Jennifer A. Hagerty

Unilateral groin surgery in children: will the addition of an ultrasound‐guided ilioinguinal nerve block enhance the duration of analgesia of a single‐shot caudal block?

Background:  Inguinal hernia repair, hydrocelectomy, and orchidopexy are commonly performed surgical procedures in children. Postoperative pain control is usually provided with a single‐shot caudal block. Blockade of the ilioinguinal nerve may lead to additional analgesia. The aim of this double‐blind, randomized controlled trial was to evaluate the efficacy of an adjuvant blockade of the ilioinguinal nerve using ultrasound (US) guidance at the end of the procedure with local anesthetic vs normal saline and to explore the potential for prolongation of analgesia with decreased need for postoperative pain medication.

Defined Populations of Bone Marrow Derived Mesenchymal Stem and Endothelial Progenitor Cells for Bladder Regeneration

PURPOSE Autologous sources of bone marrow mesenchymal stem cells and endothelial progenitor cells are attractive alternatives to cells currently used for bladder tissue regeneration. To evaluate the potential use of these cells we determined whether mesenchymal stem cells have contractile protein profiles and physiological functions similar to those of normal bladder smooth muscle cells, and determined the angiogenic potential of endothelial progenitor cells. MATERIALS AND METHODS Mesenchymal stem cells and smooth muscle cells (Lonza, Gaithersburg, Maryland) underwent proliferation and Western blot analyses. Immunofluorescence imaging was performed using antibodies against smooth muscle cell epitopes. Contractility was assessed by intracellular Ca(2+) release assays and confocal microscopy after carbachol stimulation. Endothelial progenitor cells were evaluated using a chicken chorioallantoic membrane model to determine neo-angiogenic potential. RESULTS Western blot and immunofluorescence data showed that mesenchymal stem cells endogenously expressed known smooth muscle cell contractile proteins at levels similar to those of smooth muscle cells. Ca(2+) release assays revealed that smooth muscle cells and mesenchymal stem cells responded to carbachol treatment with a mean +/- SD of 8.6 +/- 2.5 and 5.8 +/- 0.8 RFU, respectively, which was statistically indistinguishable. Proliferation trends of mesenchymal stem cells and control smooth muscle cells were also similar. Chorioallantoic membrane assay showed the growth of vasculature derived from endothelial progenitor cells. CONCLUSIONS Data demonstrate that mesenchymal stem cells and smooth muscle cells express the same contractile proteins and can function similarly in vitro. Endothelial progenitor cells also have the ability to form vasculature in an in vivo chorioallantoic membrane model. These findings provide evidence that mesenchymal stem cells and endothelial progenitor cells have characteristics that may be applicable for bladder tissue regeneration.

Robot-Assisted Laparoscopic Reoperative Repair for Failed Pyeloplasty in Children: A Safe and Highly Effective Treatment Option

PURPOSE Failed pyeloplasty represents a management dilemma, with treatment options including balloon dilation, endopyelotomy and reoperative pyeloplasty. We review our experience with robot-assisted laparoscopic reoperative repair of recurrent/persistent ureteropelvic junction obstruction in children and compare this method to other approaches. MATERIALS AND METHODS We reviewed in detail all cases of failed prior ureteropelvic junction procedures, either open or laparoscopic, managed by robot-assisted laparoscopic reoperative repair between 2006 and July 2011. RESULTS Robot-assisted laparoscopic repair was performed in 16 cases for persistent or recurrent ureteropelvic junction obstruction following a prior procedure involving the ureteropelvic junction (12 open pyeloplasties, 4 robot-assisted laparoscopic repairs). Additional interventions had been performed in 12 patients. Reoperative robot-assisted laparoscopic pyeloplasty was performed in 13 patients and reoperative robot-assisted laparoscopic ureterocalycostomy in 3. Patient age ranged from 12 months to 15.3 years (mean 6.1 years). Mean operative time and length of stay were 303 minutes and 1.6 days, respectively. Mean followup was 14.9 months. All symptomatic patients had resolution of symptoms postoperatively. A total of 14 patients (88%) had improved radiological findings. One patient underwent transfusion and conversion to an open procedure due to bleeding. CONCLUSIONS Robot-assisted laparoscopic reoperative repair of persistent/recurrent ureteropelvic junction obstruction is a safe, highly effective procedure even in the setting of multiple prior procedures. In our series all patients improved symptomatically, 88% improved radiographically and none have required further surgical intervention. Success is greater than with endopyelotomy and comparable to open reoperative repair for this challenging condition during short-term and intermediate followup.

A new computer enhanced visual learning method to train urology residents in pediatric orchiopexy: a prototype for Accreditation Council for Graduate Medical Education documentation.

PURPOSE Residency programs must continue to restructure teaching and assessment of surgical skills to improve the documentation of Accreditation Council for Graduate Medical Education competencies. To improve teaching and documenting resident performance we developed a computer enhanced visual learning method that includes a curriculum and administrative reports. The curriculum consists of 1) study of a step-by-step surgical tutorial of computer enhanced visuals that show specific surgical skills, 2) a checklist tool to objectively assess resident performance and 3) a log of postoperative feedback that is used to structure deliberate practice. All elements of the method are repeated with each case performed. We used the Accreditation Council for Graduate Medical Education index case of orchiopexy to pilot this project. MATERIALS AND METHODS All urology residents who trained at our institution from January 2006 to October 2007 performed orchiopexy using the computer enhanced visual learning method. The computer enhanced visual learning tutorial for orchiopexy consisted of customized computer visuals that demonstrate 11 steps or skills involved in routine inguinal orchiopexy, eg ligate hernia. The attending urologist rated resident competence with each skill using a 5-point Likert scale and provided specific feedback to the resident suggesting ways to improve performance. These ratings were weighted by case difficulty. The computer enhanced visual learning weighted score at entry into the clinical rotation was compared to the best performance during the rotation in each resident. RESULTS Seven attending surgeons and 24 urology residents (resident training postgraduate years 1 to 8) performed a total of 166 orchiopexies. Overall the residents at each postgraduate year performed an average of 7 cases each with complexity ratings that were not significantly different among postgraduate year groups (average 2.4, 1-way ANOVA p not significant). The 7 attending surgeons did not differ significantly in assessment of skill performance or case difficulty (1-way ANOVA p not significant). Of the 24 residents 23 (96%) showed improvement in computer enhanced visual learning score/skill performance. In the entire group the average computer enhanced visual learning weighted score increased more than 50% from entry to best performance (137 to 234 orchiopexy units, paired t test p <0.0001). CONCLUSIONS Computer enhanced visual learning is a novel method that enhances resident learning by breaking a core procedure into discrete steps and providing a platform for constructive feedback. Computer enhanced visual learning, which is a checklist tool, complies with Accreditation Council for Graduate Medical Education documentation requirements. Computer enhanced visual learning has wide applicability among surgical specialties.

Pediatric Robotic-Assisted Laparoscopic Diverticulectomy

Congenital bladder diverticula are rare anomalies of the bladder. Patients present with infection, hematuria, and/or urinary obstruction. We report on the case of a 12-year-old boy who developed gross hematuria and recurrent infection owing to a 12-cm bladder diverticulum. Robotic-assisted laparoscopic diverticulectomy was performed. We describe the first reported robotic-assisted laparoscopic diverticulectomy in a pediatric patient.

A Review of Pediatric Glans Malformations: A Handy Clinical Reference

PURPOSE Lesions of the pediatric glans penis are an uncommon but important aspect of pediatric urological care. We reviewed the available literature on this topic and did not identify a comprehensive reference resource. We compiled our multi-institutional experience with such conditions to prepare a handy clinical reference source. MATERIALS AND METHODS The diversity of pediatric glans penis lesions was documented by searching the English and nonEnglish literature as well as the archives at our institutions. Cases were included in the study if the patient(s) identified were younger than 18 years at initial presentation or documented to have first had a glans penis lesion when younger than 18 years. Hypospadiac-epispadiac anomalies of the glans were excluded. RESULTS From our institutions we identified 6 new cases of various pediatric glans lesions. Altogether the literature describes 137 distinct nondiphallia glans lesions and more than 100 cases of diphallia, including glans duplication. The nondiphallia reports consist of a total of 61 cystic lesions (44%), 33 vascular malformations (24%), 20 dermatological lesions (15%), 20 infectious lesions (15%) and 3 neurogenic lesions (2%). We did not identify a compact resource to compare these anomalies. Visual comparison permits structuring a differential diagnosis and determining urological treatment, which is typically excisional biopsy, laser treatment, sclerotherapy or topical steroid administration. CONCLUSIONS We present a visual reference of varied lesions of the pediatric glans penis, including 6 new cases, with urological significance. These lesions are always benign but they typically require surgical excision for a definitive pathological diagnosis.

Newborn society of fetal urology grade 3 hydronephrosis is equivalent to preserved percentage differential function

PURPOSE In newborn hydronephrosis (HN), the level of differential function (%df) measured by diuretic renography (DR) is used to judge the need for pyeloplasty. As DR testing is complex, we sought to determine if grading the level of HN (Society of Fetal Urology grade, SFU Gr) by a simple ultrasound correlates with percentage differential function (%df) and thereby obviates the need to perform DR. MATERIALS AND METHODS Between 1990 and 2003 our institution prospectively enrolled all cases of fetal HN who showed unilateral newborn SFU Gr HN > or =3. The cases underwent standardized testing. DR was done using the method of Well-Tempered Renography which was then followed by ultrasound (US). The US studies were performed while the hydration induced by DR was in effect. The level of %df was categorized as preserved (> or =40%) or reduced (<40%). Cases were excluded if there was an additional urological abnormality (e.g. ureterocele). RESULTS There were 71 cases that met our study criteria. The SFU Gr HN was 3 (n=33) or 4 (n=38). Kidneys with SFU Gr 3 HN showed preserved %df (33/33,100%) (mean=50.1+/-3.6) significantly more often than kidneys with SFU Gr 4 HN (27/38, 71%) (mean=42.2+/-13.9) (RR=1.41, 95% CI (1.15-1.72), p<0.001). CONCLUSION In newborns with a history of fetal HN, the postnatal finding of SFU Gr 3 HN uniformly correlates with preserved %df. Standardized hydration prior to US study is done to assure consistency in measurement of the SFU Gr HN. Determining the duration of the relationship between SFU Gr 3 HN and preserved %df will require prospective, longitudinal studies.

Pathway analysis supports association of nonsyndromic cryptorchidism with genetic loci linked to cytoskeleton-dependent functions

STUDY QUESTION What are the genetic loci that increase susceptibility to nonsyndromic cryptorchidism, or undescended testis? SUMMARY ANSWER A genome-wide association study (GWAS) suggests that susceptibility to cryptorchidism is heterogeneous, with a subset of suggestive signals linked to cytoskeleton-dependent functions and syndromic forms of the disease. WHAT IS KNOWN ALREADY Population studies suggest moderate genetic risk of cryptorchidism and possible maternal and environmental contributions to risk. Previous candidate gene analyses have failed to identify a major associated locus, although variants in insulin-like 3 (INSL3), relaxin/insulin-like family peptide receptor 2 (RXFP2) and other hormonal pathway genes may increase risk in a small percentage of patients. STUDY DESIGN, SIZE, DURATION This is a case-control GWAS of 844 boys with nonsyndromic cryptorchidism and 2718 control subjects without syndromes or genital anomalies, all of European ancestry. PARTICIPANTS/MATERIALS, SETTING, METHODS All boys with cryptorchidism were diagnosed and treated by a pediatric specialist. In the discovery phase, DNA was extracted from tissue or blood samples and genotyping performed using the Illumina HumanHap550 and Human610-Quad (Group 1) or OmniExpress (Group 2) platform. We imputed genotypes genome-wide, and combined single marker association results in meta-analyses for all cases and for secondary subphenotype analyses based on testis position, laterality and age, and defined genome-wide significance as P = 7 × 10(-9) to correct for multiple testing. Selected markers were genotyped in an independent replication group of European cases (n = 298) and controls (n = 324). We used several bioinformatics tools to analyze top (P < 10(-5)) and suggestive (P < 10(-3)) signals for significant enrichment of signaling pathways, cellular functions and custom gene lists after multiple testing correction. MAIN RESULTS AND THE ROLE OF CHANCE In the full analysis, we identified 20 top loci, none reaching genome-wide significance, but one passing this threshold in a subphenotype analysis of proximal testis position (rs55867206, near SH3PXD2B, odds ratio = 2.2 (95% confidence interval 1.7, 2.9), P = 2 × 10(-9)). An additional 127 top loci emerged in at least one secondary analysis, particularly of more severe phenotypes. Cytoskeleton-dependent molecular and cellular functions were prevalent in pathway analysis of suggestive signals, and may implicate loci encoding cytoskeletal proteins that participate in androgen receptor signaling. Genes linked to human syndromic cryptorchidism, including hypogonadotropic hypogonadism, and to hormone-responsive and/or differentially expressed genes in normal and cryptorchid rat gubernaculum, were also significantly overrepresented. No tested marker showed significant replication in an independent population. The results suggest heterogeneous, multilocus and potentially multifactorial susceptibility to nonsyndromic cryptorchidism. LIMITATIONS, REASONS FOR CAUTION The present study failed to identify genome-wide significant markers associated with cryptorchidism that could be replicated in an independent population, so further studies are required to define true positive signals among suggestive loci. WIDER IMPLICATIONS OF THE FINDINGS As the only GWAS to date of nonsyndromic cryptorchidism, these data will provide a basis for future efforts to understand genetic susceptibility to this common reproductive anomaly and the potential for additive risk from environmental exposures. STUDY FUNDING/COMPETING INTERESTS This work was supported by R01HD060769 (the Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD)), P20RR20173 (the National Center for Research Resources (NCRR), currently P20GM103464 from the National Institute of General Medical Sciences (NIGMS)), an Institute Development Fund to the Center for Applied Genomics at The Childrens Hospital of Philadelphia, and Nemours Biomedical Research. The authors have no competing interests to declare.

Phenotype Specific Association of the TGFBR3 Locus with Nonsyndromic Cryptorchidism

PURPOSE Based on a genome-wide association study of testicular dysgenesis syndrome showing a possible association with TGFBR3, we analyzed data from a larger, phenotypically restricted cryptorchidism population for potential replication of this signal. MATERIALS AND METHODS We excluded samples based on strict quality control criteria, leaving 844 cases and 2,718 controls of European ancestry that were analyzed in 2 separate groups based on genotyping platform (ie Illumina® HumanHap550, version 1 or 3, or Human610-Quad, version 1 BeadChip in group 1 and Human OmniExpress 12, version 1 BeadChip platform in group 2). Analyses included genotype imputation at the TGFBR3 locus, association analysis of imputed data with correction for population substructure, subsequent meta-analysis of data for groups 1 and 2, and selective genotyping of independent cases (330) and controls (324) for replication. We also measured Tgfbr3 mRNA levels and performed TGFBR3/betaglycan immunostaining in rat fetal gubernaculum. RESULTS We identified suggestive (p ≤ 1× 10(-4)) association of markers in/near TGFBR3, including rs9661103 (OR 1.40; 95% CI 1.20, 1.64; p = 2.71 × 10(-5)) and rs10782968 (OR 1.58; 95% CI 1.26, 1.98; p = 9.36 × 10(-5)) in groups 1 and 2, respectively. In subgroup analyses we observed strongest association of rs17576372 (OR 1.42; 95% CI 1.24, 1.60; p = 1.67 × 10(-4)) with proximal and rs11165059 (OR 1.32; 95% CI 1.15, 1.38; p = 9.42 × 10(-4)) with distal testis position, signals in strong linkage disequilibrium with rs9661103 and rs10782968, respectively. Association of the prior genome-wide association study signal (rs12082710) was marginal (OR 1.13; 95% CI 0.99, 1.28; p = 0.09 for group 1), and we were unable to replicate signals in our independent cohort. Tgfbr3/betaglycan was differentially expressed in wild-type and cryptorchid rat fetal gubernaculum. CONCLUSIONS These data suggest complex or phenotype specific association of cryptorchidism with TGFBR3 and the gubernaculum as a potential target of TGFβ signaling.

Altered infant feeding patterns in boys with acquired nonsyndromic cryptorchidism.

BACKGROUND Genetic and environmental factors likely influence susceptibility to nonsyndromic cryptorchidism, a common disease presenting at birth or in later childhood. We compared cases and controls to define differential risk factors for congenital versus acquired cryptorchidism. METHODS We compared questionnaire and clinical data from cases of congenital cryptorchidism (n = 230), acquired cryptorchidism (n = 182) and hernia/hydrocele (n = 104) with a group of healthy male controls (n = 358). Potential predictor variables (p < 0.2 in univariable analysis) were included in stepwise multivariable logistic regression models. RESULTS Temporary (odds ratio [OR], 0.5; 95% confidence interval [CI], 0.4-0.8) or exclusive (OR, 0.6; 95% CI, 0.4-0.9) breastfeeding was reduced and soy formula feeding increased (OR, 1.8; 95% CI, 1.2-2.9) in acquired but not congenital or hernia/hydrocele groups. The highest risk estimates were observed for primary soy formula feeding with limited or no breastfeeding (OR 2.5; 95% CI, 1.4-4.3; adjusted OR, 2.7; 95% CI, 1.4-5.4) in the acquired group. Primary feeding risk estimates were equivalent or strengthened when multivariable models were limited to age greater than 2 years, full-term or not small for gestational age, or Caucasian subjects. Pregnancy complications and increased maternal exposure to cosmetic or household chemicals were not consistently associated with either form of cryptorchidism in these models. CONCLUSIONS Our data support reduced breastfeeding and soy formula feeding as potential risk factors for acquired cryptorchidism. Although additional studies are needed, hormonally active components of breast milk and soy formula could influence the establishment of normal testis position in the first months of life, leading to apparent ascent of testes in childhood. Birth Defects Research (Part A), 2012.