Causes of death among people with myelomeningocele: A multi-institutional 47-year retrospective study.

PURPOSE: This study aimed to analyze organ system-based causes and non-organ system-based mechanisms of death (COD, MOD) in people with myelomeningocele (MMC), comparing urological to other COD. METHODS: A retrospective review was performed of 16 institutions in Canada/United States of non-random convenience sample of people with MMC (born > = 1972) using non-parametric statistics. RESULTS: Of 293 deaths (89% shunted hydrocephalus), 12% occurred in infancy, 35% in childhood, and 53% in adulthood (documented COD: 74%). For 261 shunted individuals, leading COD were neurological (21%) and pulmonary (17%), and leading MOD were infections (34%, including shunt infections: 4%) and non-infectious shunt malfunctions (14%). For 32 unshunted individuals, leading COD were pulmonary (34%) and cardiovascular (13%), and leading MOD were infections (38%) and non-infectious pulmonary (16%). COD and MOD varied by shunt status and age (p < = 0.04), not ambulation or birthyear (p > = 0.16). Urology-related deaths (urosepsis, renal failure, hematuria, bladder perforation/cancer: 10%) were more likely in females (p = 0.01), independent of age, shunt, or ambulatory status (p > = 0.40). COD/MOD were independent of bladder augmentation (p = >0.11). Unexplained deaths while asleep (4%) were independent of age, shunt status, and epilepsy (p >= 0.47). CONCLUSION: COD varied by shunt status. Leading MOD were infectious. Urology-related deaths (10%) were independent of shunt status; 26% of COD were unknown. Life-long multidisciplinary care and accurate mortality documentation are needed.

Extensive Pelvic Plexiform Neurofibroma Presenting As Clitoromegaly in a 3-Year-Old Female: Presentation and Management with MEK Inhibitor.

Plexiform neurofibroma (PN) involvement of the external genitalia in patients with neurofibromatosis type I (NF1) is a rare cause of nonhormonal clitoromegaly. We present a 3-year-old female with known NF1 who presented with clitoromegaly. She was identified with an extensive pelvic mass involving the bladder wall, perineum, labia, clitoris, rectum, and sacral foramina. A partial cystectomy was performed, and histopathology was consistent with PN. She has been initiated on a mitogen activated protein kinase enzyme kinase inhibitor, trametinib, which has been effective in achieving partial radiographic response of the bladder mass over 5 months. Additionally, she has experienced clinical response to trematinib with resolution of urinary urgency and frequency since initiating treatment.

Intraperitoneal administration of mesenchymal stem cells is effective at mitigating detrusor deterioration after pBOO.

Partial bladder outlet obstruction (pBOO) results in bladder fibrosis that is initiated by an inflammatory cascade and the decompensation after smooth muscle hypertrophy. We have been using an animal model to develop the hypothesis that mesenchymal stem cells (MSCs) are able to mitigate this cytokine cascade and prevent bladder deterioration. We hypothesized that intraperitoneal administration of MSCs can produce the same effects as intravenously administered cells but may require higher dosing. Intraperitoneal treatment will provide insights into the mechanisms of action and may offer advantages over intravenous administration, as it will permit allow higher doses and potentially reduce systemic exposure. Rats underwent a surgical induction of pBOO and instillation of either 1 × 106 or 5 × 106 commercially acquired MSCs into the peritoneum. RT-PCR, immunohistochemistry, and urodynamics were used to compare treatment groups with controls. pBOO resulted in a marked, statistically significant, upregulation of inflammatory markers in the bladder, including transforming growth factor-ß, hypoxia-inducible factor-1α, hypoxia-inducible factor-3α, mammalian target of rapamycin, and collagen types I and III. Moderate but inconsistent levels of downregulation were seen with 1 × 106 MSCs, but excellent and reliable downregulation was seen with 5 × 106 MSCs (P < 0.05). Immunohistochemistry confirmed that protein levels were affected in accordance with mRNA upregulation. Urodynamics demonstrated MSC treatment resulted in whole organ physiological benefits, as they prevented elevations in detrusor pressure. In conclusion, intraperitoneal administration of MSCs resulted in a similar effect as intravenous administration; however, this required a higher dose. This has significant implications for determining the mechanism of action and potential clinical application for human therapy.

Stem Cell Therapy: Current Applications and Potential for Urology.

Stem cell therapy holds the potential to revolutionize the treatment of a number of chronic conditions. Stem cells ability to home in on injured sites of the body, stimulate angiogenesis, tissue regeneration, immunomodulation, anti-inflammatory, and anti-fibrotic factors have attracted their use in the treatment of many conditions. Urology has registered one of the highest experimental successes using stem cell therapy. However, the rate of clinical applications is comparatively lower. This review takes a look at our efforts so far and what needs to be done in order to maximize the clinical benefit we can derive from stem cells.

A modification of the TIP procedure for distal hypospadias: The burrowing technique.

INTRODUCTION: The tubularized incised plate urethroplasty (TIP) hypospadias repair is a commonly performed procedure for hypospadias. Multiple series document excellent cosmetic outcome in conjunction with low complication rates. We describe a modification that we have named the "burrowing technique." We believe that this technique facilitates dissection of the glans, which improves mobility, decreases tension with closure, and potentially improves outcomes. METHODS: A retrospective review was performed of 193 coronal or mid-shaft hypospadias repairs by a single surgeon. The first 98 were performed using the TIP procedure, then the burrowing technique was developed and a subsequent 95 were analyzed for outcomes using this modification. Urethral plate characteristics and glandular size did not influence the choice of surgical technique. Cases were selected to allow for a "learning curve," and were consecutively accrued. None of the boys had undergone prior hypospadias surgery. Proximal 2 stage repairs and distal (glanular) repairs were excluded. RESULTS: A total of 193 boys underwent repair, 98 with the traditional TIP procedure and 95 using the burrowing modification. In total, 37 (19.2%) patients required re-operation for either fistulas or dehiscence; 23 (23.5%) in the non-burrowing group and 14 (14.7%) in the burrowing group, odds ratio 0.54 (p = 0.10). CONCLUSIONS: The TIP procedure has revolutionized the management of distal hypospadias. The burrowing modification increases glandular mobility simplifying the procedure and demonstrates a non-statistically significant trend in reducing reoperation rates.

Symptomatic versus asymptomatic pyeloplasties: A single institution review.

INTRODUCTION: Historically, pyeloplasties have been performed after symptoms and radiographic confirmation of an ureteropelvic junction obstruction (UPJO). However, with prenatal ultrasonography, the approach to patients has fundamentally changed. Increasingly, patients are diagnosed and treated before the advent of morbidity, based on imaging findings alone. However, optimum screening strategies and thresholds for intervention vary significantly, are controversial, and are not founded on outcome-based evidence. We examined all pyeloplasties performed at our institution and reviewed their indication for surgery. We hypothesized that, despite ubiquitous screening for UPJO, most pyeloplasties had been performed secondary to symptoms and did not benefit from antenatal screening. METHODS: A retrospective chart review was performed of all pyeloplasties performed at the Stollery Children's Hospital, Edmonton, Alberta, over the past 8 years. Patients were categorized according to indication for surgery: symptomatic or asymptomatic. RESULTS: Most (60%) of our pyeloplasties were performed for symptomatic indications. Furthermore, 12% of these patients had antenatally detected hydronephrosis that was thought to have resolved spontaneously during follow-up. Of our symptomatic patients, 37% were undergoing surveillance with the expectation for spontaneous resolution. Of the 29 patients who underwent pyeloplasty, 8 suffered a preoperative loss of function on renal scans; however, only 50% returned to within 90% of their original function. CONCLUSION: Despite active surveillance of antenatally detected hydronephrosis, most pyeloplasties at our institution were performed for de-novo symptoms. We believe that this simple observation reinforces that our current surveillance strategies are unable to predict and eliminate all morbidity from UPJO.

Mimickers and tumours in the lower urinary tract: Do we need more efficient vigilance?

Lower urinary tract symptoms are common in pediatric urology, but an atypical presentation may portend significant pathophysiology. We present 5 cases of young males with a sudden change in urinary symptoms, which resulted in the discovery of a variety of benign bladder tumours. We present the clinical, radiologic and histologic findings of these cases emphasizing on mimickers in clinics. Although rare tumours, these may be increasing in frequency and pediatric care may further be enhanced by the development of multinational registry.

Differential expression of class I small leucine-rich proteoglycans in an animal model of partial bladder outlet obstruction.

PURPOSE: Partial bladder outlet obstruction has been shown in a rat model to progress from inflammation to hypertrophy to fibrosis. Small leucine-rich proteoglycans are extracellular matrix components associated with collagen fibrillogenesis and resultant scar formation. Two such critical small leucine-rich proteoglycans are decorin and biglycan. We hypothesized that in keeping with other scar models, decorin would be down-regulated and biglycan would be up-regulated with the onset of fibrosis compared to sham. MATERIALS AND METHODS: We challenged our hypothesis with female Fisher rats that underwent ligation of the bladder neck or sham surgery. Animals were sacrificed at 4, 8 and 12 weeks, and bladders were harvested. Frozen sections were stained for immunofluorescence for decorin and biglycan. mRNA expression for decorin and biglycan was analyzed using quantitative reverse transcriptase polymerase chain reaction. RESULTS: All rats survived to specified experimental end points in good health. Immunofluorescent stains showed progressive down-regulation of decorin and up-regulation of biglycan during the 12-week course by 0.36 and 1.82-fold, respectively (p = 0.02 and p = 0.02), compared to shams. Quantitative real-time reverse transcriptase polymerase chain reaction confirmed these findings in 12-week specimens, showing a down-regulation of decorin by a factor of 0.45 (p = 0.02) and up-regulation of biglycan by a factor of 2.04-fold (p = 0.08). CONCLUSIONS: We present the first identification to our knowledge of small leucine-rich proteoglycans in normal and abnormal bladder tissue, and their differential expression in the process of bladder fibrosis, consistent with experimental findings in other anatomical sites. Further investigation into small leucine-rich proteoglycan expression and regulation may allow for the development of new antifibrotic therapeutics.

Papillary renal cell carcinoma: report of a rare entity in childhood with review of the clinical management.

We present the case of a 9-year-old boy who presents with gross hematuria and is subsequently diagnosed with a papillary (type 1) renal cell carcinoma. Management of renal cell carcinoma in the pediatric population represents a unique challenge, owing to the potential for a genetic predisposition and screening. Herein we discuss novel discoveries with respect to pediatric renal cell carcinoma and their potential impact on screening.

Foreskin management: Survey of Canadian pediatric urologists.

OBJECTIVE: To study the approaches to foreskin management of pediatric urologists in Canada. DESIGN: An online questionnaire comprising several survey questions and clinical vignettes. SETTING: Canada. PARTICIPANTS: All members of the Pediatric Urologists of Canada. MAIN OUTCOME MEASURES: Diagnoses and management strategies for common foreskin conditions seen in consultation, including how many pediatric urologists perform neonatal circumcisions, patient costs, and the reasons for performing the surgery. RESULTS: Of the 32 members surveyed, 24 (75%) responded. By far most respondents do not perform neonatal circumcisions; however, many perform circumcisions under general anesthesia for religious and cultural purposes. Typically, patient costs for circumcision range from $500 to $1000. Management of asymptomatic physiologic phimosis is very conservative, with surgeons unlikely to intervene. Neither the presence of ballooning of the foreskin during voiding nor the child's age affects physicians' tendency toward conservative management. Balanitis xerotica obliterans was the only scenario in which most respondents believed there was a need to intervene with either topical steroids or circumcision. CONCLUSION: Our data support the hypothesis that pediatric urologists across Canada are very similar in their conservative approach to the management of common foreskin issues. Our goal is to improve the knowledge base among primary care providers and subsequently decrease patient and family anxieties.

Bladder outlet obstruction: progression from inflammation to fibrosis.

OBJECTIVE: To investigate the progression of urodynamic changes, as well as histological and biochemical outcomes over a prolonged period of partial bladder outlet obstruction (pBOO) in an animal model with physiologically relevant pBOO. MATERIALS AND METHODS: Healthy, adult, female Fischer rats underwent surgical creation of a pBOO for either 2, 4, 8, or 13 weeks and were compared with sham-operated rats. Urodynamic measurements were used to compare bladder volumes and pressure. Tissue was grossly analysed with light microscopy and bladder weights and thicknesses were compared. Reverse transcription-polymerase chain reaction for collagen, transforming growth factor ß (TGF-ß), connective tissue growth factor (CTGF), hypoxia inducible factor 1α (HIF-1α), and platelet-derived growth factor (PDGF-A) was performed on all samples, as well as immunohistochemistry (IHC) for α-smooth muscle actin (α-SMA). Finally, mass spectrometry was used to quantify the collagen content of the bladders as a measure of fibrosis. RESULTS: After induction of pBOO, all rats remained healthy. Initial urodynamics showed an increase in capacity while maintaining normal pressures, but then deteriorated into small capacity, high-pressure bladders. Haematoxylin and eosin (H&E) staining showed an initial inflammatory response, and this was confirmed with significantly increased mRNA levels of TGF-ß, CTGF, HIF-1α, and PDGF. The progression to smooth muscle hypertrophy was evident on H&E and confirmed with increased bladder mass and thickness. IHC for α-SMA showed a progressive increase associated with the elevated bladder pressures. Masson's trichrome and mass spectrometry showed a progressive increase in collagen to 13 weeks. CONCLUSION: With this model, we have effectively replicated the clinical scenario, with significant pathophysiological changes occurring insidiously in otherwise healthy rats. We believe that our observed changes represent distinct phases of bladder decompensation; with an initial inflammatory response to the stress of the pBOO, smooth muscle hypertrophy to overcome the increased urethral resistance, and eventual decompensation to fibrosis. The time course of the inflammatory markers implies the need for early intervention to prevent this cascade. Novel strategies targeting these observed physiological responses could lead to improved preventative strategies, with respect to biochemical pathways and the time course of their initiation.

Testosterone exacerbates obstructive renal injury by stimulating TNF-alpha production and increasing proapoptotic and profibrotic signaling.

Upper urinary tract obstruction is a common cause of renal dysfunction in children and adults. While there is clinical evidence of an increased male incidence and mortality rate with acute renal failure, the effect of gender and testosterone on obstructive renal injury has not previously been evaluated. We hypothesized that testosterone exacerbates proinflammatory TNF-alpha production and proapoptotic and profibrotic signaling during renal obstruction, resulting in increased apoptotic cell death and tubulointerstitial fibrosis. To study this, male, female, castrated male, and testosterone-treated oophorectomized female rats were subjected to sham operation or 3 days of unilateral ureteral obstruction (UUO). Renal cortical tissue was then analyzed for TNF-alpha production; proapoptotic caspase-8, -9, and -3 activity; apoptotic cell death; profibrotic transforming growth factor-beta1 production; and alpha-smooth muscle actin expression. In a separate arm, glomerular filtration rate (inulin clearance) was measured in rats pre- and post-UUO. Male and testosterone-treated oophorectomized female rats demonstrated a significant increase in TNF-alpha production, caspase activity, apoptotic cell death, tubulointerstitial fibrosis, and renal dysfunction during UUO compared with castrated males and normal female rats subjected to the same time course of obstruction. These results demonstrate that endogenous testosterone production in normal male rats and testosterone exogenously administered to oophorectomized females significantly increases TNF production and proapoptotic and profibrotic signaling during renal obstruction, resulting in increased apoptotic cell death, tubulointerstitial fibrosis, and renal dysfunction.

Bladder augmentation: complications in the pediatric population.

Bladder augmentation is an invaluable tool for the pediatric urologist, for both the protection of the upper urinary tract and attainment of urinary continence. However, it remains a major surgical undertaking with significant morbidity. This review examines the incidence and pathophysiology of some of the most common and serious complications, which include surgical complications, such as malignancy, bowel obstruction, and bladder perforation, and medical complications including urinary tract infections and gastrointestinal dysfunction. We review the most current and pertinent literature to provide a comprehensive and practical overview of complications from bladder augmentation in the pediatric population.

Sex differences and the role of sex steroids in renal injury.

PURPOSE: There is growing evidence that significant sex differences exist in the response of the kidney to injury. In this review we explored the cumulative clinical knowledge and experimental evidence of this phenomenon. MATERIALS AND METHODS: The current clinical evidence of increased male susceptibility to acute and chronic renal injury, and experimental data elucidating potential mechanisms of this phenomenon were reviewed. RESULTS: Renal damage induced by nephron reduction, patient age and renal ischemia is tolerated differently by the sexes. Sex differences in disease susceptibility have historically been attributed to the protective effects of estrogen but recent evidence suggests that male hormones also have an important role in these differences. Vascular mediators, such as endothelin, nitric oxide and angiotensin II, appear to be influenced by sex and sex steroids. Additionally, inflammatory mediators, such as transforming growth factor-beta1, tumor necrosis factor-alpha and p38 mitogen activating protein kinase, similarly show differential expression and activity based on sex and the presence of sex steroids. These mediators have a significant impact on the kidney response to inflammation and injury. CONCLUSIONS: Greater understanding of the specific role of sex steroids in renal injury may provide new therapeutic strategies to protect against inflammatory injury and renal damage in the future.

Solid pseudopapillary tumor of the pancreas mimicking malignant adrenal pheochromocytoma.

We report a 75-year old woman with clinical, laboratory and imaging characteristics suggestive of a malignant left adrenal pheochromocytoma with invasion of the tail of the pancreas. The mass involving the tail of the pancreas and the left adrenal was excised Detailed histological diagnosis revealed that the lesion was a rare exocrine tumor of the pancreas.

Pediatric testicular tumors: contemporary incidence and efficacy of testicular preserving surgery.

PURPOSE: Testicular tumors in the pediatric population are fundamentally distinct from their adult counterparts. We reviewed a contemporary single series from a large pediatric health science center. We also examined our experience with testis conserving surgery and then used it to develop a preoperative management algorithm. MATERIALS AND METHODS: A retrospective review was performed of all testicular tumors at a single institution from 1984 to 2002. Data were compiled using the American Academy of Pediatrics testis tumor registry data collection form. We further examined partial orchiectomies for indications and outcomes with respect to cancer control and testicular viability. RESULTS: A total of 51 primary testicular lesions were identified. Patient age was prenatal to 16 years with a scrotal mass the most common presentation (81%). Mature teratoma, rhabdomyosarcoma, epidermoid cyst, yolk sac and germ cell tumors accounted for 43%, 26%, 10%, 8% and 6% of cases, respectively. This distribution was markedly different from the last reported American Academy of Pediatrics data base. Organ preserving surgery was planned and achieved in 13 cases. All surgeries were successful with respect to cancer control and testicular preservation. CONCLUSIONS: We believe that the higher incidence of teratoma is more representative of this population and yolk sac tumor is a minority diagnosis. The single institution review eliminates the interinstitutional referral heterogeneity that may have skewed larger data bases. Furthermore, the concept of testicular preserving surgery becomes an attractive option since we present its safety and efficacy. The management algorithm should facilitate the preoperative decision to perform less radical surgery and help preserve testicular tissue.