Search

Aim: To determine whether recent evidence-based United States policies on male circumcision (MC) apply to comparable Anglophone countries, Australia and New Zealand., Methods: Articles in 2005 through 2015 were retrieved from PubMed using the keyword "circumcision" together with 36 relevant subtopics. A further PubMed search was performed for articles published in 2016. Searches of the EMBASE and Cochrane databases did not yield additional citable articles. Articles were assessed for quality and those rated 2+ and above according to the Scottish Intercollegiate Grading System were studied further. The most relevant and representative of the topic were included. Bibliographies were examined to retrieve further key references. Randomized controlled trials, recent high quality systematic reviews or meta-analyses (level 1++ or 1+ evidence) were prioritized for inclusion. A risk-benefit analysis of articles rated for quality was performed. For efficiency and reliability, recent randomized controlled trials, meta-analyses, high quality systematic reviews and large well-designed studies were used if available. Internet searches were conducted for other relevant information, including policies and Australian data on claims under Medicare for MC., Results: Evidence-based policy statements by the American Academy of Pediatrics (AAP) and the Centers for Disease Control and Prevention (CDC) support infant and later age male circumcision (MC) as a desirable public health measure. Our systematic review of relevant literature over the past decade yielded 140 journal articles that met our inclusion criteria. Together, these showed that early infant MC confers immediate and lifelong benefits by protecting against urinary tract infections having potential adverse long-term renal effects, phimosis that causes difficult and painful erections and "ballooning" during urination, inflammatory skin conditions, inferior penile hygiene, candidiasis, various sexually transmissible infections in both sexes, genital ulcers, and penile, prostate and cervical cancer. Our risk-benefit analysis showed that benefits exceeded procedural risks, which are predominantly minor, by up to 200 to 1. We estimated that more than 1 in 2 uncircumcised males will experience an adverse foreskin-related medical condition over their lifetime. Wide-ranging evidence from surveys, physiological measurements, and the anatomical location of penile sensory receptors responsible for sexual sensation strongly and consistently suggested that MC has no detrimental effect on sexual function, sensitivity or pleasure. United States studies showed that early infant MC is cost saving. The evidence supporting early infant MC has further strengthened since the positive AAP and CDC reviews., Conclusion: Affirmative MC policies are needed in Australia and New Zealand. Routine provision of accurate, unbiased education, and access in public hospitals, will maximize health and financial benefits., Competing Interests: Conflict-of-interest statement: Authors are members of the Circumcision Academy of Australia, a medical body formed to provide accurate, evidence-based information on male circumcision to parents, practitioners and others, as well as contact details of doctors who perform the procedure.

Studies to elucidate dysregulated gene expression patterns in premalignant prostate lesions have identified several candidate genes with the potential to be targeted to prevent the development and progression of prostate cancer and act as biomarkers of early disease. Herein, we explored the importance of two proteins, neuropeptide Y (NPY) and macrophage inhibitory cytokine-1 (MIC-1), as biomarkers of preinvasive prostate disease and investigated the relationship of expression to biochemical recurrence following treatment for localized prostate cancer. NPY and MIC-1 protein expression was determined by immunohistochemistry on tissue microarrays containing 1,626 cores of benign, low-grade prostatic intraepithelial neoplasia (PIN), high-grade PIN (HGPIN), and prostate cancer tissue from 243 radical prostatectomy patients. Both NPY and MIC-1 showed higher proportional immunostaining in HGPIN and prostate cancer compared with benign epithelium (P < 0.0001). NPY and MIC-1 immunostaining was higher in low-grade PIN compared with other benign tissues (both P < 0.0001) and was equivalent to immunostaining in HGPIN. NPY immunostaining of prostate cancer was independently associated with relapse, after adjusting for traditional prognostic factors, as a categorical variable in 20% intervals (P = 0.0449-0.0103) and as a continuous variable (P = 0.0017). Low MIC-1 immunostaining (20% categories) was associated with pathologic stage >2C after adjusting for predictors of pathologic stage (P = 0.3894-0.0176). This is the first study to show that altered NPY and MIC-1 expression are significantly associated with prostate cancer progression and suggests that these molecules be developed further as biomarkers in the management of prostate disease.

Beta-catenin in its role as a nuclear signaling molecule has been implicated in prostate carcinogenesis primarily through modulation of androgen receptor activity. We defined the pattern of beta-catenin protein expression in the nuclei of normal, hyperplastic and malignant human prostate tissue and determined whether differences in expression were associated with disease progression and prognosis. Five normal prostates, 26 benign prostatic hypertrophy specimens, 232 radical prostatectomy specimens from patients with clinically localized prostate cancer (PC) and 20 cases of advanced PC were assessed for beta-catenin expression using immunohistochemistry. Nuclear beta-catenin expression in localized PC was significantly lower than that in benign prostate tissue (p < 0.001) and significantly higher than that in advanced PC tissue (p < 0.001). In addition, lower levels of nuclear beta-catenin expression (< 10% of cancer cells) predicted for a shorter biochemical relapse-free survival in patients with localized PC (p = 0.008) and were inversely correlated with preoperative prostate-specific antigen (PSA) levels (p = 0.01). Analysis of the low-risk subgroup of patients with preoperative PSA levels < 10 ng/ml demonstrated that lower levels of nuclear beta-catenin expression (< 10% of cancer cells) again predicted for a poorer prognosis (p = 0.006). In conclusion, lower levels of nuclear beta-catenin expression are found in malignant compared to benign prostate tissue. In addition, lower nuclear beta-catenin expression is associated with a poorer prognosis in localized PC, in particular, in the low-risk subgroup of patients with preoperative PSA levels < 10 ng/ml. Thus, the level of nuclear beta-catenin expression may be of clinical utility as a preoperative prognostic marker in low-risk localized PC.

Background: The role of the bone morphogenetic protein (BMP) pathway in prostate cancer (PC) is unclear. This study aimed to characterize aspects of the BMP pathway in PC by assessing BMP2, Smad8, and Smad4 expression in normal, hyperplastic, and malignant prostate tissue, and to correlate findings with progression to PC., Methods: Radical prostatectomy (RP) specimens from 74 patients with clinically localized PC (median follow-up 51 months, range 15-152), 44 benign prostatic hypertrophy (BPH) lesions, and 4 normal prostates (NPs) were assessed for BMP2, Smad8, and Smad4 expression using immunohistochemistry., Results: Both BMP2 (P < 0.001) and nuclear Smad4 (P < 0.0001) expression were significantly decreased in PC compared to benign prostate tissue. Nuclear Smad8 was present in normal/benign prostate tissue but absent in PC and adjacent hyperplasia. Furthermore, loss of BMP2 (P < 0.001) and decreased nuclear Smad4 (P = 0.05) expression correlated with increasing Gleason score., Conclusions: These data suggest that decreased BMP2, nuclear smad8 and nuclear Smad4 expression are associated with the progression to PC, and in particular loss of BMP2 and Smad4 are related to progression to a more aggressive phenotype., (Copyright 2004 Wiley-Liss, Inc.)

Purpose: Activation of the Wnt-signaling pathway is implicated in aberrant cellular proliferation in a variety of cancers. Secreted frizzled-related protein 4 (sFRP4) is a secreted protein with putative inhibitory activity of the Wnt-signaling cascade through binding and sequestering Wnt ligands. Because sFRP4 mRNA is overexpressed in prostate cancers (PCs), the aim of this study was to define the pattern of sFRP4 protein expression in normal and malignant human prostate tissue and to determine whether changes in expression were associated with disease progression and prognosis, as well as to define the phenotype of sFRP4-overexpression in an in vitro model of PC., Experimental Design: Polyclonal antibodies were raised against a COOH-terminal peptide of sFRP4, characterized and used to assess sFRP4 protein expression in benign prostate tissue and 229 patients with clinically localized PC (median follow-up 77 months, range 1-156). In vitro studies of the function of sFRP4 overexpression were performed using PC3 cells transfected with sFRP4., Results: Benign and malignant prostate tissue demonstrated cytoplasmic sFRP4 immunoreactivity, but there was a decrease in the expression of membranous sFRP4 in PCs compared with the hyperplastic lesions (P < 0.0001). Kaplan-Meier analysis revealed that patients whose PC expressed membranous sFRP4 in >20% of cells had improved relapse-free survival compared with those with

Background: In the current study, the authors sought to further stratify the prognosis of patients with Gleason score (GS) 7 prostate carcinoma. They assessed the influence on outcome of a predominant poorly differentiated Gleason pattern (primary Gleason pattern [GP] 4) and/or a coincident small focus of poorly differentiated tumor of higher grade (tertiary GP 5)., Methods: The authors studied 412 patients (mean postoperative follow-up, 33 months) with GS 7 tumors treated with radical prostatectomy at a single Australian campus between November 1989 and December 2002. The chi-square test, Kaplan-Meier method, and Cox proportional hazards analyses were used to evaluate the correlation between primary GP 4 and tertiary GP 5 with the occurrence of adverse pathologic features and disease recurrence., Results: In this cohort, 307 patients (75%) had primary GP 3 tumors, 105 (25%) had primary GP 4 tumors, and 17 (2.3%) had a tertiary element of high-grade tumor (GP 5). Patients with primary GP 4 tumors displayed higher rates of seminal vesicle involvement and extraprostatic extension and, along with patients with tertiary GP 5, had significantly shorter times to disease recurrence. Univariate analysis demonstrated that primary GP 4 (P = 0.0003) and tertiary GP 5 (P < 0.0001) were strong predictors of disease recurrence. Primary GP 4 (P = 0.0122) remained an independent predictor of disease recurrence on stepwise multivariate analysis., Conclusions: Primary GP 4 tumors represented an aggressive subset of GS 7 prostate carcinomas. Primary GP was an easily accessible and clinically relevant predictor of disease recurrence in patients with GS 7 prostate carcinoma., (Copyright 2003 American Cancer Society.)

We have utilized oligonucleotide microarrays to identify novel genes of potential clinical and biological importance in prostate cancer. RNA from 74 prostate cancers and 164 normal body samples representing 40 different tissues were analysed using a customized Affymetrix GeneChip oligonucleotide microarray representative of over 90% of the expressed human genome. The gene for the zinc transporter ZnT4 was one of several genes that displayed significantly higher expression in prostate cancer compared to normal tissues from other organs. A polyclonal antipeptide antibody was used to demonstrate ZnT4 expression in the epithelium of all 165 elements of benign and 326 elements of localized prostate cancers examined and in nine of 10 advanced prostate cancer specimens by immunohistochemistry. Interestingly, decreased intensity of ZnT4 immunoreactivity occurred in the progression from benign to invasive localized prostate cancer and to metastatic disease. Immunofluorescence analysis and surface biotinylation studies of cells expressing ZnT4 localised the protein to intracellular vesicles and to the plasma membrane. These findings are consistent with a role for ZnT4 in vesicular transport of zinc to the cell membrane and potentially in efflux of zinc in the prostate.

Background: Predicting outcome for men with clinically localized prostate carcinoma treated with curative intent remains imprecise and further evaluation of accepted and potential predictive factors is needed., Methods: The authors studied 696 men with localized prostate carcinoma diagnosed on transrectal biopsy and treated with radical prostatectomy at one institution between 1986 and 1999 to determine the relation between putative pretreatment prognostic factors and disease-free survival. Clinical stage, Gleason score, perineural invasion, number of biopsies containing tumor, and serum prostate specific antigen (PSA) were evaluated as predictors of extracapsular extension, seminal vesicle involvement, lymph node metastases, and surgical margin involvement as well as outcome after surgery. Kaplan-Meier method and Cox regression analyses were used to evaluate the contribution of different factors to adverse pathologic features and relapse., Results: At mean follow-up of 56.9 months (range, 1.0-177.9 months; median, 54.9 months), 26.1% (182 of 696 patients) of patients had developed a disease recurrence. Pretreatment serum PSA concentration, biopsy Gleason score, and clinical stage as well as number of biopsies involved with tumor as a percentage of the total number obtained were found to be independent predictors of outcome. In patients with PSA > 10 ng/mL, biopsy perineural invasion and percentage of biopsies containing tumor were found to independently predicted disease recurrent. Increased number of biopsies involved with tumor independently predicted extracapsular extension, margin involvement, seminal vesicle, and lymph node involvement., Conclusions: This study demonstrated that the proportion of prostate biopsy cores containing tumor is an independent predictor of outcome after subsequent radical prostatectomy and suggested that perineural invasion has a predictive role in patients with a preoperative PSA > 10 ng/ml., (Copyright 2003 American Cancer Society.)

Purpose: Although predicting outcome for men with clinically localized prostate cancer (PC) has improved, the staging system and nomograms used to do this are based on results from the North American health system. To be internationally applicable, these models require testing in cohorts from a variety of different health systems based on the predominant PC case identification methods used., Patients and Methods: We studied 732 men with localized PC treated with radical prostatectomy and no preoperative therapy between 1986 and 1999 at one Australian institution to determine the effect of clinicopathologic features on disease-free survival., Results: Preoperative serum prostate-specific antigen (PSA) concentration, Gleason score, pathologic stage, and year of surgery were independent predictors of outcome. Although margin status demonstrated only a trend toward significance in multivariate modeling overall, it proved to be independent in subgroups based on later year of surgery (1986 to 1994 v 1995 to 1998), preoperative PSA of less than 10 ng/mL, and Gleason score > or = 7. Adjuvant radiation therapy improved disease-free survival rates in patients with multiple surgical margin involvement., Conclusion: This work confirms the prognostic significance of pathologic stage, Gleason score, and preoperative serum PSA. In the context of a contemporaneous screening effect in Australia, these findings may have implications for methods that predict outcome following surgery as screening becomes more prevalent in a population. The independent prognostic effect of margin status may alter with an increase in the proportion of screening-identified PCs. Staging systems and nomograms that predict outcome following surgery require validation in cohorts with different health practices before being universally applied.

The role of estrogen and its receptors in the etiology and progression of prostate cancer (PC) is poorly understood. In normal and malignant human prostate, estrogen receptor-alpha is expressed only in the stroma, whereas estrogen receptor-beta (ERbeta) is present in both normal stroma and epithelium. Because loss of ERbeta expression is associated with prostate hyperplasia in ERbeta-null mice, this study determined patterns of ERbeta expression in normal, hyperplastic, and malignant human prostate and associations with clinical outcome. Five normal prostates from organ donors and 159 radical prostatectomy specimens from patients with clinically localized PC were assessed for ERbeta expression using immunohistochemistry. ERbeta-positivity was defined as > or =5% of cells demonstrating nuclear immunoreactivity. All of the five normal prostates showed strong ERbeta-nuclear staining in >95% of the epithelium and 35% of the stromal cells. The number of ERbeta-positive cases declined to 24.2% (38/157) in hyperplasia adjacent to carcinoma and 11.3% (18/159) in PCs. ERbeta-positivity was related to decreased relapse-free survival (log-rank P = 0.04). Thus, loss of ERbeta expression is associated with progression from normal prostate epithelium to PC, whereas those cancers that retained ERbeta expression were associated with a higher rate of recurrence. These data identify the need to further investigate the potential role of ERbeta in the regulation of prostate epithelial cell proliferation and the functional consequences of decreased ERbeta expression in the evolution of PC.

Prostate cancer (PC) is the most commonly diagnosed male cancer in industrialized societies. No molecular markers of PC progression or outcome with proven clinical utility have been described. Because the loss of normal cell cycle control is an early event in the evolution of cancer, we sought to determine whether changes in expression of the cyclin-dependent kinase inhibitor, p16INK4A, predicted outcome in this disease. We screened a cohort of 206 patients with clinically localized PC treated with radical prostatectomy for overexpression of the INK4A gene, the product of which inactivates the G1-phase cyclin dependent kinases, Cdk4 and Cdk6. p16INK4A protein expression was evaluated by immunohistochemistry in areas of high-grade intraepithelial neoplasia (HGPIN), a precursor to invasive disease, and of cancer in the same specimen. Data were evaluated for disease relapse using the Kaplan-Meier method and in a Cox proportional hazards model by assessing p16INK4A status in areas of HGPIN and cancer with other variables of known clinical relevance. Overexpression of p16INK4A in HGPIN and cancer was correlated with, but independent of, pathological stage and was associated with early relapse in PC patients treated with radical prostatectomy (log-rank test, P < 0.001). In a multivariate model adjusted for Gleason grade, pretreatment prostate-specific antigen levels, pathological stage, and margin status, overexpression of p16INK4A in HGPIN was an independent predictor of disease relapse and increased the risk of recurrence 2.24-fold (95% confidence interval, 1.28-3.93). These data provide the first evidence for a prognostic marker in HGPIN. The clinical utility of p16INK4A status in stratifying patients for aggressive treatment very early in the disease process, potentially several years prior to the onset of invasive disease, requires further investigation.

The molecular basis of androgen-independent prostate cancer is unknown; however, functional androgen receptor (AR) signaling is maintained after the acquisition of hormone-refractory disease. Because normal and malignant prostate epithelial cell proliferation is regulated by androgen stimulation via both the AR-positive stroma and epithelium, we sought to evaluate patterns of AR expression in these cells and to determine any relationships with prostate cancer progression. AR expression in the malignant epithelium and associated periepithelial and nonperiepithelial stroma was measured in a cohort of 96 patients with clinically localized prostate cancer treated with radical prostatectomy. Data were evaluated for disease relapse using the Kaplan-Meier method and in a Cox proportional hazards model with other variables of known clinical relevance, including Gleason score, pathological stage, clinical stage, and pretreatment prostate-specific antigen concentration. Concurrent overexpression of AR (> or = 70% positive nuclei) in the malignant epithelium and loss of AR immunoreactivity in the adjacent periepithelial stroma (< or = 30%) was associated with higher clinical stage (P = 0.01), higher pretreatment prostate-specific antigen level (P = 0.03), and earlier relapse after radical prostatectomy (log-rank P = 0.009). These data identify a pattern of AR expression in malignant epithelium and adjacent stroma that is associated with a poor clinical outcome in prostate cancer. Equally important, they identify the need to further investigate the mechanistic basis of loss of AR expression in the malignant stroma and its potential role in deregulation of prostate epithelial cell proliferation.

The role of p53 in the pathogenesis of, and as a predictive biomarker for, localized prostate cancer (PCa) is contested. Recent work has suggested that patterns of p53 nuclear accumulation determined by immunohistochemistry are prognostic, whereas studies using other methods question the role of p53 mutations in predicting outcome. We studied 263 men with localized PCa treated with radical prostatectomy to determine whether p53 nuclear accumulation predicts relapse and disease-specific mortality. We combined two p53 immunohistochemistry scoring systems: (a) percentage of p53-positive tumor nuclei in all major foci of cancer within the prostate; and (b) clustering, where the presence of 12 or more p53-positive cells within a x 200 power field was deemed "cluster positive." Analysis was undertaken using chi2, Kruskal-Wallis, and Mann-Whitney tests for clinicopathological variables and the Kaplan-Meier method, log-rank test, and univariate and multivariate Cox regression modeling for evaluation of contribution to relapse and disease-specific survival. At mean follow-up of 55.1 months (range, 4.9-123.0 months), 39% (102 of 263) of patients had relapsed and 2.3% (6 of 253) had died of PCa. Pretreatment serum prostate-specific antigen concentration, pathological tumor stage, lymph node involvement, Gleason score, and p53 nuclear accumulation, as determined by either percentage score or cluster status, were independent predictors of relapse in multivariate analysis. Clustering of p53-positive cells distinguished between favorable and poor prognosis patients within the lowest p53-positive stratum (>0 to <2%) and was the most discriminatory threshold for predicting relapse in the entire cohort. p53 status predicted outcome in patients with a Gleason score of 5 and above but not those with a score of 4 and below. In patients treated with neoadjuvant hormonal therapy, p53 cluster positivity carried a 90% (19 of 21) risk of relapse by 36 months. All six patients who died from PCa in the period of the study exhibited p53 nuclear accumulation in 20% or more tumor nuclei. This study demonstrates strong relationships between p53 nuclear accumulation and relapse and disease-specific mortality in a large series of localized PCas. Furthermore, the presence of clusters of p53-positive nuclei delineates a group of patients with poor prognosis not identified by traditional scoring methods and supports the hypothesis that p53 dysfunction within PCa may exist in foci of tumor cells that are clonally expanded in metastases.

Direct inhibitory effects of bacillus Calmette-Guérin (BCG) and interferon alpha 2b (IFN alpha 2b) on six human bladder carcinoma cell lines, UCRU-BL-13, UCRU-BL-17, UCRU-BL-28, 5637, T24 and J82, were studied using an in vitro proliferation assay. Effects on proliferation following exposure to BCG or IFN alpha 2b were analysed by [3H]thymidine incorporation over 7 days. BCG had an antiproliferative effect on all bladder lines, while sensitivity to IFN alpha 2b varied greatly, being as remarkably low as 1 U/ml for some lines. The antiproliferative effect was greatest when cells were exposed continuously to either agent, but was still evident with a limited exposure. When clinical concentrations were simulated in vitro, BCG+IFN alpha 2b was more effective than BCG alone and as effective as a double BCG concentration. We conclude that, in addition to their immunomodulatory effects, BCG and IFN alpha 2b directly inhibit the proliferation of human bladder cancer cells, and often at extremely low concentrations.

Thirty-four patients receiving allogeneic bone marrow transplants as treatment for haematological malignancy were prospectively randomized to receive or not to receive bladder irrigation by indwelling urinary catheter during preparation for transplant. Twenty-two patients received busulphan and cyclophosphamide, four received busulphan, cyclophosphamide and irradiation, and eight received cyclophosphamide and total body irradiation. The actuarial incidence of haemorrhagic cystitis in those randomized to receive bladder irrigation was 48% for the whole group and 52% in those receiving busulphan and cyclophosphamide only. In those randomized not to receive bladder irrigation the incidence of haemorrhagic cystitis was 29% for the overall group and 38% in those receiving busulphan and cyclophosphamide. There was no statistically significant difference between the two groups. We conclude that bladder irrigation does not minimize the risk of haemorrhagic cystitis in this patient population.

Prophylactic antibiotics significantly decrease the incidence of urinary tract infection following endoscopic prostate resection. They are ineffective in reducing the incidence of postoperative fevers, or in reducing the frequency of positive blood cultures during or after operation. A majority of prostate glands harbour colonies of potentially pathogenic organisms, and these are the commonest source of infection of the urinary tract following release by prostatic surgery.

The case histories of 17 patients in whom urinary retention was associated with an intervertebral disc protrusion which occurred, most commonly, centrally at the lumbar 4/5 level are presented. Strong pleas are made for consideration of this entity in patients with unexplained urinary retention.

Observations have been made on the choice of wound drainage in 119 general surgical or urological procedures performed by surgeons in a general hospital. Complications of the drains used are reported. Softer and more pliable drains appear to cause less morbidity than the stiffer, more rigid variety. The literature dealing with drainage is reviewed.