Transcriptomic analysis of benign prostatic hyperplasia identifies critical pathways in prostatic overgrowth and 5-alpha reductase inhibitor resistance.

BACKGROUND: The medical therapy of prostatic symptoms (MTOPS) trial randomized men with symptoms of benign prostatic hyperplasia (BPH) and followed response of treatment with a 5α-reductase inhibitor (5ARI), an alpha-adrenergic receptor antagonist (α-blocker), the combination of 5ARI and α-blocker or no medical therapy (none). Medical therapy reduced risk of clinical progression by 66% but the reasons for nonresponse or loss of therapeutic response in some patients remains unresolved. Our previous work showed that prostatic glucocorticoid levels are increased in 5ARI-treated patients and that glucocorticoids can increased branching of prostate epithelia in vitro. To understand the transcriptomic changes associated with 5ARI treatment, we performed bulk RNA sequencing of BPH and control samples from patients who received 5ARI versus those that did not. Deconvolution analysis was performed to estimate cellular composition. Bulk RNA sequencing was also performed on control versus glucocorticoid-treated prostate epithelia in 3D culture to determine underlying transcriptomic changes associated with branching morphogenesis. METHOD: Surgical BPH (S-BPH) tissue was defined as benign prostatic tissue collected from the transition zone (TZ) of patients who failed medical therapy while control tissue termed Incidental BPH (I-BPH) was obtained from the TZ of men undergoing radical prostatectomy for low-volume/grade prostatic adenocarcinoma confined to the peripheral zone. S-BPH patients were divided into four subgroups: men on no medical therapy (none: n = 7), α-blocker alone (n = 10), 5ARI alone (n = 6) or combination therapy (α-blocker and 5ARI: n = 7). Control I-BPH tissue was from men on no medical therapy (none: n = 8) or on α-blocker (n = 6). A human prostatic cell line in 3D culture that buds and branches was used to identify genes involved in early prostatic growth. Snap-frozen prostatic tissue taken at the time of surgery and 3D organoids were used for RNA-seq analysis. Bulk RNAseq data were deconvoluted using CIBERSORTx. Differentially expressed genes (DEG) that were statistically significant among S-BPH, I-BPH, and during budding and branching of organoids were used for pathway analysis. RESULTS: Transcriptomic analysis between S-BPH (n = 30) and I-BPH (n = 14) using a twofold cutoff (p < 0.05) identified 377 DEG (termed BPH377) and a cutoff < 0.05 identified 3377 DEG (termed BPH3377). Within the S-BPH, the subgroups none and α-blocker were compared to patients on 5ARI to reveal 361 DEG (termed 5ARI361) that were significantly changed. Deconvolution analysis of bulk RNA seq data with a human prostate single cell data set demonstrated increased levels of mast cells, NK cells, interstitial fibroblasts, and prostate luminal cells in S-BPH versus I-BPH. Glucocorticoid (GC)-induced budding and branching of benign prostatic cells in 3D culture was compared to control organoids to identify early events in prostatic morphogenesis. GC induced 369 DEG (termed GC359) in 3D culture. STRING analysis divided the large datasets into 20-80 genes centered around a hub. In general, biological processes induced in BPH supported growth and differentiation such as chromatin modification and DNA repair, transcription, cytoskeleton, mitochondrial electron transport, ubiquitination, protein folding, and cholesterol synthesis. Identified signaling pathways were pooled to create a list of DEG that fell into seven hubs/clusters. The hub gene centrality was used to name the network including AP-1, interleukin (IL)-6, NOTCH1 and NOTCH3, NEO1, IL-13, and HDAC/KDM. All hubs showed connections to inflammation, chromatin structure, and development. The same approach was applied to 5ARI361 giving multiple networks, but the EGF and sonic hedgehog (SHH) hub was of particular interest as a developmental pathway. The BPH3377, 5ARI363, and GC359 lists were compared and 67 significantly changed DEG were identified. Common genes to the 3D culture included an IL-6 hub that connected to genes identified in BPH hubs that defined AP1, IL-6, NOTCH, NEO1, IL-13, and HDAC/KDM. CONCLUSIONS: Reduction analysis of BPH and 3D organoid culture uncovered networks previously identified in prostatic development as being reinitiated in BPH. Identification of these pathways provides insight into the failure of medical therapy for BPH and new therapeutic targets for BPH/LUTS.

Glucocorticoids are induced while dihydrotestosterone levels are suppressed in 5-alpha reductase inhibitor treated human benign prostate hyperplasia patients.

BACKGROUND: The development of benign prostatic hyperplasia (BPH) and medication-refractory lower urinary tract symptoms (LUTS) remain poorly understood. This study attempted to characterize the pathways associated with failure of medical therapy for BPH/LUTS. METHODS: Transitional zone tissue levels of cholesterol and steroids were measured in patients who failed medical therapy for BPH/LUTS and controls. Prostatic gene expression was measured using qPCR and BPH cells were used in organoid culture to study prostatic branching. RESULTS: BPH patients on 5-α-reductase inhibitor (5ARI) showed low levels of tissue dihydrotestosterone (DHT), increased levels of steroid 5-α-reductase type II (SRD5A2), and diminished levels of androgen receptor (AR) target genes, prostate-specific antigen (PSA), and transmembrane serine protease 2 (TMPRSS2). 5ARI raised prostatic tissue levels of glucocorticoids (GC), whereas alpha-adrenergic receptor antagonists (α-blockers) did not. Nuclear localization of GR in prostatic epithelium and stroma appeared in all patient samples. Treatment of four BPH organoid cell lines with dexamethasone, a synthetic GC, resulted in budding and branching. CONCLUSIONS: After failure of medical therapy for BPH/LUTS, 5ARI therapy continued to inhibit androgenesis but a 5ARI-induced pathway increased tissue levels of GC not seen in patients on α-blockers. GC stimulation of organoids indicated that the GC receptors are a trigger for controlling growth of prostate glands. A 5ARI-induced pathway revealed GC activation can serve as a master regulator of prostatic branching and growth.

Prospective randomized trial of 2 versus 12-weeks of postoperative antibiotics after percutaneous nephrolithotomy in complex patients with infection-related kidney stones.

PURPOSE: Treatment of struvite kidney stones requires complete surgical stone removal combined with antibiotic therapy to eliminate urinary tract infections and preventive measures to reduce stone recurrence. The optimal duration of antibiotic therapy is unknown. We sought to determine if 2- or 12-weeks of antibiotics post percutaneous nephrolithotomy (PNL) for infection stones resulted in better outcomes for stone recurrence and positive urine cultures. MATERIAL AND METHODS: This multi-center, prospective randomized trial evaluated patients with the clinical diagnosis of infection stones. Patients were randomized to 2- or 12-weeks of postoperative oral antibiotics (nitrofurantoin or culture-specific antibiotic) and included if residual fragments were ≤4 mm on computed tomography imaging after PNL. Imaging and urine analyses were performed at 3-, 6-, and 12-months post-procedure. RESULTS: Thirty-eight patients were enrolled and randomized to either 2-weeks (n = 20) or 12-weeks (n = 18) of antibiotic therapy post-PNL. Eleven patients were excluded due to residual fragments >4 mm, and 3 patients were lost to follow-up. The primary outcome was the stone-free rate (SFR) at 6 months post-PNL. At 3-, 6-, and 12-months follow-up, SFRs were 72.7% versus 80.0%, 70.0% versus 57.1%, 80.0% versus 57.1% (p = ns), between 2- and 12-week-groups, respectively. At 3-, 6-, and 12-months follow-up, positive urine cultures were 50.0% versus 37.5%, 50.0% versus 83.3%, and 37.5% versus 100% between 2- and 12-week groups, respectively (p = ns). CONCLUSIONS: For patients with stone removal following PNL, neither 2-weeks nor 12-weeks of postoperative oral antibiotics is superior to prevent stones and recurrent positive urine cultures.

The prostaglandin pathway is activated in patients who fail medical therapy for benign prostatic hyperplasia with lower urinary tract symptoms.

BACKGROUND: Little is known about how benign prostatic hyperplasia (BPH) develops and why patients respond differently to medical therapy designed to reduce lower urinary tract symptoms (LUTS). The Medical Therapy of Prostatic Symptoms (MTOPS) trial randomized men with symptoms of BPH and followed response to medical therapy for up to 6 years. Treatment with a 5α-reductase inhibitor (5ARI) or an alpha-adrenergic receptor antagonist (α-blocker) reduced the risk of clinical progression, while men treated with combination therapy showed a 66% decrease in risk of progressive disease. However, medical therapies for BPH/LUTS are not effective in many patients. The reasons for nonresponse or loss of therapeutic response in the remaining patients over time are unknown. A better understanding of why patients fail to respond to medical therapy may have a major impact on developing new approaches for the medical treatment of BPH/LUTS. Prostaglandins (PG) act on G-protein-coupled receptors (GPCRs), where PGE2 and PGF2 elicit smooth muscle contraction. Therefore, we measured PG levels in the prostate tissue of BPH/LUTS patients to assess the possibility that this signaling pathway might explain the failure of medical therapy in BPH/LUTS patients. METHOD: Surgical BPH (S-BPH) was defined as benign prostatic tissue collected from the transition zone (TZ) of patients who failed medical therapy and underwent surgical intervention to relieve LUTS. Control tissue was termed Incidental BPH (I-BPH). I-BPH was TZ obtained from men undergoing radical prostatectomy for low-volume, low-grade prostatic adenocarcinoma (PCa, Gleason score ≤ 7) confined to the peripheral zone. All TZ tissue was confirmed to be cancer-free. S-BPH patients divided into four subgroups: patients on α-blockers alone, 5ARI alone, combination therapy (α-blockers plus 5ARI), or no medical therapy (none) before surgical resection. I-BPH tissue was subgrouped by prior therapy (either on α-blockers or without prior medical therapy before prostatectomy). We measured prostatic tissue levels of prostaglandins (PGF2α , PGI2 , PGE2 , PGD2 , and TxA2 ), quantitative polymerase chain reaction levels of mRNAs encoding enzymes within the PG synthesis pathway, cellular distribution of COX1 (PTGS1) and COX2 (PTGS2), and tested the ability of PGs to contract bladder smooth muscle in an in vitro assay. RESULTS: All PGs were significantly elevated in TZ tissues from S-BPH patients (n = 36) compared to I-BPH patients (n = 15), regardless of the treatment subgroups. In S-BPH versus I-BPH, mRNA for PG synthetic enzymes COX1 and COX2 were significantly elevated. In addition, mRNA for enzymes that convert the precursor PGH2 to metabolite PGs were variable: PTGIS (which generates PGI2 ) and PTGDS (PGD2 ) were significantly elevated; nonsignificant increases were observed for PTGES (PGE2 ), AKR1C3 (PGF2α ), and TBxAS1 (TxA2 ). Within the I-BPH group, men responding to α-blockers for symptoms of BPH but requiring prostatectomy for PCa did not show elevated levels of COX1, COX2, or PGs. By immunohistochemistry, COX1 was predominantly observed in the prostatic stroma while COX2 was present in scattered luminal cells of isolated prostatic glands in S-BPH. PGE2 and PGF2α induced contraction of bladder smooth muscle in an in vitro assay. Furthermore, using the smooth muscle assay, we demonstrated that α-blockers that inhibit alpha-adrenergic receptors do not appear to inhibit PG stimulation of GPCRs in bladder muscle. Only patients who required surgery to relieve BPH/LUTS symptoms showed significantly increased tissue levels of PGs and the PG synthetic enzymes. CONCLUSIONS: Treatment of BPH/LUTS by inhibition of alpha-adrenergic receptors with pharmaceutical α-blockers or inhibiting androgenesis with 5ARI may fail because of elevated paracrine signaling by prostatic PGs that can cause smooth muscle contraction. In contrast to patients who fail medical therapy for BPH/LUTS, control I-BPH patients do not show the same evidence of elevated PG pathway signaling. Elevation of the PG pathway may explain, in part, why the risk of clinical progression in the MTOPS study was only reduced by 34% with α-blocker treatment.

MOSESTM Technology for Holmium Laser Enucleation of the Prostate: A Prospective Double-Blind Randomized Controlled Trial.

PURPOSE: Holmium laser enucleation of the prostate has proven to be efficacious and safe for the treatment of benign prostatic hyperplasia. New laser technologies, such as the MOSES™ pulse laser system, improve energy delivery and may improve operative times. We sought to prospectively evaluate holmium laser enucleation of the prostate using MOSES technology in a double-blind randomized controlled trial. MATERIALS AND METHODS: This is a single-center, prospective, double-blind, randomized controlled trial comparing holmium laser enucleation of the prostate using MOSES technology to holmium laser enucleation of the prostate. Patients were randomized in a 1:1 fashion. The study was powered to evaluate for a difference in operative time. Secondary end points included enucleation, morcellation, and hemostasis times, as well as blood loss, functional outcomes and complications 6 weeks postoperatively. RESULTS: A total of 60 patients were analyzed without difference in preoperative characteristics in either group (holmium laser enucleation of the prostate using MOSES technology: 30/60, 50%, holmium laser enucleation of the prostate: 30/60, 50%). Shorter total operative time was seen in the holmium laser enucleation of the prostate using MOSES technology group compared to the holmium laser enucleation of the prostate group (mean: 101 vs. 126 minutes, p <0.01). This difference remained significant on multiple linear regression. Additionally, the holmium laser enucleation of the prostate using MOSES technology group had shorter enucleation times (mean: 68 vs. 80 minutes, p=0.03), hemostasis time (mean: 18 vs. 29 minutes, p <0.01), and less blood loss (mean: -6.3 vs. -9.0%, p=0.03), measured by a smaller change in hematocrit postoperatively, compared to the traditional holmium laser enucleation of the prostate. There was no difference in functional or safety outcomes at followup. CONCLUSIONS: We report the results of a prospective, double-blind, randomized controlled trial comparing holmium laser enucleation of the prostate using MOSES technology to traditional holmium laser enucleation of the prostate. MOSES technology resulted in an improvement in operative time and a reduction in blood loss with comparable functional outcomes and complications compared to traditional holmium laser enucleation of the prostate.

A Randomized Controlled Trial of Preoperative Prophylactic Antibiotics for Percutaneous Nephrolithotomy in Moderate to High Infectious Risk Population: A Report from the EDGE Consortium.

PURPOSE: Postoperative infectious related complications are not uncommon after percutaneous nephrolithotomy. Previously, we noted that 7 days of antibiotics did not decrease sepsis rates compared to just perioperative antibiotics in a low risk percutaneous nephrolithotomy population. This study aimed to compare the same regimens in individuals at moderate to high risk for sepsis undergoing percutaneous nephrolithotomy. MATERIALS AND METHODS: Patients were prospectively randomized in this multi-institutional study to either 2 days or 7 days of preoperative antibiotics. Enrolled patients had stones requiring percutaneous nephrolithotomy and had either a positive preoperative urine culture or existing indwelling urinary drainage tube. Primary outcome was difference in sepsis rates between the groups. Secondary outcomes included rate of nonseptic bacteriuria, stone-free rate and length of stay. RESULTS: A total of 123 patients at 7 institutions were analyzed. There was no difference in sepsis rates between groups on univariate analysis. Similarly, there were no differences in nonseptic bacteriuria, stone-free rate and length of stay. On multivariate analysis, 2 days of antibiotics increased the risk of sepsis compared to 7 days of antibiotics (OR 3.1, 95% CI 1.1-8.9, p=0.031). Patients receiving antibiotics for 2 days had higher rates of staghorn calculus than the 7-day group (58% vs 32%, p=0.006) but post hoc subanalysis did not demonstrate increased sepsis in the staghorn only group. CONCLUSIONS: Giving 7 days of preoperative antibiotics vs 2 days decreases the risk of sepsis in moderate to high risk percutaneous nephrolithotomy patients. Future guidelines should consider infectious risk stratification for percutaneous nephrolithotomy antibiotic recommendations.

Prostatic osteopontin expression is associated with symptomatic benign prostatic hyperplasia.

BACKGROUND: Male lower urinary tract symptoms (LUTS) occur in more than half of men above 50 years of age. LUTS were traditionally attributed to benign prostatic hyperplasia (BPH) and therefore the clinical terminology often uses LUTS and BPH interchangeably. More recently, LUTS were also linked to fibrogenic and inflammatory processes. We tested whether osteopontin (OPN), a proinflammatory and profibrotic molecule, is increased in symptomatic BPH. We also tested whether prostate epithelial and stromal cells secrete OPN in response to proinflammatory stimuli and identified downstream targets of OPN in prostate stromal cells. METHODS: Immunohistochemistry was performed on prostate sections obtained from the transition zone of patients who underwent surgery (Holmium laser enucleation of the prostate) to relieve LUTS (surgical BPH, S-BPH) or patients who underwent radical prostatectomy to remove low-grade prostate cancer (incidental BPH, I-BPH). Images of stained tissue sections were captured with a Nuance Multispectral Imaging System and histoscore, as a measure of OPN staining intensity, was determined with inForm software. OPN protein abundance was determined by Western blot analysis. The ability of prostate cells to secrete osteopontin in response to IL-1ß and TGF-ß1 was determined in stromal (BHPrS-1) and epithelial (NHPrE-1 and BHPrE-1) cells by enzyme-linked immunosorbent assay. Quantitative polymerase chain reaction was used to measure gene expression changes in these cells in response to OPN. RESULTS: OPN immunostaining and protein levels were more abundant in S-BPH than I-BPH. Staining was distributed across all cell types with the highest levels in epithelial cells. Multiple OPN protein variants were identified in immortalized prostate stromal and epithelial cells. TGF-ß1 stimulated OPN secretion by NHPrE-1 cells and both IL-1ß and TGF-ß1 stimulated OPN secretion by BHPrS-1 cells. Interestingly, recombinant OPN increased the mRNA expression of CXCL1, CXCL2, CXCL8, PTGS2, and IL6 in BHPrS-1, but not in epithelial cell lines. CONCLUSIONS: OPN is more abundant in prostates of men with S-BPH compared to men with I-BPH. OPN secretion is stimulated by proinflammatory cytokines, and OPN acts directly on stromal cells to drive the synthesis of proinflammatory mRNAs. Pharmacological manipulation of prostatic OPN may have the potential to reduce LUTS by inhibiting both inflammatory and fibrotic pathways.

Green tea intake and risk of incident kidney stones: Prospective cohort studies in middle-aged and elderly Chinese individuals.

OBJECTIVES: To investigate the association between green tea intake and incident stones in two large prospective cohorts. METHODS: We examined self-reported incident kidney stone risk in the Shanghai Men's Health Study (n = 58 054; baseline age 40-74 years) and the Shanghai Women's Health Study (n = 69 166; baseline age 40-70 years). Information on the stone history and tea intake was collected by in-person surveys. Multivariable Cox proportional hazards models were adjusted for baseline demographic variables, medical history and dietary intakes including non-tea oxalate from a validated food frequency questionnaire. RESULTS: During 319 211 and 696 950 person-years of follow up, respectively, 1202 men and 1451 women reported incident stones. Approximately two-thirds of men and one-quarter of women were tea drinkers at baseline, of whom green tea was the primary type consumed (95% in men, 88% in women). Tea drinkers (men: hazard ratio 0.78, 95% confidence interval 0.69-0.88; women: hazard ratio 0.8, 95% confidence interval 0.77-0.98) and specifically green tea drinkers (men: hazard ratio 0.78, 95% confidence interval 0.69-0.88; women: hazard ratio 0.84, 95% confidence interval 0.74-0.95) had lower incident risk than never/former drinkers. Compared with never/former drinkers, a stronger dose-response trend was observed for the amount of dried tea leaf consumed/month by men (hazard ratiohighest category 0.67, 95% confidence interval 0.56-0.80, Ptrend  < 0.001) than by women (hazard ratiohighest category 0.87, 95% confidence interval 0.70-1.08, Ptrend  = 0.041). CONCLUSIONS: Green tea intake is associated with a lower risk of incident kidney stones, and the benefit is observed more strongly among men.

Analysis of Epineurial Lidocaine Injection for Nerve Transfers in a Rat Sciatic Nerve Model.

PURPOSE: Nerve transfers for peripheral nerve injuries can result in variable outcomes. We investigated the neuroprotective effect of epineurial lidocaine injection in the donor nerve prior to transection, with the hypothesis that proximal axon loss would be decreased with consequent increased neuroregeneration and functional recovery. METHODS: A rat sciatic nerve model was used with 4 intervention groups: (1) lidocaine; (2) lidocaine/calcium gluconate (CG); (3) CG; or (4) saline (control). Behavioral testing and qualitative and quantitative histological evaluation was performed at 8 and 12 weeks. Histological assays included transmission electron microscopy, retrograde fluorogold labeling, and whole mount immunostaining. RESULTS: Functional assessments through the sciatic functional index and Basso, Beattie, and Bresnahan scale showed a statistically significant increase in recovery at 8 and 12 weeks with lidocaine treatment. Significantly higher axonal counts were obtained in the lidocaine-treated groups. Fragmentation and increased myelin damage was present in the CG and saline groups. Retrograde fluorogold labeling showed a statistically significant increase in the number of L4-6 dorsal root ganglion neurons in the lidocaine-treated groups. Whole mount immunostaining identified extension of the axonal growth cone past the nerve coaptation site in lidocaine-treated groups, but not in CG and saline groups. CONCLUSIONS: Our results suggest that epineurial lidocaine injection prior to donor nerve transection for nerve transfer has a neuroprotective effect, resulting in increased proximal axon counts and improved functional recovery. CLINICAL RELEVANCE: These findings may have direct clinical application because epineurial lidocaine can be used in surgery as a simple and inexpensive intervention for promoting improved clinical outcomes after nerve transfer.

A Randomized Controlled Trial of Preoperative Prophylactic Antibiotics Prior to Percutaneous Nephrolithotomy in a Low Infectious Risk Population: A Report from the EDGE Consortium.

PURPOSE: Single institution studies suggest a benefit of a week of preoperative antibiotics prior to percutaneous nephrolithotomy. These studies are limited by lower quality methodology, such as the inclusion of heterogeneous populations or nonstandard definitions of sepsis. The AUA (American Urological Association) Best Practice Statement recommends less than 24 hours of intravenous antibiotics but to our knowledge no other data exist on the duration or benefit of preoperative antibiotics. Using CONSORT (Consolidated Reporting of Trials) guidelines we sought to perform a rigorous multi-institutional trial to assess preoperative antibiotics in patients in whom percutaneous nephrolithotomy was planned and who were at low risk for infection. MATERIALS AND METHODS: This randomized controlled trial enrolled patients undergoing percutaneous nephrolithotomy who were at low risk, defined as negative preoperative urine cultures and no urinary drain. Of the subjects 43 were randomized to nitrofurantoin 100 mg twice daily for 7 days preoperatively while a control arm of 43 received no oral antibiotics. All subjects received perioperative doses of ampicillin and gentamicin. Prone percutaneous nephrolithotomy was performed by urologists blinded to randomization. The primary outcome was the development of sepsis. RESULTS: A total of 86 subjects were enrolled. Preoperative patient characteristics were similar in the treatment and control cohorts with a stone size of 19 and 17 mm, respectively (p = 0.47). Intraoperative characteristics also did not differ. The sepsis rate was not statistically different between the treatment and control groups (12% and 14%, respectively, 95% CI -0.163-0.122, p = 1.0). Other infectious parameters and complications were similar, including intensive care admission, fever, hypotension and leukocytosis. CONCLUSIONS: Our study demonstrated no advantage to providing 1 week of preoperative oral antibiotics in patients at low risk for infectious complications who undergo percutaneous nephrolithotomy. Perioperative antibiotics according to the AUA Best Practice Statement appear sufficient.

Dusting versus Basketing during Ureteroscopy-Which Technique is More Efficacious? A Prospective Multicenter Trial from the EDGE Research Consortium.

PURPOSE: There is scant evidence in the literature to support dusting vs active basket extraction during ureteroscopy for kidney stones. We prospectively evaluated and followed patients to determine which modality produced a higher stone-free rate with the fewest complications. MATERIALS AND METHODS: Members of the Endourologic Disease Group for Excellence research consortium prospectively enrolled patients with a renal stone burden ranging from 5 to 20 mm in this study. A holmium laser was used and all patients were stented postoperatively. Ureteral access sheaths were used in 100% of basketing cases while sheaths were optional when dusting. The primary study outcome was the stone-free rate at 6 weeks as determined by x-ray and ultrasound. RESULTS: A total of 84 and 75 patients were enrolled in the basketing and dusting arms, respectively. Stones in the dusting group were significantly larger (mean ± SD stone area 96.1 ± 65.3 vs 63.3 ± 46.0 mm2, p <0.001). The stone-free rate was significantly higher in the basketing group on univariate analysis (74.3% vs 58.2%, p = 0.04) but not on multivariate analysis (1.9 OR, 95% CI 0.9-4.3, p = 0.11). In patients who underwent a basketing procedure operative time was 37.7 minutes longer than in those treated with a dusting procedure (95% CI 23.8-51.7, p <0.001). There was no statistically significant difference in complication rates, hospital readmissions or additional procedures between the groups. CONCLUSIONS: The stone-free rate was higher for active basket retrieval of fragments at short-term followup on univariate analysis but not on multivariate analysis. There was no difference in postoperative complications or procedures. The 2 techniques should be in the armamentarium of the urologist.

Outcomes of Holmium Laser Enucleation of the Prostate in the Re-Treatment Setting.

PURPOSE: Holmium laser enucleation of the prostate can also be applied in the re-treatment setting when other benign prostatic hyperplasia therapies fail. We compared outcomes in men who underwent holmium laser enucleation of the prostate in the primary vs the re-treatment setting. MATERIALS AND METHODS: We retrospectively reviewed the records of 2,242 patients who underwent holmium laser enucleation of the prostate at a total of 4 academic hospitals between 2003 and 2015. Patient demographics, and operative and perioperative outcomes were compared between re-treatment and primary holmium laser enucleation of the prostate. RESULTS: Of the 360 of 2,242 men (16%) who underwent re-treatment holmium laser enucleation of the prostate the procedure was done for residual urinary symptoms in 71%. The most common primary procedure was transurethral resection of the prostate in 42% of cases. Mean time between prior benign prostatic hyperplasia surgery and re-treatment was 68 months (range 1 to 444). There were no significant differences in age, prostate size, AUA (American Urological Association) symptom score or average flow rate between the cohorts. Perioperatively, re-treatment holmium laser enucleation of the prostate was associated with significantly shorter operative time, reduced blood loss, lower specimen weight and shorter length of stay. The AUA symptom score improved in both groups, although it remained higher in men who underwent re-treatment (6.5 vs 5.0, p <0.001). The likelihood of clot retention (4.7% vs 1.8%, p = 0.01) and urethral stricture (3.3% vs 1.5%, p = 0.043) was slightly higher in the re-treatment group. CONCLUSIONS: Immediate perioperative outcomes of holmium laser enucleation of the prostate performed in the re-treatment setting were no different from those in the primary setting. While re-treatment was associated with an increased likelihood of clot retention, urethral stricture and higher AUA symptom score, these minimal differences must be considered against the overall favorable symptom improvement across both cohorts.

Holmium Laser Enucleation of the Prostate: Patient Selection and Outcomes.

PURPOSE OF REVIEW: Holmium laser enucleation of the prostate (HoLEP) is a proven technique to alleviate bladder outlet obstruction (BOO) from benign prostatic hyperplasia (BPH). Herein, we review factors relevant to selecting patients who will benefit from this procedure and expected outcomes. RECENT FINDINGS: New randomized trials have validated the excellent outcomes achieved by HoLEP in the management of BOO from BPH. Its success has been reproduced in a diverse array of patients including those on anticoagulation, with detrusor underactivity/acontractility, prostate cancer, and in the retreatment setting. HoLEP can be applied to the majority of patients with BOO from BPH regardless of prostate size, previous operations, or the condition of the detrusor. HoLEP can also be carefully considered in patients requiring anticoagulation or who are undergoing active surveillance for low-risk prostate cancer. Immediate complication rate is low and incontinence is rare. Retrograde ejaculation occurs in approximately 75% patients. Furthermore, the retreatment rate for HoLEP is lower than reported for other endoscopic BPH procedures demonstrating its durability.

NF-κB and androgen receptor variant 7 induce expression of SRD5A isoforms and confer 5ARI resistance.

BACKGROUND: Benign prostatic hyperplasia (BPH) is treated with 5α-reductase inhibitors (5ARI). These drugs inhibit the conversion of testosterone to dihydrotestosterone resulting in apoptosis and prostate shrinkage. Most patients initially respond to 5ARIs; however, failure is common especially in inflamed prostates, and often results in surgery. This communication examines a link between activation of NF-κB and increased expression of SRD5A2 as a potential mechanism by which patients fail 5ARI therapy. METHODS: Tissue was collected from "Surgical" patients, treated specifically for lower urinary tract symptoms secondary to advanced BPH; and, cancer free transition zone from "Incidental" patients treated for low grade, localized peripheral zone prostate cancer. Clinical, molecular and histopathological profiles were analyzed. Human prostatic stromal and epithelial cell lines were genetically modified to regulate NF-κB activity, androgen receptor (AR) full length (AR-FL), and AR variant 7 (AR-V7) expression. RESULTS: SRD5A2 is upregulated in advanced BPH. SRD5A2 was significantly associated with prostate volume determined by Transrectal Ultrasound (TRUS), and with more severe lower urinary tract symptoms (LUTS) determined by American Urological Association Symptom Score (AUASS). Synthesis of androgens was seen in cells in which NF-κB was activated. AR-FL and AR-V7 expression increased SRD5A2 expression while forced activation of NF-κB increased all three SRD5A isoforms. Knockdown of SRD5A2 in the epithelial cells resulted in significant reduction in proliferation, AR target gene expression, and response to testosterone (T). In tissue recombinants, canonical NF-κB activation in prostatic epithelium elevated all three SRD5A isoforms and resulted in in vivo growth under castrated conditions. CONCLUSION: Increased BPH severity in patients correlates with SRD5A2 expression. We demonstrate that NF-κB and AR-V7 upregulate SRD5A expression providing a mechanism to explain failure of 5ARI therapy in BPH patients. Prostate 76:1004-1018, 2016. © 2016 Wiley Periodicals, Inc.

NF-κB and androgen receptor variant expression correlate with human BPH progression.

BACKGROUND: Benign prostatic hyperplasia (BPH) is a common, chronic progressive disease. Inflammation is associated with prostatic enlargement and resistance to 5α-reductase inhibitor (5ARI) therapy. Activation of the nuclear factor-kappa B (NF-κB) pathway is linked to both inflammation and ligand-independent prostate cancer progression. METHODS: NF-κB activation and androgen receptor variant (AR-V) expression were quantified in transition zone tissue samples from patients with a wide range of AUASS from incidental BPH in patients treated for low grade, localized peripheral zone prostate cancer to advanced disease requiring surgical intervention. To further investigate these pathways, human prostatic stromal and epithelial cell lines were transduced with constitutively active or kinase dead forms of IKK2 to regulate canonical NF-κB activity. The effects on AR full length (AR-FL) and androgen-independent AR-V expression as well as cellular growth and differentiation were assessed. RESULTS: Canonical NF-κB signaling was found to be upregulated in late versus early stage BPH, and to be strongly associated with non-insulin dependent diabetes mellitus. Elevated expression of AR-variant 7 (AR-V7), but not other AR variants, was found in advanced BPH samples. Expression of AR-V7 significantly correlated with the patient AUASS and TRUS volume. Forced activation of canonical NF-κB in human prostatic epithelial and stromal cells resulted in elevated expression of both AR-FL and AR-V7, with concomitant ligand-independent activation of AR reporters. Activation of NF-κB and over expression of AR-V7 in human prostatic epithelial cells maintained cell viability in the face of 5ARI treatment. CONCLUSION: Activation of NF-κB and AR-V7 in the prostate is associated with increased disease severity. AR-V7 expression is inducible in human prostate cells by forced activation of NF-κB resulting in resistance to 5ARI treatment, suggesting a potential mechanism by which patients may become resistant to 5ARI therapy.

Comparison of Holmium Laser Prostate Enucleation Outcomes in Patients with or without Preoperative Urinary Retention.

PURPOSE: We determine whether outcomes of holmium laser enucleation of the prostate are similar in patients with and those without preoperative urinary retention. MATERIALS AND METHODS: From May 2008 to July 2014, 231 patients underwent holmium laser prostate enucleation for symptomatic benign prostatic hyperplasia. Retrospective analysis was performed to evaluate for differences in postoperative outcomes for patients with and those without preoperative urinary retention. RESULTS: Overall 95 patients (41%) had urinary retention before holmium laser prostate enucleation while 136 (59%) did not. Mean followup for all patients was 15.3 months. Patients with retention tended to be older, have larger prostates, and have higher scores on the AUA SS and bother questionnaires (all p <0.05). Postoperatively there was no difference in rates of complications, including urinary retention. Both groups showed significant improvement in AUA SS and bother score after the procedure at all postoperative points. Median post-void residual was less than 60 ml and median maximum flow rate on uninstrumented uroflow was greater than 18 ml per second at all postoperative points for all patients regardless of preoperative retention status. No patients required long-term catheterization and rates of postoperative complications did not differ significantly during the followup period. CONCLUSIONS: This study represents the first direct comparison to our knowledge of holmium laser prostate enucleation outcomes in patients with or without urinary retention. There was no increased risk of postoperative urinary retention in patients with preoperative retention, and both groups demonstrated significant postoperative improvement in subjective and objective voiding measures.

Narcotic Use and Postoperative Doctor Shopping by Patients with Nephrolithiasis Requiring Operative Intervention: Implications for Patient Safety.

PURPOSE: We sought to determine perioperative patterns of narcotic use and the prevalence of postoperative doctor shopping among patients with nephrolithiasis requiring operative management. MATERIALS AND METHODS: We retrospectively reviewed the records of consecutive patients residing in Tennessee who required ureteroscopy with laser lithotripsy for nephrolithiasis at a single institution from January to December 2013. Using the Tennessee CSMD (Controlled Substances Medication Database) patients were categorized by the number of postoperative narcotic providers. Doctor shopping behavior was identified as any patient seeking more than 1 narcotic provider within 3 months of surgery. Demographic and clinical characteristics associated with doctor shopping behavior were identified. RESULTS: During the study period 200 eligible patients underwent ureteroscopy with laser lithotripsy for nephrolithiasis, of whom 48 (24%) were prescribed narcotics by more than 1 provider after surgery. Compared to those receiving narcotics from a single provider, patients with multiple narcotic providers were younger (48.1 vs 54.2 years, p <0.001), less educated (high school education or less in 83.3% vs 58.7%, p = 0.014), more likely to have a history of mental illness (37.5% vs 16%, p <0.01) and more likely to have undergone prior stone procedures (66% vs 42%, p <0.01). Additionally, these patients demonstrated more frequent preoperative narcotic use (87.5% vs 63.2%), longer postoperative narcotic use (39.1 vs 6.0 days) and a higher morphine equivalent dose per prescription (44.7 vs 35.2 dose per day, each p <0.001). CONCLUSIONS: Postoperative doctor shopping is common among patients with nephrolithiasis who require operative management. Urologists should be aware of available registry data to decrease the likelihood of redundant narcotic prescribing.

Surgical Management of Stones: American Urological Association/Endourological Society Guideline, PART II.

PURPOSE: This Guideline is intended to provide a clinical framework for the surgical management of patients with kidney and/or ureteral stones. The summary presented herein represents Part II of the two-part series dedicated to Surgical Management of Stones: American Urological Association/Endourological Society Guideline. Please refer to Part I for introductory information and a discussion of pre-operative imaging and special cases. MATERIALS AND METHODS: A systematic review of the literature (search dates 1/1/1985 to 5/31/2015) was conducted to identify peer-reviewed studies relevant to the surgical management of stones. The review yielded an evidence base of 1,911 articles after application of inclusion/exclusion criteria. These publications were used to create the Guideline statements. Evidence-based statements of Strong, Moderate, or Conditional Recommendation were developed based on benefits and risks/burdens to patients. Additional directives are provided as Clinical Principles and Expert Opinions when insufficient evidence existed. RESULTS: The Panel identified 12 adult Index Patients to represent the most common cases seen in clinical practice. Three additional Index Patients were also created to describe the more commonly encountered special cases, including pediatric and pregnant patients. With these patients in mind, Guideline statements were developed to aid the clinician in identifying optimal management. CONCLUSIONS: Proper treatment selection, which is directed by patient- and stone-specific factors, remains the greatest predictor of successful treatment outcomes. This Guideline is intended for use in conjunction with the individual patient's treatment goals. In all cases, patient preferences and personal goals should be considered when choosing a management strategy.

Surgical Management of Stones: American Urological Association/Endourological Society Guideline, PART I.

PURPOSE: This Guideline is intended to provide a clinical framework for the surgical management of patients with kidney and/or ureteral stones. The summary presented herein represents Part I of the two-part series dedicated to Surgical Management of Stones: American Urological Association/Endourological Society Guideline. Please refer to Part II for an in-depth discussion of patients presenting with ureteral or renal stones. MATERIALS AND METHODS: A systematic review of the literature (search dates 1/1/1985 to 5/31/2015) was conducted to identify peer-reviewed studies relevant to the surgical management of stones. The review yielded an evidence base of 1,911 articles after application of inclusion/exclusion criteria. These publications were used to create the Guideline statements. Evidence-based statements of Strong, Moderate, or Conditional Recommendation were developed based on benefits and risks/burdens to patients. Additional directives are provided as Clinical Principles and Expert Opinions when insufficient evidence existed. RESULTS: The Panel identified 12 adult Index Patients to represent the most common cases seen in clinical practice. Three additional Index Patients were also created to describe pediatric and pregnant patients with such stones. With these patients in mind, Guideline statements were developed to aid the clinician in identifying optimal management. CONCLUSIONS: Proper treatment selection, which is directed by patient- and stone-specific factors, remains the greatest predictor of successful treatment outcomes. This Guideline is intended for use in conjunction with the individual patient's treatment goals. In all cases, patient preferences and personal goals should be considered when choosing a management strategy.