Tissue-specific quantification and localization of androgen and estrogen receptors in prostate cancer.

Androgens and estrogens, working together, promote prostate cancer (PRCA) initiation and progression, with androgens acting via androgen receptor (AR) and estrogens acting primarily through estrogen receptor α (ERα). While the interplay between these steroid hormones has been established, the interaction between steroid hormone receptors in prostatic disease remains unstudied. The goal of this study was to objectively determine the incidence, stage specificity, and tissue/cell type specificity of AR and ERα expression, both independently and simultaneously, during the progression of PRCA. Using multiplexed immunohistochemistry and multispectral imaging analysis, AR, ERα, and smooth muscle α-actin expression was detected and quantitated in benign prostate tissue (BPT), high-grade prostatic intraepithelial neoplasia (HGPIN), PRCA, and metastasis (MET) from patient specimens (n=340). Epithelial AR expression was significantly increased in HGPIN, PRCA, and MET compared with BPT, whereas ERα expression in epithelial and stromal cells was highest in HGPIN. With analysis of AR and ERα coexpression, we identified a unique population of double-positive (AR+/ERα+) cells that increased in HGPIN specimens in both the stroma and the epithelium. Double-negative (AR-/ERα-) cells significantly decreased across PRCA progression, from 65% in BPT to 30% in MET. Preliminary analysis of this AR+/ERα+ population indicates potential cell type specificity in smooth muscle α-actin-negative stromal cells. This study demonstrates stage-, tissue-, and cell type-specific AR and ERα expression changes during PRCA progression, both independently and coexpressed. A more complete understanding of steroid hormones and their receptors in the initiation and progression of prostatic disease may elucidate improved strategies for PRCA prevention or therapy.

Does Combination Therapy with Tamsulosin and Tolterodine Improve Ureteral Stent Discomfort Compared with Tamsulosin Alone? A Double-Blind, Randomized, Controlled Trial.

PURPOSE: Ureteral stent discomfort is a significant postoperative problem for many patients. Despite the use of narcotics and α-blockers patients often experience bothersome lower urinary tract symptoms and pain, which impair daily activities. We compared combination therapy with an α-blocker and an anticholinergic to monotherapy with an α-blocker. MATERIALS AND METHODS: A double-blind, randomized, controlled trial was performed from December 2012 to April 2014. A total of 80 patients were randomized, including 44 to the combination group (tamsulosin 0.4 mg and tolterodine early release 4 mg) and 36 to the monotherapy group (tamsulosin 0.4 mg and placebo). Patients with preexisting ureteral stent placement or current anticholinergic therapy were excluded from study. Patients completed USSQ (Urinary Stent Symptom Questionnaire) before stent placement on the day of surgery, the day after stent placement, the morning of stent removal and the day after stent removal. The questionnaire included questions regarding urinary symptoms, general health, body pain, and work and sexual history. RESULTS: A total of 80 patients (40 males and 40 females) were studied. Mean age was 51.5 vs 51.3 years (p = 0.95) and mean body mass index was 33.6 vs 31.9 kg/m(2) (p = 0.44) in monotherapy group 1 vs combination therapy group 2. Between the 2 groups there was no significant difference in urinary symptoms, body pain and activities of daily living from baseline to just before stent removal (p = 0.95, 0.40 and 0.95, respectively). Although there was no difference between the groups, both showed improvement in urinary symptoms from the time of initial stent insertion to just prior to stent removal (difference -0.50 for combination therapy and -0.40 for monotherapy). The mean stent indwelling time of 9.6 and 8.7 days in the combination and monotherapy groups, respectively, did not differ (p = 0.67). On ANOVA it had no significant impact on results (p = 0.64). CONCLUSIONS: Combination therapy with tamsulosin and tolterodine does not appear to improve urinary symptoms, bodily pain or quality of life in patients after ureteral stent placement for nephrolithiasis compared to tamsulosin alone. Both groups experienced worse urinary symptoms, pain and quality of life with a stent, suggesting that further research is necessary to improve stent discomfort.

SIGIRR/TIR8, an important regulator of TLR4 and IL-1R-mediated NF-κB activation, predicts biochemical recurrence after prostatectomy in low-grade prostate carcinomas.

Single Ig IL-1-related receptor (SIGIRR) is a negative regulator of toll-like receptor 4 and IL-1-mediated activation of nuclear factor κ-light-chain enhancer of activated B cells. The purpose of this study was to qualitatively and quantitatively determine SIGIRR protein expression in human prostate tissues and associate SIGIRR expression with clinical parameters. SIGIRR expression was quantified in glandular prostate tissue using immunohistochemistry and multispectral imaging, and expression was evaluated in relation to clinicopathological features of benign prostatic hyperplasia and prostate cancer (PCa). Subgroupings of low Gleason score (≤ 6 and 3 + 4) and high Gleason score (4 + 3 and ≥ 8) were used for patient outcomes. SIGIRR was predominantly expressed in the cytoplasm and nucleus of the prostatic epithelium with little expression within the stroma. Compared with normal prostate, cytoplasmic SIGIRR expression was similar in benign prostatic hyperplasia, high-grade prostatic intraepithelial neoplasia, PCa, and metastases. A decrease in nuclear expression was found in metastasis samples (P = .04). Changes in SIGIRR expression were not associated with Gleason score, pathological stage, tumor volume, surgical margin status, or serum prostate-specific antigen (P > .05). Nuclear (P = .96) and cytoplasmic (P = .89) SIGIRR expressions were not related to patient outcomes in univariable analysis, but in the analysis of patients with low Gleason scores, high cytoplasmic SIGIRR expression was associated with biochemical recurrence in both univariable (P = .01) and multivariable (hazard ratio, 2.31 [95% confidence interval 1.05-5.06]; P = .04) analyses. Similarly, in multivariable analysis of only low-stage (pT2) tumors, SIGIRR independently predicted biochemical recurrence (P = .009). We conclude that SIGIRR predicts biochemical recurrence in patients with low Gleason score and low pathological stage PCa.

Factors affecting outcomes of percutaneous nephrolithotomy in horseshoe kidneys.

OBJECTIVE: To analyze the patient- and procedure-related factors affecting the outcomes of percutaneous nephrolithotomy (PNL) in horseshoe kidneys (HSKs). METHODS: A retrospective analysis was done of patients with stones in HSKs treated with PNL in 3 referral centers between 1998 and 2013. Demographics, along with perioperative characteristics, were evaluated in detail as to whether or not they had an effect on the success and complication rates. RESULTS: A total of 54 HSKs with calculi in 53 patients were treated with PNL. Mean stone size was 28.4 ± 19.6 mm (range, 10-120 mm). Fifty-three patients were treated through a single tract, and 1 patient required additional access. Access was directed to the upper calyx (n = 27), middle calyx (n = 17), and lower calyx (n = 10) through the intercostal (n = 23) and subcostal (n = 31) areas. Flexible nephroscopy was used in 18.5% of the procedures. Postoperative complications were observed in 9 (16.7%) of the procedures. Success rate was 66.7% after a single session of PNL and increased to 90.7% with additional treatments. Although patient demographics, preoperative imaging, and other operative measures did not have significant effect on the complication rate, stone complexity and multiplicity, in combination with flexible nephroscopy, were found to significantly affect the success rate (P = .026, P = .043, and P = .021, respectively). However, in multivariate analysis stone multiplicity was the only factor that affected success rate (P = .004). CONCLUSION: Stone parameters play an important role in achieving stone-free status in HSKs. Use of flexible nephroscopy positively affects the success rate by allowing reaching the peripherally located calices.

Finasteride treatment alters tissue specific androgen receptor expression in prostate tissues.

BACKGROUND: Normal and pathologic growth of the prostate is dependent on the synthesis of dihydrotestosterone (DHT) from testosterone by 5α-reductase. Finasteride is a selective inhibitor of 5α-reductase 2, one isozyme of 5α-reductase found in abundance in the human prostate. The objective of this study was to investigate the effects of finasteride on androgen receptor expression and tissue morphology in human benign prostatic hyperplasia specimens. METHODS: Patients undergoing transurethral resection of the prostate and either treated or not treated with finasteride between 2004 and 2010 at the University of Wisconsin-Hospital were retrospectively identified using an institutional database. Prostate specimens from each patient were triple-stained for androgen receptor, prostate-specific antigen, and basal marker cytokeratin 5. Morphometric analysis was performed using the multispectral imaging, and results were compared between groups of finasteride treated and non-treated patients. RESULTS: Epithelial androgen receptor but not stromal androgen receptor expression was significantly lower in patients treated with finasteride than in non-treated patients. Androgen receptor-regulated prostate-specific antigen was not significantly decreased in finasteride-treated patients. Significant luminal epithelial atrophy and basal cell hyperplasia were prevalent in finasteride treated patients. Epithelial androgen receptor expression was highly correlated to the level of luminal epithelial atrophy. CONCLUSIONS: In this study, finasteride decreased the expression of epithelial androgen receptor in a tissue specific manner. The correlation between epithelial androgen receptor and the extent of luminal epithelial atrophy suggests that epithelial androgen receptor may be directly regulating the atrophic effects observed with finasteride treatment.

Expanding endourology for biliary stone disease: the efficacy of intracorporeal lithotripsy on refractory biliary calculi.

BACKGROUND AND PURPOSE: We evaluated the efficacy of ureteroscopic therapy (electrohydraulic lithotripsy [EHL] and intraductal laser lithotripsy [ILL]) in patients with challenging biliary stones secondary to anatomic variations resulting from a previous surgical procedure, including liver transplantation. PATIENTS AND METHODS: A retrospective chart review was performed for all patients with previous surgical alteration of the gastrointestinal (GI) tract who underwent EHL or ILL via peroral or percutaneous access for choledocholithiasis by a single surgeon at our institution from 2000 to 2012. A database containing clinical and surgical variables was created, and long-term follow-up was conducted (3-138 months; median, 99 months). RESULTS: Thirteen patients (51.7±20.0 years; M:F, 10:3) in whom endoscopic retrograde cholangiopancreatography (ERCP), percutaneous transhepatic cholangiography (PTHC), or both failed were identified. Failure of ERCP/PTHC was because of inaccessibility of the calculi in all cases. Stone clearance was achieved in 12/13 (93%) patients; 8/12 (62%) after one procedure, and 4/12 (31%) after two procedures. One patient with biliary cast syndrome needed four interventions over 9 years. Major complications were low, with only one patient with hypotension and cholangitis that resolved with 24 hours of administration of intravenous fluids and antibiotics. CONCLUSIONS: Both endoscopic and percutaneous lithotripsies are effective treatments for refractory biliary calculi resulting from the post-surgical GI tract. Although a staged second procedure may be necessary in patients with significant stone burden, this is significantly better than extensive open surgery.

Dietary hydroxyproline induced calcium oxalate lithiasis and associated renal injury in the porcine model.

BACKGROUND AND PURPOSE: We previously reported hyperoxaluria and calcium oxalate calculi in adult pigs (sows) fed hydroxyproline (HP). The purpose of this study was to grossly and histopathologically characterize intrarenal effects in this model. METHODS: In the swine facility at our campus, we maintained 21 gestating sows, of which 15 received daily treatment (5% HP mixed with dry feed) and 6 received no treatment (controls). Nine were sacrificed at 21 d (three control, six HP). All kidneys were extracted and examined grossly and for radiographic evidence of stones (GE CT scanner, 80kV, 400MA, 1 sec rotation, 0.625 mm slices). Papillary and cortical samples were processed for histologic analysis. RESULTS: Kidneys from treated sows showed significant calculi distributed within the renal papilla on CT, appeared mottled in the renal cortex and papillary areas, and had less distinct corticomedullary borders. Tiny crystals and mucinous debris lined the papillary tips, calices, and pelvis in kidneys from four of six treated sows, and multiple stones were noted at the papillary tips. Hematoxylin and eosin stain revealed crystals in collecting tubules and papillary tips in treated kidneys and none in controls. Yasue staining confirmed crystals in proximal periglomerular tubules of treated but not control animals. Tubular dilation and inflammatory/fibrotic changes were identified in kidneys from treated animals; none of these changes were evident in control kidneys. CONCLUSIONS: We report renal damage as a result of dietary-induced hyperoxaluria in adult sows. Specifically, we found crystalluria in proximal periglomerular tubules and collecting ducts, with tubular damage at all segments.

Sex steroid receptor expression and localization in benign prostatic hyperplasia varies with tissue compartment.

Androgens and estrogens, acting via their respective receptors, are important in benign prostatic hyperplasia (BPH). The goals of this study were to quantitatively characterize the tissue distribution and staining intensity of androgen receptor (AR) and estrogen receptor-alpha (ERα), and assess cells expressing both AR and ERα, in human BPH compared to normal prostate. A tissue microarray composed of normal prostate and BPH tissue was used and multiplexed immunohistochemistry was performed to detect AR and ERα. We used a multispectral imaging platform for automated scanning, tissue and cell segmentation and marker quantification. BPH specimens had an increased number of epithelial and stromal cells and increased percentage of epithelium. In both stroma and epithelium, the mean nuclear area was decreased in BPH relative to normal prostate. AR expression and staining intensity in epithelial and stromal cells was significantly increased in BPH compared to normal prostate. ERα expression was increased in BPH epithelium. However, stromal ERα expression and staining intensity was decreased in BPH compared to normal prostate. Double positive (AR and ERα) epithelial cells were more prevalent in BPH, and fewer double negative (AR and ERα) stromal and epithelial negative cells were observed in BPH. These data underscore the importance of tissue layer localization and expression of steroid hormone receptors in the prostate. Understanding the tissue-specific hormone action of androgens and estrogens will lead to a better understanding of mechanisms of pathogenesis in the prostate and may lead to better treatment for BPH.