METHODS: The primary source of evidence for this guideline is the systematic review and data extraction conducted as part of the Agency for Healthcare Research and Quality (AHRQ) Evidence Report/Technology Assessment Number 187 titled Treatment of Overactive Bladder in Women (2009). That report searched PubMed, MEDLINE®, EMBASE and CINAHL for English-language studies published from January 1966 to October 2008. The AUA conducted additional literature searches to capture treatments not covered in detail by the AHRQ report and relevant articles published between October 2008 and December 2011. The review yielded an evidence base of 151 treatment articles after application of inclusion/exclusion criteria. When sufficient evidence existed, the body of evidence for a particular treatment was assigned a strength rating of A (high), B (moderate) or C (low). Additional treatment information is provided as Clinical Principles and Expert Opinions when insufficient evidence existed. RESULTS: The evidence-based guideline statements are provided for diagnosis and overall management of the adult with OAB symptoms as well as for various treatments. The panel identified first through third line treatments as well as non-FDA approved, rarely applicable and treatments that should not be offered. CONCLUSIONS: The evidence-based statements are provided for diagnosis and overall management of OAB, as well as for the various treatments. Diagnosis and treatment methodologies can be expected to change as the evidence base grows and as new treatment strategies become obtainable.

System level changes in gene expression in maturing bladder mucosa.

PURPOSE: Bladder problems clinically present early in life as birth defects that often lead to kidney failure and late in life as overactive bladder, incontinence and related disorders. We investigated the transcriptome of mouse bladder mucosa at juvenile and adult stages by microarray to identify the pathways associated with normal, healthy growth and maturation. We hypothesized that understanding these pathways could be key to achieving bladder regeneration or reawakening normal function in the elderly population. MATERIALS AND METHODS: RNA was isolated from the mucosa at 3, 6, 20 and 30 weeks postnatally. Affymetrix® Mouse 430 v2 arrays were used to profile the expression of approximately 45,000 genes. The software program Statistical Analysis of Microarrays was used to identify genes that significantly changed during the time course. RESULTS: No genes were significantly up-regulated during maturation. However, 66 well annotated genes demonstrated a statistically significant downward trend, of which 10 of 10 were confirmed by quantitative polymerase chain reaction. The main functions affected by age were transcription, regulation of cellular processes, neurogenesis, blood vessel development and cell differentiation. Notable genes included collagens, Mmp2, SPARC and several transcription factors, including Crebbp, Runx1, Klf9, Mef2c, Nrp1, Pex1 and Tcf4. These molecules were indirectly regulated by inferred Tgfb1 and Egf growth factors. Analysis of gene promoter regions for overrepresented upstream transcription factor binding sites identified specificity protein 1 and epidermal growth factor receptor-specific transcription factor as potentially major transcriptional regulators driving maturation related changes. CONCLUSIONS: These findings identify a coherent set of genes that appear to be down-regulated during urothelial maturation. These genes may represent an attractive target for bladder regeneration or for treating age related loss of function.

Elevated AKR1C3 expression promotes prostate cancer cell survival and prostate cell-mediated endothelial cell tube formation: implications for prostate cancer progression.

BACKGROUND: Aldo-keto reductase (AKR) 1C family member 3 (AKR1C3), one of four identified human AKR1C enzymes, catalyzes steroid, prostaglandin, and xenobiotic metabolism. In the prostate, AKR1C3 is up-regulated in localized and advanced prostate adenocarcinoma, and is associated with prostate cancer (PCa) aggressiveness. Here we propose a novel pathological function of AKR1C3 in tumor angiogenesis and its potential role in promoting PCa progression. METHODS: To recapitulate elevated AKR1C3 expression in cancerous prostate, the human PCa PC-3 cell line was stably transfected with an AKR1C3 expression construct to establish PC3-AKR1C3 transfectants. Microarray and bioinformatics analysis were performed to identify AKR1C3-mediated pathways of activation and their potential biological consequences in PC-3 cells. Western blot analysis, reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and an in vitro Matrigel angiogenesis assays were applied to validate the pro-angiogenic activity of PC3-AKR1C3 transfectants identified by bioinformatics analysis. RESULTS: Microarray and bioinformatics analysis suggested that overexpression of AKR1C3 in PC-3 cells modulates estrogen and androgen metabolism, activates insulin-like growth factor (IGF)-1 and Akt signaling pathways, as well as promotes tumor angiogenesis and aggressiveness. Levels of IGF-1 receptor (IGF-1R) and Akt activation as well as vascular endothelial growth factor (VEGF) expression and secretion were significantly elevated in PC3-AKR1C3 transfectants in comparison to PC3-mock transfectants. PC3-AKR1C3 transfectants also promoted endothelial cell (EC) tube formation on Matrigel as compared to the AKR1C3-negative parental PC-3 cells and PC3-mock transfectants. Pre-treatment of PC3-AKR1C3 transfectants with a selective IGF-1R kinase inhibitor (AG1024) or a non-selective phosphoinositide 3-kinases (PI3K) inhibitor (LY294002) abolished ability of the cells to promote EC tube formation. CONCLUSIONS: Bioinformatics analysis followed by functional genomics demonstrated that AKR1C3 overexpression promotes angiogenesis and aggressiveness of PC-3 cells. These results also suggest that AKR1C3-mediated tumor angiogenesis is regulated by estrogen and androgen metabolism with subsequent IGF-1R and Akt activation followed by VEGF expression in PCa cells.

Unique patterns of molecular profiling between human prostate cancer LNCaP and PC-3 cells.

BACKGROUND: Human prostate cancer LNCaP and PC-3 cell lines have been extensively used to study prostate cancer progression and to develop therapeutic agents. Although LNCaP and PC-3 cells are generally assumed to represent early and late stages of prostate cancer, respectively, there is limited information regarding gene expression patterns between these two cell lines and its relationship to prostate cancer. METHODS: Comprehensive gene expression analysis was performed. Total RNA was isolated from cultured cells and hybridized to Illumina human BeadChips representing 24,526 transcripts. Bioinformatics analysis was applied to identify cell line specific genes as well as biological mechanisms, pathways, and functions related to the genes. RESULTS: A total of 2,198 genes were differentially expressed between LNCaP and PC-3 cells. Using a robust statistical analysis and high significance criteria, 115 and 188 genes were identified to be unique to LNCaP and PC-3 cells, respectively. LNCaP cells maintained various metabolic pathways including a gene cluster that encodes UDP-glucuronosyltransferases. Several transcription factors including Tal alpha/beta, GATA-1, and c-Myc/Max may be responsible for regulating LNCaP cell specific genes. By contrast, PC-3 cells were characterized by their unique expression of cytoskeleton-related genes and other genes including VEGFC, IL8, and TGF beta 2. CONCLUSIONS: This study showed that LNCaP and PC-3 cells represent two distinct prostate cancer cell lineages. LNCaP cells retain many prostate cell specific properties, whereas PC-3 cells have acquired a more aggressive phenotype. Future studies for prostate cancer research need to consider similarities and differences between these two cells and their relationship to prostate cancer.

Restoring barrier function to acid damaged bladder by intravesical chondroitin sulfate.

PURPOSE: Chondroitin sulfate (Stellar Pharmaceuticals, London, Ontario, Canada), which is less expensive and more inert than heparinoids, hyaluronan or pentosan polysulfate, has been introduced to restore the barrier function lost due to epithelial dysfunction in interstitial cystitis cases. To our knowledge chondroitin sulfate binding to damaged bladder as a function of the urinary pH range, its efficacy in restoring the bladder permeability barrier and the capacity of the damaged bladder to bind chondroitin sulfate have not been determined previously. MATERIALS AND METHODS: Chondroitin sulfate binding to bladder urothelium was investigated quantitatively using chondroitin sulfate highly labeled with Texas Red(R) and quantitative fluorescence microscopy in a mouse model of urothelial acid damage. The efficacy of restoring barrier function was determined using the passage of intravesically instilled (86)Rb, a potassium ion mimetic, through the urothelium into the bloodstream in a rat model of bladder damage. The binding capacity of acid damaged bladder was determined by fluorometry. RESULTS: Chondroitin sulfate bound tightly and exclusively to the mouse bladder surface damaged by acid but showed only minimal binding to undamaged bladder. There was no systematic variation in pH. The model showed some variability in the degree of damage induced. In rats chondroitin sulfate instillation restored permeability to (86)Rb to control levels. Binding was saturable at a mean +/- SEM 0.67 +/- 0.13 mg/cm(2) of the bladder surface. CONCLUSIONS: Chondroitin sulfate binds preferentially to damaged urothelium and restores the impermeability barrier. This suggests that the glycosaminoglycan layer is a major contributor to bladder urothelial impermeability. As determined by binding capacity, the dose applied in humans in Canada (400 mg per instillation) is sufficient to achieve maximum efficacy.

From microarray to biology: an integrated experimental, statistical and in silico analysis of how the extracellular matrix modulates the phenotype of cancer cells.

A statistically robust and biologically-based approach for analysis of microarray data is described that integrates independent biological knowledge and data with a global F-test for finding genes of interest that minimizes the need for replicates when used for hypothesis generation. First, each microarray is normalized to its noise level around zero. The microarray dataset is then globally adjusted by robust linear regression. Second, genes of interest that capture significant responses to experimental conditions are selected by finding those that express significantly higher variance than those expressing only technical variability. Clustering expression data and identifying expression-independent properties of genes of interest including upstream transcriptional regulatory elements (TREs), ontologies and networks or pathways organizes the data into a biologically meaningful system. We demonstrate that when the number of genes of interest is inconveniently large, identifying a subset of "beacon genes" representing the largest changes will identify pathways or networks altered by biological manipulation. The entire dataset is then used to complete the picture outlined by the "beacon genes." This allow construction of a structured model of a system that can generate biologically testable hypotheses. We illustrate this approach by comparing cells cultured on plastic or an extracellular matrix which organizes a dataset of over 2,000 genes of interest from a genome wide scan of transcription. The resulting model was confirmed by comparing the predicted pattern of TREs with experimental determination of active transcription factors.

Abnormal expression of differentiation related proteins and proteoglycan core proteins in the urothelium of patients with interstitial cystitis.

PURPOSE: Expression of the proteoglycan core proteins biglycan, decorin, perlecan and syndecan-1, and differentiation related markers of keratins 18 and 20 were examined to determine the origins of the loss of the glycosaminoglycan layer and investigate more fully the altered differentiation of the urothelium in interstitial cystitis. MATERIALS AND METHODS: Formalin fixed biopsies from 27 patients with interstitial cystitis and 5 controls were immunohistochemically labeled for the described proteins and scored using a modification of previous scoring for other markers. Inflammation was scored from hematoxylin and eosin stained slides. By combining previous with new data, cluster analysis showed the relationships among the markers and samples. RESULTS: Interstitial cystitis specimens clustered into 4 groups, ranging from most biomarkers abnormal to most biomarkers normal, but all clustered separately from normal controls. One group of interstitial cystitis specimens mainly showed aberrant expression of E-cadherin, which might represent an early abnormality. The biomarkers fell into 2 major groupings. One group consisted of chondroitin sulfate, perlecan, biglycan, decorin and the tight junction protein ZO-1. A second cluster consisted of uroplakin, the epithelial marker keratin 18 and 20, and the morphology of the layer. E-cadherin and syndecan-1 showed little relation to the other 2 clusters or to each other. Inflammation correlated moderately with syndecan-1 but to no other marker. CONCLUSIONS: Findings strongly suggest abnormal differentiation in the interstitial cystitis urothelium with a loss of barrier function markers and altered differentiation markers being independent and occurring independently of inflammation. Loss of the glycosaminoglycan layer was associated with a loss of biglycan and perlecan on the luminal layer.

Comparison of GreenLight laser and transurethral resection of the prostate baseline characteristics and outcomes: lessons learned from the Clinical Research Office of the Endourological Society GreenLight Laser Study.

BACKGROUND: To compare baseline characteristics and outcomes of patients undergoing GreenLight laser vaporization (GL) or transurethral resection of the prostate (TURP) in a real life setting. METHODS: In this prospective observational cohort, the Clinical Research Office of the Endourological Society (CROES) collected data of consecutive GL or TURP treated patients. Treatment involved one of three GL laser powers (80 W, 120 W or 180 W) based on availability in each participating centre, or TURP. Data on baseline characteristics as well as functional measures were collected at three time points: 6-12 weeks, 6, and 12months after surgery. Functional measures included urinary flow parameters, perceived prostate function (IPSS), perceived erectile function (IIEF-5) and complications. RESULTS: Seven hundred thirteen patients underwent GL, and 234 patients underwent TURP. Overall, patients treated with GL show higher BMI, IIEF and medication use, together with lower urinary function (voided volume, incontinence, urinary retention) at baseline. After the procedure, despite higher antibiotic and antimuscarinic use and shorter hospital stay, readmission rates, PVR, PSA were higher, but Qmax, and IIEF were lower in the GL group. The rate of post-operative complications was 10.3% and 5.2% for the TURP and GL group, respectively (P=0.006). CONCLUSIONS: We were unable to categorically state which procedure is superior. This observational study confirms that treatment decision for either TURP or GL is not based on patient characteristics.

Sclerosing mesenteritis progressing to ureteral obstruction.

Sclerosing mesenteritis is part of a spectrum of benign, inflammatory diseases of the abdominal mesentery. It has been called retractile mesenteritis, and other forms include mesenteric panniculitis and mesenteric lipodystrophy. The disease rarely involves the retroperitoneum. We present a case of sclerosing mesenteritis that progressed to ureteral involvement.

Screening and identification of differentially expressed transcripts in circulating cells of prostate cancer patients using suppression subtractive hybridization.

BACKGROUND: Tumor metastasis and changes in host immunosurveillance are important components in cancer development. Tumor cell invasion into the bloodstream is an essential step for systemic metastasis. Currently, the detection of tumor cells in the circulation is mainly dependent upon the utilization of known epithelial cell markers. However, expression of these molecules is not limited to cancer patients; healthy people also have a small number of epithelial cells in their circulation. Utilizing these markers to detect circulating tumor cells (CTCs) cannot adequately explain the mechanisms of tumor cell survival or their development of metastatic potential in peripheral blood. The immune system can also evolve along with the cancer, actually promoting or selecting the outgrowth of tumor variants. Unfortunately, both metastasis and immunosurveillance remain mysterious and are debatable because we have yet to define the molecules that participate in these processes. We are interested in identifying the existence of expressed genes, or mRNA species, that are specifically associated with circulating cells of cancer-bearing patients using prostate cancer (PCa) as a model. RESULTS: We established two comprehensive subtracted cDNA libraries using a molecular technique called suppression subtractive hybridization. This technique selectively amplifies transcripts that are specifically expressed in circulating cells of either PCa patients or healthy men. Following sequencing reaction, we showed that 17 out of 23 (73.9%) sequenced clones did not match any mRNAs in the GenBank database. This result suggests that genes associated with alterations in circulating cells of cancer-bearing patients are largely unknown. Semi-quantitative RT-PCR confirmed that two genes are up-regulated in circulating cells of PCa patients, whereas another two genes are down-regulated in the same patients. CONCLUSION: The comprehensive gene expression analysis is capable of identifying differentially expressed genes in circulating cells of healthy men and PCa patients. We did not attempt to enrich specific cell types in this study because phenotypes of CTCs and subsets of leukocytes participating in immunosurveillance remain largely unknown. Continuous studies of these differentially expressed genes will eventually lead us to understand the mechanisms involved in tumor metastasis and immune modulation during cancer development.

Recent trends in surgical treatment of localized prostate cancer.

Prostate cancer and its various forms of treatment remain a source of significant controversy and morbidity despite recent advances. In response, there is an increasing trend toward the development of treatments aimed at cancer prevention and at maximizing the preservation of function without sacrificing cancer control. This article reviews the current prostate cancer literature and reports on improvements in existing surgical treatments and developing technologies aimed toward achieving these goals. Specific therapies addressed include improvements in surgical techniques, laparoscopy, robotics, cryosurgical and thermal ablation, and high-intensity focused ultrasound.

Clinical strategies in the management of biochemical recurrence after radical prostatectomy.

Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer death in men, following lung cancer. Although radical prostatectomy continues to be a curative treatment for most patients diagnosed with prostate cancer, nearly 25% of patients undergoing radical prostatectomy will have biochemical recurrence as defined by an increase in serum prostate-specific antigen (PSA) level to >0.4 ng/mL after prostatectomy or a rapid doubling of the PSA over a 10-year follow-up period. The clinical challenges, an overview of available data, and a framework for the integration of this information for clinical management of biochemical recurrence postprostatectomy for prostate carcinoma are presented in this article. Therapeutic options, in addition to conservative management and watchful waiting, include radiation therapy and androgen deprivation. These options are discussed herein along with expected outcomes.

A model for 3-dimensional growth of bladder cancers to investigate cell-matrix interactions.

Elucidating the mechanisms by which the phenotype of cancer cells is modulated by the extracellular matrix (ECM) potentially identifies mechanisms that could be exploited for cancer control. Three readily available bladder cancer cell lines of different aggressiveness were grown on a bioscaffold material (Small Intestine Submucosa: SIS) under a variety of media and nutrient schedules to determine the influence of epigenetic factors on phenotype. The aggressive TCCSUP and J82 lines displayed an invasive phenotype when fed twice weekly with medium containing 10% fetal calf serum (FCS), but grew as a layered, noninvasive structure when fed daily with the same nutrient. The papillary RT4 cells grew as a nearly normal appearing layered phenotype when fed with medium containing 10% FCS, regardless of the feeding schedule. The papillary phenotype appeared only when the fetal calf serum concentration was reduced to 1% and the cells were fed twice weekly. Immunohistochemical staining showed E-cadherin was detected in the nucleus of the TCCSUP line rather than on the cell periphery, thus, demonstrating that normalization of the TCCSUP line into a layered phenotype did not alter the fundamental dysregulation of the cadherin-B-catenin-cytoskeleton complex. In contrast, in the RT4 cells the biomarker was distributed discretely around the cell periphery in 10% fetal calf serum but in the nucleus in 1% fetal calf serum and twice weekly feeding. Modulating the phenotype of cancer cells from invasive to noninvasive through manipulation of matrix and nutrient components presents a model system for identifying the key factors involved in invasiveness and may identify new therapeutic targets and markers.