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26.  Ultra-early versus early salvage androgen deprivation therapy for post-prostatectomy biochemical recurrence in pT2-4N0M0 prostate cancer 
BMC Urology  2014;14(1):81.
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.
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.
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.
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.
PMCID: PMC4203971  PMID: 25323845
Androgen deprivation therapy; Biochemical recurrence; Prostate cancer; Radical prostatectomy; Salvage androgen deprivation therapy
27.  Retroperitoneoscopic single site renal biopsy surgery: right indications for the right technique 
BMC Urology  2014;14(1):80.
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.
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.
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.
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.
PMCID: PMC4287478  PMID: 25312741
Retroperitoneoscopy; Single-site surgery; LESS; Renal biopsy
28.  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.
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.
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.
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.
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.
PMCID: PMC4195911  PMID: 25277310
Prostate specific antigen; Radical prostatectomy; Surgical margins; Adjuvant radiotherapy
29.  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.
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.
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.
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.
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.
PMCID: PMC4236714  PMID: 25255740
Benign prostate hyperplasia; Dutasteride plus tamsulosin fixed-dose combination; Budget impact; Costs; Health resources
30.  Percutaneous cryoablation for tuberous sclerosis-associated renal angiomyolipoma with neoadjuvant mTOR inhibition 
BMC Urology  2014;14:77.
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.
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.
PMCID: PMC4177726  PMID: 25258166
Tuberous sclerosis; Angiomyolipoma; Kidney; Sirolimus; Cryoablation
31.  Preoperative lymphocyte-to-monocyte ratio predicts clinical outcome in patients undergoing radical cystectomy for transitional cell carcinoma of the bladder: a retrospective analysis 
BMC Urology  2014;14:76.
Inflammation is a critical component of tumorigenesis, and many cancers arise from sites of infection, chronic irritation, and inflammation. Inflammatory cytokines triggered by tumors alter hematologic components, including neutrophil, lymphocyte, and monocyte counts. The neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios have been shown to be valuable prognostic markers in various types of cancers, including bladder cancer. Risk stratification based on clinicopathologic data is insufficient to support treatment-related choices in patients with bladder cancer. Novel prognostic markers are therefore needed. An elevated pretreatment lymphocyte-to-monocyte ratio (LMR) is reportedly associated with improved overall survival (OS) and a longer time to treatment recurrence (TTR) in some types of cancers. However, these data are lacking in patients with bladder cancer. The aim of the present study was to investigate the effect of the preoperative LMR on OS and TTR in a cohort of patients with bladder cancer.
Sixty-eight patients with transitional cell carcinoma of the bladder were included in this retrospective analysis. The associations between a high and low LMR with OS and TTR were analyzed using Kaplan–Meier curves and compared by the log-rank test.
In our study cohort, an elevated preoperative LMR was significantly associated with an increased TTR (P = 0.001) and OS (P = 0.020). Patients with an LMR of ≤2.87 showed a median TTR of 2.0 years (95% CI, 0.27–3.73), whereas patients with an LMR of >2.87 had a median TTR of 11.1 years (95% CI, 2.31–19.88) (P = 0.001). Patients with an LMR of ≤2.81 showed a median OS of 2.7 years (95% CI, 0.63–4.70), whereas patients with an LMR of >2.81 had a median OS of 6.0 years (95% CI, 3.60–8.40) (P = 0.020). The clinical stage at diagnosis was the only clinicopathologic feature associated with the LMR, while tumor invasion depth showed borderline significance.
The LMR is an easily measured and inexpensive prognostic marker that was significantly correlated with OS and TTR in the present retrospective analysis. However, because of the small sample size in this study, larger multicenter, prospective studies are needed.
PMCID: PMC4171398  PMID: 25234356
Urinary bladder neoplasms; Transitional cell carcinoma; Inflammation; Lymphocytes; Monocytes
32.  Robotic radical nephrectomy for renal cell carcinoma: a systematic review 
BMC Urology  2014;14:75.
Laparoscopic radical nephrectomy (LRN) is the actual gold-standard for the treatment of clinically localized renal cell carcinoma (RCC) (cT1-2 with no indications for nephron-sparing surgery). Limited evidence is currently available on the role of robotics in the field of radical nephrectomy. The aim of the current study was to provide a systematic review of the current evidence on the role of robotic radical nephrectomy (RRN) and to analyze the comparative studies between RRN and open nephrectomy (ON)/LRN.
A Medline search was performed between 2000–2013 with the terms “robotic radical nephrectomy”, “robot-assisted laparoscopic nephrectomy”, “radical nephrectomy”. Six RRN case-series and four comparative studies between RRN and (ON)/pure or hand-assisted LRN were identified.
Current literature produces a low level of evidence for RRN in the treatment of RCC, with only one prospective study available. Mean operative time (OT) ranges between 127.8-345 min, mean estimated blood loss (EBL) ranges between 100–273.6 ml, and mean hospital stay (HS) ranges between 1.2-4.3 days. The comparison between RRN and LRN showed no differences in the evaluated outcomes except for a longer OT for RRN as evidenced in two studies. Significantly higher direct costs and costs of the disposable instruments were also observed for RRN. The comparison between RRN and ON showed that ON is characterized by shorter OT but higher EBL, higher need of postoperative analgesics and longer HS.
No advantage of robotics over standard laparoscopy for the treatment of clinically localized RCC was evidenced. Promising preliminary results on oncologic efficacy of RRN have been published on the T3a-b disease. Fields of wider application of robotics should be researched where indications for open surgery still persist.
PMCID: PMC4171399  PMID: 25234265
Robotic nephrectomy; Robotic radical nephrectomy; Robot-assisted laparoscopic radical nephrectomy; Radical nephrectomy; Renal cell carcinoma
33.  Renal surgery for kidney cancer in Germany 2005–2006: length of stay, risk of postoperative complications and in-hospital death 
BMC Urology  2014;14:74.
Representative statistics of surgical care among patients with kidney cancer are scant. With the introduction of the diagnosis related group system in Germany, it is now possible to provide nationwide statistics on surgical care. We studied in-hospital mortality risk in relation to comorbidity and complications, length of hospital stay in relation to surgical approach and comorbidity, and risk of complications in relation to surgical approach among kidney cancer patients undergoing nephrectomy.
We analyzed the nationwide hospitalization file of the years 2005 and 2006 including 23,753 hospitalizations with a diagnosis of renal cancer and partial or complete nephrectomy and classified comorbidity (Charlson comorbidity index) and complications. Length of stay, risk of in-hospital complications and in-hospital death were analyzed by linear regression and log-linear regression (relative risks (RR) and 95% confidence intervals (95% CI)).
The overall in-hospital mortality was 1.4%. Per one unit increase of the Charlson comorbidity index, the adjusted risk of in-hospital mortality increased by 53% (95% CI 47-59%). The risks of bleeding or acute posthaemorrhagic anemia, respiratory, urological and gastrointestinal complications and infections ranged between 1.1% and 2.7% with the exception of bleeding or acute posthaemorrhagic anemia with 18.4%. Complications were associated with an increased adjusted in-hospital mortality risk. Highest adjusted mortality risk ratios were observed for gastrointestinal (RR = 3.61, 95% CI 2.32-5.63) and urological complications (RR = 3.62, 95% CI 2.62-5.00). The risk of haemorrhage or acute posthaemorrhagic anemia was lower for total laparoscopic nephrectomies than total open nephrectomies. The adjusted risk of gastrointestinal complications was lower for partial open compared to total open nephrectomy (adjusted RR = 0.66, 95% CI 0.45-0.97). Total laparoscopic nephrectomy was associated with shorter length of stay (−3.3 days; 95% CI 2.9-3.7 days) compared to total open nephrectomy. The estimated age-adjusted increase of length of stay per one unit increase of the Charlson comorbidity index was 1.3 days (95% CI 1.2-1.4 days).
In this representative population-based analysis, we found that the surgical approach is associated with the risk of complications and length of hospital stay. Furthermore, in the era of ageing populations, renal cancer patients with comorbidities should be counseled about their increased in-hospital mortality risk.
PMCID: PMC4169703  PMID: 25217295
Hospital mortality; Intraoperative complications; Kidney cancer; Length of stay; Nephrectomy; Postoperative complications
34.  Renal cell carcinoma with intramyocardial metastases 
BMC Urology  2014;14:73.
Cardiac metastases from renal cell carcinoma without vena caval involvement are extremely rare with a limited number of cases reported in the worldwide literature until now. Nevertheless, this rare location of metastasis may significantly influence patient treatment and prognosis. Cooperation between oncology, cardiology, and urology teams are indispensable in cases of patients suffering from intramyocardial tumors. For these individuals, treatment guidelines based on large-scale studies are unavailable and only case/case series analysis may provide clinicians with decision assistance.
Case presentation
In this paper, we report a case of a 50-year-old Caucasian male diagnosed with a 10.2 × 10.3 × 10.0 cm lower pole left renal mass in January 2002. He was subsequently treated with immunochemotherapy, tyrosine kinase inhibitors (TKIs), and mTOR inhibitors (mTORIs) - that is sunitinib, everolimus, and sorafenib. In March 2012, contrast-enhancing tumors in the left myocardium (∅22 mm) and in the interventricular septum (∅26 mm) were seen on CT. Cardiology testing was conducted and the patient was treated with pazopanib with a profound response. Overall survival since the clear cell renal cell carcinoma (ccRCC) diagnosis was 11 years 2 months and since diagnosis of multiple heart metastases was 1 year.
Cardiac metastases present a unique disease course in renal cell carcinoma. Cardiac metastases may remain asymptomatic, as in the case of this patient at the time of diagnosis. The most common cardiac presentation of renal cell carcinoma is hypertension, but other cardiac presentations include shortness of breath, cough, and arrhythmias. Targeted systemic therapy with tyrosine kinase inhibitors may be useful for this group of patients, but necrosis in the myocardium can result in tamponade and death. Regular cardiac magnetic resonance imaging scans are required for treatment monitoring.
PMCID: PMC4158341  PMID: 25193011
Renal cell carcinoma; Myocardium; Metastasis; Pazopanib; Axitinib
35.  The impact of tumour size on the probability of synchronous metastasis and survival in renal cell carcinoma patients: a population-based study 
BMC Urology  2014;14:72.
The observed low metastatic potential and favorable survival of small incidentally detected renal cell carcinomas (RCCs) have been a part of the rationale for recommending partial nephrectomy as a first treatment option and active surveillance in selected patients. We examined the relationship between tumor size and the odds of synchronous metastases (SMs) (primary outcome) and disease specific survival (secondary outcome) in a nationwide RCC registry.
Retrospective study of the 794 RCC patients diagnosed in Iceland between 1971 and 2005. Histological material and TNM staging were reviewed centrally. The presence of SM and survival were recorded. Cubic spline analysis was used to assess relationship between tumor size and probability of SM. Univariate and multivariate statistics were used to estimate prognostic factors for SM and survival.
The probability of SM increased in a non-linear fashion with increasing tumor size (11, 25, 35, and 50%) for patients with tumors of ≤4, 4.1-7.0, 7.1-10.0, and >10 cm, respectively. On multivariate analysis, tumor size was an independent prognostic factor for disease-specific survival (HR = 1.05, 95% CI 1.02-1.09, p < 0.001), but not for SM.
Tumor size affected the probability of disease-specific mortality but not SM, after correcting for TNM staging in multivariate analysis. This confirms the prognostic ability of the 2010 TNM staging system for renal cell cancer in the Icelandic population.
PMCID: PMC4159381  PMID: 25174263
Renal cell carcinoma; Size; Metastasis; Survival
36.  Panobinostat synergizes with bortezomib to induce endoplasmic reticulum stress and ubiquitinated protein accumulation in renal cancer cells 
BMC Urology  2014;14:71.
Inducing endoplasmic reticulum (ER) stress is a novel strategy used to treat malignancies. Inhibition of histone deacetylase (HDAC) 6 by the HDAC inhibitor panobinostat hinders the refolding of unfolded proteins by increasing the acetylation of heat shock protein 90. We investigated whether combining panobinostat with the proteasome inhibitor bortezomib would kill cancer cells effectively by inhibiting the degradation of these unfolded proteins, thereby causing ubiquitinated proteins to accumulate and induce ER stress.
Caki-1, ACHN, and 769-P cells were treated with panobinostat and/or bortezomib. Cell viability, clonogenicity, and induction of apoptosis were evaluated. The in vivo efficacy of the combination was evaluated using a murine subcutaneous xenograft model. The combination-induced ER stress and ubiquitinated protein accumulation were assessed.
The combination of panobinostat and bortezomib induced apoptosis and inhibited renal cancer growth synergistically (combination indexes <1). It also suppressed colony formation significantly (p <0.05). In a murine subcutaneous tumor model, a 10-day treatment was well tolerated and inhibited tumor growth significantly (p <0.05). Enhanced acetylation of the HDAC6 substrate alpha-tubulin was consistent with the suppression of HDAC6 activity by panobinostat, and the combination was shown to induce ER stress and ubiquitinated protein accumulation synergistically.
Panobinostat inhibits renal cancer growth by synergizing with bortezomib to induce ER stress and ubiquitinated protein accumulation. The current study provides a basis for testing the combination in patients with advanced renal cancer.
PMCID: PMC4153447  PMID: 25176354
Panobinostat; Bortezomib; Endoplasmic reticulum stress; Ubiquitinated protein; Histone acetylation; Renal cancer; Combination therapy
37.  Clinical, molecular and cytogenetic analysis of 46, XX testicular disorder of sex development with SRY-positive 
BMC Urology  2014;14:70.
To review the possible mechanisms proposed to explain the etiology of 46, XX sex reversal by investigating the clinical characteristics and their relationships with chromosomal karyotype and the SRY(sex-determining region Y)gene.
Five untreated 46, XX patients with SRY-positive were referred for infertility. Clinical data were collected, and Karyotype analysis of G-banding in lymphocytes and Fluorescence in situ hybridization (FISH) were performed. Genomic DNA from peripheral blood of the patients using QIAamp DNA Blood Kits was extracted. The three discrete regions, AZFa, AZFb and AZFc, located on the long arm of the Y chromosome, were performed by multiplex PCRs(Polymerase Chain Reaction) amplification. The set of PCR primers for the diagnosis of microdeletion of the AZFa, AZFb and AZFc region included: sY84, sY86, sY127, sY134, sY254, sY255, SRY and ZFX/ZFY.
Our five patients had a lower body height. Physical examination revealed that their testes were small in volume, soft in texture and normal penis. Semen analyses showed azoospermia. All patients had a higher follicle-stimulating hormone(FSH), Luteinizing Hormone(LH) level, lower free testosterone, testosterone level and normal Estradiol, Prolactin level. Karyotype analysis of all patients confirmed 46, XX karyotype, and FISH analysis showed that SRY gene were positive and translocated to Xp. Molecular analysis revealed that the SRY gene were present, and the AZFa, AZFb and AZFc region were absent.
This study adds cases on the five new 46, XX male individuals with SRY-positive and further verifies the view that the presence of SRY gene and the absence of major regions in Y chromosome should lead to the expectance of a completely masculinised phenotype, abnormal hormone levels and infertility.
PMCID: PMC4149805  PMID: 25169080
46; XX testicular disorder of sex development (DSD); SRY-positive; Sexual hormone
38.  Histologic and functional outcomes of small intestine submucosa-regenerated bladder tissue 
BMC Urology  2014;14:69.
Intestinal bladder augmentation has more disadvantages. One of the most promising alternative methods is tissue engineering in combination with surgical construction. Small intestine submucosa (SIS) is commonly used materials in tissue engineer. The aim of this study is determine the histologic and functional characteristics of SIS as bladder wall replacement in a rabbit augmentation model.
18 New Zealand adult male rabbits, weight 2.5 ± 0.5Kg, were used in this study. The rabbits were divided into 3 groups of 6 based on the number of days post-operative (A, 4 weeks; B, 12 weeks; C, 24 weeks). All of the animals underwent urodynamic testing under anesthesia before cystoplasty with SIS patch. The cystometrograms were repeated 4, 12, and 24 weeks after surgery with the same method. SIS-regenerated bladder strips (10 × 3 × 3 mm) and normal bladder strips (10 × 3 × 3 mm) from the same bladder were obtained at 4, 12, and 24 weeks for in vitro detrusor strip study. The frequency and amplitude of the strip over 15 min was recorded. The regenerated tissue and normal tissue underwent histologic and immunocytochemical analysis. The results were quantified as optical density (OD) values.
Histologically, the SIS-regenerated bladders of group C (24 weeks post-operation) resembled normal bladder in that all 3 layers (mucosa with submucosa, smooth muscle, and serosa) were present. In the in vitro detrusor strip study, there were no significant differences in autorhythmicity and contractility between regenerated and normal tissues in group C (p > 0.05). Immunohistochemical analysis indicated that the quantity of A-actin grew to a normal level. Urodynamic testing showed that compliance remained stable in all groups post-operatively, and the volume increased 24 weeks post-operatively.
Regenerated tissue has similar histologic and functional characteristics. SIS seems to be a viable material in the reconstruction of the rabbit urinary bladder.
PMCID: PMC4150863  PMID: 25148849
Small intestine submucosa; Regenerated bladder; Bladder augmentation; Urodynamics
39.  Protocol for a prospective magnetic resonance imaging study on supraspinal lower urinary tract control in healthy subjects and spinal cord injury patients undergoing intradetrusor onabotulinumtoxinA injections for treating neurogenic detrusor overactivity 
BMC Urology  2014;14:68.
The control of the lower urinary tract is a complex, multilevel process involving both the peripheral and central nervous system. Due to lesions of the neuraxis, most spinal cord injury patients suffer from neurogenic lower urinary tract dysfunction, which may jeopardise upper urinary tract function and has a negative impact on health-related quality of life. However, the alterations to the nervous system following spinal cord injury causing neurogenic lower urinary tract dysfunction and potential effects of treatments such as intradetrusor onabotulinumtoxinA injections on lower urinary tract control are poorly understood.
This is a prospective structural and functional magnetic resonance imaging study investigating the supraspinal lower urinary tract control in healthy subjects and spinal cord injury patients undergoing intradetrusor onabotulinumtoxinA injections for treating neurogenic detrusor overactivity.
Neuroimaging data will include structural magnetic resonance imaging (T1-weighted imaging and diffusion tensor imaging) as well as functional, i.e. blood oxygen level-dependent sensitive magnetic resonance imaging using a 3 T magnetic resonance scanner. The functional magnetic resonance imaging will be performed simultaneously to three different bladder stimulation paradigms using an automated magnetic resonance compatible and synchronised pump system.
All subjects will undergo two consecutive and identical magnetic resonance imaging measurements. Healthy subjects will not undergo any intervention between measurements but spinal cord injury patients will receive intradetrusor onabotulinumtoxinA injections for treating neurogenic detrusor overactivity.
Parameters of the clinical assessment including bladder diary, urinalysis, medical history, neuro-urological examination, urodynamic investigation as well as standardised questionnaires regarding lower urinary tract function and quality of life will serve as co-variates in the magnetic resonance imaging analysis.
This study will identify structural and functional alterations in supraspinal networks of lower urinary tract control in spinal cord injury patients with neurogenic detrusor overactivity compared to healthy controls. Post-treatment magnetic resonance imaging measurements in spinal cord injury patients will provide further insights into the mechanism of action of treatments such as intradetrusor onabotulinumtoxinA injections and the effect on supraspinal lower urinary tract control.
Trial registration NCT01768910.
PMCID: PMC4144688  PMID: 25132340
Urinary bladder; Spinal cord injury; Neuroimaging; Magnetic resonance imaging; Neurogenic detrusor overactivity; OnabotulinumtoxinA intradetrusor injections
40.  Prediction of clinical manifestations of transurethral resection syndrome by preoperative ultrasonographic estimation of prostate weight 
BMC Urology  2014;14:67.
This study aimed to investigate the relationship between preoperative estimated prostate weight on ultrasonography and clinical manifestations of transurethral resection (TUR) syndrome.
The records of patients who underwent TUR of the prostate under regional anesthesia over a 6-year period were retrospectively reviewed. TUR syndrome is usually defined as a serum sodium level of < 125 mmol/l combined with clinical cardiovascular or neurological manifestations. This study focused on the clinical manifestations only, and recorded specific central nervous system and cardiovascular abnormalities according to the checklist proposed by Hahn. Patients with and without clinical manifestations of TUR syndrome were compared to determine the factors associated with TUR syndrome. Receiver operating characteristic curve analysis was used to determine the optimal cutoff value of estimated prostate weight for the prediction of clinical manifestations of TUR syndrome.
This study included 167 patients, of which 42 developed clinical manifestations of TUR syndrome. There were significant differences in preoperative estimated prostate weight, operation time, resected prostate weight, intravenous fluid infusion volume, blood transfusion volume, and drainage of the suprapubic irrigation fluid between patients with and without clinical manifestations of TUR syndrome. The preoperative estimated prostate weight was correlated with the resected prostate weight (Spearman’s correlation coefficient, 0.749). Receiver operator characteristic curve analysis showed that the optimal cutoff value of estimated prostate weight for the prediction of clinical manifestations of TUR syndrome was 75 g (sensitivity, 0.70; specificity, 0.69; area under the curve, 0.73).
Preoperative estimation of prostate weight by ultrasonography can predict the development of clinical manifestations of TUR syndrome. Particular care should be taken when the estimated prostate weight is > 75 g.
PMCID: PMC4143887  PMID: 25128188
TUR syndrome; Hyponatremia; Transurethral resection of prostate
41.  A pilot prospective study to evaluate whether the bladder morphology in cystography and/or urodynamic may help predict the response to botulinum toxin a injection in neurogenic bladder refractory to anticholinergics 
BMC Urology  2014;14:66.
We have observed different clinical responses to botulinum toxin A (BTX-A) in patients who had similar urodynamic parameters before the procedure. Furthermore, some bladders evaluated by cystography and cystoscopy during the procedure had different characteristics that could influence the outcome of the treatment. The aim of this study was to assess whether cystography and urodynamic parameters could help predict which patients with neurogenic detrusor overactivity (NDO) refractory to anticholinergics respond better to treatment with injection of BTX-A.
In total, 34 patients with spinal cord injury were prospectively evaluated. All patients emptied their bladder by clean intermittent catheterization (CIC) and had incontinence and NDO, despite using 40 mg or more of intravesical oxybutynin and undergoing detrusor injection of BTX-A (300 IU). Pretreatment evaluation included urodynamic, and cystography. Follow-up consisted of urodynamic and ambulatory visits four months after treatment. The cystography parameters used were bladder shape, capacity and presence of diverticula. Urodynamic parameters used for assessment were maximum cystometric capacity (MCC), maximum detrusor pressure (MDP), compliance and reflex volume (RV).
After injection of BTX-A, 70% of the patients had success, with 4 months or more of continence. Before the treatment, there were significant differences in most urodynamic parameters between those who responded successfully compared to those who did not. Patients who responded successfully had greater MCC (p = 0.019), higher RV (p = 0.041), and greater compliance (p = 0.043). There was no significant difference in the MDP (0.691). The cystography parameters were not significantly different between these groups bladder shape (p = 0.271), capacity (p > 0.720) and presence of diverticula (p > 0.999). Statistical analyses were performed using SPSS (version 20.0) and included Student’s t-test for two paired samples and Fisher’s exact test, with a significance threshold of 0.05.
This study suggests that the cystography parameters evaluated cannot be used to help predict the response to injection of BTX-A in the treatment of refractory NDO. However, the urodynamic parameters were significantly different in patients who responded to the treatment, with the exception of the MDP.
PMCID: PMC4139716  PMID: 25123234
Neurogenic detrusor overactivity; Botulinum toxin A; Cystography; Urodynamic; Neurogenic bladder
42.  Could Hyaluronic acid (HA) reduce Bacillus Calmette-Guérin (BCG) local side effects? Results of a pilot study 
BMC Urology  2014;14:64.
Bacillus Calmette-Guérin (BCG) is considered the most effective treatment to reduce recurrence and progression of non-muscle invasive bladder cancer (NMIBC) but can induce local side effects leading to treatment discontinuation or interruption. Aim of this exploratory study is to investigate if the sequential administration of Hyaluronic acid (HA) may reduce local side effects of BCG.
30 consecutive subjects undergoing BCG intravesical administration for high risk NMIBC were randomized to receive BCG only (Group A) or BCG and HA (Group B). A 1 to 10 Visual Analog Scale (VAS) for bladder pain, International Prostate Symptom Score (IPSS) and number of micturitions per day were evaluated in the two groups before and after six weekly BCG instillations. Patients were also evaluated at 3 and 6 months by means of cystostopy and urine cytology.
One out of 30 (3,3%) patients in group A dropped out from the protocol, for local side effects. Mean VAS for pain was significantly lower in group B after BCG treatment (4.2 vs. 5.8, p = 0.04). Post vs. pre treatment differences in VAS for pain, IPSS and number of daily micturitions were all significantly lower in group B. Three patients in group A and 4 in group B presented with recurrent pathology at 6 month follow up.
These preliminary data suggest a possible role of HA in reducing BCG local side effects and could be used to design larger randomized controlled trials, assessing safety and efficacy of sequential BCG and HA administration.
Trial registration
NCT02207608 ( 01/08/2014
Policlinico Tor Vergata Ethics Committee, resolution n 69–2011.
PMCID: PMC4137267  PMID: 25123116
BCG; Hyaluronic acid; Non-muscle invasive bladder cancer; Non bacterial cystitis
43.  Protocol for a randomized, placebo-controlled, double-blind clinical trial investigating sacral neuromodulation for neurogenic lower urinary tract dysfunction 
BMC Urology  2014;14:65.
Sacral neuromodulation has become a well-established and widely accepted treatment for refractory non-neurogenic lower urinary tract dysfunction, but its value in patients with a neurological cause is unclear. Although there is evidence indicating that sacral neuromodulation may be effective and safe for treating neurogenic lower urinary tract dysfunction, the number of investigated patients is low and there is a lack of randomized controlled trials.
Methods and design
This study is a prospective, randomized, placebo-controlled, double-blind multicenter trial including 4 sacral neuromodulation referral centers in Switzerland. Patients with refractory neurogenic lower urinary tract dysfunction are enrolled. After minimally invasive bilateral tined lead placement into the sacral foramina S3 and/or S4, patients undergo prolonged sacral neuromodulation testing for 3–6 weeks. In case of successful (defined as improvement of at least 50% in key bladder diary variables (i.e. number of voids and/or number of leakages, post void residual) compared to baseline values) prolonged sacral neuromodulation testing, the neuromodulator is implanted in the upper buttock. After a 2 months post-implantation phase when the neuromodulator is turned ON to optimize the effectiveness of neuromodulation using sub-sensory threshold stimulation, the patients are randomized in a 1:1 allocation in sacral neuromodulation ON or OFF. At the end of the 2 months double-blind sacral neuromodulation phase, the patients have a neuro-urological re-evaluation, unblinding takes place, and the neuromodulator is turned ON in all patients. The primary outcome measure is success of sacral neuromodulation, secondary outcome measures are adverse events, urodynamic parameters, questionnaires, and costs of sacral neuromodulation.
It is of utmost importance to know whether the minimally invasive and completely reversible sacral neuromodulation would be a valuable treatment option for patients with refractory neurogenic lower urinary tract dysfunction. If this type of treatment is effective in the neurological population, it would revolutionize the management of neurogenic lower urinary tract dysfunction.
Trial registration
Trial registration number:; Identifier: NCT02165774.
PMCID: PMC4139491  PMID: 25123172
Urinary bladder; Neurogenic lower urinary tract dysfunction; Sacral neuromodulation; Randomized; Placebo-controlled; Double-blind trial
44.  Modern extraction techniques and their impact on the pharmacological profile of Serenoa repens extracts for the treatment of lower urinary tract symptoms 
BMC Urology  2014;14:63.
Bioactive compounds from plants (i.e., Serenoa repens) are often used in medicine in the treatment of several pathologies, among which benign prostatic hyperplasia (BPH) associated to lower urinary tract symptoms (LUTS).
There are different techniques of extraction, also used in combination, with the aim of enhancing the amount of the target molecules, gaining time and reducing waste of solvents. However, the qualitative and quantitative composition of the bioactives depends on the extractive process, and so the brands of the recovered products from the same plant are different in terms of clinical efficacy (no product interchangeability among different commercial brands).
In this review, we report on several and recent extraction techniques and their impact on the composition/biological activity of S. repens-based available products.
PMCID: PMC4136420  PMID: 25112532
Benign prostatic hyperplasia; Serenoa repens; Extraction techniques; Supercritical fluid extraction; Lipidosterolic composition; Content standardization
45.  Efficacy and safety of Ho:YAG Laser Lithotripsy for ureteroscopic removal of proximal and distal ureteral calculi 
BMC Urology  2014;14:62.
Laser lithotripsy is an established endourological modality. Ho:YAG laser have broadened the indications for ureteroscopic stone managements to include larger stone sizes throughout the whole upper urinary tract. Aim of current work is to assess efficacy and safety of Ho:YAG laser lithotripsy during retrograde ureteroscopic management of ureteral calculi in different locations.
88 patients were treated with ureteroscopic Ho:YAG laser lithotripsy in our institute. Study endpoint was the number of treatments until the patient was stone-free. Patients were classified according to the location of their stones as Group I (distal ureteric stones, 51 patients) and group II (proximal ureteral stones, 37). Group I patients have larger stones as Group II (10.70 mm vs. 8.24 mm, respectively, P = 0.020).
Overall stone free rate for both groups was 95.8%. The mean number of procedures for proximal calculi was 1.1 ± 0.1 (1–3) and for distal calculi was 1.0 ± 0.0. The initial treatment was more successful in patients with distal ureteral calculi (100% vs. 82.40%, respectively, P = 0.008). No significant difference in the stone free rate was noticed after the second laser procedure for stones smaller versus larger than 10 mm (100% versus 94.1%, P = 0.13). Overall complication rate was 7.9% (Clavien II und IIIb). Overall and grade-adjusted complication rates were not dependant on the stone location. No laser induced complications were noticed.
The use of the Ho:YAG laser appears to be an adequate tool to disintegrate ureteral calculi independent of primary location. Combination of the semirigid and flexible ureteroscopes as well as the appropriate endourologic tools could likely improve the stone clearance rates for proximal calculi regardless of stone-size.
PMCID: PMC4132277  PMID: 25107528
Ureteral calculi; Ureteroscopy; Holmium-YAG laser; Lithotripsy
46.  Interpositional substitution of free vas deferens segment autografts in rat: feasibility and potential implications 
BMC Urology  2014;14:61.
Insufficient vas length for performing a tension-free vasovasostomy is a problem occasionally encountered by microsurgeons. Herein we evaluated utilization of a non-vascularized vas deferens autograft in a rat model.
Segments of isolated vas deferens, 2.5 cm in length, were used as bilateral autografts in 15 rats. Each autograft was implanted between the two transected ends of vas deferens using end-to-end anastomosis. Fertility, sperm motility, and graft survival was evaluated and compared with the control group.
At the end of the 3 months, 9/15 (60%) rats were able to breed successfully and 24 (80%) vas grafts were patent and viable. Large granulomata developed at the proximal anastomosis sites in 6 (20%) autografts that failed. Unilateral minimal fluid leakage was observed in 6 (20%) of the proximal (testicular end) anastomosis sites in those rats that were able to breed. Histological evaluations demonstrated that graft survival was associated with mild to severe changes in the structure of the vas autograft. On semen analysis 76% of the sperms in the experimental group had forward motility compared to 78% in the control group (p > 0.05).
Vas autograft can successfully be performed in a rat model with ultimate breeding capability.
PMCID: PMC4148407  PMID: 25103862
Vas deferens; Autograft; Microsurgery; Fertility; Histology; Spermatozoa
47.  Measuring the improvement in health-related quality of life using King’s health questionnaire in non-obese and obese patients with lower urinary tract symptoms after alpha-adrenergic medication: a preliminary study 
BMC Urology  2014;14:60.
The efficacy of medical treatment among obese men with lower urinary tract symptoms (LUTS) has been less clear, especially regarding the improvement of QoL. We aimed to investigate the difference in efficacy and consequent satisfaction of life quality after medical treatment of male LUTS according to obesity.
An 8-week prospective study was performed for a total of 140 patients >50 years old with International Prostate Symptom Scores (IPSS) > 12 points and prostate volume > 20 mL. Obesity was determined by either body mass index (BMI) or waist circumference (WC). Patients were divided into 2 groups according to BMI or WC. Patients received tamsulosin at a dose of 0.4 mg daily for 8 weeks. The changes from baseline in the IPSS, maximal urinary flow rate (Qmax), post-void residual volume, questionnaire of quality of life (QoL), and King’s Health Questionnaire (KHQ) were analyzed.
Of the 150 enrolled patients, 96 completed the study. Seventy-five patients (78.1%) had BMI ≥ 23 kg/m2, and 24 (25.0%) had WC > 90 cm. Overall, the IPSS, IPSS QoL, and total KHQ showed significant improvement. Obese (BMI ≥ 23 kg/m2) and non-obese (BMI < 23 kg/m2) both showed improvement of the IPSS and IPSS QoL scores, but only the obese (BMI ≥ 23 kg/m2) group showed improvement of the total KHQ score (P < 0.001 vs. P = 0.55). Only the obese (WC > 90 cm) group showed improvement of the IPSS and total KHQ scores (P < 0.001).
Our preliminary study showed the different efficacy of an alpha-blocker for improvement of LUTS and life quality according to obesity. Obese patients, defined by BMI or WC, showed the tendency toward a more favorable improvement of LUTS and life quality.
Trial registration
Current Controlled Trials 2010–058. Registered 2 September 2010 in Soonchunhyang Univeristy Hospital
PMCID: PMC4126641  PMID: 25099073
Alpha-blocker; Prostatic hyperplasia; Body mass index; Waist circumference
48.  Photodynamic diagnosis of shed prostate cancer cells in voided urine treated with 5-aminolevulinic acid 
BMC Urology  2014;14:59.
Past attempts at detecting prostate cancer (PCa) cells in voided urine by traditional cytology have been impeded by undesirably low sensitivities but high specificities. To improve the sensitivities, we evaluate the feasibility and clinical utility of photodynamic diagnosis (PDD) of prostate cancer by using 5-aminolevulinic acid (5-ALA) to examine shed prostate cancer cells in voided urine samples.
One hundred thirty-eight patients with an abnormal digital rectal exam (DRE) and/or abnormal prostate-specific antigen (PSA) levels were recruited between April 2009 and December 2010. Voided urine specimens were collected before prostate biopsy. Urine specimens were treated with 5-ALA and imaged by fluorescence microscopy and reported as protoporphyrin IX (PPIX) positive (presence of cells demonstrating simultaneous PPIX fluorescence) or PPIX negative (lack of cells demonstrating fluorescence).
Of the 138 patients, PCa was detected on needle biopsy in 81 patients (58.7%); of these 81 patients with PCa, 60 were PPIX-positive (sensitivity: 74.1%). Although 57 patients did not harbor PCa by conventional diagnostic procedures, 17 of these at-risk patients were found to be PPIX-positive (specificity: 70.2%). PPIX–PDD was more sensitive compared with DRE and transrectal ultrasound and more specific compared with PSA and PSA density. The incidence of PPIX–PDD positivity did not increase with increasing total PSA levels, tumor stage or Gleason score.
To our knowledge, this is the first successful demonstration of PPIX in urine sediments treated with 5-ALA used to detect PCa in a noninvasive yet highly sensitive manner. However, further studies are warranted to determine the role of PPIX–PPD for PCa detection.
PMCID: PMC4130698  PMID: 25086448
5-aminolevulinic acid; Prostate cancer; Photodynamic diagnosis; Urine cytology
49.  The MAPP research network: design, patient characterization and operations 
BMC Urology  2014;14:58.
The “Multidisciplinary Approach to the Study of Chronic Pelvic Pain” (MAPP) Research Network was established by the NIDDK to better understand the pathophysiology of urologic chronic pelvic pain syndromes (UCPPS), to inform future clinical trials and improve clinical care. The evolution, organization, and scientific scope of the MAPP Research Network, and the unique approach of the network’s central study and common data elements are described.
The primary scientific protocol for the Trans-MAPP Epidemiology/Phenotyping (EP) Study comprises a multi-site, longitudinal observational study, including bi-weekly internet-based symptom assessments, following a comprehensive in-clinic deep-phenotyping array of urological symptoms, non-urological symptoms and psychosocial factors to evaluate men and women with UCPPS. Healthy controls, matched on sex and age, as well as “positive” controls meeting the non-urologic associated syndromes (NUAS) criteria for one or more of the target conditions of Fibromyalgia (FM), Chronic Fatigue Syndrome (CFS) or Irritable Bowel Syndrome (IBS), were also evaluated. Additional, complementary studies addressing diverse hypotheses are integrated into the Trans-MAPP EP Study to provide a systemic characterization of study participants, including biomarker discovery studies of infectious agents, quantitative sensory testing, and structural and resting state neuroimaging and functional neurobiology studies. A highly novel effort to develop and assess clinically relevant animal models of UCPPS was also undertaken to allow improved translation between clinical and mechanistic studies. Recruitment into the central study occurred at six Discovery Sites in the United States, resulting in a total of 1,039 enrolled participants, exceeding the original targets. The biospecimen collection rate at baseline visits reached nearly 100%, and 279 participants underwent common neuroimaging through a standardized protocol. An extended follow-up study for 161 of the UCPPS participants is ongoing.
The MAPP Research Network represents a novel, comprehensive approach to the study of UCPPS, as well as other concomitant NUAS. Findings are expected to provide significant advances in understanding UCPPS pathophysiology that will ultimately inform future clinical trials and lead to improvements in patient care. Furthermore, the structure and methodologies developed by the MAPP Network provide the foundation upon which future studies of other urologic or non-urologic disorders can be based.
Trial registration identifier: NCT01098279 “Chronic Pelvic Pain Study of Individuals with Diagnoses or Symptoms of Interstitial Cystitis and/or Chronic Prostatitis (MAPP-EP)”.
PMCID: PMC4126395  PMID: 25085119
Urologic chronic pelvic pain syndromes; Interstitial cystitis; Chronic prostatitis; Urine biomarkers; Plasma biomarkers; Non-urologic associated syndromes; Quantitative sensory testing (QST); Neuroimaging
50.  The MAPP research network: a novel study of urologic chronic pelvic pain syndromes 
BMC Urology  2014;14:57.
Urologic chronic pelvic pain syndrome (UCPPS) may be defined to include interstitial cystitis/bladder pain syndrome (IC/BPS) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). The hallmark symptom of UCPPS is chronic pain in the pelvis, urogenital floor, or external genitalia often accompanied by lower urinary tract symptoms. Despite numerous past basic and clinical research studies there is no broadly identifiable organ-specific pathology or understanding of etiology or risk factors for UCPPS, and diagnosis relies primarily on patient reported symptoms. In addition, there are no generally effective therapies. Recent findings have, however, revealed associations between UCPPS and “centralized” chronic pain disorders, suggesting UCPPS may represent a local manifestation of more widespread pathology in some patients. Here, we describe a new and novel effort initiated by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the U.S. National Institutes of Health (NIH) to address the many long standing questions regarding UCPPS, the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. The MAPP Network approaches UCPPS in a systemic manner, in which the interplay between the genitourinary system and other physiological systems is emphasized. The network’s study design expands beyond previous research, which has primarily focused on urologic organs and tissues, to utilize integrated approaches to define patient phenotypes, identify clinically-relevant subgroups, and better understand treated natural history and pathophysiology. Thus, the MAPP Network provides an unprecedented, multi-layered characterization of UCPPS. Knowledge gained is expected to provide important insights into underlying pathophysiology, a foundation for better segmenting patients for future clinical trials, and ultimately translation into improved clinical management. In addition, the MAPP Network’s integrated multi-disciplinary research approach may serve as a model for studies of urologic and non-urologic disorders that have proven refractory to past basic and clinical study.
Trial registration identifier: NCT01098279 “Chronic Pelvic Pain Study of Individuals with Diagnoses or Symptoms of Interstitial Cystitis and/or Chronic Prostatitis (MAPP-EP)”.
PMCID: PMC4134515  PMID: 25085007
Urological chronic pelvic pain syndromes; Interstitial cystitis; Chronic prostatitis; Translational research; Multi-disciplinary

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