Radiology reporting of micturating cystourethrograms (MCUGs): What the paediatric urologists want to know.

BACKGROUND: Micturating cystourethrograms (MCUGs) are commonly requested to exclude vesicoureteric reflux (VUR) and bladder outlet obstruction (BOO). Useful additional information including timing and bladder volume at the start of reflux, urethral anomalies and post-void drainage can be obtained from the cystograms, but are not routinely reported by radiologists. OBJECTIVE: The study aim was to retrospectively review MCUG reports against a proposed reporting proforma, and then re-analyse the effect of the proforma on report quality. STUDY DESIGN: A retrospective analysis of paediatric MCUG reports was undertaken from two patient cohorts. Cohorts A (41 reports) and B (51 reports) comprised reports written before (2011-12) and following (2016-17) distribution of the standardised reporting proforma, respectively. Reports were assessed with respect to the parameters outlined on the standardised MCUG reporting proforma, including presence, grade and timing of VUR amongst others. Findings from both cohorts were compared and statistically analysed (p < 0.05 significant) to establish if the proforma influenced the content of reports. RESULTS: Statistically significant improvements were demonstrated in the reporting of: bladder outline normal/abnormal - reported in 92% after the proforma vs 56% before (p < 0.001); urethra normal/abnormal - 87% vs 68% (p = 0.033); contrast volume instilled - 84% vs 61% (p = 0.011); bladder emptying - 69% vs 17% (p < 0.001). In patients with VUR, reporting of VUR timing - 96% vs 33% (p < 0.001) and VUR grade - 91% vs 40% (p = 0.002) were also significantly improved. CONCLUSION: Implementation of a standardised MCUG reporting proforma produced substantial improvements in report quality and consistency, with statistically significant improvements noted in six of seven key features.

The search for the definition, etiology, and effective diagnosis of upper urinary tract obstruction: the Whitaker test then and now.

INTRODUCTION: Robert Whitaker, inspired by Dr William W Scott at the Brady Institute at Johns Hopkins and by Sir David Innes Williams at Great Ormond Street Hospital for Children in the late 1960s, spent much of his career exploring the meaning of persistent dilatation of the upper urinary tract, in an attempt to define obstruction and to find a means of diagnosing it accurately. OBJECTIVE: This is a historical review of Bob Whitaker's journey from his definition of obstruction to the inception of his eponymous test. RESULTS: In 1975, he proposed a theory to explain the pathophysiology behind obstructive hydronephrosis and megaureter. He was among the first pediatric urologists to observe that 'it is wrong… to assume that dilatation necessarily indicates obstruction', a statement that was widely stated and even appeared in the textbooks at the time. He defined obstruction as 'an increased pressure in the pelvicalyceal system of the kidney at normal physiological flow rates such that the renal function is adversely affected'. This realization led to the development of a percutaneous pressure-measuring technique at controlled flows, later referred to as the Whitaker test. It predated and later assisted in the interpretation of diuretic renograms. DISCUSSION: Whitaker questioned the etiology of 'hydronephrosis' and challenged other hypotheses proposed at the time, which often included causes of mechanical occlusion at the ureteropelvic junction (UPJ) or ureterovesical junction (UVJ). Whitaker's hypothesis is that 'obstruction' at UPJ and UVJ levels is not mechanical but the result of a failure of normal peristalsis to form and propagate a bolus. This, in turn, depends on the potentially abnormal distensibility of the renal pelvic and ureteric wall whether it be congenital or acquired. The aim of this review is to recall the history of the development of a technique to evaluate dilated upper urinary tracts and to re-evaluate various theories that might explain the etiology of the dilatation in the light of more recent evidence. Robert (or Bob, to his colleagues) Whitaker was among the founder members of the British Association of Paediatric Urologists, which now has more than 50 members, in 1992. Together with his colleagues Philip Ransley and David Thomas, Whitaker established the annual pediatric urology course for pediatric surgery and urology trainees in Cambridge, U.K., which still runs to this day. He retired from his surgical practice in 1990 and up until the present time has taught clinical anatomy in the Cambridge University School of Medicine.

Report on The Society for Fetal Urology panel discussion on the selection criteria and intervention for fetal bladder outlet obstruction.

INTRODUCTION: The Society for Fetal Urology panel section at the 2016 Fall Congress featured a multidisciplinary discussion on appropriate patient selection, the conservative versus surgical management, and postnatal renal outcome of fetuses with lower urinary tract obstruction (LUTO). SELECTION CRITERIA FOR INTERVENTION: Rodrigo Ruano shared his experience of prenatal intervention, presenting the outcome of 111 fetuses with severe LUTO treated with vesicoamniotic shunting (VAS) (n = 16), cystoscopy (n = 34) or no intervention (n = 61) in a non-randomized series. Multivariate analysis at the 6-month follow-up suggested a significantly higher probability of survival with fetal intervention versus no intervention. A clear trend for normal renal function was present in the fetal cystoscopy group, but not in the VAS group. In cases in which there was a postnatal diagnosis of posterior urethral valves (n = 57), fetal cystoscopy was effective in improving both the 6-month survival rate and renal function, while VAS was associated with an improvement in the 6-month survival rate. In an attempt to better define which fetuses would benefit from intervention, Michael Braun explained the proposed LUTO classification system that incorporates: (1) fetal urinary biomarkers of renal injury; (2) amniotic fluid levels as a surrogate for the severity of obstruction; and (3) imaging studies to identify signs of renal dysplastic or cystic changes. Intervention was not recommended in patients at low risk of either renal disease or pulmonary hypoplasia (Stage 1). Vesicoamniotic shunting was performed in patients at high risk of either progressive renal injury or pulmonary hypoplasia without evidence of severe pre-existing renal damage (Stage 2). For those patients, who at the time of evaluation had evidence of severe renal disease (Stage 3), fetal intervention was individualized and often based on bladder capacity and bladder refilling after vesicocentesis. He went on to present the nephrologic outcome of fetuses managed over the last 3 years utilizing the selection criteria. Craig Peters supported the concept of selective criteria and discussed the cautious viewpoint, namely: (1) the procedure may be unnecessary, as it is possible for patients to do well, in spite of severe prenatal obstruction; and (2) the risk of giving partial treatment by allowing the baby to survive to delivery with the daunting postnatal journey of renal and pulmonary insufficiency. CONCLUSION: Standardized patient selection utilizing a staging system is undoubtedly the way forward and will enable comparable long-term renal and bladder functional outcome studies.

Application of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement to publications on endoscopic treatment for vesicoureteral reflux.

OBJECTIVE: Following an increasing number of submissions on endoscopic treatment of vesicoureteral reflux (VUR), the Journal of Pediatric Urology sought to establish a quality guideline that would enable reviewers to select the best papers for publication in the journal. The "Strengthening the Reporting of Observational Studies in Epidemiology" (STROBE) Statement, established in 2007, is a 22-item checklist designed to assist with clear reporting of observational studies. This checklist includes a description of methodological items and instructions on how to use them to transparently report observational studies. The aim of the present study was to apply the STROBE principle to observational studies about endoscopic management of VUR, and to establish a "check-list" to assist authors with good-quality submissions. STUDY DESIGN: The 22 STROBE criteria were listed and applied to publications on endoscopic treatment by utilizing examples from the current literature, with additional suggestions about how future studies could build upon the information already published on the subject. RESULTS: Based on this strategy, a checklist that is particular to endoscopic treatment studies was produced as a guideline for authors and reviewers. DISCUSSION: Application of the STROBE statement principles, in combination with key VUR data, will allow better quality submissions and a higher chance of positive reviews and acceptance rates.

Kruppel-like factor 4 signals through microRNA-206 to promote tumor initiation and cell survival.

Tumor cell heterogeneity poses a major hurdle in the treatment of cancer. Mammary cancer stem-like cells (MaCSCs), or tumor-initiating cells, are highly tumorigenic sub-populations that have the potential to self-renew and to differentiate. These cells are clinically important, as they display therapeutic resistance and may contribute to treatment failure and recurrence, but the signaling axes relevant to the tumorigenic phenotype are poorly defined. The zinc-finger transcription factor Kruppel-like factor 4 (KLF4) is a pluripotency mediator that is enriched in MaCSCs. KLF4 promotes RAS-extracellular signal-regulated kinase pathway activity and tumor cell survival in triple-negative breast cancer (TNBC) cells. In this study, we found that both KLF4 and a downstream effector, microRNA-206 (miR-206), are selectively enriched in the MaCSC fractions of cultured human TNBC cell lines, as well as in the aldehyde dehydrogenase-high MaCSC sub-population of cells derived from xenografted human mammary carcinomas. The suppression of endogenous KLF4 or miR-206 activities abrogated cell survival and in vivo tumor initiation, despite having only subtle effects on MaCSC abundance. Using a combinatorial approach that included in silico as well as loss- and gain-of-function in vitro assays, we identified miR-206-mediated repression of the pro-apoptotic molecules programmed cell death 4 (PDCD4) and connexin 43 (CX43/GJA1). Depletion of either of these two miR-206-regulated transcripts promoted resistance to anoikis, a prominent feature of CSCs, but did not consistently alter MaCSC abundance. Consistent with increased levels of miR-206 in MaCSCs, the expression of both PDCD4 and CX43 was suppressed in these cells relative to control cells. These results identify miR-206 as an effector of KLF4-mediated prosurvival signaling in MaCSCs through repression of PDCD4 and CX43. Consequently, our study suggests that a pluripotency factor exerts prosurvival signaling in MaCSCs, and that antagonism of KLF4-miR-206 signaling may selectively target the MaCSC niche in TNBC.

Regulation of anti-apoptotic signaling by Kruppel-like factors 4 and 5 mediates lapatinib resistance in breast cancer.

The Kruppel-like transcription factors (KLFs) 4 and 5 (KLF4/5) are coexpressed in mouse embryonic stem cells, where they function redundantly to maintain pluripotency. In mammary carcinoma, KLF4/5 can each impact the malignant phenotype, but potential linkages to drug resistance remain unclear. In primary human breast cancers, we observed a positive correlation between KLF4/5 transcript abundance, particularly in the human epidermal growth factor receptor 2 (HER2)-enriched subtype. Furthermore, KLF4/5 protein was rapidly upregulated in human breast cancer cells following treatment with the HER2/epidermal growth factor receptor inhibitor, lapatinib. In addition, we observed a positive correlation between these factors in the primary tumors of genetically engineered mouse models (GEMMs). In particular, the levels of both factors were enriched in the basal-like tumors of the C3(1) TAg (SV40 large T antigen transgenic mice under control of the C3(1)/prostatein promoter) GEMM. Using tumor cells derived from this model as well as human breast cancer cells, suppression of KLF4 and/or KLF5 sensitized HER2-overexpressing cells to lapatinib. Indicating cooperativity, greater effects were observed when both genes were depleted. KLF4/5-deficient cells had reduced basal mRNA and protein levels of the anti-apoptotic factors myeloid cell leukemia 1 (MCL1) and B-cell lymphoma-extra large (BCL-XL). Moreover, MCL1 was upregulated by lapatinib in a KLF4/5-dependent manner, and enforced expression of MCL1 in KLF4/5-deficient cells restored drug resistance. In addition, combined suppression of KLF4/5 in cultured tumor cells additively inhibited anchorage-independent growth, resistance to anoikis and tumor formation in immunocompromised mice. Consistent with their cooperative role in drug resistance and other malignant properties, KLF4/5 levels selectively stratified human HER2-enriched breast cancer by distant metastasis-free survival. These results identify KLF4 and KLF5 as cooperating protumorigenic factors and critical participants in resistance to lapatinib, furthering the rationale for combining anti-MCL1/BCL-XL inhibitors with conventional HER2-targeted therapies.

Retroperitoneoscopic left upper moiety heminephroureterectomy for dribbling incontinence.

A 7-year-old girl underwent a prone, retroperitoneoscopic left upper moiety heminephroureterectomy for a non-functioning upper moiety associated with a dilated, ectopic ureter. The dilated ureter was noted prenatally, but postnatal investigations failed to demonstrate the duplex system. The child remained asymptomatic until she represented at 6 years of age, with dribbling of urine. She went on to have an ultrasound scan, dimercaptosuccinic acid and magnetic resonance urogram, which identified a grossly-dilated fluid-filled structure in proximity of the left kidney, but failed to demonstrate the small non-functioning left upper moiety. A computed tomography urogram was more helpful in establishing the diagnosis. Retroperitoneoscopy via three 5-mm ports allowed clear visualisation of both the left duplex ureters, as well as the small non-functioning upper moiety, which had been challenging on the pre-operative imaging. The procedure is described in the accompanying video. The child was discharged home the following day and has been completely well and dry at 6 months' follow-up.

Clinical and gonadal features and early surgical management of 45,X/46,XY and 45,X/47,XYY chromosomal mosaicism presenting with genital anomalies.

OBJECTIVE: The 45,X/46,XY and 45,X/47,XYY group of patients includes some of those previously diagnosed with 'mixed gonadal dysgenesis'. Our aim was to establish the clinical and gonadal spectrum, and early surgical management, of patients with chromosomal mosaicism presenting with genital anomalies. PATIENTS AND METHODS: We performed a retrospective review of patients with 45,X/46,XY or 45,X/47,XYY mosaicism presenting with genital ambiguity between 1988 and 2009. At least one gonadal biopsy or gonadectomy specimen was available for each patient. Gonadal histology was re-evaluated by a paediatric pathologist. RESULTS: Of 31 patients with 45,X/46,XY (n = 28) or 45,X/47,XYY (n = 3) mosaicism and genital anomalies, 19 (61%) were raised male. Histology of 46 gonads was available from patients who had undergone a gonadectomy or gonadal biopsy, at a median age of 9.5 months. 18 gonads were palpable at presentation, including 5 (28%) histologically unremarkable testes, 2 streak gonads, and 1 dysgenetic gonad with distinct areas of testicular and ovarian stroma but no oocytes. All intra-abdominal gonads were found to be dysgenetic testes (of which 2 were noted to have pre-malignant changes) or streaks, apart from 1 histologically unremarkable testis. 15 (48%) patients had other anomalies, most commonly cardiac and renal; 4 (13%) had a Turner phenotype. CONCLUSION: The anatomy and gonadal histology of 45,X/46,XY and 45,X/47,XYY individuals with genital ambiguity do not conform to a set pattern, and hence management of each patient should be individualized according to detailed anatomical and histological assessment.

Outcome of the Lima periurethral constrictor in children and adolescents: a European perspective.

PURPOSE: The Lima constrictor was described in 1996 as a less complex and less expensive alternative to the artificial urinary sphincter for use in cases of pediatric neuropathic sphincter incontinence. The device provides a fixed periurethral resistance which creates continence, yet allows urethral catheterization without the need to deflate the cuff. We report our multicenter experience, and continence, revision and erosion rates. MATERIALS AND METHODS: We performed a retrospective review of 14 consecutive patients who underwent insertion of the periurethral constrictor (Silimed, Rio de Janeiro, Brazil) between 2005 and 2011. Data are presented as medians (range). RESULTS: A total of 14 patients (13 male, 1 female) with spina bifida (10), sacral agenesis (3) and Hirschsprung disease (1) underwent insertion of the constrictor at a median age of 12 years (range 8 to 20). All patients were wet despite clean intermittent catheterization, medical therapy and/or previous surgery. Eleven patients underwent simultaneous bladder augmentation and/or Mitrofanoff formation. The constrictor was activated a median of 8 weeks (range 2 to 99) after the procedure in 11 patients whereas 3 became dry without activation. Complications occurred in 4 patients (29%), including spontaneous bladder perforation and constrictor erosion (1), tubing disconnection requiring revision (2) and wound infection (1). At a median of 23 months of followup (range 7 to 77) 13 patients were dry and 1 was damp. All patients performed urethral or Mitrofanoff clean intermittent catheterization. The continence rate with the device in situ was 92%. CONCLUSIONS: At a median followup of 23 months the Lima constrictor provided a 92% continence rate with erosion and revision rates of 7% and 14%, respectively. Interim results suggest that the constrictor provides a safe and effective surgical option, particularly in patients who are unable to void to completion.

Congenital lung lesions: classification and concordance of radiological appearance and surgical pathology.

Congenital lung lesions are diagnosed antenatally in the majority of cases. Postnatal management includes chest radiography and CT-scanning, followed by either surgical resection or CT surveillance. Pre-operatively, lesions are often "labelled" as CCAM (and the Stocker classification incorrectly applied), sequestration, or lobar emphysema, and their frequent "hybrid" nature sometimes missed. The aim of our study was to correlate antenatal and postnatal radiological diagnoses and classification of congenital lung lesions with surgical and pathological outcome. Twenty-six consecutive cases of antenatally-diagnosed cystic lung lesions managed at our centre between January 2003 and April 2007 were reviewed. Diagnoses were: cystic adenomatoid malformations (CCAM) in 13 cases (50.0%), three bronchopulmonary sequestrations (11.5%), "hybrid" lesions in eight cases (30.8%), one isolated lobar emphysema (3.8%) and a normal lung segment with anomalous systemic supply (3.8%). Overall concordance rate between prenatal ultrasound and resection pathology was 61.5%, whereas CT findings correlated with pathology in 65.4% of cases. Incorrect radiological classification resulted in one morbidity, when an attempted thoracoscopic resection of a presumed CCAM had to be converted to an open procedure due to bleeding from an unsuspected anomalous vessel. The common embryological origin of these lesions, and the need for standardisation of reporting is discussed. We propose that lesions should be classified anatomically according to their nature, arterial supply and venous drainage in order to reduce discrepancies between radiological, intra-operative and pathological reporting.

Exomphalos major suspension: a novel technique.

A 38-week gestation female neonate with an antenatally diagnosed exomphalos major was born with respiratory insufficiency requiring initially high frequency oscillation, nitric oxide and inotropic support. The exomphalos was vertically stabilized by means of a novel technique prior to the application of a silo and formal closure. The technique is described and compared with others.

Experimental short-term fetal bladder outflow obstruction: I. Morphology and cell biology associated with urinary flow impairment.

PURPOSE: In fetal sheep, combined urethral and urachal obstruction initiated at 75 days' gestation and maintained for 30 days led to dysmorphic bladders, similar to those found in humans with prune belly syndrome, and uniformly disrupted kidney development. We aimed to create a less severe model of fetal bladder outlet obstruction, more closely resembling infants with posterior urethral valves, and additionally to further our understanding on the role of the urachus. We hypothesized that milder morphological renal tract changes would occur after shorter term experimental obstruction. MATERIALS AND METHODS: Male fetal lambs were assigned to urachal and urethral ligation, urachal ligation only or sham operations. Analyses were performed after 9 days. RESULTS: Concurrent urachal and urethral obstruction resulted in increased bladder weight, and protein and DNA content. Detrusor smooth muscle was well maintained, as assessed by light and electron microscopy, although urothelia showed basal apoptosis. Bladder obstruction led to hydronephrosis but failed to produce significant perturbations in urine osmolality. The nephrogenic cortex was either well preserved or was replaced by glomerular cysts; the latter group tended to have heavier bladders. Urachal obstruction alone produced similar changes suggesting that the male sheep fetal urethra is a high-resistance conduit in mid-gestation. CONCLUSIONS: Concurrent urachal and urethral obstruction, or urachal obstruction alone, initiated in mid-gestation and maintained for 9 days leads to bladder overgrowth but preserved renal tubular function. In future, it will be interesting to determine whether bladder decompression around this stage leads to reversal of bladder overgrowth and/or ameliorates severe renal tract damage described after longer term fetal bladder outflow obstruction.

Experimental short-term partial fetal bladder outflow obstruction: II. Compliance and contractility associated with urinary flow impairment.

PURPOSE: Posterior urethral valves (PUV) is the commonest cause of congenital bladder outlet obstruction. Despite valve ablation in the neonatal period, up to 70% of patients develop renal failure by their teenage years, and progressive bladder dysfunction. This study forms part of a continuing project examining the relationship between severity and duration of obstruction and urinary tract dysfunction. Here is the assessed result of short-term (9-day) obstruction. MATERIALS AND METHODS: Fourteen male fetal lambs at 75 days' gestation were assigned to one of three groups: urachal ligation, urachal ligation with partial urethral obstruction, sham-operated controls. Pregnancy proceeded for 9 days. At autopsy, filling cystometry was performed with the urinary tract in situ and the bladder harvested for nerve counts using PGP 9.5 immunohistochemistry, or in vitro measurement of contractile function. RESULTS: Obstruction was associated with an increase in bladder:fetal weight ratio. Compliance was variable in the obstructed bladders, but the calculated wall stress per unit strain was either similar or less than controls. Nerve-mediated or agonist-induced contraction magnitude in tissue from obstructed bladders and nerve counts did not differ from controls. CONCLUSIONS: Nine days of outflow obstruction at mid-gestation generated a bladder of increased weight but without evidence of contractile failure. An increase in bladder compliance as a function of bladder growth was observed even at this stage, and represents one of the initial responses to outflow tract obstruction.

The sensitivity of antenatal ultrasound for predicting renal tract surgery in early childhood.

OBJECTIVE: To establish the sensitivity of antenatal ultrasound for identifying the need for renal tract surgery in infancy and early childhood. METHODS: A retrospective analysis of the surgical records in children under 5 years of age undergoing renal tract surgery in a regional pediatric urological surgery referral unit was carried out. All records between May 1997 and July 2002 were examined to assess the relationship between prenatal ultrasound findings and postnatal surgical pathology. RESULTS: A total of 106 operations had been performed. The detection rate of multicystic renal dysplasia was 100% (17/17). The equivalent detection rates for pelviureteral junction obstruction, duplex renal system and vesicoureteral reflux were 82.8, 67 and 26.1%, respectively. None of the babies with renal tumors had abnormal antenatal ultrasound findings. The diagnosis of postnatal renal surgical pathology was made on the basis of prenatal scan findings in 59.6% of cases, while recurrent urinary tract infection led to the diagnosis in 26.0%. CONCLUSIONS: Approximately 40% of children requiring surgery for renal tract pathology will have a normal antenatal ultrasound examination. The prevalence of abnormal antenatal ultrasound findings varies depending on the type of renal tract pathology. Despite these findings, the commonest indicator for surgery remains abnormal prenatal scan findings, followed by recurrent urinary tract infections.

A preliminary study of natural-fill radiotelemetered ovine fetal cystometry.

OBJECTIVE: To determine whether fetal cystometric studies by radiotelemetry are feasible in the fetal lamb, and potentially suitable for chronically monitoring fetal bladder pressures in an experimental fetal model of bladder outlet obstruction (BOO), as in utero BOO (e.g. caused by posterior urethral valves) results in significant postnatal bladder dysfunction but the pathophysiological progression of fetal bladder maldevelopment remains poorly understood. MATERIALS AND METHODS: The procedure required fetal sheep surgery and anaesthesia. Radiotelemetry implants comprised catheters that transmitted pressure fluctuations to an implant body; data were then transmitted using radio frequency to a receiver that passed this information to a computer. Four fetuses were used with different methods of catheter placement to optimize the technique. RESULTS: Recordings were possible in three of the four sheep; during observation there were: (i) quiet periods with no abdominal or bladder pressure rises; (ii) synchronous activity in the bladder and abdomen; and (iii) discriminate activity, associated with intravesical activity only. Four patterns of discriminate bladder activity were observed, defined as void, immature void, staccato activity and 'unstable' type activity. CONCLUSIONS: Radiotelemetry cystometry for long-term monitoring is feasible in the experimental fetus without causing death or morbidity, or inhibiting growth. The method can discriminate reproducible patterns of detrusor activity. Recorded 'voiding' types were consistent between experiments and as reported in other fetal animal studies.

Benign lipoblastoma arising in the neck.

Lipoblastoma and lipoblastomatosis are rare benign tumours of embryonal fat that exhibit a tendency to invade locally but not to metastasize. This condition most often presents before the age of 3 years, affects males more than females, and is typified by a slowly-growing, usually subcutaneous mass arising in a limb. Cases involving the head and neck are extremely rare, with only nine cases in the neck having been described to date. This tenth case arose in a 13-month-old male presenting with a rapidly enlarging lump in the right side of the neck, clinically mimicking a cystic hygroma. Diagnosis is by histology, and treatment involves complete surgical resection. We report this tenth known case of lipoblastoma in the neck and review the literature.