Allergic asthma is a disease initiated by a breach of the lung mucosal barrier and an inappropriate Th2 inflammatory immune response that results in M2 polarization of alveolar macrophages (AM). The ...number of M2 macrophages in the airway correlates with asthma severity in humans. Sex differences in asthma suggest that sex hormones modify lung inflammation and macrophage polarization. Asthmatic women have more M2 macrophages than asthmatic men and androgens have been used as an experimental asthma treatment. In this study, we demonstrate that although androgen (dihydrotestosterone) reconstitution of castrated mice reduced lung inflammation in a mouse model of allergic lung inflammation, it enhanced M2 polarization of AM. This indicates a cell-specific role for androgens. Dihydrotestosterone also enhanced IL-4-stimulated M2 macrophage polarization in vitro. Using mice lacking androgen receptor (AR) in monocytes/macrophages (AR
LysMCre), we found that male but not female mice exhibited less eosinophil recruitment and lung inflammation due to impaired M2 polarization. There was a reduction in eosinophil-recruiting chemokines and IL-5 in AR-deficient AM. These data reveal an unexpected and novel role for androgen/AR in promoting M2 macrophage polarization. Our findings are also important for understanding pathology in diseases promoted by M2 macrophages and androgens, such as asthma, eosinophilic esophagitis, and prostate cancer, and for designing new approaches to treatment.
We report a 1-year update of functional urinary and sexual recovery, oncologic outcomes and postoperative complications in patients who completed a randomized controlled trial comparing posterior ...(Retzius sparing) with anterior robot-assisted radical prostatectomy.
A total of 120 patients with clinically low-intermediate risk prostate cancer were randomized to undergo robot-assisted radical prostatectomy via the posterior and anterior approach in 60 each. Surgery was performed by a single surgical team at an academic institution. An independent third party ascertained urinary and sexual function outcomes preoperatively, and 3, 6 and 12 months after surgery. Oncologic outcomes consisted of positive surgical margins and biochemical recurrence-free survival. Biochemical recurrence was defined as 2 postoperative prostate specific antigen values of 0.2 ng/ml or greater.
Median age of the cohort was 61 years and median followup was 12 months. At 12 months in the anterior vs posterior prostatectomy groups there were no statistically significant differences in the urinary continence rate (0 to 1 security pad per day in 93.3% vs 98.3%, p = 0.09), 24-hour pad weight (median 12 vs 7.5 gm, p = 0.3), erection sufficient for intercourse (69.2% vs 86.5%) or postoperative Sexual Health Inventory for Men score 17 or greater (44.6% vs 44.1%). In the posterior vs anterior prostatectomy groups a nonfocal positive surgical margin was found in 11.7% vs 8.3%, biochemical recurrence-free survival probability was 0.84 vs 0.93 and postoperative complications developed in 18.3% vs 11.7%.
Among patients with clinically low-intermediate risk prostate cancer randomized to anterior (Menon) or posterior (Bocciardi) approach robot-assisted radical prostatectomy the differences in urinary continence seen at 3 months were muted at the 12-month followup. Sexual function recovery, postoperative complication and biochemical recurrence rates were comparable 1 year postoperatively.
Purpose Cryptorchidism is one of the most common pediatric disorders of the male endocrine glands and the most common genital disorder identified at birth. This guideline is intended to provide ...physicians and non-physician providers (primary care and specialists) with a consensus of principles and treatment plans for the management of cryptorchidism (typically isolated non-syndromic). Materials and Methods A systematic review and meta-analysis of the published literature was conducted using controlled vocabulary supplemented with key words relating to the relevant concepts of cryptorchidism. The search strategy was developed and executed by reference librarians and methodologists to create an evidence report limited to English-language, published peer-reviewed literature. This review yielded 704 articles published from 1980 through 2013 that were used to form a majority of the guideline statements. Clinical Principles and Expert Opinions were used for guideline statements lacking sufficient evidence-based data. Results Guideline statements were created to inform clinicians on the proper methods of history-taking, physical exam, and evaluation of the boy with cryptorchidism, as well as the various hormonal and surgical treatment options. Conclusions Imaging for cryptorchidism is not recommended prior to referral, which should occur by 6 months of age. Orchidopexy (orchiopexy is the preferred term) is the most successful therapy to relocate the testis into the scrotum, while hormonal therapy is not recommended. Successful scrotal repositioning of the testis may reduce but does not prevent the potential long-term issues of infertility and testis cancer. Appropriate counseling and follow-up of the patient is essential.
Abstract Evidence-based health care decision making requires comparison of all relevant competing interventions. In the absence of randomized controlled trials involving a direct comparison of all ...treatments of interest, indirect treatment comparisons and network meta-analysis provide useful evidence for judiciously selecting the best treatment(s). Mixed treatment comparisons, a special case of network meta-analysis, combine direct evidence and indirect evidence for particular pairwise comparisons, thereby synthesizing a greater share of the available evidence than traditional meta-analysis. This report from the International Society for Pharmacoeconomics and Outcomes Research Indirect Treatment Comparisons Good Research Practices Task Force provides guidance on technical aspects of conducting network meta-analyses (our use of this term includes most methods that involve meta-analysis in the context of a network of evidence). We start with a discussion of strategies for developing networks of evidence. Next we briefly review assumptions of network meta-analysis. Then we focus on the statistical analysis of the data: objectives, models (fixed-effects and random-effects), frequentist versus Bayesian approaches, and model validation. A checklist highlights key components of network meta-analysis, and substantial examples illustrate indirect treatment comparisons (both frequentist and Bayesian approaches) and network meta-analysis. A further section discusses eight key areas for future research.
Purpose The purpose of this guideline is to provide a clinical framework for follow-up of clinically localized renal neoplasms undergoing active surveillance, or following definitive therapy. ...Materials and Methods A systematic literature review identified published articles in the English literature between January 1999 and 2011 relevant to key questions specified by the Panel related to kidney neoplasms and their follow-up (imaging, renal function, markers, biopsy, prognosis). Study designs consisting of clinical trials (randomized or not), observational studies (cohort, case-control, case series) and systematic reviews were included. Results Guideline statements provided guidance for ongoing evaluation of renal function, usefulness of renal biopsy, timing/type of radiographic imaging and formulation of future research initiatives. A lack of studies precluded risk stratification beyond tumor staging; therefore, for the purposes of postoperative surveillance guidelines, patients with localized renal cancers were grouped into strata of low- and moderate- to high-risk for disease recurrence based on pathological tumor stage. Conclusions Evaluation for patients on active surveillance and following definitive therapy for renal neoplasms should include physical examination, renal function, serum studies and imaging and should be tailored according to recurrence risk, comorbidities and monitoring for treatment sequelae. Expert opinion determined a judicious course of monitoring/surveillance that may change in intensity as surgical/ablative therapies evolve, renal biopsy accuracy improves and more long-term follow-up data are collected. The beneficial impact of careful follow-up will also need critical evaluation as further study is completed.
Purpose The American Urological Association established the Vesicoureteral Reflux Guideline Update Committee in July 2005 to update the management of primary vesicoureteral reflux in children ...guideline. The Panel defined the task into 5 topics pertaining to specific vesicoureteral reflux management issues, which correspond to the management of 3 distinct index patients and the screening of 2 distinct index patients. This report summarizes the existing evidence pertaining to children with diagnosed reflux including those young or older than 1 year without evidence of bladder and bowel dysfunction and those older than 1 year with evidence of bladder and bowel dysfunction. From this evidence clinical practice guidelines were developed to manage the clinical scenarios insofar as the data permit. Materials and Methods The Panel searched the MEDLINE® database from 1994 to 2008 for all relevant articles dealing with the 5 chosen guideline topics. The database was reviewed and each abstract segregated into a specific topic area. Exclusions were case reports, basic science, secondary reflux, review articles and not relevant. The extracted article to be accepted should have assessed a cohort of children with vesicoureteral reflux and a defined care program that permitted identification of cohort specific clinical outcomes. The reporting of meta-analysis of observational studies elaborated by the MOOSE (Meta-analysis Of Observational Studies in Epidemiology) group was followed. The extracted data were analyzed and formulated into evidence-based recommendations. Results A total of 2,028 articles were reviewed and data were extracted from 131 articles. Data from 17,972 patients were included in this analysis. This systematic meta-analysis identified increasing frequency of urinary tract infection, increasing grade of vesicoureteral reflux and presence of bladder and bowel dysfunction as unique risk factors for renal cortical scarring. The efficacy of continuous antibiotic prophylaxis could not be established with current data. However, its purported lack of efficacy, as reported in selected prospective clinical trials, also is unproven owing to significant limitations in these studies. Reflux resolution and endoscopic surgical success rates are dependent upon bladder and bowel dysfunction. The Panel then structured guidelines for clinical vesicoureteral reflux management based on the goals of minimizing the risk of acute infection and renal injury, while minimizing the morbidity of testing and management. These guidelines are specific to children based on age as well as the presence of bladder and bowel dysfunction. Recommendations for long-term followup based on risk level are also included. Conclusions Using a structured, formal meta-analytic technique with rigorous data selection, conditioning and quality assessment, we attempted to structure clinically relevant guidelines for managing vesicoureteral reflux in children. The lack of robust prospective randomized controlled trials limits the strength of these guidelines but they can serve to provide a framework for practice and set boundaries for safe and effective practice. As new data emerge, these guidelines will necessarily evolve.
Androgens, the predominant male sex hormones, drive the development and maintenance of male characteristics by binding to androgen receptor (AR). As androgens are systemically distributed throughout ...the whole organism, they affect many tissues and cell types in addition to those in male sexual organs. It is now clear that the immune system is a target of androgen action. In the lungs, many immune cells express ARs and are responsive to androgens. In this review, we describe the effects of androgens and ARs on lung myeloid immune cells-monocytes and macrophages-as they relate to health and disease. In particular, we highlight the effect of androgens on lung diseases, such as asthma, chronic obstructive pulmonary disease and lung fibrosis. We also discuss the therapeutic use of androgens and how circulating androgens correlate with lung disease. In addition to human studies, we also discuss how mouse models have helped to uncover the effect of androgens on monocytes and macrophages in lung disease. Although the role of estrogen and other female hormones has been broadly analyzed in the literature, we focus on the new perspectives of androgens as modulators of the immune system that target myeloid cells during lung inflammation.
Objective
To evaluate oncological outcomes in patients undergoing robot‐assisted radical prostatectomy (RARP) at a high‐volume tertiary centre with focus on biochemical recurrence (BCR); previous ...studies on oncological outcomes for patients undergoing RARP for prostate cancer are limited to small series.
Patients and Methods
In all, 5152 consecutive patients underwent RARP from 2001 to 2010; 4803 patients comprised the study cohort after exclusions.
BCR was defined as a serum prostate‐specific antigen (PSA) level of ≥0.2 ng/mL with a confirmatory value.
BCR‐free survival (BCRFS), metastasis‐free survival (MFS) and cancer‐specific survival (CSS) were estimated using the Kaplan–Meier method and Cox hazards regression models were generated.
Results
The mean preoperative PSA level was 6.1 ng/mL, pathological Gleason grade and stage were ≥7 in 68% and ≥pT3 in 34% of patients.
There was BCR in 470 patients (9.8%), 31 patients developed metastatic disease (0.7%) and 13 patients died from prostate cancer (0.3%) during a mean (range) follow‐up of 34.6 (1–116.7) months.
Actuarial 8‐year BCRFS, MFS and CSS were 81%, 98.5% and 99.1%, respectively. In patients with node‐positive disease, actuarial 5‐year BCRFS, MFS, and CSS were 26%, 82%, and 97%.
For organ‐confined disease, predictors of BCR included pathology Gleason grade (primary Gleason 5 vs 3, hazard ratio HR 5.52, P = 0.018; Gleason 4 vs 3, HR 1.97, P = 0.001), preoperative PSA level (10–20 vs ≤10 ng/mL, HR 2.38, P = 0.001), and surgical margin status (positive vs negative, HR 3.84, P < 0.001)
Conclusions
RARP appears to confer effective long‐term biochemical control.
To our knowledge, this is the largest report of oncological outcomes in a RARP series to date.
Abstract Background Ongoing efforts are focused on minimizing or eliminating renal ischemia during robot-assisted partial nephrectomy (RPN). Although various techniques allowing the elimination of ...renal hilar clamping have been described, large multi-institutional studies assessing perioperative and functional outcomes of this approach are lacking. Objective To evaluate perioperative and functional outcomes of RPN without hilar clamping and to assess comparative effectiveness relative to clamped RPN. Design, setting, and participants A multi-institutional data analysis of prospectively collected records of 886 RPNs performed by high-volume surgeons across five academic institutions between 2007 and 2011 was carried out. A total of 66 patients who underwent RPN without hilar clamping were identified. After the exclusion of 17 patients, perioperative results of 49 patients were compared against propensity score matched clamped controls. Intervention RPN without hilar clamping. Outcome measurements and statistical analysis Descriptive statistics and propensity score matching. Results and limitations Patients undergoing off-clamp RPN had a mean tumor size of 2.5 cm (standard deviation SD: ±2.1) and a mean RENAL nephrometry score of 5.3 (SD: ±1.5). The mean preoperative estimated glomerular filtration rate (eGFR) was 81 (SD: ±29). The mean estimated blood loss (EBL) was 210 ml (SD: ±212), and the mean operative time was 155 min (SD: ±46). No Clavien 3–5 complications were recorded. The mean postoperative change in eGFR was 3% at first follow-up (1–3 mo), and no patient required postoperative dialysis. The positive surgical margin rate was 3% ( n = 2), with no disease recurrence reported at a mean follow-up of 21 mo. In propensity score matched analyses, the off-clamp RPN patients had a significantly shorter mean operative time (156 min compared with 185 min, p < 0.001), a higher EBL (228 ml compared with 157 ml, p = 0.009), and a smaller decrease in eGFR (2% compared with −6%, p = 0.008). The retrospective analysis was the main limitation of this study. Conclusions With appropriately selected patients and adequate surgeon experience, off-clamp RPN is safe and feasible. Off-clamp RPN was associated with higher EBL, shorter operative times, and smaller decrease in renal function.
Abstract Background Previous studies attempting to assess complications after robot-assisted radical prostatectomy (RARP) are limited by their small numbers, short follow-up, or lack of risk factor ...analysis. Objective To document complications after RARP by strict application of standardized reporting criteria. Design, setting, and participants Between January 2005 and December 2009, 3317 consecutive patients underwent RARP at a tertiary referral center. Median follow-up was 24.2 mo (interquartile range: 12.4–36.9). Intervention Transperitoneal RARP was performed by one of five surgeons—two experienced, three beginners. Measurements Complications were captured by exhaustive review of multiple datasets, including our prospective prostate cancer database, claims data, and electronic medical and institutional morbidity and mortality records, and reported according to the Martin–Donat criteria. Complications were stratified by type (medical/surgical), Clavien classification, and timing of onset. Multivariable analysis of factors predictive of complications was performed. Results and limitations The median hospitalization time was 1 d. There were 368 complications in 326 patients (9.8%), including a transfusion rate of 2.2%. We detected 79 medical complications in 78 patients (2.4%) and 289 surgical complications in 264 patients (8.0%). There were 242 minor (Clavien 1–2) and 126 major (Clavien 3–5) complications. Two hundred ninety-nine (81.3%) complications occurred within 30 d, 17 (4.6%) within 31–90 d, and 52 (14.1%) after 90 d from surgery. On multivariable analysis, preoperative prostate-specific antigen values and cardiac comorbidity were predictive for medical complications, whereas age, gastroesophageal reflux disease, and biopsy Gleason score were predictive of surgical complications. Limitations of this study include representing results from a single high-volume referral center and not including the learning curve of the two most experienced surgeons. Conclusions RARP is a safe operation, with an overall complication rate of 9.8%. Most complications occurred within 30 d of surgery.
PDF
