External validation of a low fidelity dry-lab platform to enhance loupes surgical skills techniques for hypospadias repair.

INTRODUCTION: Hypospadias repair is an index pediatric urology procedure that requires trainee familiarity with surgical loupes. A previous low-fidelity, 6-step curriculum was proposed that deconstructed the most important steps of loupe surgery. We expanded on this curriculum with an intermediate-fidelity silicone hypospadias model and designed an abbreviated version of the 6-step curriculum to precede the hypospadias repair simulation. OBJECTIVE: To assess the validity of our prior, low-fidelity conceptual model using the metric of improved performance on the intermediate-fidelity silicone hypospadias model. STUDY DESIGN: A silicone model was first prototyped with the design software Solidworks™, and then fabricated using a cast made of a mixture of silicone rubbers designed to function like skin and soft tissue (Mold Star 20T, Dragon skin FX-pro and Slacker). Casts were used to create the penile shaft model and the dorsal hooded foreskin model. The urethral plate was cast separately on a flat surface. The model was then assembled by hand. The model used for simulation included the penile shaft and urethral plate, while the dorsal-hooded foreskin was prepared to simulate the penile anatomy separately. Trainees were then divided into two groups. Group 1 practiced the low-fidelity curriculum (3 tasks) and then performed dissection of the urethral plate and suturing using the intermediate-fidelity hypospadias model. Group 2 practiced hypospadias repair prior to the low-fidelity curriculum. Both groups' models were scored by 3 blinded urologists. Trainees were then asked to complete a post simulation satisfaction survey. Data analysis was performed in IBM SPSS Statistics for Macintosh (Version 28.0 Armonk, NY: IBM Corp). RESULTS: Twenty-two candidates across Wisconsin, USA, and Dublin, Ireland participated in the study. This included 7 s-year residents, 9 third-year residents, 2 fourth-year residents, and 3 fifth-year residents. Both Groups 1 and 2 had a similar distribution of trainees (p = 0.60). Group 1 outperformed group 2 in all tasks (p < 0.05, Table 1). Trainees reported that the platform was very useful (91%). DISCUSSION: Our curriculum showed improvement in trainee ability and comfort to perform hypospadias repair. Advantages of such a simulated curriculum include improving current resident training in microsurgery, improving surgical ergonomics for trainees prior to real-time experience, and decreasing the learning curve for trainees pursuing pediatric urology. CONCLUSION: An intermediate-fidelity hypospadias platform externally validates the conceptual model implemented in the low-fidelity loupes curriculum. This appears to lead to improvement in loupe surgical skills regardless of trainee level.

The impact of multiple donor renal arteries on perioperative complications and allograft survival in paediatric renal transplantation.

BACKGROUND: The impact of using allografts with multiple renal arteries in paediatric kidney transplantation has not been clearly established. The aim of this study was to determine whether kidney grafts with multiple arteries pose any adverse effects upon perioperative surgical outcomes, and graft survival up to 12 months post-transplant. OBJECTIVE: The objective of this study was to perform a comparative analysis of a minimum of 12-month graft survival and transplant renal function in paediatric renal transplant recipients receiving single versus multiple donor arteries, and to assess perioperative and early post-operative surgical outcomes. STUDY DESIGN: A retrospective divisional chart review of 379 transplants performed (2000-2018), of which 90 (23.7%) contained multiple donor arteries. The number of arteries of the graft, donor type, vascular reconstruction technique, occurrence of urological and vascular complications, estimated GFR and graft survival up to 12 months post-transplantation, graft loss and mortality were analysed. Comparisons in baseline characteristics and outcome measures were made between both groups. RESULTS: No significant differences were found in age (p = 0.42), BMI (p = 0.39), estimated intraoperative blood loss (p = 0.14), overall (p = 0.63) or warm ischaemic time (p = 0.37). 51.3% patients with multiple donor arteries underwent an ex vivo reconstruction. There were no differences in the site of arterial anastomosis (aorta, external iliac, internal iliac), or anastomotic type (end-side; end-end). Whilst there was a significantly higher post-operative lymphocoele rate in the multiple vessel cohort (p = 0.024), there was no increase in post-transplant urine leaks, rejection episodes, graft loss (1.1% multiple vs 2.1% single), perioperative complications (p = 0.68), or estimated GFR at 1 month (p = 0.9) or at 1 year (p = 0.67). DISCUSSION: We demonstrated in this study that there was no significant difference in postoperative complications up to 3 months, eGFR and renal function up to 1 year, and graft survival up to 4 years post transplantation irrespective of allograft type or reconstruction technique. There was however, a higher rate of lymphocoeles in the multiple artery cohort. The results seen here broadly mirror trends seen in adult studies, however, there is little data available from paediatric series. CONCLUSION: Our study demonstrates that multiple renal artery allografts - previously been considered to carry a high complication risk - can be safely used for paediatric renal transplantation with equivalent perioperative complications and graft outcomes to single artery allografts.

Cost, training and simulation models for robotic-assisted surgery in pediatric urology.

INTRODUCTION: Laparoscopic procedures in pediatric urology have been shown to be safe and effective over the last number of years. Coupled with this is the technological trend to provide minimally invasive options for even the most complex pediatric patients. Whilst robotic platforms continue to try to demonstrate superior patient outcomes in adults with mixed results, the utilization of robotic platforms for pediatric urology is increasing. METHODS: A review of the current literature was undertaken to assess the evidence for training models and cost-effectiveness of robotic-assisted pediatric urology. CONCLUSIONS: A growing body of evidence in this field has demonstrated that robotic platforms are safe and effective in children and can provide additional reconstructive benefits due to motion scaling, magnification, stereoscopic views, instrument dexterity and tremor reduction. The main drawbacks remain the financial implications associated with this platform through purchase, maintenance, and disposable costs. This review addresses some of the addresses issues pertaining to cost, training and simulation for robotic-assisted surgery in pediatric urology.

Modified staged repair of bladder exstrophy: a strategy to prevent penile ischemia while maintaining advantage of the complete primary repair of bladder exstrophy.

INTRODUCTION: Penile ischemic injury is a reported catastrophic complication after complete primary repair of exstrophy (CPRE). Aiming to improve the bladder exstrophy-epispadias repair outcomes, the study institution adopted a modified staged exstrophy repair to incorporate the advantages of CPRE by avoiding concurrent epispadias repair and adding bilateral ureteral re-implantation and bladder neck tailoring (staged repair of bladder exstrophy with bilateral ureteral re-implantation [SRBE-BUR]) at the initial repair. It was hypothesized that such modifications minimize penile complications and prevent upper tract deterioration while enhancing bladder resistance and consequent capacity. Here, a comparative series of outcomes between CPRE and SRBE-BUR is reported. METHODS: A retrospective cohort study including all exstrophy-epispadias male neonates managed in the study institution from January 2000 to December 2014 was performed. Patients were divided into those who underwent CPRE-BUR (group 1) and SRBE-BUR (group 2) (Figure). Baseline characteristics, peri-operative data, and long-term surgical outcomes were collected and analyzed for between-group comparison. Fisher exact and Mann-Whitney U tests were performed for statistical analysis. RESULTS: A total of 21 eligible patients were included: 10 in group 1 and 11 in group 2. Baseline characteristics were comparable. Two patients in group 1 had intra-operative penile ischemic injury (one with subsequent penile tissue loss), whereas none of the group 2 patients had intra-operative complications. No significant difference between the groups was noted for operative time; however, significantly lesser blood loss was noted in group 2. Comparable long-term surgical outcomes such as additional surgical intervention, urinary continence, bladder capacity, vesicoureteral reflux, hydronephrosis and recurrent urinary tract infections (UTIs) were noted. In addition, although subjective, better penile length and cosmesis were achieved by staging the repair (Figure). CONCLUSION: The SRBE with bilateral ureteral re-implantation is a safe alternative for the repair of the exstrophy-epispadias repair as it prevents the catastrophic complication of penile tissue loss, while having comparable long-term outcomes with the CPRE. Delaying epispadias repair avoids penile injury besides possible improvement of its overall cosmesis.

Return to emergency department after pediatric urology procedures.

BACKGROUND: Unplanned postoperative return visits to the emergency department (ED) and readmission represent a quality bench outcome and pose a considerable cost burden to health-care systems. OBJECTIVE: The aim of this study is to evaluate ED return visits after pediatric urology procedures in a tertiary care children's hospital, trying to identify potential causes. This may constitute a platform for future improvement areas. MATERIALS AND METHODS: A Quality Board-approved retrospective study was performed identifying all urologic cases completed between October 2012 and September 2015. Baseline demographics, American Society of Anesthesia class, operating surgeon, type of admission, type and duration of surgical procedure, and type of anesthesia given were evaluated. Patients who returned to the ED within 30 days of the surgery date were identified. The ED records were reviewed for time of return, etiology for visit, and management received. Univariate and subsequent multivariate logistic regression statistical analyses were performed to identify variables associated with ED return. Odds ratio (OR) and 95% confidence intervals (95% CIs) were generated to determine the significance of relationships. RESULTS: Total of 4125 cases was identified. Median age was 32.9 months, with 85.1% of them being male. 349 (8.5%) cases returned to the ED within 30 days of the surgery. The majority of the returned patients, 295 (84.5%), managed conservatively with medications or reassurance, whereas 54 (15.5%) required readmission, and of those readmitted, 15 (4.3%) cases needed further surgical interventions, mainly urinary tract drainage procedures. Multivariate logistic regression analysis identified that the age, residence, admission type, inguinoscrotal surgery, and duration of surgical procedure were significantly associated with ED return (Table). The most common reason for the ED visit was UTI in 17.2%, followed by stent and catheter issues in 14.3%, wound-related in 14.3%, and bleeding in 11.7%. DISCUSSION: Pediatric literature show varying rates of ED return ranging from 2.4% to 2.6% after urologic procedures. Our return to ED rate exceeds that found in US studies, which can perhaps be attributed to the differences between the Canadian and US health-care systems. As found with other studies, age, inpatient admission, procedure type, and increased operative time were related to ED returns, possibly because of the difficulty of young children expressing themselves and the presumed complex nature of longer operations that mostly need inpatient admission. The most common reason for ED return in this study as in others was presumptive UTI. A known limitation of this study is its retrospective nature, along with the possible missed visits of patients who presented to outside hospitals. CONCLUSION: We present an account of the status of ED return visits after pediatric urology procedures in our institute. The majority of ED returns can be managed conservatively and are probably preventable.

The use of postoperative prophylactic antibiotics in stented distal hypospadias repair: a systematic review and meta-analysis.

INTRODUCTION: The current literature on the use of antibiotics perioperatively for many pediatric procedures, including hypospadias, is inconsistent. There is currently no clear evidence for the use of postoperative antibiotic prophylaxis for stented distal hypospadias repair. OBJECTIVE: This study aims to synthesize and assess the available literature on the use versus non-use of postoperative antibiotic prophylaxis for stented distal hypospadias repair. METHODOLOGY: Systematic literature search was performed on March 2018 for evaluation of trials that assessed the use and non-use of postoperative prophylactic antibiotics among stented distal hypospadias repair in children. Methodological quality of the studies was assessed according to the study design as recommended by the Cochrane Collaboration. The outcome assessed includes composite overall posthypospadias repair complications of infection and wound healing complications. The event rate for each treatment group was extracted to extrapolate intervention relative risk (RR) and corresponding 95% confidence interval (CI). Mantel-Haenszel method with random effect model was used in pooling of effect estimates from the included studies. Heterogeneity was assessed with subgroup analysis performed according to the study design. Publication bias was likewise determined. The protocol of this review was registered in PROSPERO (CRD42018087301) and reported in accordance with preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. RESULT: A total of seven studies (four cohorts, three randomized controlled trials) with 986 stented distal hypospadias repairs (408 with no post-operative prophylactic antibiotics and 578 given postoperative prophylactic antibiotics) were included for the meta-analysis. Moderate to serious risk of bias was noted among the cohort studies, while the included randomized controlled trials (RCT) were of high risk of bias. Inconsistencies of effect estimates between subgroups and publication bias with small study effect were likely present. The overall pooled effect estimates comparing treatment groups showed no significant difference for outcomes of overall composite postoperative complication (RR 0.93, 95% CI 0.45, 1.93). Assessment of composite infection related complications and wound healing complications likewise did not show any significant between-group differences (RR 1.28, 95% CI 0.49, 3.35 and RR 1.01, 95% CI 0.48, 2.12; respectively) (Table). Asymptomatic bacteriuria was noted to be significantly higher among the intervention group with no postoperative prophylactic antibiotics (RR 4.01, 95% CI 1.11, 14.54). CONCLUSION: The available evidence to date was assessed to be of high risk. The low level of evidence generated suggests that there is limited utility in the use of postoperative prophylactic antibiotics to prevent clinically significant posthypospadias repair complications.

Stent-related complications after hypospadias repair: a prospective trial comparing Silastic tubing and Koyle urethral stents.

INTRODUCTION: There is a paucity of data comparing urethral stents after hypospadias repair. The aim of this study is to compare Silastic tubing vs Koyle stents (Cook Medical), addressing outcomes related to stent-related complications, added visits to healthcare providers in the early postoperative period, and postoperative complications at clinic follow-up. MATERIALS AND METHODS: Following an alternate week allocation, 150 patients were prospectively assigned to have Silastic tubes (n = 76) and Koyle stents (n = 74) after hypospadias repair. Exclusion criteria included fistula repairs, drainage via alternative catheter, or stentless repairs. Silastic tubes were secured with 5-0 Prolene and removed during a planned clinic visit. Koyle stents were secured with 7-0 PDS and left to fall out spontaneously. Questionnaires capturing postoperative outcomes were completed. RESULTS AND DISCUSSION: Median age was 13 and 11 months in the Silastic and Koyle stent groups, respectively (P = 0.48). There was no statistically significant difference in hypospadias location. Blockage/kinking of stents occurred in 8% (n = 6) of the Silastic and 9% (n = 7) Koyle stent groups, P = 0.78. Although follow-up was short, there was no difference in fistula rate among the Silastic (21%, n = 14) versus Koyle stent group (17%, n = 11), P = 0.66. There was a twofold higher rate of emergency department (ED) visits in the Silastic (32%, n = 24) versus Koyle stent group (16%, n = 12), P = 0.03. Half of ED visits in the Silastic group were related to stents falling out before planned removal. The authors propose that Silastic stents falling out before the removal date may have led to increased parental anxiety and thus a visit to the ED. With improved parental education, the authors propose that many of these visits may have been preventable. CONCLUSIONS: There were no significant differences in stent-related complications or fistula rate between the Silastic and Koyle stent groups. Although there were a twofold higher number of visits to the ED in the Silastic stent group, the authors propose that this was due to parental education rather than the stent itself.

Postoperative pain and analgesia administration in children after urological outpatient procedures.

INTRODUCTION: There are limited data about pain patterns, analgesic requirements and factors predicting opioid requirements of children undergoing outpatient urologic surgery. This prospective study aimed to assess recovery profiles and pain medication requirements. METHODS: Patients between 6 months and 12 years of age were recruited prospectively between December 2013 and June 2014. Demographic and operative characteristics were collected. Following discharge home, the parents were asked to administer both acetaminophen and ibuprofen Q6H at a weight-adjusted dose, based on a schedule, until the end of postoperative day 2, and to administer the medication as required on postoperative day 3. Pain severity was recorded using validated pain scores (Face, Legs, Activity, Cry, Consolability/Parents' Postoperative Pain Measurement). A morphine prescription was provided for breakthrough pain. A Likert scale was used to assess parent's satisfaction with the pain management. RESULTS: A total of 249 patients were recruited, 111 patients (45%) returned appropriately completed surveys and were included in the final analysis. Mean age was 44.1 months (SD = 37.3). The performed procedures were orchidopexy (31), hypospadias repair (26), hernia/hydrocele repair (15), Fowler-Stephens procedure (13), meatoplasty (7), phalloplasty (4), scrotoplasty (1), circumcision (7), and diagnostic laparoscopy (5). After discharge home 17 patients (15.3%) received morphine. Mean utilization of non-opioid analgesia was 79% on postoperative day 1, 67% on day 2, 36% on day 3, and 2% on day 4. Parental satisfaction was high (92.0% satisfied/very satisfied). No patient, anaesthetic or surgical factors were associated with opioid use or prolonged need for postoperative analgesia. CONCLUSION: The combination of scheduled non-opioid medications for maintenance and opioids for breakthrough pain provided satisfactory pain control after outpatient urologic surgery in children. There were no specific patient, anesthetic or surgical factors that predicted postoperative opioid requirements.

Stone growth patterns and risk for surgery among children presenting with hypercalciuria, hypocitraturia and cystinuria as underlying metabolic causes of urolithiasis.

INTRODUCTION: Hypercalciuria, hypocitraturia and cystinuria are the most common underlying metabolic stone abnormalities in children. The present study compared stone growth patterns, stone burden, and the risk of stone-related surgery among these underlying metabolic conditions. METHODS: A retrospective cohort of 356 children with renal stones, followed from 2000 to 2015, was studied. Differences among metabolic groups were determined using Kruskal-Wallis test; the Scheffé-test was used for multiple comparisons to determine differences among single groups. Independent sample t-test was used when adequate, given the sample size, and Chi-squared test was used for categorical variables. Stone growth rates were calculated as differences in diameter divided by time elapsed between U/Ss (mm/year). Logistic regression was performed to assess the effect of initial stone size on the likelihood of surgery. RESULTS: Median stone size at presentation was significantly different among groups, with cystinuria being the group with the largest proportion of stones >10 mm, while patients with stones <5 mm were likely to have a normal metabolic workup (P < 0.05). Stones with a higher growth rate were found in the operative group, while slower growing stones were mostly managed conservatively (3.4 mm/year vs 0.8 mm/year, respectively; P = 0.014). However, stone growth rates were not significantly different among metabolic groups. On the other hand, the rate of new stone formation in cystinuric patients at their first follow-up was 30.4%, which was significantly higher than in patients with hypercalciuria (16.3%) or with a normal metabolic workup (17.2%; P < 0.05). Compared with stones <5 mm, stones measuring 5-10 mm were more than four times more likely to result in surgery, whereas the likelihood of surgery for 10-20 mm or >20 mm stones was almost 16 or 34 times, respectively (P < 0.001). CONCLUSIONS: It is believed that this is the first study to evaluate stone growth patterns, stone burden and surgical risk among children with hypercalciuria, hypocitraturia and cystinuria. Cystinuric patients presented with larger stones at the time of diagnosis, higher new stone formation rates, and were at higher risk of surgery. While no significant difference of growth rate was found among metabolic groups, stones with a higher growth rate were significantly more likely to result in surgical treatment than slower growing stones. Initial stone size, location of largest stone, previous urinary tract infection, and patient's metabolic type significantly influenced the likelihood of a surgical intervention. Better understanding of the natural history ultimately helps surgeons and clinicians defining prognosis, treatment, and prevention plans for pediatric urolithiasis.

Serum sonic hedgehog (SHH) and interleukin-(IL-6) as dual prognostic biomarkers in progressive metastatic breast cancer.

Serum from one hundred and ten breast cancer patients and thirty healthy female volunteers, were prospectively collected and evaluated for serum levels of Shh and IL-6 using human Shh and IL-6 specific enzyme-linked immunoassays. All patients were regularly monitored for event free survival (EFS) and overall survival (OS). Overall outcome analysis was based on serum Shh and IL-6 levels. In patients with progressive metastatic BC, both serum Shh and IL-6 concentrations were elevated in 44% (29 of 65) and 63% (41 of 65) of patients, respectively, at a statistically significant level [Shh (p = 0.0001) and IL-6 (p = 0.0001)] compared to the low levels in healthy volunteers. Serum levels tended to increase with metastatic progression and lymph node positivity. High serum Shh and IL-6 levels were associated with poor EFS and OS opposite to the negative or lower levels in serum Shh and IL-6. The elevated levels of both serum Shh and IL-6 were mainly observed in BC patients who had a significantly higher risk of early recurrence and bone metastasis, and associated with a worse survival for patients with progressive metastatic BC. Further studies are warranted for validating these biomarkers as prognostic tools in a larger patient cohort and in a longer follow-up study.

Overexpression of sonic hedgehog in the triple negative breast cancer: clinicopathological characteristics of high burden breast cancer patients from Bangladesh.

Dysregulation of Hedgehog (Hh) signaling pathway has been documented in mammary gland development and breast cancer (BC) progression. Despite the remarkable progress in therapeutic interventions, BC related mortality in Bangladesh increased in the last decade. Triple negative breast cancer (TNBC) still presents a critical therapeutic challenge. Thus effective targeted therapy is urgently needed. In this study, we report the clinicopathological characteristics and prognosis of BC patients from Bangladesh. Routine immunohistochemical analysis and high throughput RNA-Seq data from the TCGA library were used to analyze the expression pattern and association of high and low level of Shh expression in a collection of BC patients with a long-term follow-up. High levels of Shh were observed in a subset of BC tumors with poor prognostic pathological features. Higher level of Shh expression correlated with a significantly poorer overall survival of patients compared with patients whose tumors expressed a low level of Shh. These data support the contention that Shh could be a novel biomarker for breast cancer that is involved in mediating the aggressive phenotype of BC. We propose that BC patients exhibiting a higher level of Shh expression, representing a subset of BC patients, would be amenable to Shh targeted therapy.

Non-biological determinants of paediatric bladder bowel dysfunction: A pilot study.

OBJECTIVES: Children with bladder and bowel dysfunction (BBD) constitute a significant proportion of referrals at paediatric urology clinics worldwide, presenting with a wide range of symptom severity that may significantly affect quality of life. Non-biological factors may play a key role in triggering BBD severity, but these underpinning causes of BBD during childhood are still unknown. The aim of this study was to identify the effects of personal, family related and environmental variables on the severity of BBD symptoms in school-aged children. STUDY DESIGN: A pilot, prospective, observational study was conducted on 53 children diagnosed with BBD, and their legal guardian(s), on their first referred visit to a paediatric BBD clinic led by nurse practitioners. Upon receiving consent, patients and their legal guardian(s) completed three study questionnaires, with the guidance of research coordinators. The first questionnaire was the Dysfunctional Voiding Scoring System (DVSS); the second, a three-part questionnaire used to collect demographic information and data on the patient, their family and environmental characteristics; and the third gathered a detailed history of the child's lifestyle regimen, focusing on their bowel and bladder function. RESULTS: Most of the children were female (66%), with an average age of 8.35 years. Most children attended public schools (74%) and none reported failing a grade. The mean parental age was 41.4 years (SD = 4.9 years), 62% of the families had two children and 53% were Caucasian. The mean DVSS score for this sample was 9.9 (SD = 4.2, range 2-21). Daycare attendance, school problems and unplanned pregnancy showed statistically significant influences on the severity of BBD and were associated with higher DVSS scores according to the Table below. CONCLUSIONS: Children with BBD attending urology outpatient clinics as new referrals had more severe symptoms when they were born from an unplanned pregnancy, attended daycare and/or had school problems. These findings suggest that interventions aimed at decreasing BBD severity, or preventing its onset in school-aged children, should focus on the environment surrounding them, specifically on the interaction between personal, familial and environmental factors. These factors seem to have an important effect on paediatric continence, as children grow and develop under numerous societal influences and social interactions.

Simultaneous Targeting of Bladder Tumor Growth, Survival, and Epithelial-to-Mesenchymal Transition with a Novel Therapeutic Combination of Acetazolamide (AZ) and Sulforaphane (SFN).

BACKGROUND: Current chemotherapies for advanced stage metastatic bladder cancer often result in severe side effects, and most patients become drug resistant over time. Thus, there is a need for more effective therapies with minimal side effects. OBJECTIVE: The acid/base balance in tumor cells is essential for tumor cell functioning. We reasoned that simultaneous targeting of pH homeostasis and survival pathways would improve therapeutic efficacy. We evaluated the effectiveness of targeting pH homeostasis with the carbonic anhydrase inhibitor acetazolamide (AZ) in combination with the survival pathway targeting isothiocyanate sulforaphane (SFN) on the HTB-9 and RT112(H) human bladder tumor cell lines. MATERIALS AND METHODS: We assessed viability, proliferation, and survival in vitro and effect on xenografts in vivo. RESULTS: Combination AZ + SFN treatment induced dose-dependent suppression of growth, produced a potent anti-proliferative and anti-clonogenic effect, and induced apoptosis through caspase-3 and PARP activation. The anti-proliferative effect was corroborated by significant reductions in Ki-67, pHH3, cyclin D1, and sustained induction of the cell cycle inhibitors, p21 and p27. Both active p-Akt (Ser473) and p-S6 were significantly downregulated in the AZ + SFN combination treated cells with a concomitant inhibition of Akt kinase activity. The inhibitory effects of the AZ + SFN combination treatment showed similar efficacy as the dual PI3K/mTOR pathway inhibitor NVP-BEZ235, albeit at an expected higher dose. In terms of the effect on the metastatic potential of these bladder cancers, we found downregulated expression of carbonic anhydrase 9 (CA9) concomitant with reductions in both E-cadherin, N-cadherin, and vimentin proteins mitigating the epithelial-to-mesenchymal transition (EMT), suggesting negation of this program. CONCLUSION: We suggest that reductions in these components could be linked with downregulation of the survival mediated Akt pathway and suggested an active role of the Akt pathway in bladder cancer. Altogether, our in vitro and pre-clinical model data support the potential use of an AZ + SFN combination for the treatment of bladder cancer.

Sonic hedgehog (Shh) signaling promotes tumorigenicity and stemness via activation of epithelial-to-mesenchymal transition (EMT) in bladder cancer.

Activation of the sonic hedgehog (Shh) signaling pathway controls tumorigenesis in a variety of cancers. Here, we show a role for Shh signaling in the promotion of epithelial-to-mesenchymal transition (EMT), tumorigenicity, and stemness in the bladder cancer. EMT induction was assessed by the decreased expression of E-cadherin and ZO-1 and increased expression of N-cadherin. The induced EMT was associated with increased cell motility, invasiveness, and clonogenicity. These progression relevant behaviors were attenuated by treatment with Hh inhibitors cyclopamine and GDC-0449, and after knockdown by Shh-siRNA, and led to reversal of the EMT phenotype. The results with HTB-9 were confirmed using a second bladder cancer cell line, BFTC905 (DM). In a xenograft mouse model TGF-ß1 treated HTB-9 cells exhibited enhanced tumor growth. Although normal bladder epithelial cells could also undergo EMT and upregulate Shh with TGF-ß1 they did not exhibit tumorigenicity. The TGF-ß1 treated HTB-9 xenografts showed strong evidence for a switch to a more stem cell like phenotype, with functional activation of CD133, Sox2, Nanog, and Oct4. The bladder cancer specific stem cell markers CK5 and CK14 were upregulated in the TGF-ß1 treated xenograft tumor samples, while CD44 remained unchanged in both treated and untreated tumors. Immunohistochemical analysis of 22 primary human bladder tumors indicated that Shh expression was positively correlated with tumor grade and stage. Elevated expression of Ki-67, Shh, Gli2, and N-cadherin were observed in the high grade and stage human bladder tumor samples, and conversely, the downregulation of these genes were observed in the low grade and stage tumor samples. Collectively, this study indicates that TGF-ß1-induced Shh may regulate EMT and tumorigenicity in bladder cancer. Our studies reveal that the TGF-ß1 induction of EMT and Shh is cell type context dependent. Thus, targeting the Shh pathway could be clinically beneficial in the ability to reverse the EMT phenotype of tumor cells and potentially inhibit bladder cancer progression and metastasis.

Buccal grafts for urethroplasty in pre-pubertal boys: what happens to the neourethra after puberty?

OBJECTIVE: Buccal mucosa grafts (BMG) are often used in complex urethral reconstruction. Following pubertal endogenous androgen stimulation (EAS) in prepubertal boys, there are concerns that the neourethra may not grow proportionally to the phallus. To address the paucity of literature on the topic, this article reports on data for post-pubertal follow up after pre-pubertal BMG urethroplasties (BMGU). PATIENTS AND METHODS: Retrospective chart review of boys who underwent staged BMGU before the age of 12 years at a single referral center between 2000 and 2010 and who were followed up until after puberty. Demographic information, initial meatal location, quality of graft before tubularization, flow rate parameters (FRP) and complications were captured. RESULTS: Of the 137 patients who underwent staged BMGU during the study period, 10 satisfied the inclusion criteria. Mean patient age at first stage BMGU was eight years (range five to eleven years). The mean follow-up was 40.6 months (9-66 months). The grafts were harvested from the cheek and lower lip in seven and three cases, respectively. The mean interval between the first and second stage was 15.8 months (6-87 months). Complications included one urethro-cutaneous fistula and two cases of glanular dehiscence. The final position of the meatus was glanular in nine boys and coronal in one. Importantly, no recurrent ventral curvature (VC) was found during the second stage BMGU or reported after puberty. All patients demonstrated normal maximum flow after puberty (mean 25.7 ml/s). CONCLUSION: Buccal mucosa grafts appear to grow proportionally to the phallus after pubertal EAS. No recurrent VC or inadequate FRP were observed in this series. Despite the small number of subjects, the results are reassuring and support continued use of BMG in the pediatric pre-pubertal population.

Comparison between laparoscopic and open radical nephrectomy for the treatment of primary renal tumors in children: single-center experience over a 5-year period.

OBJECTIVES: To compare the outcomes of laparoscopic nephrectomy (LN) with open radical nephrectomy (ORN) in the management of consecutive pediatric neoplasms. PATIENTS AND METHODS: Retrospective cohort study of consecutive children treated for primary renal tumors between 2006 and 2011, segregated based on surgical modality (LN/ORN). Pre-, intra- and postoperative data and outcomes were collected. RESULTS: Demographics from the 45 patients (13 LN, 32 ORN) were similar, and tumors in the LN group were smaller [6.59 ± 1.8 cm vs. 10.99 ± 2.99 cm ORN (p < 0.05)]. Six patients had preoperative chemotherapy (two LN, four ORN). No tumor ruptures occurred with either technique. Wilms tumor (seven LN, 24 ORN) was the most common diagnosis, followed by renal cell carcinoma (four LN, four ORN). Procedure length was similar between groups (282 ± 79 LN, 263 ± 81 min ORN). Mean length of stay was significantly shorter for LN (2.9 vs. 5.9 days; p = 0.002). Postoperative narcotic requirements and use of nasogastric tube were higher in the ORN group. After a median follow-up of 18 (LN) and 33 months (ORN), 1 and 4 recurrences occurred, respectively. CONCLUSIONS: LN is an attractive alternative to open surgery in carefully selected cases of pediatric renal tumors. Procedure length and incidence of intra-operative rupture were not increased, while post-operative recovery and hospital stay were shorter for LN. Longer follow-up is mandatory to confirm comparable oncological outcomes to ORN.

A guideline to clinical utility of prostate specific antigen.

Prostate cancer has emerged as the most common tumor effecting adult men. In the USA, 300,000 cases each year, and some 40,000 deaths per year are expected from this disease. Once prostate cancer gets to an advanced stage, one cannot prevent its progression and cure is no longer possible. Thus, to effect the course of prostate cancer and to diminish the death rate from this disease, it should be detected at its early stages. The prostate specific antigen serum test is the best tumor marker present but it is certainly not perfect. The proper utility of prostate specific antigen testing, and analysis of prostate specific antigen parameters, will allow us to detect prostate cancer at earlier stages, and prevent progression and death rates from this disease. In this manuscript, we review the current status of prostate specific antigen testing for early detection and staging of prostate cancer, as well as its role for monitoring response to various forms of therapy.