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News 04 Dec.2013
Molecular Cancer Research
October 2, 2013; doi: 10.1158/1541-7786.MCR-13-0332-T
Activation of the Wnt pathway through use of AR79, a glycogen synthase kinase 3beta inhibitor, promotes prostate cancer growth in soft tissue and bone
1Department of Urology, University of Michigan 2Emerging Innovations Unit, AstraZeneca R&D 3Department of Immunology, Tianjin Medical University 4Department of Pathology, University of Michigan 5Department of Periodontics and Oral Medicine, University of Michigan
Due to its bone anabolic activity, methods to increase Wnt activity, such as inhibitors of dickkopf-1 and sclerostin, are being clinically explored. Glycogen synthase kinase (GSK3β) inhibits Wnt signaling through inducing beta-catenin degradation. Therefore, AR79, an inhibitor of GSK3β, is being evaluated as a bone anabolic agent. However, Wnt activation has potential to promote tumor growth.
The goal of this study was to determine if AR79 impacted progression of prostate cancer (PCa). PCa tumors were established in subcutaneous and bone sites of mice followed by AR79 administration. Tumor growth, beta-catenin activation, proliferation (Ki67 expression) and apoptosis (caspase 3 activity) were measured. Additionally, PCa and osteoblast cell lines were treated with AR79 and beta-catenin status, proliferation (with beta-catenin knocked down in some cases) and proportion of the ALDH+CD133+ stem-like cells was determined. AR79 promoted PCa growth, decreased phospho-beta-catenin expression and increased total and nuclear beta-catenin expression in tumors and increased tumor-induced bone remodeling.
Additionally, it decreased caspase 3 and increased Ki67 expression. In addition, AR79 increased bone formation in normal mouse tibiae. AR79 inhibited beta-catenin phosphorylation, increased nuclear β-catenin accumulation in PCa and osteoblast cell lines and increased proliferation of PCa cells in vitro through beta-catenin. Furthermore, AR79 increased the ALDH+CD133+ cancer stem cell-like proportion of the PCa cell lines. We conclude that AR79, while being bone anabolic, promotes PCa cell growth through Wnt pathway activation.
These data suggest that clinical application of pharmaceuticals that promote Wnt pathway activation should be used with caution as they may enhance tumor growth.
Copyright © 2013, American Association for Cancer Research.
Combination therapy with solifenacin and tamsulosin oral controlled absorption system in a single tablet for lower urinary tract symptoms in men: Efficacy and safety results from the randomised controlled neptune
van Kerrebroeck P, et al. – This study aims to assess the efficacy and safety of a fixed–dose combination (FDC) of solifenacin and an oral controlled absorption system (OCAS) formulation of tamsulosin compared with placebo and compared with tamsulosin OCAS (TOCAS)
monotherapy in men with moderate to severe storage symptoms and voiding symptoms.
The FDC of solifenacin 6 mg plus TOCAS significantly improved storage and voiding symptoms, as well as QoL parameters, compared with placebo. This FDC also improved storage symptoms and QoL compared with TOCAS alone in men with moderate to severe storage symptoms and voiding symptoms, and it was well tolerated.
Methods:A double–blind 12–wk phase 3 study in 1334 men with storage and voiding LUTS: total International Prostate Symptom Score (IPSS) ≥13, maximum urinary flow rate (Qmax) 4.0–12.0 ml/s, two or more urgency episodes per 24 h of Patient Perception of Intensity of Urgency Scale grade 3 or 4, and eight or more micturitions per 24 h.
Patients were randomised to placebo, TOCAS 0.4 mg, FDC solifenacin 6 mg plus TOCAS 0.4 mg, or FDC solifenacin 9 mg plus TOCAS 0.4 mg.
Primary efficacy end points were (1) total IPSS and (2) Total Urgency and Frequency Score (TUFS). An FDC met the success criteria if it demonstrated superiority compared with placebo and noninferiority compared with TOCAS for total IPSS, as well as superiority compared with TOCAS for TUFS.
Results:Reductions in total IPSS and TUFS were observed with both solifenacin 6 mg plus TOCAS (–7.0 and –8.1, respectively) and solifenacin 9 mg plus TOCAS (–6.5 and –7.6, respectively) compared with TOCAS (–6.2 and –6.7, respectively) and placebo (–5.4 and –4.4, respectively).
Solifenacin 6 mg plus TOCAS met all prespecified success criteria for both primary end points, while solifenacin 9 mg plus TOCAS met success criteria compared with placebo but not compared with TOCAS.
Both FDCs improved quality of life (QoL) measures and were well tolerated, with low incidences of acute urinary retention.
Journal of Urology 04 Dec.2013
Optimization of Spermatogenesis-Regulating Hormones in Patients with Non-Obstructive Azoospermia and its Impact on Sperm Retrieval: A Multicentre Study
A. Hussein, Y. Ozgok, L. Ross, P. Rao and C. Niederberger
Minia Infertility Research and Treatment Unit, El-Minia University, El-Minia, Egypt
BJU Int 2013; 111: E110-E114.
OBJECTIVE: To evaluate the effect of optimizing serum level of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone on sperm retrieval for intracytoplasmic sperm injection.
PATIENTS AND METHODS: A total of 612 patients with non-obstructive azoospermia were evaluated with routine history, physical examination and hormonal assessment. Of these, 116 patients underwent microsurgical (micro)-testicular sperm extraction (TESE) without any medical treatment and formed the control group and the remaining 496 patients were administered clomiphene citrate in a titrated dose. Patients were classified into four groups according to their response to clomiphene citrate. Group 1: patients with an obvious increase in FSH and total testosterone (n = 372). Group 2: patients showing an increase in FSH with no or little increase in LH and total testosterone (n = 62). For these patients we continued with clomiphene citrate and added human chorionic gonadotrophin (hCG). Group 3: patients with no increase in the levels of the three hormones (n = 46). Group 4: included patients with continuously decreasing serum testosterone levels in response to the increasing dose of clomiphene citrate (n = 16). Accordingly, patients in groups 3 and 4 discontinued clomiphene citrate and started hCG and human menopausal gonadotropin (hMG). Semen analyses were performed periodically and, in patients who remained azoospermic, micro-TESE was performed.
RESULTS: Sperm were noted in 54 patients (10.9%) in semen analysis after treatment in all groups (with no significant difference) at a mean (sd) concentration of 2.3 (4.1) million/mL. For the 442 patients who remained azoospermic after treatment, successful sperm retrieval was significantly higher (57%) compared with the control group (33.6%).
CONCLUSION: For patients with non-obstructive azoospermia, clomiphene citrate, hCG and hMG administration, leading to an increased level of FSH and total testosterone, results in an increased rate of sperm in the ejaculate and increased likelihood of successful micro-TESE.
Incremental Value of Magnetic Resonance Imaging for Clinically High Risk Prostate Cancer in 922 Radical Prostatectomies
In Gab Jeong, Ju Hyun Lim, Dalsan You, Mi-Hyun Kim, Hyuk Jae Choi, Jeong Kon Kim, Kyoung-Sik Cho, Jun Hyuk Hong, Hanjong Ahn, Choung-Soo Kim
Purpose:We investigated the incremental value of magnetic resonance imaging in addition to clinical variables for predicting pathological outcomes and disease recurrence in patients with clinically high risk prostate cancer.
Materials and Methods:A total of 922 consecutive patients with clinically high risk prostate cancer underwent magnetic resonance imaging before radical prostatectomy. We created multivariate logistic regression and Cox proportional hazards models with clinical variables only or combined with magnetic resonance imaging data to predict pathological outcomes and biochemical recurrence. The models were compared using ROC curves and the Harrell concordance index.
Results:The proportion of patients with pathological extracapsular extension, seminal vesicle invasion and lymph node metastasis was 57.5%, 12.7% and 6.3%, respectively. The sensitivity and specificity of extracapsular extension, seminal vesicle invasion and lymph node metastasis detection were 43% and 84.2%, 34.9% and 93.8%, and 14.0% and 96.9%, respectively. The area under the ROC curve of the model with clinical variable and magnetic resonance imaging data was greater than that of the model with clinical variables alone to predict extracapsular extension and seminal vesicle invasion (0.734 vs 0.697, p = 0.001 and 0.750 vs 0.698, p <0.001, respectively). The 5-year biochemical recurrence-free survival rate was 56.1%. To predict biochemical recurrence the concordance index of the multivariate model with clinical variables only and with clinical variables plus magnetic resonance imaging data was 0.563 and 0.599, respectively (p = 0.003).
Conclusions:Magnetic resonance imaging findings have incremental value in addition to clinical variables for predicting pathological outcomes and disease recurrence.
Journal of Urology 04 Dec.2013
Interactions between Lower Urinary Tract Symptoms and Cardiovascular Risk Factors Determine Distinct Patterns of Erectile Dysfunction
João A.B.A. Barbosa, Eduardo Muracca, Élcio Nakano, Adriana R. Assalin, Paulo Cordeiro, Mario Paranhos, José Cury, Miguel Srougi, Alberto A. Antunes
Purpose:An epidemiological association between lower urinary tract symptoms and erectile dysfunction is well established. However, interactions among multiple risk factors and the role of each in pathological mechanisms are not fully elucidated
Materials and Methods:We enrolled 898 men undergoing prostate cancer screening for evaluation with the International Prostate Symptom Score (I-PSS) and simplified International Index of Erectile Function-5 (IIEF-5) questionnaires. Age, race, hypertension, diabetes, dyslipidemia, metabolic syndrome, cardiovascular disease, serum hormones and anthropometric parameters were also evaluated. Risk factors for erectile dysfunction were identified by logistic regression. The 333 men with at least mild to moderate erectile dysfunction (IIEF 16 or less) were included in a latent class model to identify relationships across erectile dysfunction risk factors.
Results:Age, hypertension, diabetes, lower urinary tract symptoms and cardiovascular event were independent predictors of erectile dysfunction (p <0.05). We identified 3 latent classes of patients with erectile dysfunction (R2 entropy = 0.82). Latent class 1 had younger men at low cardiovascular risk and a moderate/high prevalence of lower urinary tract symptoms. Latent class 2 had the oldest patients at moderate cardiovascular risk with an increased prevalence of lower urinary tract symptoms. Latent class 3 had men of intermediate age with the highest prevalence of cardiovascular risk factors and lower urinary tract symptoms. Erectile dysfunction severity and lower urinary tract symptoms increased from latent class 1 to 3.
Conclusions:Risk factor interactions determined different severities of lower urinary tract symptoms and erectile dysfunction. The effect of lower urinary tract symptoms and cardiovascular risk outweighed that of age. While in the youngest patients lower urinary tract symptoms acted as a single risk factor for erectile dysfunction, the contribution of vascular disease resulted in significantly more severe dysfunction. Applying a risk factor interaction model to prospective trials could reveal distinct classes of drug responses and help define optimal treatment strategies for specific groups.
Prognostic Impact of Preoperative Neutrophil-to-Lymphocyte Ratio in Localized Nonclear Cell Renal Cell Carcinoma
Michela de Martino, Allan J. Pantuck, Sebastian Hofbauer, Matthias Waldert, Shahrokh F. Shariat, Arie S. Belldegrun, Tobias Klatte
Purpose:The preoperative neutrophil-to-lymphocyte ratio was proposed as a prognostic factor for localized clear cell renal cell carcinoma. We evaluated its role in nonclear cell renal cell carcinoma.
Materials and Methods:We queried 2 prospective kidney cancer databases. Patients who underwent full resection of localized (T1-3 N0/+ M0) nonclear cell renal cell carcinoma by radical or partial nephrectomy were included in analysis. Associations of the continuously coded neutrophil-to-lymphocyte ratio with disease-free survival were assessed with univariable and multivariable Cox regression models. Prognostic accuracy was evaluated with the Harrell concordance index.
Results:Our final cohort included 281 patients. The 5-year disease-free survival rate was 88.1%. The neutrophil-to-lymphocyte ratio was significantly associated with disease-free survival. With each 1.0 increase in the ratio the risk of recurrence increased by 15% (HR 1.15, p = 0.028). On multivariable analysis TNM group (HR 2.84, p = 0.025), Fuhrman grade (HR 3.40, p <0.001) and the neutrophil-to-lymphocyte ratio (HR 1.17, p = 0.022) were independently associated with disease-free survival. Adding the neutrophil-to-lymphocyte ratio improved the accuracy of a base model to predict disease-free survival from 78.8% to 80.8%.
Conclusions:The neutrophil-to-lymphocyte ratio is an independent prognostic factor for disease-free survival after surgery with curative intent for localized nonclear cell renal cell carcinoma. It significantly increases the accuracy of established prognostic factors. The neutrophil-to-lymphocyte ratio may provide a meaningful adjunct for patient counseling and clinical trial design.
Journal of Urology 04 Dec.2013
Air Cystoscopy is Superior to Water Cystoscopy for the Diagnosis of Active Hematuria
Alexandru Ciudin, Mihai Gabriel Diaconu, David Gosalbez, Lluis Peri, Eduardo Garcia-Cruz, Agustin Franco, Antonio Alcaraz
Purpose:We evaluated the clinical use of air cystoscopy, including its possible advantages and disadvantages over water cystoscopy.
Materials and Methods:Two independent observers prospectively studied consecutive patients who underwent water cystoscopy first and then air cystoscopy at our center from May to September 2012. The indication for rigid cystoscopy in the operating room was noted independently by either observer. Findings after rigid cystoscopy were correlated with the results of flexible water and air cystoscopy using the Pearson correlation and Student t-test.
Results:Included in the study were 57 patients with active hematuria, of whom 36 had bladder cancer, and 257 with a history of bladder tumor. The cause of bleeding was clearly identified on water cystoscopy in 22 patients (38%), including tumors in 17 and prostate bleeding in 5, and by air cystoscopy in 49 (86%), including tumors in 32 and prostate bleeding in 17. For diagnosing bladder tumors air cystoscopy had higher sensitivity than water cystoscopy (88% vs 47%, p = 0.003) and similar specificity (97% vs 100%, p = 0.93). In the 295 patients without hematuria there was no difference in the indication compared to that identified on rigid cystoscopy (43 vs 43, p = 1.0). Water cystoscopy revealed more small papillary tumors than air cystoscopy but the number was not significantly different (76 vs 67, p = 0.26). All such implants identified on water cystoscopy alone were less than 2 mm. No complication specifically related to air cystoscopy was noted.
Conclusions:We found no statistical difference between water and air cystoscopy in patients without hematuria. Air cystoscopy had higher sensitivity and specificity for diagnosing active hematuria while adding almost no specific complications to the procedure.
Extraprostatic Extension into Periprostatic Fat is a More Important Determinant of Prostate Cancer Recurrence than an Invasive Phenotype
Jada Kapoor, Benjamin Namdarian, John Pedersen, Chris Hovens, Daniel Moon, Justin Peters, Anthony J. Costello, Paul Ruljancich, Niall M. Corcoran
Purpose:Although micrometastasis development correlates closely with the depth of invasion of many tumor types, it is unclear whether invasion into but not through the prostatic pseudocapsule has a negative impact on prognosis, similar to extraprostatic extension. We defined the impact of pseudocapsular invasion on the risk of post-prostatectomy biochemical recurrence.
Materials and Methods:Patients with pT2-3a prostate cancer were identified from a prospectively recorded database. Those with pT2 disease were categorized according to pseudocapsular invasion presence or absence. The impact of pseudocapsular invasion on biochemical recurrence was determined by univariable and multivariable Cox regression analysis.
Results:In a cohort of 1,338 patients we identified 595 with organ confined cancer positive for pseudocapsular invasion. Compared to tumors without evidence of invasion, pseudocapsular invasion was positively associated with higher Gleason grade and tumor volume (1.2 vs 1.9 cc, each p <0.001). On univariable analysis there was no difference in biochemical recurrence-free survival between patients with vs without pseudocapsular invasion, although those with extraprostatic extension had significantly lower biochemical recurrence-free survival (p <0.001). This was confirmed on multivariable analysis, which revealed that extraprostatic extension was a significant independent predictor of biochemical recurrence (HR 1.53, p = 0.018). The presence of pseudocapsular invasion had no effect (HR 0.81, p = 0.33).
Conclusions:Pseudocapsular invasion is not a pathological feature associated with an adverse outcome after prostatectomy. Thus, the depth of tumor invasion is not a continuum of risk and access to periprostatic adipose tissue is a more important determinant of disease behavior than an invasive phenotype.
European Urology, Evidence Based Medicine
The study aims to perform a systematic review of complications from prostate biopsy. Preparation for biopsy should include antimicrobial prophylaxis and pain management. Prostate biopsy is frequently associated with minor bleeding and urinary symptoms that usually do not require intervention. Infectious complications can be serious, requiring prompt management and continued work into preventative strategies.
· A literature search was performed using PubMed and Embase, supplemented with additional references.
· Articles were reviewed for data on the following complications: hematuria, rectal bleeding, hematospermia, infection, pain, lower urinary tract symptoms (LUTS), urinary retention, erectile dysfunction, and mortality.
· After biopsy, hematuria and hematospermia are common but typically mild and self-limiting.
· Severe rectal bleeding is uncommon.
· Despite antimicrobial prophylaxis, infectious complications are increasing over time and are the most common reason for hospitalization after biopsy.
· Pain may occur at several stages of prostate biopsy and can be mitigated by anesthetic agents and anxiety-reduction techniques.
· Up to 25% of men have transient LUTS after biopsy, and <2% have frank urinary retention, with slightly higher rates reported after transperineal template biopsy.
· Biopsy-related mortality is rare.
· Preparation for biopsy should include antimicrobial prophylaxis and pain management.
· Prostate biopsy is frequently associated with minor bleeding and urinary symptoms that usually do not require intervention.
· Infectious complications can be serious, requiring prompt management and continued work into preventative strategies.
Nature Reviews Urology Year published03 December 2013
Nature Reviews Urology(2013) doi:10.1038/nrurol.2013.266
Worldwide, familial and epidemiological studies have generated considerable evidence of an inherited component to prostate cancer. Indeed, rare highly penetrant genetic mutations have been implicated.
Genome-wide association studies (GWAS) have also identified 76 susceptibility loci associated with prostate cancer risk, which occur commonly but are of low penetrance. However, these mutations interact multiplicatively, which can result in substantially increased risk. Currently, approximately 30% of the familial risk is due to such variants. Evaluating the functional aspects of these variants would contribute to our understanding of prostate cancer aetiology and would enable population risk stratification for screening. Furthermore, understanding the genetic risks of prostate cancer might inform predictions of treatment responses and toxicities, with the goal of personalized therapy.
However, risk modelling and clinical translational research are needed before we can translate risk profiles generated from these variants into use in the clinical setting for targeted screening and treatment.
News 02 Dec.2013
Nature Reviews Urology , | doi:10.1038/nrurol.2013.230
Chris F. Heyns, Shaun G. Smit, André van der Merwe & Amir D. Zarrabi
The use of highly active antiretroviral therapy (HAART) in HIV-infected people has led to a dramatic decrease in the incidence of opportunistic infections and virus-related malignancies such as non-Hodgkin lymphoma and Kaposi sarcoma, but not cervical or anal cancer.
Advanced-stage cervical cancer is associated with a high incidence of urological complications such as hydronephrosis, renal failure, and vesicovaginal fistula.
Adult male circumcison can significantly reduce the risk of male HIV acquisition. Although HAART does not completely eradicate HIV, compliance with medication increases life expectancy.
HIV infection or treatment can result in renal failure, which can be managed with dialysis and transplantation (as for HIV-negative patients).
Although treatment for erectile dysfunction—including phosphodiesterase 5 inhibitors, intracavernosal injection therapy, and penile prosthesis—can increase the risk of HIV transmission, treatment decisions for men with erectile dysfunction should not be determined by HIV status.
The challenges faced when administering chemotherapy to HIV-infected patients with cancer include late presentation, immunodeficiency, drug interactions, and adverse effects associated with compounded medications. Nonetheless, HIV-infected patients should receive the same cancer treatment as HIV-negative patients.
The urologist is increasingly likely to encounter HIV-positive patients who present with the same urological problems as the general population, because HAART confers a prolonged life expectancy. Performing surgery in an HIV-infected individual raises safety issues for both the patient (if severely immunocompromised) and the surgeon, but the risk of HIV transmission from patients on fully suppressive HAART is small.