The Urinary Proteomic Profile Implicates Key Regulators for Urologic Chronic Pelvic Pain Syndrome (UCPPS): A MAPP Research Network Study.

Urologic chronic pelvic pain syndrome (UCPPS) is a condition of unknown etiology characterized by pelvic pain and urinary frequency and/or urgency. As the proximal fluid of this syndrome, urine is an ideal candidate sample matrix for an unbiased study of UCPPS. In this study, a large, discovery-phase, TMT-based quantitative urinary proteomics analysis of 244 participants was performed. The participants included patients with UCPPS (n = 82), healthy controls (HC) (n = 94), and disparate chronic pain diseases, termed positive controls (PC) (n = 68). Using training and testing cohorts, we identified and validated a small and distinct set of proteins that distinguished UCPPS from HC (n = 9) and UCPPS from PC (n = 3). The validated UCPPS: HC proteins were predominantly extracellular matrix/extracellular matrix modifying or immunomodulatory/host defense in nature. Significantly varying proteins in the UCPPS: HC comparison were overrepresented by the members of several dysregulated biological processes including decreased immune cell migration, decreased development of epithelial tissue, and increased bleeding. Comparison with the PC cohort enabled the evaluation of UCPPS-specific upstream regulators, contrasting UCPPS with other conditions that cause chronic pain. Specific to UCPPS were alterations in the predicted signaling of several upstream regulators, including alpha-catenin, interleukin-6, epidermal growth factor, and transforming growth factor beta 1, among others. These findings advance our knowledge of the etiology of UCPPS and inform potential future clinical translation into a diagnostic panel for UCPPS.

Enhanced Recovery After Surgery for an Uncommon Complex Urological Procedure: The Complete Primary Repair of Bladder Exstrophy.

PURPOSE: ERAS (enhanced recovery after surgery) protocols are designed to optimize perioperative care and expedite recovery. Historically, complete primary repair of bladder exstrophy has included postoperative recovery in the intensive care unit and extended length of stay. We hypothesized that instituting ERAS principles would benefit children undergoing complete primary repair of bladder exstrophy, decreasing length of stay. We describe implementation of a complete primary repair of bladder exstrophy-ERAS pathway at a single, freestanding children's hospital. MATERIALS AND METHODS: A multidisciplinary team developed an ERAS pathway for complete primary repair of bladder exstrophy, which launched in June 2020 and included a new surgical approach that divided the lengthy procedure into 2 consecutive operative days. The complete primary repair of bladder exstrophy-ERAS pathway was continuously refined, and the final pathway went into effect in May 2021. Post-ERAS patient outcomes were compared with a pre-ERAS historical cohort (2013-2020). RESULTS: A total of 30 historical and 10 post-ERAS patients were included. All post-ERAS patients had immediate extubation (P = .04) and 90% received early feeding (P < .001). The median intensive care unit and overall length of stay decreased from 2.5 to 1 days (P = .005) and from 14.5 to 7.5 days (P < .001), respectively. After final pathway implementation, there was no intensive care unit use (n=4). Postoperatively, no ERAS patient required escalation of care, and there was no difference in emergency department visits or readmissions. CONCLUSIONS: Applying ERAS principles to complete primary repair of bladder exstrophy was associated with decreased variations in care, improved patient outcomes, and effective resource utilization. Although ERAS has typically been utilized for high-volume procedures, our study highlights that an enhanced recovery pathway is both feasible and adaptable to less common urological surgeries.

Comparing Pediatric Ureteroscopy Outcomes with SuperPulsed Thulium Fiber Laser and Low-Power Holmium:YAG Laser.

PURPOSE: The thulium fiber laser is a promising new lithoptripsy technology never before studied in the pediatric population. Our center adopted the first platform in North America, the SuperPulsed thulium fiber laser (SPTF). We aimed to compare outcomes in pediatric ureteroscopy using the SPTF to those using the gold standard, low-power holmium:yttrium-aluminum-garnet (Ho:YAG) laser. MATERIALS AND METHODS: This is a retrospective, consecutive cohort study of unilateral ureteroscopy with laser lithotripsy performed in pediatric patients from 2016 to 2021 as an early adopter of the SPTF. Thirty-day complications and stone-free status, defined as the absence of a stone fragment on followup imaging within 90 days, were analyzed using logistic regression. Operative times were compared using linear regression. Propensity scores for use of SPTF were used in regression analyses to account for potential cohort imbalance. RESULTS: A total of 125 cases were performed in 109 pediatric patients: 93 with Ho:YAG and 32 with SPTF. No significant difference was noted in age (p=0.2), gender (p=0.6), stone burden (p >0.9) or stone location (p=0.1). The overall stone-free rate was 62%; 70% with SPTF and 59% with Ho:YAG. The odds of having a residual stone fragment were significantly lower with SPTF than with Ho:YAG (OR=0.39, 95% CI: 0.19-0.77, p=0.01). There was no significant difference in operative time (p=0.8). Seven (25%) complications were noted with SPTF and 19 (22%) with Ho:YAG (p=0.6). CONCLUSIONS: The SPTF laser was associated with a higher stone-free rate than the low-power Ho:YAG laser without compromising operative time and safety.

Malignancy Yield of Testis Pathology in Older Boys and Adolescents with Cryptorchidism.

PURPOSE: We performed a retrospective, single-institution study to characterize the pathological findings of testis tissue specimens from older boys and adolescents with cryptorchidism. MATERIALS AND METHODS: With institutional review board approval, pathology reports were obtained for testicular specimens from patients age 10 years or older at a pediatric hospital from 1994 to 2016. Reports were excluded if they lacked clinical records, lacked testicular parenchyma, were from a descended testis or were from a patient with differences of sexual development. Variables of interest included age, testis location, procedure and pathological findings. Presence of malignancy among intra-abdominal versus extra-abdominal undescended testes was compared using Fisher's Exact Test. RESULTS: Seventy-one patients met inclusion criteria. The median age was 15.3 years (range 10.1-27.7). None had a history of testicular malignancy. Forty-five unilateral orchiectomies, 22 unilateral orchiopexies with biopsy and 4 bilateral procedures were performed. Seventeen testes (22.7%) were intra-abdominal, 42 (56.0%) were in the inguinal canal, 9 (12.0%) were at the external inguinal ring, 3 (4.0%) were in the superficial inguinal pouch and 4 (5.3%) were in the scrotum. Malignancy was detected in 2/71 patients (2.8%). By location, 2/16 patients (12.5%) with intra-abdominal testis and 0/55 patients (0%) with extra-abdominal testis demonstrated malignancy (p=0.048). CONCLUSIONS: Among males with cryptorchidism ages 10 years and older without differences of sexual development, 2/16 patients with intra-abdominal testis and 0/55 patients with extra-abdominal testis demonstrated malignancy. In older boys and adolescents, orchiectomy or biopsy is indicated for intra-abdominal testes but may not be necessary for extra-abdominal undescended testes.

Characterizing Patients with Recurrent Urinary Tract Infections in Vesicoureteral Reflux: A Pilot Study of the Urinary Proteome.

Recurrent urinary tract infections (UTIs) pose a significant burden on the health care system. Underlying mechanisms predisposing children to UTIs and associated changes in the urinary proteome are not well understood. We aimed to investigate the urinary proteome of a subset of children who have vesicoureteral reflux (VUR) and recurrent UTIs because of their risk of developing infection-related renal damage. Improving diagnostic modalities to identify UTI risk factors would significantly alter the clinical management of children with VUR. We profiled the urinary proteomes of 22 VUR patients with low grade VUR (1-3 out of 5), a history of recurrent UTIs, and renal scarring, comparing them to those obtained from 22 age-matched controls. Urinary proteins were analyzed by mass spectrometry followed by protein quantitation based on spectral counting. Of the 2,551 proteins identified across both cohorts, 964 were robustly quantified, as defined by meeting criteria with spectral count (SC) ≥2 in at least 7 patients in either VUR or control cohort. Eighty proteins had differential expression between the two cohorts, with 44 proteins significantly up-regulated and 36 downregulated (q <0.075, FC ≥1.2). Urinary proteins involved in inflammation, acute phase response (APR), modulation of extracellular matrix (ECM), and carbohydrate metabolism were altered among the study cohort.

Top-Down versus Bottom-Up Approach in Children Presenting with Urinary Tract Infection: Comparative Effectiveness Analysis Using RIVUR and CUTIE Data.

PURPOSE: The initial imaging approach to children with urinary tract infection (UTI) is controversial. Along with renal/bladder ultrasound, some advocate voiding cystourethrogram (VCUG), ie a bottom-up approach, while others advocate dimercaptosuccinic acid (DMSA) scan, ie a top-down approach. Comparison of these approaches is challenging. In the RIVUR/CUTIE trials, however, all subjects underwent both VCUG and DMSA scan. Our objective was to perform a comparative effectiveness analysis of the bottom-up vs top-down approach. MATERIALS AND METHODS: We simulated 1,000 hypothetical sets of 500 children using RIVUR/CUTIE data. In the top-down approach, patients underwent initial DMSA scan, and only those with renal scarring underwent VCUG. In the bottom-up approach, the initial study was VCUG. We assumed all children with vesicoureteral reflux (VUR) received continuous antibiotic prophylaxis (CAP). Outcomes included recurrent UTI, number of VCUGs and CAP exposure. We assumed a 25% VUR prevalence in children with initial UTI with sensitivity analysis using 40% VUR prevalence. RESULTS: Median age of the original RIVUR/CUTIE cohort was 12 months. First DMSA scan was performed at a median of 8.2 weeks (IQR 5-11.8) after the index UTI. In the simulated cohort, slightly higher yet statistically significantly recurrent UTI was associated with the top-down compared with the bottom-up approach (24.4% vs 18.0%, p=0.045). On the other hand, the bottom-up approach resulted in more VCUG (100% vs 2.4%, p <0.001). Top-down resulted in fewer CAP-exposed patients (25% vs 0.4%, p <0.001) and lower overall CAP exposure (5 vs 162 days/person, p <0.001). Sensitivity analysis was performed with 40% VUR prevalence with similar results. CONCLUSIONS: The top-down approach was associated with slightly higher recurrent UTI. Compared to the bottom-up approach, it significantly reduced the need for VCUG and CAP.

Changes in Clinical Presentation and Renal Outcomes among Children with Febrile Urinary Tract Infection: 2005 vs 2015.

PURPOSE: Recent studies have demonstrated trends of decreasing voiding cystourethrogram utilization rates and delayed vesicoureteral reflux diagnosis in some children. It is possible that such delays could lead to more children sustaining repeated episodes of febrile urinary tract infection, and potential kidney injury, prior to diagnosis and treatment. MATERIALS AND METHODS: Using single institutional, cross-sectional cohorts of patients in 2 time periods (2005 and 2015), we compared clinical presentation and renal outcomes among patients 13 years and younger with history of febrile urinary tract infection presenting for initial voiding cystourethrogram. Outcomes included 1) recurrent urinary tract infection, 2) presence of vesicoureteral reflux, 3) grade of vesicoureteral reflux, and 4) renal scarring. Associations between year of presentation and outcomes of recurrent urinary tract infection and vesicoureteral reflux diagnosis were evaluated using multivariable logistic regression models. For the outcome of renal scarring, a logistic regression model was fitted for propensity score matched cohorts. RESULTS: Compared to children presenting in 2005, those in 2015 had 3 times the odds of recurrent urinary tract infection (OR 3.01, 95% CI 2.18-4.16, p <0.0001). Time period was not associated with the odds of vesicoureteral reflux (OR 0.98, 95% CI 0.77-1.23, p=0.85). Those in 2015 were more likely to present with vesicoureteral reflux grade >3 (OR 2.22, 95% CI 1.13-4.34, p=0.02) but not vesicoureteral reflux grade >2 (OR 1.11, 95% CI 0.74-1.67, p=0.60). Renal scarring was more common among children presenting in 2015 (OR 2.9, 95% CI 1.03-8.20, p=0.04). CONCLUSIONS: Compared to 2005, children presenting in 2015 for post-urinary tract infection voiding cystourethrogram have increased likelihood of recurrent urinary tract infection and renal scarring, despite similar likelihood of vesicoureteral reflux diagnosis.

Interobserver Reliability of the Antenatal Consensus Classification System for Urinary Tract Dilatation.

OBJECTIVES: The consensus classification system for urinary tract dilatation (UTD) was designed to be more objective and reproducible than previously used systems. We sought to evaluate interobserver reliability of UTD components and overall scores in a prenatal population undergoing third-trimester ultrasound examinations. METHODS: We retrospectively identified patients who underwent antenatal ultrasound examinations for UTD between 28 and 40 weeks' gestation. All images from individual studies of 300 fetuses were reviewed independently by 5 experienced sonologists (1 maternal-fetal medicine specialist and 4 radiologists). Urinary tract dilatation scores (normal, A1, or A2/3) and Society for Fetal Urology (SFU) scores were assigned. Interobserver agreement between raters was evaluated with the Fleiss κ statistic. RESULTS: Overall interobserver agreement for the antenatal UTD risk score showed substantial agreement among all 5 readers (κ = 0.657 [95% confidence interval, 0.632, 0.683]; P < .001). All 5 readers applied the same UTD risk score in 53.7% of cases. Some variability in the antenatal UTD score and individual elements was observed. At least 2 UTD risk scores were assigned to a specific individual patient in 46.3% of cases (139 of 300), and all 3 UTD risk scores were assigned to a specific individual patient in 1.7% of cases (5 of 300). In 18.0% of cases (54 of 300), at least 2 readers assigned a UTD score different from that assigned by the other readers. Agreement was lowest for parenchymal appearance (κ = 0.225). Agreement for the SFU system was fair (κ = 0.368; P < .001). CONCLUSIONS: Interobserver agreement for the antenatal UTD grading system was substantial. Compared to the SFU system, the antenatal UTD system showed better agreement among readers.

Why Does Prevention of Recurrent Urinary Tract Infection not Result in Less Renal Scarring? A Deeper Dive into the RIVUR Trial.

PURPOSE: The RIVUR (Randomized Intervention for Children with Vesicoureteral Reflux) trial reported that antibiotic prophylaxis reduced recurrent urinary tract infection but antibiotic prophylaxis was not associated with decreased new renal scarring. However, the original reports did not assess the relationship among recurrent urinary tract infection, new renal scarring and antibiotic prophylaxis in detail. Therefore, we investigated the relationship among these issues. MATERIALS AND METHODS: We included subjects with dimercaptosuccinic acid scan within 6 months of enrollment and at least 1 followup dimercaptosuccinic acid scan from the RIVUR trial. The primary outcome was recurrent urinary tract infection associated new renal scarring, defined as recurrent urinary tract infection and new changes on dimercaptosuccinic acid scan. Due to a low number of events, propensity score was used to adjust for confounders. Multivariate logistic regression was fitted to investigate the associations between the covariates and the outcome. RESULTS: A total of 489 patients (91% female, mean age 20.3 months) were included in the study. Any new renal scarring was more common among those with recurrent urinary tract infection (OR 4.1, 95% CI 2.0-8.5, p <0.01) after adjusting for age, sex, index urinary tract infection, duplication, bowel bladder dysfunction and antibiotic prophylaxis. Recurrent urinary tract infection associated new renal scarring occurred in 5 of 244 (2%) patients on antibiotic prophylaxis and 13 of 245 (5%) on placebo. Compared to antibiotic prophylaxis, placebo was associated with a higher risk of recurrent urinary tract infection associated new renal scarring (OR 3.1, 95% CI 1.0-8.8, p=0.04) after adjusting for age, sex, race, index urinary tract infection, bowel bladder dysfunction, duplication, hydronephrosis, vesicoureteral reflux grade and baseline renal scarring. There were no differences in scar severity at final dimercaptosuccinic acid scan (p=0.88) or change from baseline (p=0.53) between antibiotic prophylaxis and placebo. CONCLUSIONS: Recurrent urinary tract infection was associated with new renal scarring in the RIVUR trial. When limited to recurrent urinary tract infection associated new renal scarring, antibiotic prophylaxis was associated with a decreased risk of this outcome. It remains unclear why new renal scarring developed in a proportion of subjects without recurrent urinary tract infection. The results should be carefully interpreted due to the inherent limitations.

Interobserver and Intra-Observer Reliability of the Urinary Tract Dilation Classification System in Neonates: A Multicenter Study.

PURPOSE: The Urinary Tract Dilation classification system was designed to be more objective and reproducible than currently available grading systems. We evaluated the reliability and consistency of the system in newborns. MATERIALS AND METHODS: Of 1,046 infants 0 to 90 days old undergoing ultrasound for hydronephrosis 243 were randomly selected for study inclusion. Seven readers (4 radiologists and 3 urologists) at 4 institutions classified complete, de-identified ultrasound studies on a Web based platform. Interobserver and intra-observer agreement was evaluated using the Fleiss kappa statistic. RESULTS: Interobserver agreement for Urinary Tract Dilation risk score was moderate among the 7 readers (kappa = 0.421, 95% CI 0.404-0.438). Interobserver agreement using the Society for Fetal Urology scale was worse than with the Urinary Tract Dilation classification (kappa = 0.344, 95% CI 0.330-0.359). All 7 readers assigned the same Urinary Tract Dilation score in 19.3% of cases (47 of 243). In 38.7% of cases (94 of 243) at least 3 readers assigned a Urinary Tract Dilation score different from that assigned by the other readers. In 7% of cases (17 of 243) at least 3 readers assigned a score of P0/P1, while at least 3 readers scored the same cases as P2/P3. At least 3 different Urinary Tract Dilation risk scores were assigned to the same patient in 30.45% of patients (74 of 243). Among individual Urinary Tract Dilation elements calyceal dilatation and bladder status had the highest disagreement. Five readers regraded 80 cases and agreed with their previous Urinary Tract Dilation risk score in 63.8% to 75.0% of cases (kappa 0.458 to 0.729). CONCLUSIONS: Interobserver agreement using the Urinary Tract Dilation grading system is fair to moderate, with variable agreement on individual elements of the system. Agreement was higher for the Urinary Tract Dilation system compared to the Society for Fetal Urology scale.

Omalizumab facilitates rapid oral desensitization for peanut allergy.

BACKGROUND: Peanut oral immunotherapy is a promising approach to peanut allergy, but reactions are frequent, and some patients cannot be desensitized. The anti-IgE medication omalizumab (Xolair; Genentech, South San Francisco, Calif) might allow more rapid peanut updosing and decrease reactions. OBJECTIVE: We sought to evaluate whether omalizumab facilitated rapid peanut desensitization in highly allergic patients. METHODS: Thirty-seven subjects were randomized to omalizumab (n = 29) or placebo (n = 8). After 12 weeks of treatment, subjects underwent a rapid 1-day desensitization of up to 250 mg of peanut protein, followed by weekly increases up to 2000 mg. Omalizumab was then discontinued, and subjects continued on 2000 mg of peanut protein. Subjects underwent an open challenge to 4000 mg of peanut protein 12 weeks after stopping study drug. If tolerated, subjects continued on 4000 mg of peanut protein daily. RESULTS: The median peanut dose tolerated on the initial desensitization day was 250 mg for omalizumab-treated subjects versus 22.5 mg for placebo-treated subject. Subsequently, 23 (79%) of 29 subjects randomized to omalizumab tolerated 2000 mg of peanut protein 6 weeks after stopping omalizumab versus 1 (12%) of 8 receiving placebo (P < .01). Twenty-three subjects receiving omalizumab versus 1 subject receiving placebo passed the 4000-mg food challenge. Overall reaction rates were not significantly lower in omalizumab-treated versus placebo-treated subjects (odds ratio, 0.57; P = .15), although omalizumab-treated subjects were exposed to much higher peanut doses. CONCLUSION: Omalizumab allows subjects with peanut allergy to be rapidly desensitized over as little as 8 weeks of peanut oral immunotherapy. In the majority of subjects, this desensitization is sustained after omalizumab is discontinued. Additional studies will help clarify which patients would benefit most from this approach.

Sperm Retrieval in Adolescents and Young Adults with Klinefelter Syndrome: A Prospective, Pilot Study.

OBJECTIVE: To assess sperm retrieval rates in adolescents and young adults with Klinefelter syndrome, with the ultimate goal of improving fertility in this population. Secondary aims were to evaluate other clinical characteristics of the cohort and identify predictors of sperm retrieval. STUDY DESIGN: Patients 12-25 years of age with Klinefelter syndrome (47,XXY) were recruited at the Boston Children's Hospital. Physical examination, biochemical evaluation, scrotal ultrasonography, and semen analysis were performed. Neurocognitive data were collected. Microdissection sperm extraction (unilateral micro-testicular sperm extraction) was offered to individuals with no sperm in their ejaculates. Given the small sample size, analysis was primarily descriptive. RESULTS: Fifteen patients were enrolled. None had sperm in their ejaculates. Ten patients underwent unilateral micro-testicular sperm extraction. Sperm retrieval rate was 50%. From a neurocognitive standpoint, subjects reported problems with peers, conduct, and overall difficulties. Incidentally, one-third of the patients were found to have testicular microlithiasis and 17% of subjects with renal ultrasound imaging had bilateral renal medullary nephrocalcinosis. CONCLUSIONS: This pilot study suggests that sperm retrieval rates in adolescents and young adults with Klinefelter syndrome are comparable with those reported in older men. However, larger studies are needed to confirm our findings. The clinical significance of the scrotal and renal ultrasound findings merits further investigation. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01817296.

Imaging after urinary tract infection in older children and adolescents.

PURPOSE: There are few guidelines and little data on imaging after urinary tract infections in older children. We determined the clinical yield of renal and bladder ultrasound, and voiding cystourethrogram in older children and adolescents after urinary tract infection. MATERIALS AND METHODS: We analyzed findings on voiding cystourethrogram, and renal and bladder ultrasound as well as the clinical history of patients who underwent the 2 studies on the same day between January 2006 and December 2010. We selected for study patients 5 to 18 years old who underwent imaging for urinary tract infection. Those with prior postnatal genitourinary imaging or prenatal hydronephrosis were excluded from analysis. RESULTS: We identified a cohort of 153 patients, of whom 74% were 5 to 8 years old, 21% were 8 to 12 years old and 5% were 12 to 18 years old. Of the patients 77% were female, 78% had a febrile urinary tract infection history and 55% had a history of recurrent urinary tract infections. Renal and bladder ultrasound findings revealed hydronephrosis in 7.8% of patients, ureteral dilatation in 3.9%, renal parenchymal findings in 20% and bladder findings in 12%. No patient had moderate or greater hydronephrosis. Voiding cystourethrogram showed vesicoureteral reflux in 34% of cases and bladder or urethral anomalies in 12%. Reflux was grade I, II-III and greater than III in 5.9%, 26% and 2% of patients, respectively. For any voiding cystourethrogram abnormality the sensitivity and specificity of any renal and bladder ultrasound abnormality were 0.49 (95% CI 0.37-0.62) and 0.76 (95% CI 0.66-0.84), respectively. Positive and negative predictive values were 0.58 (95% CI 0.44-0.71) and 0.69 (0.59-0.77), respectively. CONCLUSIONS: In older children with a history of urinary tract infection the imaging yield is significant. However, imaging revealed high grade hydronephrosis or high grade vesicoureteral reflux in few patients. Renal ultrasound is not reliable for predicting voiding cystourethrogram findings such as vesicoureteral reflux.

Management of Proximal Hypospadias with 2-Stage Repair: 20-Year Experience.

PURPOSE: We describe our experience with 2-stage proximal hypospadias repair. We report outcomes, and patient and procedure characteristics associated with surgical complications. MATERIALS AND METHODS: We retrospectively studied patients with proximal hypospadias who underwent staged repair between January 1993 and December 2012. Demographics, preoperative management and operative technique were reviewed. Complications included glans dehiscence, fistula, meatal stenosis, nonmeatal stricture, urethrocele/diverticula and residual chordee. Cox proportional hazards model was used to evaluate the associations between time to surgery for complications and patient and procedure level factors. RESULTS: A total of 134 patients were included. Median patient age was 8.8 months at first stage surgery and 17.1 months at second stage surgery, and median time between surgeries was 8 months. Median followup was 3.8 years. Complications were seen in 71 patients (53%), with the most common being fistula (39 patients, 29.1%). Reoperation was performed in 66 patients (49%). Median time from urethroplasty to surgery for complication was 14.9 months. Use of preoperative testosterone decreased risk of undergoing surgery for complication by 27% (HR 0.73, 95% CI 0.55-0.98, p = 0.04). In addition, patients identified as Hispanic were at increased risk for undergoing surgery for complications (HR 2.40, 95% CI 1.28-4.53, p = 0.01). CONCLUSIONS: We review the largest cohort of patients undergoing 2-stage hypospadias repair at a single institution. Complications and reoperation rates were approximately 50% in the setting of complex genital reconstruction.

Defining the cellular precursors to human breast cancer.

Human breast cancers are broadly classified based on their gene-expression profiles into luminal- and basal-type tumors. These two major tumor subtypes express markers corresponding to the major differentiation states of epithelial cells in the breast: luminal (EpCAM(+)) and basal/myoepithelial (CD10(+)). However, there are also rare types of breast cancers, such as metaplastic carcinomas, where tumor cells exhibit features of alternate cell types that no longer resemble breast epithelium. Until now, it has been difficult to identify the cell type(s) in the human breast that gives rise to these various forms of breast cancer. Here we report that transformation of EpCAM(+) epithelial cells results in the formation of common forms of human breast cancer, including estrogen receptor-positive and estrogen receptor-negative tumors with luminal and basal-like characteristics, respectively, whereas transformation of CD10(+) cells results in the development of rare metaplastic tumors reminiscent of the claudin-low subtype. We also demonstrate the existence of CD10(+) breast cells with metaplastic traits that can give rise to skin and epidermal tissues. Furthermore, we show that the development of metaplastic breast cancer is attributable, in part, to the transformation of these metaplastic breast epithelial cells. These findings identify normal cellular precursors to human breast cancers and reveal the existence of a population of cells with epidermal progenitor activity within adult human breast tissues.

Practice patterns and resource utilization for infants with bladder exstrophy: a national perspective.

PURPOSE: Substantial variability exists in bladder exstrophy care, and little is known about costs associated with the condition. We define the care patterns and first year cost for patients with bladder exstrophy at select freestanding pediatric hospitals in the United States. MATERIALS AND METHODS: We used the Pediatric Health Information System database to identify patients with bladder exstrophy born between January 1999 and December 2010 who underwent primary closure in the first 120 days of life. Demographic, surgical, postoperative and cost data for all encounters were assessed. Multivariate linear regression was used to examine the association between patient, surgeon and hospital characteristics and costs. RESULTS: Of the 381 patients who underwent primary closure within the first 120 days of life 279 (73%) did so within the first 3 days of life. A total of 119 patients (31%) underwent pelvic osteotomy, including 51 of 279 (18%) who underwent closure within the first 3 days of life, 38 of 67 (56%) who underwent closure between 4 and 30 days of life, and 30 of 35 (86%) who underwent closure between 31 and 120 days of life (p = 0.0017). Median inflation adjusted, first year cost in United States dollars per patient was $66,577 (IQR $45,335 to $102,398). Presence of nonrenal comorbidity and completion of primary closure after 30 days of life increased first year costs by 24% and 53%, respectively. Increased post-closure length of stay was associated with greater costs. CONCLUSIONS: At select freestanding United States pediatric hospitals the majority of bladder exstrophy closures are performed within the first 3 days of life. Most, but not all, patients undergoing closure after the neonatal period undergo osteotomy. The presence of nonrenal comorbidity and increased postoperative length of stay are associated with greater costs.

Integration of proteomic and transcriptomic profiles identifies a novel PDGF-MYC network in human smooth muscle cells.

BACKGROUND: Platelet-derived growth factor-BB (PDGF-BB) has been implicated in the proliferation, migration and synthetic activities of smooth muscle cells that characterize physiologic and pathologic tissue remodeling in hollow organs. However, neither the molecular basis of PDGFR-regulated signaling webs, nor the extent to which specific components within these networks could be exploited for therapeutic benefit has been fully elucidated. RESULTS: Expression profiling and quantitative proteomics analysis of PDGF-treated primary human bladder smooth muscle cells identified 1,695 genes and 241 proteins as differentially expressed versus non-treated cells. Analysis of gene expression data revealed MYC, JUN, EGR1, MYB, RUNX1, as the transcription factors most significantly networked with up-regulated genes. Forty targets were significantly altered at both the mRNA and protein levels. Proliferation, migration and angiogenesis were the biological processes most significantly associated with this signature, and MYC was the most highly networked master regulator. Alterations in master regulators and gene targets were validated in PDGF-stimulated smooth muscle cells in vitro and in a model of bladder injury in vivo. Pharmacologic inhibition of MYC and JUN confirmed their role in SMC proliferation and migration. Network analysis identified the diaphanous-related formin 3 as a novel PDGF target regulated by MYC and JUN, which was necessary for PDGF-stimulated lamellipodium formation. CONCLUSIONS: These findings provide the first systems-level analysis of the PDGF-regulated transcriptome and proteome in normal smooth muscle cells. The analyses revealed an extensive cohort of PDGF-dependent biological processes and connected key transcriptional effectors to their regulation, significantly expanding current knowledge of PDGF-stimulated signaling cascades. These observations also implicate MYC as a novel target for pharmacological intervention in fibroproliferative expansion of smooth muscle, and potentially in cancers in which PDGFR-dependent signaling or MYC activation promote tumor progression.

Comparison of 2 delivery vehicles for viscous budesonide to treat eosinophilic esophagitis in children.

OBJECTIVES: Oral viscous budesonide (OVB) using Splenda as a delivery vehicle has become an attractive therapeutic option for children with eosinophilic esophagitis (EoE). Many families are wary of giving the artificial sweetener in high doses to their children. The aim of the present study was to determine whether OVB mixed with Neocate Nutra, a hypoallergenic nutritional supplement, is at least as efficacious as OVB mixed with Splenda at healing EoE. METHODS: Our institutional review board approved a retrospective chart review of patients with well-documented EoE treated with OVB at the Boston Children's Hospital Eosinophilic Gastrointestinal Disorder program between June 2008 and June 2013. Primary outcome measured was histologic response defined as change in peak eosinophil count to <15 eosinophils per high-power field (eos/HPF) after at least 10 weeks of OVB therapy. RESULTS: A total of 46 children were treated with OVB mixed with Splenda, and 14 were treated with OVB mixed with Neocate Nutra. The 2 groups were not significantly different in their demographic (race, age, sex) or clinical (initial eosinophil count, proton pump inhibitor use, or concomitant dietary elimination) characteristics. On follow-up endoscopy, 30 of 46 patients on Splenda and 13 of 14 patients on Neocate Nutra achieved histologic response. Mean pretreatment and posttreatment peak eosinophil counts for the children taking Neocate Nutra were 62 eos/HPF ([high-power field] range 20-120 eos/HPF) and 9 eos/HPF (range 0-100 eos/HPF), respectively. Mean pretreatment and posttreatment peak eosinophil counts for the Splenda group were 59.5 eos/HPF (range 20-180 eos/HPF) and 25.5 eos/HPF (range 0-200 eos/HPF), respectively. The odds ratio (OR) of success with Neocate Nutra as compared with Splenda was 6.93 (95% CI 0.83-57.91, P = 0.0728), demonstrating the noninferiority of Neocate Nutra. CONCLUSIONS: We demonstrate that OVB mixed with Neocate Nutra is at least as effective as OVB mixed with Splenda at treating children with EoE. Neocate Nutra is an innovative, effective, and palatable mixing agent to create a viscous budesonide slurry for families who prefer not to use the standard recipe with Splenda.

Variation in the documentation of findings in pediatric voiding cystourethrogram.

BACKGROUND: Few standards exist for reporting results of voiding cystourethrogram (VCUG). OBJECTIVE: To assess the variation in reporting of VCUG findings from different facilities using a standardized assessment tool. MATERIALS AND METHODS: VCUG reports were evaluated for demographic, technical, anatomical and functional information. Reports were categorized by age, gender, indication and vesicouretal reflux (VUR) status. Institutions were classified as a free-standing pediatric hospital (n = 3), pediatric hospital within a hospital (n = 11), or non-pediatric facility (n = 24) and reports were classified as having been read by a pediatric radiologist or not. Each category of outside reports (n = 152) was randomly matched with a twice-larger group of Hospital A reports from the same category (n = 304). Multivariate linear regression was used to analyze the association between the primary outcome (percentage of items described in dictated VCUG report) and the type of radiologist and institution. RESULTS: Of the 456 studies, 66% were in girls, 56% were in those <12 months old, and the indication was urinary tract infection (UTI) in 81%. The mean percentage of items reported was 67 ± 14% (74 ± 7% at free-standing pediatric hospitals, 61 ± 10% at pediatric hospitals within a hospital, and 48 ± 11% at non-pediatric facilities). In multivariate analysis, VCUG reports generated at non-pediatric facilities had 17% fewer items included (95% CI: 14.5-19.7%, P < 0.0001), and pediatric hospitals within a hospital had 9% fewer items included (5.9-12.5%, P < 0.0001) when compared to free-standing pediatric hospitals. Reports read by a pediatric radiologist had 12% more items included (9.1-15.3%, P < 0.0001) compared to those read by a non-pediatric radiologist. CONCLUSION: More complete VCUG reports were observed when generated at free-standing pediatric hospitals and when interpreted by a pediatric radiologist.

A machine learning algorithm predicting risk of dilating VUR among infants with hydronephrosis using UTD classification.

BACKGROUNDS: Urinary Tract Dilation (UTD) classification has been designed to be a more objective grading system to evaluate antenatal and post-natal UTD. Due to unclear association between UTD classifications to specific anomalies such as vesico-ureteral reflux (VUR), management recommendations tend to be subjective. OBJECTIVE: We sought to develop a model to reliably predict VUR from early post-natal ultrasound. STUDY DESIGN: Radiology records from single institution were reviewed to identify infants aged 0-90 days undergoing early ultrasound for antenatal UTD. Medical records were reviewed to confirm diagnosis of VUR. Primary outcome defined as dilating (≥Gr3) VUR. Exclusion criteria include major congenital urologic anomalies (bilateral renal agenesis, horseshoe kidney, cross fused ectopia, exstrophy) as well as patients without VCUG. Data were split into training/testing sets by 4:1 ratio. Machine learning (ML) algorithm hyperparameters were tuned by the validation set. RESULTS: In total, 280 patients (540 renal units) were included in the study (73 % male). Median (IQR) age at ultrasound was 27 (18-38) days. 66 renal units were found to have ≥ grade 3 VUR. The final model included gender, ureteral dilation, parenchymal appearance, parenchymal thickness, central calyceal dilation. The model predicted VUR with AUC at 0.81(0.73-0.88) on out-of-sample testing data. Model is shown in the figure. DISCUSSION: We developed a ML model that can predict dilating VUR among patients with hydronephrosis in early ultrasound. The study is limited by the retrospective and single institutional nature of data source. This is one of the first studies demonstrating high performance for future diagnosis prediction in early hydronephrosis cohort. CONCLUSIONS: By predicting dilating VUR, our predictive model using machine learning algorithm provides promising performance to facilitate individualized management of children with prenatal hydronephrosis, and identify those most likely to benefit from VCUG. This would allow more selective use of this test, increasing the yield while also minimizing overutilization.