Biodegradable drug-eluting stents: Targeting urothelial tumors of upper urinary tract

INTRODUCTION & OBJECTIVES: Urothelial tumors of upper urinary tract are ranked among the most common types of cancers worldwide. The current standard therapy to prevent recurrence is intravesical Bacillus Calmetteâ Guerin (BCG) immunotherapy, but it presents several disadvantages such as BCG failure and intolerance. Another way is to use chemotherapy, which is generally better tolerated that BCG. In this case, drugs such as epirubicin, doxorubicin, paclitaxel and gemcitabine are used. Nevertheless, intravesical chemotherapy only prevents recurrence in the short-term. These failings can be partially attributed to the short residence time and low bioavailability of the drug within the upper urinary tract and the cancer cells, resulting in a need for frequent drug instillation. To avoid these problems, biodegradable ureteral stents impregnated by supercritical fluid CO2 (SCF) with each of the four anti-cancer drugs were produced. MATERIAL & METHODS: Four formulations with different concentrations of gelatin and alginate and crosslink agent were tested and bismuth was added to confer radiopaque properties to the stent. The preliminary in vivo validation studies in female domestic pigs was conducted at the University of Minho, Braga, after formal approval by the institutionâ s review board and in accordance with its internal ethical protocol for animal experiments. Paclitaxel, epirubicin, doxorubicin and gemcitabine were impregnated in the stents and the release kinetics was measured in artificial urine solution (AUS) for 9 days by UV spectroscopy in a microplate reader. The anti-tumoral effect of the developed stents in transitional cell carcinoma (TCC) and HUVEC primary cells, used as control, was evaluated. RESULTS: The in vivo validation of this second-generation of ureteral stents performed was herein demonstrated. Biodegradable ureteral stents were placed in the ureters of a female pigs, following the normal surgical procedure. The animals remained asymptomatic, with normal urine flow. The in vitro release study in AUS of the stent impregnated showed a higher release in the first 72h for the four anti-cancer drugs impregnated after this time the plateau was achieved and the stent degraded after 9 days. The direct and indirect contact of the anti-cancer biodegradable stents with the TCC and HUVEC cell lines confirm the anti-tumor effect of the stents impregnated with the four anti-cancer drugs, reducing around 75% of the viability of the TCC cell line after 72h and no killing effect in the HUVEC cells. CONCLUSIONS: The use of biodegradable ureteral stent in urology clinical practice not only reduce the stent-related symptoms but also open new treatment therapyâ s, like in urothelial tumors of upper urinary tract. Furthermore, we have demonstrated the clinical validation in vivo pig model. This study has thus shown the killing efficacy of the anti-cancer drug eluting biodegradable stents in vitro for the TCC cell line, with no toxicity observed in the control, non-cancerous cells.The direct and indirect contact of the anti-cancer biodegradable stents with the TCC and HUVEC cell lines confirm the anti-tumor effect of the stents impregnated with the four anti-cancer drugs, reducing around 75% of the viability of the TCC cell line after 72h and no killing effect in the HUVEC cells. This study has thus shown the killing efficacy of the anti-cancer drug eluting biodegradable stents in vitro for the TCC cell line, with no toxicity observed in the control, non-cancerous cells.

Multiple factor analysis of metachronous upper urinary tract transitional cell carcinoma after radical cystectomy

Transitional cell carcinoma (TCC) of the urothelium is often multifocal and subsequent tumors may occur anywhere in the urinary tract after the treatment of a primary carcinoma. Patients initially presenting a bladder cancer are at significant risk of developing metachronous tumors in the upper urinary tract (UUT). We evaluated the prognostic factors of primary invasive bladder cancer that may predict a metachronous UUT TCC after radical cystectomy. The records of 476 patients who underwent radical cystectomy for primary invasive bladder TCC from 1989 to 2001 were reviewed retrospectively. The prognostic factors of UUT TCC were determined by multivariate analysis using the COX proportional hazards regression model. Kaplan-Meier analysis was also used to assess the variable incidence of UUT TCC according to different risk factors. Twenty-two patients (4.6%). developed metachronous UUT TCC. Multiplicity, prostatic urethral involvement by the bladder cancer and the associated carcinoma in situ (CIS) were significant and independent factors affecting the occurrence of metachronous UUT TCC (P = 0.0425, 0.0082, and 0.0006, respectively). These results were supported, to some extent, by analysis of the UUT TCC disease-free rate by the Kaplan-Meier method, whereby patients with prostatic urethral involvement or with associated CIS demonstrated a significantly lower metachronous UUT TCC disease-free rate than patients without prostatic urethral involvement or without associated CIS (log-rank test, P = 0.0116 and 0.0075, respectively). Multiple tumors, prostatic urethral involvement and associated CIS were risk factors for metachronous UUT TCC, a conclusion that may be useful for designing follow-up strategies for primary invasive bladder cancer after radical cystectomy.

Immune expression of E-cadherin and alpha, beta and gamma-Catenin adhesion molecules and prognosis for upper urinary tract urothelial carcinomas

Introduction: Cell adhesion molecules (CAM) are required for maintaining a normal epithelial phenotype, and abnormalities in CAM expression have been related to cancer progression, including bladder urothelial carcinomas. There is only one study that correlates E-cadherin and alpha-, beta- and gamma-catenin expression with prognosis of upper tract urothelial carcinomas. Our aim is to study the pattern of immune expression of these CAMs in urothelial carcinomas from the renal pelvis and ureter in patients who have been treated surgically. Our goal is to correlate these expression levels and characteristics with well-known prognostic parameters for disease-free survival. Materials and Methods: We evaluated specimens from 20 patients with urothelial carcinomas of the renal pelvis and ureter who were treated with nephroureterectomy or ureterectomy between June 1997 and January 2007. CAM expression was evaluated by immunohistochemistry in a tissue microarray and correlated with histopathological characteristics and patient outcomes after a mean follow-up of 55 months. Results: We observed a relationship between E-cadherin expression and disease recurrence. Disease recurrence occurred in 87.5% of patients with strong E-cadherin expression. Only 50.0% of patients with moderate expression and 0% of patients with weak or no expression of E-cadherin had disease recurrence (p = 0.014). There was also a difference in disease-free survival. Patients with strong E-cadherin expression had a mean disease-free survival rate of 49.1 months, compared to 83.9 months for patients with moderate expression (p = 0.011). Additionally, an absence of a-catenin expression was associated with tumors that were larger than 3 cm (p = 0.003). Conclusions: We demonstrated for the first time that immune expression of E-cadherin is related to tumor recurrence and disease-free survival rates, and the absence of a-catenin expression is related to tumor size in upper tract urothelial carcinomas.

Antegrade perfusion with bacillus Calmette-Guérin in patients with non-muscle-invasive urothelial carcinoma of the upper urinary tract: who may benefit?

There is paucity of data on bacillus Calmette-Guérin (BCG) perfusion in patients with non-muscle-invasive urothelial carcinoma (NMIUC) of the upper urinary tract (UUT).

Bacillus Calmette-Guérin Failure in Patients with Non-Muscle-invasive Urothelial Carcinoma of the Bladder May Be Due to the Urologist's Failure to Detect Urothelial Carcinoma of the Upper Urinary Tract and Urethra

BACKGROUND: Various reasons exist for so-called bacillus Calmette-Guérin (BCG) failure in patients with non-muscle-invasive urothelial bladder carcinoma (NMIBC). OBJECTIVE: To explore whether urothelial carcinoma of the upper urinary tract (UUT) and/or prostatic urethra may be a cause for BCG failure. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of 110 patients with high-risk NMIBC repeatedly treated with intravesical BCG, diagnosed with disease recurrence, and followed for a median time of 9.1 yr. INTERVENTION: Two or more intravesical BCG induction courses without maintenance. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary outcome was pattern of disease recurrence (BCG failure) within the urinary tract categorised into UUT and/or urethral carcinoma (with or without intravesical recurrence), and intravesical recurrence alone. Secondary outcome was survival. Predictors of UUT and/or urethral carcinoma and the effect of pattern of disease recurrence on cancer-specific survival were assessed with multivariable Cox regression analysis adjusting for multiple clinical and tumour characteristics. RESULTS AND LIMITATIONS: Of the 110 patients, 57 (52%) had UUT and/or urethral carcinoma (with or without intravesical recurrence), and 53 (48%) had intravesical recurrence alone. In patients with UUT and/or urethral carcinoma, bladder carcinoma in situ (Tis) before the first and second BCG course was present in 42 of 57 (74%) and 47 of 57 (82%) patients, respectively. On multivariable analysis, bladder Tis before the first and/or second BCG course was the only independent predictor of UUT and/or urethral carcinoma. Of the 110 patients, 69 (63%) were alive at last follow-up visit, 18 (16%) had died due to metastatic urothelial carcinoma, and 23 (21%) had died of other causes. Pattern of disease recurrence within the urinary tract was not an independent predictor of cancer-specific survival. Main study limitations were retrospective design and limited power for survival analysis. CONCLUSIONS: In our patients with high-risk NMIBC failing after two or more courses of intravesical BCG, UUT and/or urethral carcinoma was detected in >50% of the cases during follow-up. The vast majority of these patients had bladder Tis before the first and/or second BCG course. In patients experiencing the so-called BCG failure, a diagnostic work-up of UUT and prostatic urethra should always be performed to exclude urothelial carcinoma before additional intravesical therapy or even a radical cystectomy is considered.

Stricture of the Afferent Isoperistaltic Tubular Segment: A Late and Rare Cause of Bilateral Dilation of the Upper Urinary Tract After Ileal Bladder Substitution

OBJECTIVE To evaluate the etiology and treatment of bilateral hydronephrosis not responding to bladder substitute drainage after ileal bladder substitution using an afferent isoperistaltic tubular segment. MATERIALS AND METHODS A retrospective analysis was performed of a consecutive series of 739 patients who had undergone bladder substitution from April 1985 to August 2012. RESULTS Of the 739 ileal bladder substitute patients, 10 (1.4%) developed bilateral hydronephrosis unresponsive to complete bladder substitute drainage. The etiology was stenosis of the afferent isoperistaltic tubular segment. The median interval to presentation was 131 months (range 45-192). The incidence of afferent tubular segment stenosis was significantly higher in the 61 ileal bladder substitute patients with recurrent urinary tract infection (9 [15%]) than in the 678 without recurrent urinary tract infection (1 [0.15%]; P <.001). Urine cultures revealed mixed infections (34%), Escherichia coli (18%), Staphylococcus aureus (13%), enterococci (11%), Candida (8%), Klebsiella (8%), and others (8%). Seven patients underwent 10 endourologic interventions, only 1 of which was successful (10%). After failed endourologic treatment, 7 open surgical revisions with resection of the stricture were performed, with all 7 (100%) successful. CONCLUSION Bilateral dilation of the upper urinary tract after ileal orthotopic bladder substitution unresponsive to complete bladder substitute drainage is likely to be caused by stenosis of the afferent isoperistaltic tubular segment. The stenosis occurs almost exclusively in patients with long-lasting, recurrent urinary tract infection and can develop many years after the ileal bladder substitution. Minimally invasive endourologic treatment is usually unsuccessful; however, open surgical revision offers excellent results.

Functional Multiparametric Magnetic Resonance Imaging of the Kidneys Using Blood Oxygen Level-Dependent and Diffusion-Weighted Sequences: a Reliable Tool for Monitoring Acute Upper Urinary Tract Obstruction.

PURPOSE Little data is available on noninvasive MRI-based assessment of renal function during upper urinary tract (UUT) obstruction. In this study, we determined whether functional multiparametric kidney MRI is able to monitor treatment response in acute unilateral UUT obstruction. MATERIAL AND METHODS Between 01/2008 and 01/2010, 18 patients with acute unilateral UUT obstruction due to calculi were prospectively enrolled to undergo kidney MRI with conventional, blood oxygen level-dependent (BOLD) and diffusion-weighted (DW) sequences on emergency admission and after release of obstruction. Functional imaging parameters of the obstructed and contralateral unobstructed kidneys derived from BOLD (apparent spin relaxation rate [R2*]) and DW (total apparent diffusion coefficient [ADCT], pure diffusion coefficient [ADCD] and perfusion fraction [FP]) sequences were assessed during acute UUT obstruction and after its release. RESULTS During acute obstruction, R2* and FP values were lower in the cortex (p=0.020 and p=0.031, respectively) and medulla (p=0.012 and p=0.190, respectively) of the obstructed compared to the contralateral unobstructed kidneys. After release of obstruction, R2* and FP values increased both in the cortex (p=0.016 and p=0.004, respectively) and medulla (p=0.071 and p=0.044, respectively) of the formerly obstructed kidneys to values similar to those found in the contralateral kidneys. ADCT and ADCD values did not significantly differ between obstructed and contralateral unobstructed kidneys during or after obstruction. CONCLUSIONS In our patients with acute unilateral UUT obstruction due to calculi, functional kidney MRI using BOLD and DW sequences allowed for the monitoring of pathophysiologic changes of obstructed kidneys during obstruction and after its release.

Radionuclide investigations of the urinary tract in the era of multimodality imaging.

This article presents the role of nuclear medicine procedures in investigating renal and parenchymal disease, as well as upper urinary tract abnormalities. More specifically, the use of scintigraphy is described in the exploration of urinary tract dilatation and UTIs, vesicoureteric reflux, renovascular hypertension, and renal transplants. With a low radiation burden and the absence of sedation, these nuclear medicine procedures are easy to perform and can provide clinicians with valuable data on renal perfusion and the function of individual kidneys, as well as on urinary tract dynamics. However, knowledge of limitations and technical pitfalls is essential in understanding the role of scintigraphy among contemporary imaging methods and the unique information it supplies in nephrourology.

Uroradiological screening for upper and lower urinary tract anomalies in patients with hypospadias: a systematic literature review.

INTRODUCTION: Hypospadias is associated with anomalies of the urinary tract, but the exact prevalence and significance of these anomalies are still controversial. OBJECTIVES: To assess the percentage of patients with hypospadias and associated urological anomalies, either requiring or not requiring medical or surgical attention. MATERIAL AND METHODS: We searched several databases using the following Mesh terms: hypospadias AND urination, ultrasonography, urinary tract/abnormalities, urinary bladder/radiography, ureteral obstruction, hydronephrosis or vesico-ureteral reflux. Type of uroradiological studies performed, type of urological anomalies, medical or surgical interventions, number of patients available, enrolled and undergoing uroradiological studies and number of patients with abnormal uroradiological exams were recorded. RESULTS: We found 24 studies. Four studies included 100% of available patients. In the other ones, the percentage of patients undergoing uroradiological screening varied from 12 to 82%. Frequency of anomalies varied from 0 to 56%. The most common anomalies were kidney position anomalies, vesico-ureteral reflux and hydronephrosis. CONCLUSIONS: The data published about screening patients with hypospadias for associated anomalies of their urinary tract are of poor quality. The clinical significance of the anomalies found is difficult to evaluate. We found no relationship between the severity of the hypospadias and associated anomalies of the upper or lower urinary tract.

Use of Inverted Fluoroscope`s C-arm During Endoscopic Treatment of Urinary Tract Obstruction in Pregnancy: A Practicable Solution to Cut Radiation

OBJECTIVES To describe the use of pulsed fluoroscopic guidance, to perform endoscopic procedures in pregnant women, by inverting the fluoroscope`s c-arm using a lead thyroid collar to shield the fetus from the direct X-ray beam. The use of radiation during treatment of pregnant patients with urolithiasis remains a recurring dilemma. METHODS Between May 2006 and December 2008, endoscopic treatment due to ureteral stones was attempted in 8 pregnant women. In all cases, we use an inverted fluoroscope`s c-arm during endoscopic treatment associated with 2 lead neck thyroid collars to shield the uterus, protecting the fetus from direct radiation. Indication for treatment was symptomatic ureteral stones unresponsive to medical treatment in 7 and persistent fever in 1. RESULTS Mean ureteral stone size was 8.1 +/- 4.8 mm, located in the left ureter in 5 (62.5%) cases. Three (37.5%) patients had stone located in the upper ureter, 2 (25%) in the middle ureter, and 3 (37.5) in the distal ureter. In 6 cases, ureteral stones were treated using the semi-rigid ureteroscope, whereas in 1 case a flexible ureteroscope was needed. One woman was treated with insertion of a double-J stent due to associated urinary infection. No women has early delivery related to the endoscopic procedure, and all neonates were perfectly normal. CONCLUSIONS We present a technique for endoscopic procedures in pregnant women inverting the fluoroscope`s c-arm and protecting the fetus from the direct X-ray beam. This practical approach should be specially considered when no portable ultrasound and radiologic assistance in available in the operating room. UROLOGY 75: 1505-1508, 2010. (c) 2010 Published by Elsevier Inc.

Differentiation of epithelial cells in the urinary tract

Uroplakins, cytokeratins and the apical plasma membrane were studied in the epithelia of mouse urinary tract. In the simple epithelium covering the inner medulla of the renal pelvis, no uroplakins or cytokeratin 20 were detected and cells had microvilli on their apical surface. The epithelium covering the inner band of the outer medulla became pseudostratified, with the upper layer consisting of large cells with stalks connecting them to the basal lamina. Uroplakins and cytokeratin 20 were not expressed in these cells. However, some superficial cells appeared without connections to the basal lamina; these cells expressed uroplakins Ia, Ib, II and III and cytokeratin 20, they contained sparse small uroplakin-positive cytoplasmic vesicles and their apical surface showed both microvilli and ridges. Cytokeratin 20 was seen as dots in the cytoplasm. This epithelium therefore showed partial urothelial differentiation. The epithelium covering the outer band of the outer medulla gradually changed from a two-layered to a three-layered urothelium with typical umbrella cells that contained all four uroplakins. Cytokeratin 20 was organized into a complex network. The epithelium possessed an asymmetric unit membrane at the apical cell surface and fusiform vesicles. Umbrella cells were also observed in the ureter and urinary bladder. In males and females, the urothelium ended in the bladder neck and was continued by a non-keratinized stratified epithelium in the urethra in which no urothelial cell differentiation markers were detected. We thus show here the expression, distribution and organization of specific proteins associated with the various cell types in the urinary tract epithelium.

Protocol for a randomized, placebo-controlled, double-blind clinical trial investigating sacral neuromodulation for neurogenic lower urinary tract dysfunction

BACKGROUND 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. DISCUSSION 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 http://www.clinicaltrials.gov; Identifier: NCT02165774.

Nat2, Xrcc1 And Hogg1 Polymorphisms, Cigarette Smoking, Alcohol Consumption And Risk Of Upper Aerodigestive Tract Cancer.

To evaluate associations between polymorphisms of the N-acetyltransferase 2 (NAT2), human 8-oxoguanine glycosylase 1 (hOGG1) and X-ray repair cross-complementing protein 1 (XRCC1) genes and risk of upper aerodigestive tract (UADT) cancer. A case-control study involving 117 cases and 224 controls was undertaken. The NAT2 gene polymorphisms were genotyped by automated sequencing and XRCC1 Arg399Gln and hOGG1 Ser326Cys polymorphisms were determined by Polymerase Chain Reaction followed by Restriction Fragment Length Polymorphism (PCR-RFLP) methods. Slow metabolization phenotype was significantly associated as a risk factor for the development of UADT cancer (p=0.038). Furthermore, haplotype of slow metabolization was also associated with UADT cancer (p=0.014). The hOGG1 Ser326Cys polymorphism (CG or GG vs. CC genotypes) was shown as a protective factor against UADT cancer in moderate smokers (p=0.031). The XRCC1 Arg399Gln polymorphism (GA or AA vs. GG genotypes), in turn, was a protective factor against UADT cancer only among never-drinkers (p=0.048). Interactions involving NAT2, XRCC1 Arg399Gln and hOGG1 Ser326Cys polymorphisms may modulate the risk of UADT cancer in this population.

Urinary Tract Infection In Renal Transplant Recipients: Incidence, Risk Factors, And Impact On Graft Function.

Urinary tract infection (UTI) is the most common infection posttransplant. However, the risk factors for and the impact of UTIs remain controversial. The aim of this study was to identify the incidence of posttransplant UTIs in a series of renal transplant recipients from deceased donors. Secondary objectives were to identify: (1) the most frequent infectious agents; (2) risk factors related to donor; (3) risk factors related to recipients; and (4) impact of UTI on graft function. This was a retrospective analysis of medical records from renal transplant patients from January to December 2010. Local ethics committee approved the protocol. The incidence of UTI in this series was 34.2%. Risk factors for UTI were older age, (independent of gender), biopsy-proven acute rejection episodes, and kidneys from deceased donors (United Network for Organ Sharing criteria). For female patients, the number of pretransplant pregnancies was an additional risk factor. Recurrent UTI was observed in 44% of patients from the UTI group. The most common infectious agents were Escherichia coli and Klebsiella pneumoniae, for both isolated and recurrent UTI. No difference in renal graft function or immunosuppressive therapy was observed between groups after the 1-year follow-up. In this series, older age, previous pregnancy, kidneys from expanded criteria donors, and biopsy-proven acute rejection episodes were risk factors for posttransplant UTI. Recurrence of UTI was observed in 44%, with no negative impact on graft function or survival.