PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (405)
 

Clipboard (0)
None
Journals
Year of Publication
more »
1.  Neoadjuvant chemotherapy for primary adenocarcinomas of the urinary bladder: a single-site experience 
BMC Urology  2015;15(1):3.
Background
Adenocarcinoma of the urinary bladder is a rare malignancy. Radical surgery is suggested as the best available treatment for early-stage disease, but there is currently no consensus on standard chemotherapy regimen for advanced stage. We assessed the feasibility and effect of neoadjuvant chemotherapy with gemcitabine and cisplatin (GC) plus S-1 for patients with locally advanced primary adenocarcinomas of the urinary bladder.
Methods
Six patients with locally advanced urachal or non-urachal (n = 3, each) primary adenocarcinoma of the bladder were treated from October 2010 to October 2013 at a single center. All the patients were treated with 3 cycles (21d, each) of GC plus S-1 (gemcitabine, 1000 mg/m2, days 1 and 8; cisplatin, 70 mg/m2, day 2; and S-1, 50 mg bid, day 1-14). After neoadjuvant chemotherapy, patients with urachal cancer were treated with en bloc radical cystectomy and umbilectomy; the remaining 3 patients were treated with cystectomy.
Results
All patients successfully completed the neoadjuvant chemotherapy without serious side effects. Two patients were assessed as complete response, 2 as partial response, 1 as stable disease and 1 as progressive disease.
Conclusions
Despite the limitations of a small study population, the GC plus S-1 regimen for locally advanced primary adenocarcinoma of the urinary bladder was effective, and facilitated the success of surgery to a certain extent. Short follow-up time was also a limitation of our study. More studies are needed to evaluate the results.
doi:10.1186/1471-2490-15-3
PMCID: PMC4328949  PMID: 25631709
Neoadjuvant chemotherapy; Primary adenocarcinomas of bladder; Survival
2.  Expression of parathyroid hormone/parathyroid hormone-related peptide receptor 1 in normal and diseased bladder detrusor muscles: a clinico-pathological study 
BMC Urology  2015;15(1):2.
Background
To investigate the expression of parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor 1 (PTH1R) in clinical specimens of normal and diseased bladders. PTHrP is a unique stretch-induced endogenous detrusor relaxant that functions via PTH1R. We hypothesized that suppression of this axis could be involved in the pathogenesis of bladder disease.
Methods
PTH1R expression in clinical samples was examined by immunohistochemistry. Normal kidney tissue from a patient with renal cancer and bladder specimens from patients undergoing ureteral reimplantation for vesicoureteral reflux or partial cystectomy for urachal cyst were examined as normal control organs. These were compared with 13 diseased bladder specimens from patients undergoing bladder augmentation. The augmentation patients ranged from 8 to 31 years old (median 15 years), including 9 males and 4 females. Seven patients had spinal disorders, 3 had posterior urethral valves and 3 non-neurogenic neurogenic bladders (Hinman syndrome).
Results
Renal tubules, detrusor muscle and blood vessels in normal control bladders stained positive for PTH1R. According to preoperative urodynamic studies of augmentation patients, the median percent bladder capacity compared with the age-standard was 43.6% (range 1.5–86.6%), median intravesical pressure at maximal capacity was 30 cmH2O (range 10–107 cmH2O), and median compliance was 3.93 ml/cmH2O (range 0.05–30.3 ml/cmH2O). Detrusor overactivity was observed in five cases (38.5%). All augmented bladders showed negative stainings in PTH1R expression in the detrusor tissue, but positive staining of blood vessels in majority of the cases.
Conclusions
Downregulation of PTH1R may be involved in the pathogenesis of human end-stage bladder disease requiring augmentation.
doi:10.1186/1471-2490-15-2
PMCID: PMC4320578  PMID: 25604159
Parathyroid hormone-related peptide; Parathyroid hormone 1 receptor; Bladder compliance; Smooth muscle
3.  Effectiveness of preoperative pelvic floor muscle training for urinary incontinence after radical prostatectomy: a meta-analysis 
BMC Urology  2014;14(1):99.
Background
Radical prostatectomy (RP) is the most common treatment for patients with localized prostate cancer. Urinary incontinence (UI) is a significant bothersome sequela after radical prostatectomy that may dramatically worsen a patient’s quality of life. Pelvic floor muscle training (PFMT) is the main conservation treatment for men experiencing urinary incontinence; however, whether additional preoperative PFMT can hasten the reestablishment of continence is still unclear. The objective of this meta-analysis is to determine whether the effectiveness of preoperative plus postoperative PFMT is better than postoperative PFMT only for the re-establishment of continence after RP.
Methods
A meta-analysis was performed after a comprehensive search of available randomized controlled trials (RCTs). Quality of the included studies was assessed by the Cochrane Risk of Bias tool. Efficacy data were pooled and analyzed using Review Manager (RevMan) Version 5.0. Pooled analyses of continence rates 1, 3, 6, and 12 months postoperatively, using relative risk (RR) and 95% confidence intervals (CIs), were conducted. For data deemed not appropriate for synthesis, a narrative overview was conducted.
Results
Five eligible studies were ultimately included in this analysis. No significant differences in continence rates were detected at the early (1- and 3-month) time points: RR = 1.21, 95% CI = 0.71–2.08, P = 0.48; RR = 1.1, 95% CI = 0.09–1.34, P = 0.34, respectively), interim (6-month time point: RR = 0.98, 95% CI = 0.93–1.04, P = 0.59), or late recovery stage (RR = 0.93, 95% CI = 0.67–1.29, P = 0.66). Outcomes reported were time to continence in two trials and quality of life in three, but results were inconclusive because of insufficient data.
Conclusion
According to this meta-analysis, additional preoperative PFMT did not improve the resolution of UI after RP at early (≤3-month), interim (6-month), or late (1-year) recovery stages. However, the results of time to continence and quality of life were inconclusive because of insufficient data. More high-quality RCTs are needed for better evaluation of the effectiveness of preoperative PFMT on post-prostatectomy UI.
doi:10.1186/1471-2490-14-99
PMCID: PMC4274700  PMID: 25515968
Pelvic floor muscle training; Urinary incontinence; Prostate cancer; Meta-analysis
4.  Black and White men younger than 50 years of age demonstrate similar outcomes after radical prostatectomy 
BMC Urology  2014;14(1):98.
Background
Black men with prostate cancer are diagnosed at a younger age, present with more aggressive disease, and experience higher mortality. We sought to assess pathological features and biochemical recurrence (BCR) in young men undergoing radical prostatectomy (RP) to determine if there is a difference between black and white men closer to the time of disease initiation.
Methods
We identified 551 white and 99 black men at a tertiary cancer center who underwent RP at ≤50 years of age. Baseline and pathological features were compared between the two groups. Cox proportional hazards models were utilized to examine the association of race and BCR, and Kaplan-Meier curves were generated to determine biochemical recurrence-free survival (bRFS).
Results
There were no differences in median age at surgery, biopsy Gleason score, or comorbidity. Black men had higher preoperative PSA (6.1 ng/ml vs 4.7 ng/ml, p = 0.004), but a greater percentage were cT1c (78% vs 63%), compared to white men. On multivariate analysis, black men demonstrated significantly lower odds of non-organ confined disease (OR 0.39; 95% CI: 0.18, 0.81; p = 0.01) and extracapsular extension (ECE) (OR 0.38; 95% CI: 0.18, 0.81, p = 0.01), and had no difference in Gleason score upgrading and seminal vesicle invasion compared to white men. There was no significant difference in bRFS in men with organ-confined disease; however, among men with locally advanced disease black men trended towards greater BCR (p = 0.052). Black men had 2-year bRFS of 56% vs 75% in white men.
Conclusions
In this single institution study, there does not appear to be a racial disparity in outcomes among younger men who receive RP for prostate cancer. Black and white men in our cohort demonstrate similar bRFS with pathologically confirmed organ-confined disease. There may be greater risk of BCR among black men locally advanced disease compared to white men, suggesting that locally advanced disease is biologically more aggressive in black men.
doi:10.1186/1471-2490-14-98
PMCID: PMC4269868  PMID: 25495177
Prostate cancer; Radical prostatectomy; Race; Biochemical recurrence; Disparities; Age
5.  Oncologic results of Nephron sparing endoscopic approach for upper tract low grade transitional cell carcinoma in comparison to nephroureterectomy – a case control study 
BMC Urology  2014;14(1):97.
Background
There is paucity of data as to the results of the endoscopic approach in comparison to the golden standard of nephro-ureterectomy in elective, low grade TCC, patients. Our purpose is to report our results of a nephron sparing approach compared to nephro-ureterectomy in those patients.
Methods
From a retrospective data base we identified 25 patients and 23 patients who underwent a nephron sparing ureterosocpic resection and nephro-reterectomy for low grade UT-TCC, respectively. The endoscopic technique included endoscopic tumor biopsy followed by primary resection and/or fulguration. The nephron sparing group was followed by bi-annual ureteroscopy and upper tract imaging, timely cystoscopy and urine cytology collection. Data for overall and disease related mortality, bladder and ureteral TCC recurrence and renal function are reported in both groups.
Results
Median follow - up time was 26 months. 11 (44%) patients developed bladder recurrence at a median period of 9 months after initial ureteroscopy, compared to 9 (39%) in the NUx group (P < 0.05). Recurrent ureteral low grade TCC was observed in 9 patients (median: 9 months). All were treated endoscopicaly successfully. Renal function remained stable in the nephron sparing group. No disease related mortality was recorded in the nephron-sparing group while one patient died of his disease following NUx.
Conclusions
Disease related mortality following a nephron sparing endoscopic approach or nephroureterectomy for low grade upper tract TCC is excellent. However, the nephron sparing approach is associated with a relatively high rate of ureteral and bladder recurrence. Therefore, a stringent follow-up protocol is required.
doi:10.1186/1471-2490-14-97
PMCID: PMC4265434  PMID: 25468319
Upper tract TCC; Nephron sparing; Ureteroscopy
6.  A rare case of unilateral adrenal hyperplasia accompanied by hypokalaemic periodic paralysis caused by a novel dominant mutation in CACNA1S: features and prognosis after adrenalectomy 
BMC Urology  2014;14(1):96.
Background
Acute hypokalaemic paralysis is characterised by acute flaccid muscle weakness and has a complex aetiological spectrum. Herein we report, for the first time, a case of unilateral adrenal hyperplasia accompanied by hypokalaemic periodic paralysis type I resulting from a novel dominant mutation in CACNA1S. We present the clinical features and prognosis after adrenalectomy in this case.
Case presentation
A 43-year-old Han Chinese male presented with severe hypokalaemic paralysis that remitted after taking oral potassium. The patient had suffered from periodic attacks of hypokalaemic paralysis for more than 20 years. A computed tomography (CT) scan of the abdomen showed a nodular mass on the left adrenal gland, although laboratory examination revealed the patient had not developed primary aldosteronism. The patient underwent a left adrenalectomy 4 days after admission, and the pathological examination further confirmed a 1.1 cm benign nodule at the periphery of the adrenal gland. Three months after the adrenalectomy, a paralytic attack recurred and the patient asked for assistance from the Department of Medical Genetics. His family history showed that two uncles, one brother, and a nephew also had a history of periodic paralysis, although their symptoms were milder. The patient’s CACNA1S and SCN4A genes were sequenced, and a novel missense mutation, c.1582C > T (p.Arg528Cys), in CACNA1S was detected. Detection of the mutation in five adult male family members, including three with periodic paralysis and two with no history of the disease, indicated that this mutation caused hypokalaemic periodic paralysis type I in his family. Follow-up 2 years after adrenalectomy showed that the serum potassium concentration was increased between paralyses and the number and severity of paralytic attacks were significantly decreased.
Conclusion
We identified a novel dominant mutation, c.1582C > T (p.Arg528Cys), in CACNA1S that causes hypokalaemic periodic paralysis. The therapeutic effect of adrenalectomy indicated that unilateral adrenal hyperplasia might make paralytic attacks more serious and more frequent by decreasing serum potassium. This finding suggests that the surgical removal of hyperplastic tissues might relieve the symptoms of patients with severe hypokalaemic paralysis caused by other incurable diseases, even if the adrenal lesion does not cause primary aldosteronism.
doi:10.1186/1471-2490-14-96
PMCID: PMC4259161  PMID: 25430699
Unilateral adrenal hyperplasia; Hypokalaemic periodic paralysis; CACNA1S; Adrenalectomy
7.  Prognostic value of preoperative neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios, and multiphasic renal tomography findings in histological subtypes of renal cell carcinoma 
BMC Urology  2014;14(1):95.
Background
To determine the relationship between renal cell carcinoma subtypes and the associated mortality and biochemical parameters. An additional aim was to analyze multiphasic multidetector computed tomography findings.
Methods
This study is a hospital-based retrospective investigation, using 211 patients with a diagnosis of renal cell carcinoma upon computed tomography examination. The histological subtypes included clear cell in 119 patients, chromophobe cell in 30 patients, papillary cell in 25 patients, mixed cell in 32 patients, and sarcomatoid cell in 4 patients.
Results
The mean age of the patients participating in this study was 61.18 ± 11.81 years, and the mortality rate was 10.4% (n = 22) through the 2-year follow-up. The ratios of both the neutrophil-to-lymphocyte upon admission to the hospital and platelet-to-lymphocyte of the non-surviving group were significantly higher than those of the surviving group (p < 0.05). When the analysis of the 2-year survival of the patients was examined according to the median platelet-to-lymphocyte ratio values, the Kaplan-Meier survival curves were significantly different between the surviving and non-surviving groups (p = 0.01). In two-way analysis of variance test, statistically significant results which were influenced by mortality (p = 0.028) and were found between renal cell carcinoma subtypes in the computed tomography density of corticomedullary phase (p = 0.001).
Conclusions
The neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio may represent widely available biomarkers in renal cell carcinoma, and the logistic regression model indicated that neutrophil-to-lymphocyte ratio was a significant predictor for mortality. According to the median platelet-to-lymphocyte ratio values, the Kaplan-Meier survival curves were significantly different between the surviving and non-surviving groups.
doi:10.1186/1471-2490-14-95
PMCID: PMC4280708  PMID: 25427576
Renal cell carcinoma; Neutrophil-to-lymphocyte ratio; Platelet-to-lymphocyte ratio; Multiphasic multidetector tomography; Mortality
8.  Prostatic artery embolization versus conventional TUR-P in the treatment of benign prostatic hyperplasia: protocol for a prospective randomized non-inferiority trial 
BMC Urology  2014;14(1):94.
Background
Benign prostatic hyperplasia (BPH) is a prevalent entity in elderly men and transurethral resection of the prostate (TURP) still represents the gold standard of surgical treatment despite its considerable perioperative morbidity. Recently, prostatic artery embolization (PAE) was described as a novel effective and less invasive treatment alternative. Despite promising first results, PAE still has to be considered experimental due to a lack of good quality studies. Prospective randomized controlled trials comparing PAE with TUR-P are highly warranted.
Methods/design
This is a single-centre, prospective, randomized, non-inferiority trial comparing treatment effects and adverse events of PAE and TURP in a tertiary referral centre. One hundred patients who are electable for both treatment options are randomized to either PAE or TURP. Changes of the International Prostate Symptom Score (IPSS) after 3 months are defined as primary endpoint. Changes in bladder diaries, laboratory analyses, urodynamic investigations and standardised questionnaires are assessed as secondary outcome measures. In addition contrast-enhanced magnetic resonance imaging of the pelvis before and after the interventions will provide crucial information regarding morphological changes and vascularisation of the prostate. Adverse events will be assessed on every follow-up visit in both treatment arms according to the National Cancer Institute Common Terminology Criteria for Adverse events and the Clavien classification.
Discussion
The aim of this study is to assess whether PAE represents a valid treatment alternative to TURP in patients suffering from BPH in terms of efficacy and safety.
Trial registration
ClinicalTrials.gov NCT02054013.
doi:10.1186/1471-2490-14-94
PMCID: PMC4258033  PMID: 25425136
Prostate; Benign prostatic hyperplasia; Transurethral resection of the prostate; Embolization; Prostatic artery embolization; Comparative clinical trial
9.  2-octyl cyanoacrylate versus reintervention for closure of urethrocutaneous fistulae after urethroplasty for hypospadias: a randomized controlled trial 
BMC Urology  2014;14(1):93.
Background
Urethrocutaneous fistulae (UCFs) represent one of the most frequent causes of morbidity after urethroplasty. Hypospadias can be repaired using different surgical techniques, but—regardless of technique—the incidence of UCF ranges between 10% and 40%. Surgical repair of UCF remains the treatment of choice, even if some patients need further surgery because of recurrences. Cyanoacrylates have been used as skin suture substitutes, and some evidence suggests a beneficial effect when these adhesives are used as an adjuvant in the management of UCF. Here we describe the results of management of UCF using 2-octyl cyanoacrylate (OCA) compared with surgical repair.
Methods
A randomized clinical trial conducted from January 2008 to December 2012 included 42 children with UCF complications after urethroplasty for hypospadias. Twenty-one children were assigned to receive OCA as ambulatory patients and 21 were treated surgically. The main outcome variable was closure of the UCF. The estimated costs of both treatments were also calculated, as were absolute risk reduction (ARR), relative risk reduction (RRR) and number needed to treat (NNT) to prevent a surgical intervention.
Results
The mean numbers of UCF were 1.3 in the OCA group (n = 28) and 1.1 in the surgical group (n = 25) with no statistically significant difference. The external orifices measured were 2.96 ± 1.0 mm and 3.8 ± 0.89 mm, respectively (NS). Sixty per cent of the UCFs treated with cyanoacrylate were completely closed and 68% of the surgical group healed completely (NS). More than one reoperation to improve complications was needed in the surgical group (3.5 ± 1.2). The clinical significance of the therapeutic usefulness of OCA was demonstrated by an ARR of 0.08, RRR of 0.25 and NNT of 12 to avoid further surgical treatment. The total costs of adhesive applications and reoperations were $US 14,809.00 and $US 158,538.50, respectively.
Conclusions
The results showed a similar success rate for both treatments. However, sealant use should be considered before surgical treatment because this is a simple outpatient procedure with a reasonable success rate.
Trial registration
ClinicalTrials.gov Identifier: NCT02115191. Date: April 13, 2014.
doi:10.1186/1471-2490-14-93
PMCID: PMC4246544  PMID: 25416602
Hypospadias; Urethrocutaneous fistula; 2-Octyl cyanoacrylate; Fistula repair
10.  Staging lymphadenectomy in patients with localized high risk prostate cancer: comparison of the laparoendoscopic single site (LESS) technique with conventional multiport laparoscopy 
BMC Urology  2014;14(1):92.
Background
In patients with localized high-risk prostate cancer awaiting radiation therapy, pelvic lymphadenectomy (PL) is a reliable minimally invasive staging procedure. We compared outcomes after laparoendoscopic single site PL (LESSPL) with those after conventional multiport laparoscopic PL (MLPL).
Methods
A retrospective case-control study was carried out at the authors’ center. For LESSPL the reusable X-Cone single port was combined with straight and prebent laparoscopic instruments and an additional 3 mm needlescopic grasper. MLPL was performed via four trocars of different sizes using standard laparoscopic instruments.
Results
Patients who underwent either LESSPL (n = 20) or MLPL (n = 97) between January 2008 and July 2013, were included in the study. Demographic data were comparable between groups. Patients in the LESSPL group tended to be older and had a significantly higher ASA-score. The mean operating time was 172.4 ± 34.1 min for LESSPL and 116.6 ± 40.1 min for MLPL (P < .001). During LESSPL, no conversion to MLPL was necessary. An average of 12 lymph nodes per patient was retrieved, with no significant difference between study groups. Postoperative pain scores were similar between groups. The hospital stay was 2.3 ± 0.7 days after LESSPL and 3.1 ± 1.2 days after MLPL (P = .01). Two days postoperatively, significantly more patients after LESSPL than after MLPL recovered their normal physical activity (P < .001). Six months postoperatively, no complications were registered in the LESSPL group and cosmetic results were excellent.
Conclusions
In the present study, shorter hospitalization and quicker postoperative recovery were major benefits of LESSPL over MLPL. In patients with localized prostate cancer, staging LESS pelvic lymphadenectomy may be a safe alternative to conventional multiport laparoscopy.
doi:10.1186/1471-2490-14-92
PMCID: PMC4247718  PMID: 25412566
Laparoscopy; LESS; Single port; Prostate cancer staging
11.  Bladder irrigation and urothelium disruption: a reminder apropos of a case of fatal fluid absorption 
BMC Urology  2014;14(1):91.
Background
Irrigation or washouts of the bladder are usually performed in various clinical settings. In the 1980s Elliot and colleagues argued that urothelial damage could occur after washouts and irrigations of the bladder. The exact mechanism underlying urothelial damage has not yet been discovered. To our knowledge, this is the first report of fatal fluid overload and pulmonary edema, due to urothelium disruption occurring during bladder irrigation, approached performing complete histological and immunohistochemical investigation on bladder specimens. The exposed case deserves attention since it demonstrates that, although very rarely, irrigation or washouts of the bladder may have unexpected serious clinical consequences.
Case presentation
An 85 year-old Caucasian man, unable to eat independently and whose fluid intake was controlled, underwent continuous bladder irrigation with a 3-way catheter due to a severe episode of macrohematuria. During the third day of hospitalization, while still undergoing bladder irrigation, he suddenly experienced extreme shortness of breath, breathing difficulties, and cough with frothy sputum. His attending nurse immediately noted that there was no return of the fluid (5 liters) introduced through bladder irrigation. He was treated urgently with hemodialysis. At the beginning of the dialysis treatment, the patient had gained 7.4 kg since the previous measurement (24 hours prior) without any clear explanation. Although a significant weight loss (from 81 to 76 kg) due to the dialysis procedure, the patient died shortly after the final treatment. The autopsy revealed that the brain and the lungs were heavily edematous. Microscopic examination of bladder specimens revealed interstitial and mucosal swelling, and loss of the superficial cell layer. Intermediate and basal urothelial cells were preserved. Altogether the abovementioned findings were suggestive of a diffuse disruption of the urothelium. In conclusion the death of the man was attributed to an acute severe pulmonary edema due to massive fluid absorption.
Conclusion
Our case demonstrates that urothelium disruption may occur during irrigation and washouts of the bladder, also in the absence of other well-known predisposing conditions. Inappropriate use of bladder irrigation should be avoided and a close attention is required of the fluid balance is mandatory when irrigating the bladder.
doi:10.1186/1471-2490-14-91
PMCID: PMC4247597  PMID: 25410651
Bladder irrigation; Fluid absorption; Pulmonary edema; Urothelium disruption
12.  Pure intracorporeal laparoscopic radical cystectomy with orthotopic “U” shaped ileal neobladder 
BMC Urology  2014;14(1):89.
Background
Radical cystectomy with pelvic lymph node dissection represents the standard treatment for muscle-invasive, and high-risk non-muscle-invasive bladder cancers. Aim of this study was to report our case series of 30 patients undergoing totally laparoscopic radical cystectomy (LRC) with reconstruction of an intracorporeal orthotopic ileal neobladder. Intra- and perioperative results and the functional and oncological outcomes 9 months after operation are reported.
Methods
Between October 2010 and December 2012, 30 male patients underwent LRC with a pure laparoscopic orthotopic ileal “U”- shaped neobladder diversion. The men had a median age of 67 years, a median body mass index of 22.3, and a mean ASA score of 2.2; they represented various clinical stages of disease.
Results
None of the patients required conversion to open surgery, and no perioperative mortalities were reported. The median operating time was 365 min, and the median blood loss was 290 mL, with a transfusion rate of 26.6%. All surgical margins were negative; 8 patients with non–organ-confined disease or positive lymph nodes received adjuvant chemotherapy. Early complications (within 30 days) occurred in 7 patients, and late complications occurred in 6 patients. The mean hospital stay was 9 days. At 9 months after surgery, the daytime continence rate was 83.3% and the nighttime continence rate was 73.3%.
Conclusions
Pure LRC with intracorporeal orthotopic ileal neobladder reconstruction may represent a viable alternative to open radical cystectomy, with a significant reduction in patient morbidity. Future, large, randomized controlled trials with extensive follow-up are needed to confirm our encouraging results.
doi:10.1186/1471-2490-14-89
PMCID: PMC4239397  PMID: 25403723
Laparoscopic radical cystectomy; Orthotopic neobladder; Urinary diversion; Ileal neobladder; Bladder cancer
13.  Pain and satisfaction during rigid cystoscopic ureteral stent removal: a preliminary study 
BMC Urology  2014;14(1):90.
Background
Cystoscopy evokes discomfort and pain, especially in males. The cystoscopic retrograde approach is standard in the removal of ureteral stents. However the satisfaction and degree of pain during the procedure according to the use of several pain controlling methods are unclear.
Methods
This is a cross-sectional survey of 60 patients who underwent cystoscopic ureteral stent removal under intravenous analgesics (group 1, n = 20), midazolam induction (group 2, n = 20), and propofol (group 3, n = 20). Procedural pain and post-procedure satisfaction were determined, and cost differences between the approaches were clarified.
Results
Group 2 and 3 showed significantly less pain than group 1 (P < 0.001) and significantly higher satisfaction rate than group 1 (P < 0.001). Comparison of groups 2 and 3 revealed showed significantly less pain and higher satisfaction rate in group 3 (P < 0.001 for both). In Group 1, 17 (85.0%) patients wanted other treatment modalities, compared to eight group 2 patients (40.0%) and no group 3 patients.
Conclusions
Considering the potential pain and dissatisfaction of rigid cystoscopic ureteral stent removal, procedures utilizing moderate sedation with midazolam or general anesthesia using propofol without muscle relaxation should be considered.
Trial registration
KCT0001260.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2490-14-90) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2490-14-90
PMCID: PMC4242475  PMID: 25406892
Stent; Stent exchange; Stent removal; Cystscopy; Urolithiasis; Pain
14.  Malignant acanthosis nigricans associated with prostate cancer: a case report 
BMC Urology  2014;14(1):88.
Background
Acanthosis nigricans is characterized by hyperpigmentation and hyperkeratosis of the skin or mucous membranes. Its malignant form is associated with internal neoplasms, especially gastric adenocarcinoma (55–61%). Coexistence with prostate cancer is uncommon. In the paraneoplastic type of this dermatosis, the skin and mucous lesions are characteristically of more sudden onset and more severe than those in the benign form. The efficacy of various treatment strategies remains disappointing.
Case presentation
We here report a case of 66-year-old Caucasian patient with metastatic prostate cancer and a mild form of acanthosis nigricans that preceded the diagnosis of malignancy and resolved with chemotherapy in parallel with the prostate cancer. The dermatosis recurred when the prostate cancer progressed.
Conclusion
Concurrent acanthosis nigricans and prostate cancer is rare, and few such cases have been reported. Anti-tumor therapy occasionally results in regression of this dermatosis. Underlying malignant disease should be suspected in individuals with elderly-onset of acanthosis nigricans.
doi:10.1186/1471-2490-14-88
PMCID: PMC4239373  PMID: 25399333
Acanthosis nigricans; Prostate cancer; Paraneoplastic syndrome
15.  Cystic renal cell carcinoma: a report of 67 cases including 4 cases with concurrent renal cell carcinoma 
BMC Urology  2014;14(1):87.
Background
Cystic renal cell carcinoma (CRCC) is relatively rare; CRCC is frequently misdiagnosed as a benign renal cyst. CRCC carries an excellent prognosis following surgical treatment. The aim of our study was to summarize the management of CRCC and to characterize the prognosis of affected patients.
Methods
A retrospective study of 67 patients with CRCC was conducted at our center between January 2005 and April 2013. Patient prognosis as well as the clinical manifestations, imaging characteristics, treatment, and pathologic features of CRCC were summarized based on available medical record data.
Results
We identified 67 cases of CRCC, representing 2.5% of all renal cell carcinoma cases. The tumor was discovered incidentally in 70% of the cases. Ultrasonography was found to be a useful screening tool, but computed tomography remains the imaging study of choice for identifying malignant features. Magnetic resonance imaging can be used in equivocal cases. Regarding treatment, radical nephrectomy was performed in 52% of the cases, and partial nephrectomy was selected in the remaining 48% of cases. None of the 46 patients (68% of the study group) available for follow-up showed any evidence of recurrence.
Conclusions
CRCC is an uncommon subtype of renal cell carcinoma, occurring in 2.5% of cases. CRCC carries an excellent prognosis after surgical treatment. Partial nephrectomy should be regarded as the preferred surgical technique for CRCC.
doi:10.1186/1471-2490-14-87
PMCID: PMC4233089  PMID: 25381150
Cystic renal cell carcinoma; Diagnosis; Nephrectomy; Partial nephrectomy
16.  Determinants and effects of positive surgical margins after prostatectomy on prostate cancer mortality: a population-based study 
BMC Urology  2014;14(1):86.
Background
The objective of this population-based study was to assess patient, physician and tumour determinants associated with positive surgical margins after prostatectomy, and to assess the effects of positive surgical margins on prostate cancer-specific survival.
Methods
We included 1’254 prostate cancer patients recorded at the Geneva Cancer Registry who had radical prostatectomy during 1990–2008. To assess factors associated with positive margins, we used logistic regression. We assessed the effects of positive margins on prostate cancer-specific survival by Cox proportional hazard models accounting for numerous other prognostics factors including prostate and tumour volume, the total percentage of tumour, radiotherapy, surgical approach and surgeon’s caseload.
Results
Among men undergoing prostatectomy, 479 (38%) had positive margins. In the multivariate logistic regression analysis, period, clinical- and pathological T stage, Prostate Specific Antigen (PSA) level, Gleason score and percentage of tumour in the prostate were significantly associated to positive margins. Ten-year prostate cancer-specific survival was 96.6% for the negative margins group and 92.0% for the positive margins group (log rank p = 0.008). In the Cox survival analysis adjusted for tumour characteristics, surgical margin status per se was not an independent prognostic factor while age, pathological T, PSA level and Gleason score remained associated with prostate cancer-specific survival.
Conclusions
More aggressive tumour characteristics were strong determinants for positive margins. Furthermore, surgical margin status per se was not an independent prognostic factor for prostate cancer-specific survival after adjusting by the gravity of the disease in the multivariate analysis.
doi:10.1186/1471-2490-14-86
PMCID: PMC4234867  PMID: 25374000
Prostate cancer; Prostate cancer-specific survival; Prostatectomy; Surgical margins
17.  Changes in prostaglandin E2 in patients with idiopathic overactive bladder syndrome after botulinum toxin type A treatment: is there a clinical benefit? 
BMC Urology  2014;14(1):85.
Background
The causality of overactive bladder syndrome (OAB) is still not fully understood. Several studies indicate a significant increase of prostaglandin E2 (PGE2) in patients with OAB. However, in order to clarify whether these compounds can help to objectify the clinical diagnosis, further studies are needed. This prospective study aims to analyze PGE2 blood levels (sPGE2) in patients with OAB before and after botulinum toxin type A (BoNT-A) therapy.
Methods
Blood samples were obtained from 56 patients (52y, 18–87) with idiopathic OAB. sPGE2 levels were measured before and 4 weeks after BoNT-A treatment by enzyme linked immunosorbent assay (ELISA). 31 healthy persons with normal bladder function served as control group (59 y, 21–72). sPGE2 was set in relation to clinical data and the severity of OAB (wet/dry). The statistical data analysis was performed by using the non-parametric Mann–Whitney U test and paired t-test.
Results
Significant higher sPGE2 levels were detected in patients with OAB compared to members of the control group (2750 pg/ml vs. 1674 pg/ml, p < 0.005). Furthermore sPGE2 levels were increased in patients with OAB wet compared to OAB dry (p <0.01). In 30 patients sPGE2 levels decreased significantly after BoNT-A treatment compared to baseline (2995 pg/ml vs. 1486 pg/ml, p <0.005). Patients reported an average drug effect of 9 month (0–19); incontinence pads were needed significantly less frequent (p < 0.05). 3 patients reported no postoperative effect. sPGE2 increased in two patients compared to initial levels, a single patient showed a remotely decreased sPGE2. Six patients were treated repeatedly with BoNT-A after showing an sPGE2 re-rise.
Conclusions
sPGE2-level is increased in patients with OAB. We could prove a significant decrease of sPGE2 after BoNT-A treatment. In this small cohort we could demonstrate a correlation between OAB and sPGE2, especially in the non-responder group. The use of sPGE2 as a biomarker in diagnostics and follow-up after therapy seems promising. To what extent sPGE2 can be useful as such needs to be examined prospectively in a larger population.
doi:10.1186/1471-2490-14-85
PMCID: PMC4230352  PMID: 25370343
Prostaglandin E2; Overactive bladder; Biomarker; Botulinum toxin type-A
18.  Tolterodine extended release in the treatment of male oab/storage luts: a systematic review 
BMC Urology  2014;14(1):84.
Background
Overactive bladder (OAB)/ storage lower urinary tract symptoms (LUTS) have a high prevalence affecting up to 90% of men over 80 years. The role of sufficient therapies appears crucial. In the present review, we analyzed the mechanism of action of tolterodine extended-release (ER) with the aim to clarify its efficacy and safety profile, as compared to other active treatments of OAB/storage LUTS.
Methods
A wide Medline search was performed including the combination of following words: “LUTS”, “BPH”, “OAB”, “antimuscarinic”, “tolterodine”, “tolterodine ER”. IPSS, IPSS storage sub-score and IPSS QoL (International Prostate Symptom Score) were the validated efficacy outcomes. In addition, the numbers of urgency episodes/24 h, urgency incontinence episodes/24 h, incontinence episodes/24 h and pad use were considered. We also evaluated the most common adverse events (AEs) reported for tolterodine ER.
Results
Of 128 retrieved articles, 109 were excluded. The efficacy and tolerability of tolterodine ER Vs. tolterodine IR have been evaluated in a multicenter, double-blind, randomized placebo controlled study in 1529 patients with OAB. A 71% mean reduction in urgency incontinence episodes was found in the tolterodine ER group compared to a 60% reduction in the tolterodine IR (p < 0.05). Few studies evaluated the clinical efficacy of α-blocker/tolterodine combination therapy. In patients with large prostates (prostate volume >29 cc) only the combination therapy significantly reduced 24-h voiding frequency (2.8 vs. 1.7 with tamsulosin, 1.4 with tolterodine, or 1.6 with placebo). A recent meta-analysis evaluating tolterodine in comparison with other antimuscarinic drugs demonstrated that tolterodine ER was significantly more effective than placebo in reducing micturition/24 h, urinary leakage episodes/24 h, urgency episodes/24 h, and urgency incontinence episodes/24 h. With regard to adverse events, tolterodine ER was associated with a good adverse event profile resulting in the third most favorable antimuscarinic. Antimuscarinic drugs are the mainstay of pharmacological therapy for OAB / storage LUTS; several studies have demonstrated that tolterodine ER is an effective and well tolerated formulation of this class of treatment.
Conclusion
Tolterodine ER resulted effective in reducing frequency urgency and nocturia and urinary leakage in male patients with OAB/storage LUTS. Dry mouth and constipation are the most frequently reported adverse events.
doi:10.1186/1471-2490-14-84
PMCID: PMC4230346  PMID: 25348235
Lower urinary tract symptoms; Overactive bladder; Storage LUTS; Tolterodine; Urge incontinence; Frequency; Nocturia
19.  The impact of fellowship training on pathological outcomes following radical prostatectomy: a population based analysis 
BMC Urology  2014;14(1):82.
Background
Radical prostatectomy (RP) is a common treatment for prostate cancer (PCa). Morbidity, mortality and pathological outcomes may be superior in academic institutions. One explanation may be the involvement of oncology fellowship trained urologists within academic institutions. The literature examining pathological outcomes often lacks individual surgeon data. The objective of this study was to compare pathological outcomes following RP between fellowship trained and non-fellowship trained urologists.
Methods
Population-based, retrospective chart review of men diagnosed with PCa between 2003 and 2008, the majority treated with open approach RP (>99%). Pathological outcomes were compared between oncology fellowship trained academic (FTA), non-fellowship trained academic (NFTA) and non-academic (NA) urologists. Relationships with pathological outcomes were examined utilizing multivariable logistic regression.
Results
83.1% of eligible patients were included in our analysis resulting in 1075 patients. In multivariable analysis, surgeon group was an independent predictor of positive surgical margin (PSM) (p < 0.0001). NFTA and NA urologists were more likely to have PSM compared to FTA urologists (OR 2.50; 95% CI: 1.44 - 4.35 and OR 2.10; 95% CI: 1.53 - 2.88, respectively). However, the proportion of PSM between NFTA and NA urologists was not significant (p = 0.492). In addition, pathological stage (p = 0.0004), Gleason sum (p < 0.0001), and surgeon volume (p = 0.017) were associated with PSM. Limitations include retrospective design and lack of clinical and functional outcomes.
Conclusions
Uro-oncology fellowship trained surgeons had significantly lower rates of PSM than non-fellowship trained surgeons in this population based cohort. This study demonstrates the importance of surgeon-related variables on pathological outcomes and highlights the value of additional urologic oncology fellowship training.
doi:10.1186/1471-2490-14-82
PMCID: PMC4216843  PMID: 25339410
Education; Fellowship; Pathology; Prostatectomy; Prostatic neoplasms
20.  Bilateral spermatic cord en bloc ligation by laparoendoscopic single-site surgery: preliminary experience compared to conventional laparoscopy 
BMC Urology  2014;14(1):83.
Background
Laparo Endoscopic Single-site Surgery (LESS) represents an evolution of minimally invasive surgery and aims to improve cosmetic outcome and reduce surgical trauma and complications associated with traditional laparoscopy. This study was performed to present our preliminary experience in bilateral spermatic cord ligation with the LESS technique and compare the results with the outcomes of conventional laparoscopic surgery.
Methods
Between June 2007 and May 2013, 24 patients were referred to our institute for bilateral varicocelectomy. The indications for this type of procedure were bilateral varicocele with impairment of semen parameters or chronic bilateral testicular pain. All procedures were performed via the same surgeon. The patients were divided into two groups according to the type of laparoscopic surgery. Group A included 10 patients underwent LESS technique while group B included the remaining 14 patients that underwent conventional laparoscopy.
Results
The comparison between the two techniques showed some important advantages for LESS: shorter operating time (45.4 min vs. 88.3 (P < .001), shorter hospital stay (16.6 hours vs. 51.4 hours) (P < .001), early return to the normal activity (2.3 days vs. 4.7 days) and better cosmetic outcomes. No conversions from LESS to conventional laparoscopy were necessary and blood loss was insignificant in all patients.
All patients in the LESS group reported full satisfaction with the cosmetic outcome, whereas 85.7% of patients after conventional laparoscopy were fully satisfied with cosmesis.
Conclusions
Bilateral spermatic cord ligation with LESS is an alternative to conventional laparoscopy. The procedure was successfully performed in all patients. The trans-umbilical approach offers the advantage of a better cosmetic result, shorter hospital stay and less postoperative pain.
doi:10.1186/1471-2490-14-83
PMCID: PMC4219038  PMID: 25341821
Laparo Endoscopic Single-site Surgery (LESS); Transumbilical access; Bilateral spermatic cord ligation
21.  Ultra-early versus early salvage androgen deprivation therapy for post-prostatectomy biochemical recurrence in pT2-4N0M0 prostate cancer 
BMC Urology  2014;14(1):81.
Background
The optimal timing of salvage androgen deprivation therapy (ADT) for biochemical recurrence after radical prostatectomy is controversial. We compared the outcomes of ultra-early versus early salvage ADT.
Methods
Among 855 patients undergoing radical prostatectomy at our institution between 2000 and 2012, we identified 121 with adjuvant-treatment-naïve pT2-4N0M0 prostate cancer who received salvage ADT for biochemical recurrence. These patients were divided into an ultra-early salvage ADT group (n = 51), who started salvage ADT before meeting the standardized definition of biochemical recurrence in Japan (two consecutive prostate-specific antigen [PSA] values ≥0.2 ng/ml), and an early salvage ADT group (n = 70) who started salvage ADT when they met the definition. The ultra-early ADT group consisted of those who started salvage ADT with a single PSA value ≥0.2 ng/ml (n = 30) or with two consecutive PSA values >0.1 ng/ml and rising (n = 21). The primary endpoint was biochemical recurrence after salvage ADT, defined as a single PSA value ≥0.2 ng/ml after PSA nadir following salvage ADT. Secondary endpoints were clinical metastasis and cancer-specific survival. A Cox proportional hazards model was used for multivariate analysis. The median follow-up was 65.5 months.
Results
Biochemical recurrence occurred in one patient (2.0%) in the ultra-early group and in 12 (17.1%) in the early salvage ADT group. Multivariate analysis identified ultra-early salvage ADT and preoperative Gleason score ≤7 as independent negative predictors of biochemical recurrence after salvage ADT. Only one patient in the early salvage ADT group developed clinical metastasis to a left supraclavicular lymph node, and no patient died from prostate cancer during follow-up. The major limitations of this study were its retrospective design, selection bias, and the possibility that the ultra-early salvage ADT group may have included patients without biochemical recurrence.
Conclusions
Ultra-early salvage ADT was an independent negative predictor of biochemical recurrence after salvage ADT in post-prostatectomy patients. Further consideration should be given to the use of salvage ADT before meeting the current definition of biochemical recurrence.
doi:10.1186/1471-2490-14-81
PMCID: PMC4203971  PMID: 25323845
Androgen deprivation therapy; Biochemical recurrence; Prostate cancer; Radical prostatectomy; Salvage androgen deprivation therapy
22.  Retroperitoneoscopic single site renal biopsy surgery: right indications for the right technique 
BMC Urology  2014;14(1):80.
Bacground
Laparoendoscopic single-site surgery (LESS) has been developed in an attempt to further reduce the morbidity and scarring associated with laparoscopic surgery. In patients in whom there are indications to perform a laparoscopic renal biopsy, LESS surgery is a valid alternative to mini invasive surgery and is becoming more common. We report our experience on 14 renal biopsy procedures performed in a retroperitoneal LESS.
Methods
LESS renal biopsy was performed in 14 patients 18 to 80 years old (mean age 58.3 years) during a 36 month period. All procedures were performed by a single operator. The patient was in a standard flank position. The procedure was performed using a 2.5 cm, single incision via a retroperitoneal access at the Petit’s triangle. A 5 mm biopsy forceps was used to collect the specimen under direct vision, and haemostasis was obtained with an Argon beam probe and the application of oxidized regenerated cellulose gauze.
Results
Biopsy was performed successfully in all cases. Mean operative time was 52.64 min, blood loss was minimal, and the hospital stay ranged from 12 to 24 hours. None of the patients required narcotics or additional analgesia in the postoperative period. No postoperative complications occurred.
Conclusions
The LESS technique is safe, reliable (100% success), easy to learn, and offers subjective cosmetic benefits to the patient. Minimal hospitalization requirement following retroperitoneal LESS biopsy is an additional timely advantage over laparoscopic renal biopsy. We think that with the right indications (marked obesity, failure of previous percutaneous biopsy attempts, a solitary kidney and coagulopathy) LESS renal biopsy is a good alternative to laparoscopy. Our next step will be a randomized prospective study of LESS compared with laparoscopy for renal biopsy to support our findings.
doi:10.1186/1471-2490-14-80
PMCID: PMC4287478  PMID: 25312741
Retroperitoneoscopy; Single-site surgery; LESS; Renal biopsy
23.  The use of early postoperative prostate-specific antigen to stratify risk in patients with positive surgical margins after radical prostatectomy 
BMC Urology  2014;14(1):79.
Background
It is well recognized that the presence of positive surgical margins (PSM) after radical prostatectomy (RP) adversely affects cancer specific outcomes and recent evidence from randomized trials supports the use of adjuvant radiotherapy in these cases. However, not all of the patients with PSM develop disease recurrence and the policy of adjuvant radiation could result in considerable over-treatment. We investigated the ability of early postoperative prostate specific antigen (PSA) and PSA decline rates to stratify the risk of disease progression during the first weeks after the surgery thereby allowing adequate time for planning eventual adjuvant therapy.
Methods
We studied 116 consecutive patients with the finding of PSM after RP for localized prostate cancer between 2001 and 2012. No patients were treated with radiation or hormonal therapy. An intensive postoperative PSA monitoring using ultrasensitive assay started first at day 14 after the surgery, then at day 30, 60, 90 and 180, and subsequently in 3 monthly intervals. Biochemical recurrence (BCR) presented the failure of surgical treatment and it was defined as PSA ≥0.2 ng/ml. The ability of PSA decline parameters to predict BCR was assessed using Cox regression model and area under the curve (AUC) calculation.
Results
Overall 55 (47%) patients experienced BCR during median follow-up of 31.4 months (range 6–69). Preoperative PSA, pathologic Gleason sum and pathologic grade failed to reveal any association with observation of BCR. Postoperative PSA levels achieved significant predictive accuracy already on day 30 (AUC 0.74). PSA >0.073 ng/ml at day 30 increased significantly the risk of BCR (HR 4.35, p < 0.001). Predictive accuracy was significantly exceeded on day 60 (AUC 0.84; p < 0.001), while further enhancements on day 90 (AUC 0.84) and 180 (AUC 0.91) were not significant.
Conclusions
The level of ultrasensitive PSA yields valuable information about the prostatectomy outcome already at the first month after the surgery and should aid risk stratification in patients with PSM. Patients not likely to experience subsequent disease progression may be spared the toxicity of immediate adjuvant radiotherapy.
doi:10.1186/1471-2490-14-79
PMCID: PMC4195911  PMID: 25277310
Prostate specific antigen; Radical prostatectomy; Surgical margins; Adjuvant radiotherapy
24.  Dutasteride plus Tamsulosin fixed-dose combination first-line therapy versus Tamsulosin Monotherapy in the treatment of benign prostatic hyperplasia: a budget impact analysis in the Greek healthcare setting 
BMC Urology  2014;14:78.
Background
The purpose of this study was to explore the budget impact of dutasteride plus tamsulosin fixed-dose combination (DUT + TAM FDC) versus tamsulosin monotherapy, in the treatment of patients with benign prostatic hyperplasia (BPH) from the perspective of the Greek healthcare insurance system.
Methods
A Microsoft Excel-based model was developed to estimate the financial consequences of adopting DUT + TAM FDC within the Greek healthcare setting. The model, compared six mutually exclusive health states in two alternative treatment options: current standard of care and the introduction of DUT + TAM FDC in the market. The model used clinical inputs from the CombAT study; data on resource use associated with the management of BPH in Greece were derived from expert panel, and unit cost data were derived from official reimbursement tariffs. A payer perspective was taken into account. As patient distribution data between public and private sectors are not available in Greece two scenarios were investigated, considering the whole eligible population in each scenario. A 4 year time horizon was taken into account and included treatment costs, number of transurethral resections of the prostate (TURPs) and acute urinary retention (AUR) episodes avoided.
Results
The clinical benefit from the market adoption of DUT + TAM FDC in Greece was 1,758 TURPs and 972 episodes of AUR avoided cumulatively in a four year period. The increase in total costs from the gradual introduction of DUT + TAM FDC to the Greek healthcare system ranges from €1.3 million in the first year to €5.8 million in the fourth year, for the public sector, and €1.2 million to €4.0 million, for the private sector. This represents an increase of 1.91% to 7.94% for the public sector and 1.10% 3.29% in the private sector, during the 4-year time horizon.
Conclusions
Budget impact analysis (BIA) results indicated that the gradual introduction of DUT + TAM FDC, would increase the overall budget of the disease, however providing better clinical outcomes. DUT + TAM FDC drug acquisition cost is partly offset by the reduction in the costs associated with the treatment of the disease.
doi:10.1186/1471-2490-14-78
PMCID: PMC4236714  PMID: 25255740
Benign prostate hyperplasia; Dutasteride plus tamsulosin fixed-dose combination; Budget impact; Costs; Health resources
25.  Percutaneous cryoablation for tuberous sclerosis-associated renal angiomyolipoma with neoadjuvant mTOR inhibition 
BMC Urology  2014;14:77.
Background
Renal angiomyolipomas (AMLs) are frequent in tuberous sclerosis and are responsible for a significant proportion of the morbidity in adulthood, mainly from bleeding complications, which are correlated to the size of the AMLs. We describe the case of a 19-year-old female with multiple bilateral renal angiomyolipomas.
Case presentation
The renal AMLs measured up to 6 cm in size. She was first treated with a low dose of the mammalian target of rapamycin (mTOR) inhibitor sirolimus (up to 3 mg/day over a 12-month period) and following significant AML size reduction, percutaneous cryoablation was performed. No side-effects of either treatment were reported. At 12 months post-cryoablation, no recurrence of the AML was noted.
Conclusion
This is the first report of this treatment strategy and the case study reveals that combining a low dose of an mTOR inhibitor with percutaneous cryoablation to treat small tumors mitigates the side-effects while providing a good clinical outcome. This therapeutic approach is a novel tool for the clinician involved in the management of patients with tuberous sclerosis.
doi:10.1186/1471-2490-14-77
PMCID: PMC4177726  PMID: 25258166
Tuberous sclerosis; Angiomyolipoma; Kidney; Sirolimus; Cryoablation

Results 1-25 (405)