Update on Urological Management of Spina Bifida from Prenatal Diagnosis to Adulthood.

PURPOSE: We review the current literature regarding urological management of spina bifida from prenatal diagnosis to adulthood. MATERIALS AND METHODS: We searched MEDLINE(®), EMBASE(®) and PubMed(®) for English articles published through December 2014 using search terms "spina bifida," "spinal dysraphism" and "bladder." Based on review of titles and abstracts, 437 of 1,869 articles were identified as addressing topics related to open spina bifida in pediatric patients, or long-term or quality of life outcomes in adults with spina bifida. We summarize this literature to inform clinical guidelines and create a framework for disease management. RESULTS: The birth prevalence of spina bifida in the United States has recently plateaued at approximately 30 per 100,000. With improved management more individuals are surviving to adulthood, with an economic impact of $319,000 during the lifetime of an individual with spina bifida. Recent advances in prenatal surgery have demonstrated that prenatal closure of spina bifida is possible. To assess safety and efficacy, the National Institutes of Health sponsored Management of Myelomeningocele Study was undertaken, in which subjects were randomized to prenatal or postnatal closure. Until the urological results of this trial are published, the impact of prenatal intervention on future bladder function remains unclear. Controversy continues regarding the optimal use and timing of urodynamic studies, and the indications for initiation of clean intermittent catheterization and anticholinergics in infants and children. Many favor expectant management, while others argue for a more proactive approach. Based on the current literature, both approaches appear to protect the child from renal injury, although delayed intervention may increase rates of bladder augmentation. The current literature regarding this topic is difficult to interpret and compare due to heterogeneity of patient populations, variable outcome measures and lack of reporting of quality of life outcomes. Surgical intervention is indicated for those at risk for renal deterioration and/or is considered for children who fail to achieve satisfactory continence with medical management. Traditionally surgery concentrates on the bladder and bladder neck, and creation of catheterizable channels. For those with a hostile bladder, enterocystoplasty remains the gold standard for bladder augmentation, although use of bowel for augmentation remains suboptimal due to secondary complications, including increased risk of infections, metabolic abnormalities, neoplastic transformation and risk of life threatening perforation. Recent advances in tissue engineering technology may provide an alternative to traditional augmentation. However, recent results from phase II trials using current techniques to augment the bladder with engineered bladder tissue are disappointing. Catheterizable channels to the bladder and ascending colon further facilitate continence measures and promote independent care. While surgical reconstruction is clearly successful in improving continence, recent outcome studies have questioned the true impact of this type of surgery on quality of life. With improved survival transitional care issues, including health related independence, sexual health needs and development of a support system, are increasingly important. Transitional care remains a significant issue for which few public health measures are being quantitatively evaluated. CONCLUSIONS: Despite consensus regarding early urological involvement in the care of patients with spina bifida, controversy remains regarding optimal management. Major reconstructive urological surgeries still have a major role in the management of these cases to protect the upper urinary tract and to achieve continence. However, future studies are needed to better clarify the true impact on quality of life that these interventions have on patients and their families. Transition of urological care to adulthood remains a major avenue for improvement in disease management.

Anatomical Targeting Improves Delivery of Unconjugated Nanoparticles to the Testicle.

PURPOSE: Nanoparticles, which are submicroscopic particles typically ranging from 100 to 300 nm, are interesting as potential treatment of testicular disorders because they can be engineered to allow delivery to privileged tissues, such as across the blood-brain barrier or theoretically the blood-testis barrier. We compared the effects of anatomical and/or ligand targeting on testicular nanoparticle uptake in a rat model. MATERIALS AND METHODS: A total of 48 rats were divided into 6 groups, including a control group and groups that received intra-arterial injection of unconjugated nanoparticles with and without saline flush, intravenous injection of unconjugated nanoparticles, intra-arterial injection of follicle stimulating hormone conjugated nanoparticles, intravenous injection of follicle stimulating hormone conjugated nanoparticles and intra-arterial injection of transactivating transcriptor conjugated nanoparticles. A dose response curve was assessed for intra-arterially injected unconjugated nanoparticles. Using high performance liquid chromatography and histological analysis we determined nanoparticle uptake by the testicle at 4 hours. RESULTS: Intra-arterial injection resulted in a 5.8-fold increase in uptake compared to intravenous injection at 35 mg/kg of unconjugated nanoparticles (3.7 vs 0.6 µg nanoparticles per gm testicle, p = 0.04). Anatomical targeting failed to improve testicular uptake in FSH conjugated nanoparticles (intra-arterial vs intravenous injection 0.33 vs 0.38 µg FSH nanoparticles per gm testicular tissue, p = 0.73). On fluorescence microscopy nanoparticles were noted in the testicular interstitium and seminiferous tubules, and absent from the testicular vasculature. CONCLUSIONS: Arterial injection for anatomical targeting of nanoparticles to the testis is feasible, improves unconjugated nanoparticle delivery to testicular tissue and enables nanoparticles to cross the gonadal vascular endothelium and the blood-testis barrier.

Prospective evaluation of a pediatric urodynamics protocol before and after limiting urine cultures.

PURPOSE: While our institution has historically obtained a urine culture (UCx) from every child at the time of urodynamics (UDS), no consensus exists on UDS UCx utility, and practice varies widely. This study aims to prospectively study our symptomatic post-UDS UTI rate before and after implementing a targeted UCx protocol. MATERIALS AND METHODS: A 2-part prospective study of patients undergoing UDS at one pediatric hospital was undertaken, divided into Phase 1 (7/2016-6/2017) with routine UCx at the time of UDS and Phase 2 (7/2019-6/2020) after implementation of a protocol limiting UCx at the time of UDS to only a targeted subset of patients. The primary outcome was symptomatic post-UDS UTI, defined as positive UCx ≥10ˆ4 CFU/mL and fever ≥38.5 °C or new urinary symptoms within seven days of UDS. RESULTS: A total of 1,154 UDS were included: 553 in 483 unique patients during Phase 1 and 601 in 533 unique patients during Phase 2. Age, sex, race, ethnicity, and bladder management did not differ significantly between phases. All 553 UDS in Phase 1 had UCx at the time of UDS, compared to 34% (204/601) in Phase 2. The rate of positive UCx decreased from 39% in Phase 1-35% in Phase 2. Three patients developed symptomatic post-UDS UTI in each study period, resulting in a stable post-UDS UTI rate of 0.5% (3/553) in Phase 1 and 0.5% (3/601) in Phase 2. These patients varied in age, sex, UDS indication, and bladder management. Four of the six (67%) patients had positive UCx at the time of UDS, one had a negative UCx, and one had no UCx under the targeted UCx protocol. Predictors of symptomatic post-UDS UTI could not be evaluated. DISCUSSION: In the largest prospective study to date, we found that symptomatic post-UDS UTI was <1% and that UCx at the time of UDS can safely be limited at our hospital. This reduction has important implications for cost containment and antibiotic stewardship. We will continue iterative modifications to our protocol, which may eventually include the elimination of UCx at the time of UDS in all groups. CONCLUSIONS: This 2-part prospective evaluation at one pediatric hospital determined that the symptomatic post-UDS UTI rate remained <1% with no identifiable predictors after limiting previously universal UCx at the time of UDS to only a targeted subset of patients.

Integrated Ultrasound With Urodynamics Illustrates Effect of Bladder Volume on Upper Tract Dilation: Should we Trust Surveillance Ultrasounds?

OBJECTIVE: To evaluate if ultrasound during urodynamics (uUS) will show that traditional ultrasound (tUS) routinely underestimates the potential magnitude of upper tract dilation (UTD). METHODS: Prospective pilot study of 10 consecutive patients ≥ 5 years of age undergoing same day uUS and tUS. Using randomized images, the study pediatric radiologist determined anterior-posterior renal pelvic diameter (APD), bladder volume, vesicoureteral reflux (VUR) and UTD grades. A single pediatric urologist determined urodynamic bladder capacity and assigned either hostile, intermediate, abnormal but safe, or normal national spina bifida patient registry classification (NSBPR). RESULTS: Bladder volume on tUS was significantly smaller than final bladder volume on uUS (180 vs 363 ml: P<.001). On average, patient reported maximum catheterized/voided volumes were also 82 ml greater than final bladder capacity on uUS. UTD was upgraded in 25% of kidneys and APD increased by 0.6 cm on uUS over that seen on tUS (P=.001). Units with VUR had greater increases in APD (1.2 P=.007 vs. 0.3 cm P=0.06). Changes in APD stratified by NSBPR revealed average increases of up to 1.3 cm. CONCLUSION: Despite instructions to the contrary, patients come for tUS with a relatively empty bladder as compared to either their urodynamic or patient-reported capacity. This translates to a significant underestimation of UTD with tUS, most notably in those with VUR. Alternatives to traditional protocols include insisting patients wait until their bladder is truly full for tUS, retrograde filling their bladder, or performing uUS. Accurate assessment of UTD severity may help guide long term management.

Reassessing the utility of routine urine culture with urodynamics: UTI incidence and risk factors.

INTRODUCTION: There is no consensus regarding use of periprocedural antibiotics or routine urine cultures during urodynamics study (UDS) in children. At our hospital, we historically have obtained urine cultures during UDS. However, even with positive cultures, few patients require treatment. Most are successfully managed with increased hydration and frequent bladder emptying. PURPOSE: To evaluate clinical characteristics, antibiotic treatment, and outcomes in patients undergoing UDS to identify (1) risk factors for urinary tract infection (UTI) after UDS, and (2) patients who may benefit from routine urine culture. STUDY DESIGN: Retrospective review of 769 patients who underwent 1057 UDS between January 2013 and January 2015. Positive urine culture was defined as ≥104 colony forming units/ml. Afebrile UTI was defined as new symptoms within 7 days. Febrile UTI was new symptoms with fever (≥38.5 °C). Fisher's exact test was used for comparative analyses. RESULTS: Nearly all patients had a urine culture taken immediately prior to UDS (94%, 993/1057). Patients on clean intermittent catheterization (CIC) were more likely to be on pre-UDS antibiotics, 22.8% (106/464) vs. 17.9% of those not on CIC (106/593) (p = 0.04). Of patients who had a urine culture, it was positive in 40% (402/993) with more positive cultures in patients on CIC vs. not (72.0%, 316/439 vs. 15.5%, 86/554, p < 0.0001). Factors significantly associated with clinical/possible post-UDS UTI included clinical UTI within 30 days before UDS, immunosuppression, overnight Foley catheter use, febrile UTI as indication, and symptoms on day of procedure (Table). Fifteen patients (1.4%, 95% confidence interval 0.7-2.1%) developed a clinical/possible post-UDS UTI, of which 40% (6/15) were febrile, with one requiring hospitalization. Of patients with post-UDS UTIs, 33% (5/15) had negative cultures at the time of UDS. DISCUSSION: If urine cultures were obtained selectively based on our study findings, 78% of pre-UDS urine cultures could be eliminated, while "missing" clinically relevant cultures in only 0.4% (4/1057). Study limitations include the retrospective design. However, prospective data collection will now be possible by using standardized, templated UDS and post-UDS follow-up notes with extractable data elements that automatically populate a database. CONCLUSION: Post-UDS UTI is uncommon (1.4%), even in the setting of bacteriuria. This finding calls into question the utility of routine pre-UDS urine culture. Data from this study and a future prospective study will be used to refine a new working protocol, with the goal of targeting future urine cultures to a high-risk subset of patients.

The Role of Genetically Modified Mesenchymal Stem Cells in Urinary Bladder Regeneration.

Recent studies have demonstrated that mesenchymal stem cells (MSCs) combined with CD34+ hematopoietic/stem progenitor cells (HSPCs) can function as surrogate urinary bladder cells to synergistically promote multi-faceted bladder tissue regeneration. However, the molecular pathways governing these events are unknown. The pleiotropic effects of Wnt5a and Cyr61 are known to affect aspects of hematopoiesis, angiogenesis, and muscle and nerve regeneration. Within this study, the effects of Cyr61 and Wnt5a on bladder tissue regeneration were evaluated by grafting scaffolds containing modified human bone marrow derived MSCs. These cell lines were engineered to independently over-express Wnt5a or Cyr61, or to exhibit reduced expression of Cyr61 within the context of a nude rat bladder augmentation model. At 4 weeks post-surgery, data demonstrated increased vessel number (~250 vs ~109 vessels/mm2) and bladder smooth muscle content (~42% vs ~36%) in Cyr61OX (over-expressing) vs Cyr61KD (knock-down) groups. Muscle content decreased to ~25% at 10 weeks in Cyr61KD groups. Wnt5aOX resulted in high numbers of vessels and muscle content (~206 vessels/mm2 and ~51%, respectively) at 4 weeks. Over-expressing cell constructs resulted in peripheral nerve regeneration while Cyr61KD animals were devoid of peripheral nerve regeneration at 4 weeks. At 10 weeks post-grafting, peripheral nerve regeneration was at a minimal level for both Cyr61OX and Wnt5aOX cell lines. Blood vessel and bladder functionality were evident at both time-points in all animals. Results from this study indicate that MSC-based Cyr61OX and Wnt5aOX cell lines play pivotal roles with regards to increasing the levels of functional vasculature, influencing muscle regeneration, and the regeneration of peripheral nerves in a model of bladder augmentation. Wnt5aOX constructs closely approximated the outcomes previously observed with the co-transplantation of MSCs with CD34+ HSPCs and may be specifically targeted as an alternate means to achieve functional bladder regeneration.

Superoxide dismutase-loaded biodegradable nanoparticles targeted with a follicle-stimulating hormone peptide protect Sertoli cells from oxidative stress.

OBJECTIVE: To evaluate targeted superoxide dismutase (SOD)-loaded biodegradable nanoparticles' (NPs) ability to protect Sertoli cells from hydrogen peroxide (H2O2)-induced oxidative stress. DESIGN: Cell culture controlled experimental study. SETTING: Research laboratory. CELLS: Mouse testis Sertoli cells (TM4). INTERVENTIONS: Sertoli cells were exposed to 0-200 µg/mL plain media, unconjugated NPs, or FSH peptide-conjugated NPs for 2 or 24 hours to assess uptake. Next, Sertoli cells were exposed to 0-50 mmol H2O2 with 0-1 mg/mL unconjugated SOD-loaded NPs, FSH-conjugated SOD-loaded NPs, or equivalent units of SOD in solution as a control for 2-6 hours to assess influence on cell survival after oxidative stress. MAIN OUTCOME MEASURE(S): Cell viability, flow cytometry, and microscopy. RESULT(S): FSH peptide targeting improved uptake of NPs by Sertoli cells. FSH-conjugated SOD-NPs significantly protected Sertoli cells at 6 hours of H2O2--induced oxidative stress, with 100% survival with FSH-conjugated SOD-NPs compared with unconjugated SOD-NPs (45%) or SOD in solution (36%). CONCLUSION(S): Conjugation of NPs with FSH peptide improves cellular uptake and survival when SOD-loaded NPs are coincubated with Sertoli cells undergoing oxidative stress. This study represents a step toward developing NPs for the targeted treatment of testicular oxidative stress.

Robotic and laparoscopic radical cystectomy for bladder cancer: long-term oncologic outcomes.

BACKGROUND: Extended oncologic outcomes after minimally invasive cystectomy have not been previously reported. OBJECTIVE: To report outcomes of robot-assisted radical cystectomy (RARC) and laparoscopic radical cystectomy (LRC) for bladder cancer (BCa) at up to 12-yr follow-up. DESIGN, SETTING, AND PARTICIPANTS: All 121 patients undergoing RARC or LRC for BCa between December 1999 and September 2008 at a tertiary referral center were retrospectively evaluated from a prospectively maintained database. INTERVENTION: RARC or LRC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary end points were overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) calculated using Kaplan-Meier curves. Secondary end points were survival analysis by number of lymph nodes (LNs) and type of procedure. Surgical outcomes, including complications, were analyzed. RESULTS AND LIMITATIONS: Most tumors were muscle invasive (≥ pT2; n=81; 67%) urothelial carcinomas (n=102; 84%). Extended LN dissection was performed in 98 patients (81%), with a median of 14 nodes removed (interquartile range [IQR]: 8-18). Twenty-four patients (20%) had node-positive disease (N1: 10 [8%]; N2: 14 [12%]). Eight patients (6.6%) had positive soft tissue margins. Median follow-up was 5.5 yr (mean: 5.9; IQR: 4.2-8.2; range: 0.13-12.1). At last follow-up, 58 patients (48%) had no evidence of disease, 3 (2%) were alive with recurrence, 59 (49%) had died, and status was unknown in 1. Twenty-eight patients (23%) died from cancer-specific causes, 20 (17%) from unrelated causes, and 11 (9%) from unknown causes. The 10-yr actuarial OS, CSS, and RFS rates were 35%, 63%, and 54%, respectively. At last follow-up, OS for pT0, pTis/a, pT1, pT2, and pT3 versus pT4 was 67%, 73%, 53%, 50%, and 16% versus 0%, respectively (p=0.02). At last follow-up, CSS for pT0, pTis/a, pT1, pT2, and pT3 versus pT4 was 100%, 91%, 74%, 77%, and 56% versus 0%, respectively (p=0.03). CONCLUSIONS: The longest oncologic outcomes following RARC and LRC for BCa reported demonstrates results similar to those reported for open RC. Continued analysis and direct randomized comparison between techniques is necessary.

Evaluation of a case-based urology learning program.

OBJECTIVE: To address the challenges that today's trainees encounter, such as information overload and reduced immersion in the field, and recognizing their preference for novel educational resources, an electronic case-based urology learning program was developed. Each case was designed to illustrate the basic principles of the disease process and the fundamentals of evaluation and management using the Socratic method, recapitulating a prototypical patient encounter. METHODS: A 21-question survey was developed after review of published reports of classroom and clinical learning environment surveys. The target group was 2 pilot urology training programs (the Cleveland Clinic and University Hospitals-Case Medical Center). The responses were entirely anonymous. RESULTS: A total of 32 trainees participated (8 fellows and 24 residents), representing a 53% response rate. Most trainees (79%) were able to process cases within an average of ≤ 10 minutes. Of the trainees, 91% reported referring back to particular cases for patient care, to review for examinations, or for studying. Most trainees believed a case-based urology learning program would be a potentially important resource for clinical practice (69%) and for preparing for the in-service (63%) or board (69%) examinations. Most trainees believed the program met its goals of illustrating the basics principles of the disease process (88%), outlining the fundamentals of evaluation and management (94%), and improving the trainees' knowledge base (91%). CONCLUSION: An electronic case-based urology learning program is feasible and useful and stimulates learning at all trainee levels.

Drug delivery to the testis: current status and potential pathways for the development of novel therapeutics.

Nanotechnology has been increasingly utilized for the targeting and delivery of novel therapeutic agents to different tissues and cell types. The current therapeutic options for testicular disorders fall short in many instances due to difficulty traversing the blood-testis barrier, systemic toxicities, and complicated dosing regiments. For testicular tissue, potential targeting can be obtained either via anatomic methods or specific ligands such as luteinizing hormone or follicle-stimulating hormone analogs. Potential novel therapeutic agents include DNA, RNA, cytokines, peptide receptor antagonists, peptide receptor agonists, hormones, and enzymes. Nanotherapeutic treatment of testicular cancer, infertility, testicular torsion, orchalgia, hypogonadism, testicular infections, and cryptorchidism within the framework of potential target cells are an emerging area of research. While there are many potential applications of nanotechnology in drug delivery to the testis, this remains a relatively unexplored field. This review highlights the current status as well as potential future of nanotechnology in the development of novel therapeutics for testicular disorders.