Contemporary disparities in progression to orchiopexy for cryptorchidism as reported in the Pediatric Health Information System (PHIS) database.

INTRODUCTION: When evaluating the timeliness of orchiopexy for cryptorchidism, health disparities are apparent among Hispanic and African American males and those with public insurance. Since the publication of these data, the COVID-19 pandemic has stressed our healthcare system and significantly affected the provision of pediatric urology care. OBJECTIVE: We sought to assess if certain groups were disproportionately affected in progression to orchiopexy after the diagnosis of cryptorchidism during and after the pandemic in US freestanding children's hospitals. STUDY DESIGN: Using the PHIS database, pediatric patients ≤5 years who underwent orchiopexy between January 2018 and December 2022 were retrospectively analyzed. Exclusion criteria included prematurity, retractile testes, and testicular torsion. Primary outcomes were age at orchiopexy and the proportion of individuals undergoing timely orchiopexy for cryptorchidism. RESULTS: Over the study period 3140 patients ≤5 years old underwent orchiopexy for cryptorchidism. Non-Hispanic Blacks and Hispanics were significantly less likely to have timely orchiopexy and underwent orchiopexy 2.13 and 3.60 months later compared to whites (p < 0.01). As compared to pre-COVID-19, during the pandemic the proportion of patients who had timely surgery was higher and the median age was significantly lower (p = 0.01 and p < 0.01, respectively) in white patients only. Over the study period, patients with public insurance were less likely to have timely orchiopexy and underwent orchiopexy 2.94 months later (p < 0.01) than patients with private insurance. Compared to during the pandemic, post-pandemic a significantly lower proportion of publicly insured patients have since undergone timely orchiopexy (p = 0.04). Patients in the West were less likely to have timely orchiopexy and had a higher age at time of orchiopexy (p < 0.01) than other regions. However, in the West during the pandemic, the proportion of children who had timely surgery was higher compared to pre-and post-COVID-19 (p < 0.01). DISCUSSION: Overall, regardless of insurance status, race, or location, a significant proportion of patients did not undergo timely orchiopexy. During the pandemic white patients had a lower median age and an increased proportion underwent timely orchiopexy, despite the number of orchiopexies remaining constant. Disparities in the post-COVID-19 era have been further exacerbated for publicly insured patients, who a significantly lower proportion of have since undergone timely orchiopexy. Specific efforts are required across the United States to increase timely orchiopexy for all boys. CONCLUSIONS: Progression to timely orchiopexy remains low for all boys in the era surrounding COVID-19; certain groups appear to be more adversely affected.

Inter-disciplinary provider development of an online, interactive adolescent varicocele decision aid prototype.

BACKGROUND: Decision-making regarding varicocele management can be a complex process for patients and families. However, to date, no studies have presented ways to mitigate the decisional conflict surrounding varicoceles. OBJECTIVE: To facilitate a discussion among physicians in order to develop a framework of the decision-making process regarding adolescent varicocele management, which will inform the development of the first online, interactive decision aid. MATERIALS AND METHODS: Semi-structured interviews with pediatric urologists and interventional radiologists were conducted to discuss their rationale for varicocele decision-making. Interviews were audio recorded, transcribed, and coded. Key themes were identified, grouped, and then qualitatively analyzed using thematic analysis. Utilizing the common themes identified and the Ottawa Decision Support Framework, a decision aid prototype was developed and transformed into a user-friendly website: varicoceledecisionaid.com. RESULTS: Pediatric urologists (n = 10) and interventional radiologists (n = 2) were interviewed. Key themes identified included: (1) definition/epidemiology; (2) observation as an appropriate management choice; (3) reasons to recommend repair; (4) types of repair; (5) reasons to recommend one repair over another; (6) shared decision-making; and (7) appropriate counseling. With this insight, a varicocele decision aid prototype was developed that engages patients and parents in the decision-making process. DISCUSSION AND CONCLUSIONS: This is the first interactive and easily accessible varicocele decision aid prototype developed by inter-disciplinary physicians for patients. This tool aids in decision-making surrounding varicocele surgery. It can be used before or after consultation to help families understand more about varicoceles and their repair, and why intervention may or may not be offered. It also considers a patient and family's personal values. Future studies will incorporate the patient and family perspective into the decision-making aid as well as implement and test the usability of this decision aid prototype in practice and in the wider urologic community.

Does KUB play a role in the diagnosis of bladder bowel dysfunction?

INTRODUCTION: Kidney ureter bladder radiography (KUB) is widely used for the evaluation of constipation in children with bladder and bowel dysfunction (BBD); however, there is varying evidence to support its routine diagnostic use. One drawback to KUB is radiation exposure. The dangers of radiation in children are well-documented, and per As Low As Reasonably Achievable, non-beneficial radiation should be avoided. This risk is especially high in children who undergo repeated imaging in the follow up of constipation treatment. OBJECTIVE: We sought to assess the utility of KUB in diagnosing children with BBD by comparing it to four diagnostic tests and/or validated instruments: the Dysfunctional Voiding Symptom Score (DVSS), Rome IV criteria, rectal diameter on ultrasound (RD), and the Bristol Stool Form Score (BSFS). STUDY DESIGN: We prospectively enrolled a cohort of patients presenting to an academic pediatric urology practice with symptoms of BBD. Severity of stool burden on KUB (mild, moderate, or severe), RD on ultrasound (≥3.4 cm), DVSS, Rome IV, and BSFS were obtained for each patient. All imaging was interpreted by a pediatric radiologist and pediatric urologist. Primary outcomes were the association between the four diagnostic tests and KUB stool burden. Bivariate analysis of all individual variables versus KUB was performed, as well as multivariate regressions to determine if multiple measures were predictive of KUB stool burden when combined. RESULTS: Between October 2020 and May 2022, 50 patients were enrolled. All children were under the age of 18, with a median age of 8 years (IQR 3-13). 38 % were male. Median BMI-for-age-percentile was 80.8 (IQR 50.3-98.3). When comparing individual variables to KUB in bivariate analyses, it was found that RD on ultrasound is predictive of significant stool burden on KUB (p = 0.03). No other individual variables were predictive. In the multivariate analyses, no combination of tests was found to be predictive of KUB. DISCUSSION: We compared the effectiveness of four commonly used diagnostic tests in children with BBD to validate the use of KUB. In conclusion, our results support the use of RD on ultrasound as a non-radiating alternative to KUB to assess stool burden. Data also suggest that KUB for fecal load does not correlate with urinary (DVSS) or bowel (Rome IV, BSFS) symptoms in BBD, and that symptoms scores should still be used independently for diagnosis and monitoring of treatment response. CONCLUSION: In conclusion, KUB has a limited role in the diagnosis of BBD.

The Assessment of TikTok as a Source of Quality Health Information on Varicoceles.

OBJECTIVE: To evaluate the quality of varicocele information on TikTok, a popular video platform that adolescent patients are now turning to as a source of medical information before visiting a doctor. METHODS: Using the key word "varicocele," we retrieved the top 225 videos listed on TikTok in May 2022. We extracted general video and engagement data. Video information was coded and analyzed for the completeness of different types of content (definition, symptoms, evaluation, management, and outcomes). The quality of consumer health information was rated using the DISCERN instrument. RESULTS: Thirty-six videos met inclusion criteria; 17 were created by general users, 16 by healthcare professionals or systems (2 by urologists), and 3 by scientific communities. Healthcare professionals had more views than non-healthcare (P = .05). The quality of health information using the DISCERN instrument was "poor" from health care professional videos and "very poor" from non-health care professionals. However, the quality of information provided by healthcare professionals was statistically better than that of non-healthcare (P< .05). Video content mainly focused on symptoms: 50% of videos from healthcare providers had some or extensive content and 41% of non-healthcare had some content. 23% of videos had misinformation. CONCLUSION: The overall quality of information for varicoceles on TikTok is not acceptable and does not meet patient needs. It is imperative that urologists create robust, accurate content, and partner with these platforms to connect users with higher quality information. TikTok users should also be mindful that information may not be medically accurate.

Epoxyeicosatrienoic acid administration or soluble epoxide hydrolase inhibition attenuates renal fibrogenesis in obstructive nephropathy.

Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites with biological effects, including antiapoptotic, anti-inflammatory, and antifibrotic functions. Soluble epoxide hydrolase (sEH)-mediated hydrolysis of EETs to dihydroxyeicosatrienoic acids (DHETs) attenuates these effects. Recent studies have demonstrated that inhibition of sEH prevents renal tubulointerstitial fibrosis and inflammation in the chronic kidney disease model. Given the pathophysiological role of the EET pathway in chronic kidney disease, we investigated if administration of EET regioisomers and/or sEH inhibition will promote antifibrotic and renoprotective effects in renal fibrosis following unilateral ureteral obstruction (UUO). EETs administration abolished tubulointerstitial fibrogenesis, as demonstrated by reduced fibroblast activation and collagen deposition after UUO. The inflammatory response was prevented as demonstrated by decreased neutrophil and macrophage infiltration and expression of cytokines in EET-administered UUO kidneys. EET administration and/or sEH inhibition significantly reduced M1 macrophage markers, whereas M2 macrophage markers were highly upregulated. Furthermore, UUO-induced oxidative stress, tubular injury, and apoptosis were all downregulated following EET administration. Combined EET administration and sEH inhibition, however, had no additive effect in attenuating inflammation and renal interstitial fibrogenesis after UUO. Taken together, our findings provide a mechanistic understanding of how EETs prevent kidney fibrogenesis during obstructive nephropathy and suggest EET treatment as a potential therapeutic strategy to treat fibrotic diseases.NEW & NOTEWORTHY Epoxyeicosatrienoic acids (EETs) are cytochrome P-450-dependent antihypertensive and anti-inflammatory derivatives of arachidonic acid, which are highly abundant in the kidney and considered renoprotective. We found that EET administration and/or soluble epoxide hydrolase inhibition significantly attenuates oxidative stress, renal cell death, inflammation, macrophage differentiation, and fibrogenesis following unilateral ureteral obstruction. Our findings provide a mechanistic understanding of how EETs prevent kidney fibrogenesis during obstructive nephropathy and suggest that EET treatment may be a potential therapeutic strategy to treat fibrotic diseases.

Hypospadias in toddlers: a multivariable study of prognostic factors in distal to mid-shaft hypospadias and review of literature.

Background: Tubularized incised plate urethroplasty is the most common hypospadias repair technique. However, there are unanswered questions and debates about the anatomical prognostic factors affecting the repair outcomes. This study tried to address some of the problems in the studies compromising the results of the current body of literature. Methods: A prospective cohort of 101 males aged 1-3 years undergoing primary distal to mid-shaft hypospadias repair were enrolled in the study. Complications including edema, erection, inadvertent removal of the urethral stent, surgical wound infection, bladder spasm, hematoma, and hemorrhage were evaluated. Studies in the current literature were reviewed to achieve a better perspective for future investigations. Results: Persistent complications were found in 16 cases (15.8%) including fistula formation, the persistence of chordee, meatal stenosis, glans, and urethral dehiscence. The mean follow-up time was 6.6±3.4 months. In the single-variable analysis, the meatal location, the length and width of the urethral plate, and the reversible acute postoperative events were significantly associated with the complications. Furthermore, fistula formation was associated with acute surgical site infection (p<0.001). However, the multivariable regression study revealed the presurgical meatal location to be the only statistically significant factor (p=0.03). Notably, the glans diameter or glanular groove shape, urethral plate dimensions, or presence of mild chordee were not independently associated with the outcomes (p>0.05). Conclusions: Our study on the toddlers with hypospadias surgery revealed that the location of urethral meatal was the main predicting factor in the development of major complications. Furthermore, the fistula formation at the infected surgical site emphasizes the importance of postsurgical care.

Hepatic and proximal tubule angiotensinogen play distinct roles in kidney dysfunction, glomerular and tubular injury, and fibrosis progression.

Components of the renin-angiotensin system, including angiotensinogen (AGT), are critical contributors to chronic kidney disease (CKD) development and progression. However, the specific role of tissue-derived AGTs in CKD has not been fully understood. To define the contribution of liver versus kidney AGT in the CKD development, we performed 5/6 nephrectomy (Nx), an established CKD model, in wild-type (WT), proximal tubule (PT)- or liver-specific AGT knockout (KO) mice. Nx significantly elevated intrarenal AGT expression and elevated blood pressure (BP) in WT mice. The increase of intrarenal AGT protein was completely blocked in liver-specific AGT KO mice with BP reduction, suggesting a crucial role for liver AGT in BP regulation during CKD. Nx-induced glomerular and kidney injury and dysfunction, as well as fibrosis, were all attenuated to a greater extent in liver-specific AGT KO mice compared with PT-specific AGT KO and WT mice. However, the suppression of interstitial fibrosis in PT- and liver-specific AGT KO mouse kidneys was comparable. Our findings demonstrate that liver AGT acts as a critical contributor in driving glomerular and tubular injury, renal dysfunction, and fibrosis progression, whereas the role of PT AGT was limited to interstitial fibrosis progression in chronic renal insufficiency. Our results provide new insights for the development of tissue-targeted renin-angiotensin system intervention in the treatment of CKD.NEW & NOTEWORTHY Chronic kidney disease (CKD) is a major unmet medical need with no effective treatment. Current findings demonstrate that hepatic and proximal tubule angiotensinogen have distinct roles in tubular and glomerular injury, fibrogenesis, and renal dysfunction during CKD development. As renin-angiotensin system components, including angiotensinogen, are important targets for treating CKD in the clinic, the results from our study may be applied to developing better tissue-targeted treatment strategies for CKD and other fibroproliferative diseases.

Bilateral Ureterovesical Junction Obstruction Resulting in Anuria in a 3-Week-Old Infant.

Bilateral megaureter with ureterovesical junction obstruction is exceedingly rare. We present a case of a 3-week-old boy who presented in acute renal failure and found to have bilateral megaureter. He was initially decompressed with bilateral percutaneous nephrostomy tubes and once stable underwent bilateral ureterostomy. At 6 months old, renal ultrasound showed stable mild right sided hydronephrosis.

A novel urinary biomarker protein panel to identify children with ureteropelvic junction obstruction - A pilot study.

INTRODUCTION AND OBJECTIVE: Reliable urinary biomarker proteins would be invaluable in identifying children with ureteropelvic junction obstruction (UPJO) as the existing biomarker proteins are inconsistent in their predictive ability. Therefore, the aim of this study was to identify consistent and reliable urinary biomarker proteins in children with UPJO. METHODS: To identify candidate biomarker proteins, total protein from age-restricted (<2 years) and sex-matched (males) control (n = 22) and UPJO (n = 21) urine samples was analyzed by mass spectrometry. Proteins that were preferentially identified in UPJO samples were selected (2-step process) and ranked according to their diagnostic odds ratio value. The top ten proteins with highest odds ratio values were selected and tested individually by ELISA. The total amount of each protein was normalized to urine creatinine and the median with interquartile ranges for control and UPJO samples was determined. Additionally, fold change (UPJO/Control) of medians of the final panel of 5 proteins was also determined. Finally, we calculated the average + 3(SD) and average + 4(SD) values of each of the 5 proteins in the control samples and used it as an arbitrary cutoff to classify individual control and UPJO samples. RESULTS: In the first step of our selection process, we identified 171 proteins in UPJO samples that were not detected in the majority of the control samples (16/22 samples, or 72.7%). Of the 171 proteins, only 50 proteins were detected in at least 11/21 (52.4%) of the UPJO samples and hence were selected in the second step. Subsequently, these 50 proteins were ranked according to the odds ratio value and the top 10 ranked proteins were validated by ELISA. Five of the 10 proteins - prostaglandin-reductase-1, ficolin-2, nicotinate-nucleotide pyrophosphorylase [carboxylating], immunoglobulin superfamily-containing leucine-rich-repeat-protein and vascular cell adhesion molecule-1 were present at higher levels in the UPJO samples (fold-change of the median protein concentrations ranging from 2.9 to 9.4) and emerged as a panel of biomarkers to identify obstructive uropathy. Finally, the order of prevalence of the 5 proteins in UPJO samples is PTGR1>FCN2>QPRT>ISLR>VCAM1. CONCLUSION: In summary, this unique screening strategy led to the identification of previously unknown biomarker proteins that when screened collectively, may reliably distinguish between obstructed vs. non-obstructed infants and may prove useful in identifying informative biomarker panels for biological samples from many diseases.

Local Control of Perineal Rhabdomyosarcoma: Are Current Recommendations Adequate?

Rhabdomyosarcoma (RMS) is a rare malignancy that can develop in nearly any soft-tissue of the body. Location of the primary tumor affects treatment strategy and prognosis, and RMS of the perineal areas can be especially difficult to treat successfully. RMS is treated systemically with chemotherapy. Local control options include surgical excision, radiation treatment, or a combination of the 2. Treating RMS with radiation treatment can be challenging due to the absence of standardized dosage protocols, along with the presence of conflicting recommendations in the literature. Each case of perineal RMS may benefit from a more individualized treatment plan.

Proximal tubule cyclophilin D regulates fatty acid oxidation in cisplatin-induced acute kidney injury.

Regardless of the etiology, acute kidney injury involves aspects of mitochondrial dysfunction and ATP depletion. Fatty acid oxidation is the preferred energy source of the kidney and is inhibited during acute kidney injury. A pivotal role for the mitochondrial matrix protein, cyclophilin D in regulating overall cell metabolism is being unraveled. We hypothesize that mitochondrial interaction of proximal tubule cyclophilin D and the transcription factor PPARα modulate fatty acid beta-oxidation in cisplatin-induced acute kidney injury. Cisplatin injury resulted in histological and functional damage in the kidney with downregulation of fatty acid oxidation genes and increase of intrarenal lipid accumulation. However, proximal tubule-specific deletion of cyclophilin D protected the kidneys from the aforementioned effects. Mitochondrial translocation of PPARα, its binding to cyclophilin D, and sequestration led to inhibition of its nuclear translocation and transcription of PPARα-regulated fatty acid oxidation genes during cisplatin-induced acute kidney injury. Genetic or pharmacological inhibition of cyclophilin D preserved nuclear expression and transcriptional activity of PPARα and prevented the impairment of fatty acid oxidation and intracellular lipid accumulation. Docking analysis identified potential binding sites between PPARα and cyclophilin D. Thus, our results indicate that proximal tubule cyclophilin D elicits impaired mitochondrial fatty acid oxidation via mitochondrial interaction between cyclophilin D and PPARα. Hence, targeting their interaction may be a potential therapeutic strategy to prevent energy depletion, lipotoxicity and cell death in cisplatin-induced acute kidney injury.

Cell-intrinsic sphingosine kinase 2 promotes macrophage polarization and renal inflammation in response to unilateral ureteral obstruction.

Sphingosine Kinase-2 (Sphk2) is responsible for the production of the bioactive lipid Sphingosine-1 Phosphate, a key regulator of tissue repair. Here we address the in vivo significance of Sphingosine Kinase -2 in renal inflammation/fibrosis in response to unilateral ureteral obstruction using both genetic and pharmacological strategies. Obstructed kidneys of Sphk2-/- mice showed reduced renal damage and diminished levels of the renal injury markers TGFß1 and αSMA when compared to wild type controls. We found a consistently significant increase in anti-inflammatory (M2) macrophages in obstructed Sphk2-/- kidneys by flow cytometry and a decrease in mRNA levels of the inflammatory cytokines, MCP1, TNFα, CXCL1 and ILß1, suggesting an anti-inflammatory bias in the absence of Sphk2. Indeed, metabolic profiling showed that the pro-inflammatory glycolytic pathway is largely inactive in Sphk2-/- bone marrow-derived macrophages. Furthermore, treatment with the M2-promoting cytokines IL-4 or IL-13 demonstrated that macrophages lacking Sphk2 polarized more efficiently to the M2 phenotype than wild type cells. Bone marrow transplant studies indicated that expression of Sphk2-/- on either the hematopoietic or parenchymal cells did not fully rescue the pro-healing phenotype, confirming that both infiltrating M2-macrophages and the kidney microenvironment contribute to the damaging Sphk2 effects. Importantly, obstructed kidneys from mice treated with an Sphk2 inhibitor recapitulated findings in the genetic model. These results demonstrate that reducing Sphk2 activity by genetic or pharmacological manipulation markedly decreases inflammatory and fibrotic responses to obstruction, resulting in diminished renal injury and supporting Sphk2 as a novel driver of the pro-inflammatory macrophage phenotype.

PSMA redirects cell survival signaling from the MAPK to the PI3K-AKT pathways to promote the progression of prostate cancer.

Increased abundance of the prostate-specific membrane antigen (PSMA) on prostate epithelium is a hallmark of advanced metastatic prostate cancer (PCa) and correlates negatively with prognosis. However, direct evidence that PSMA functionally contributes to PCa progression remains elusive. We generated mice bearing PSMA-positive or PSMA-negative PCa by crossing PSMA-deficient mice with transgenic PCa (TRAMP) models, enabling direct assessment of PCa incidence and progression in the presence or absence of PSMA. Compared with PSMA-positive tumors, PSMA-negative tumors were smaller, lower-grade, and more apoptotic with fewer blood vessels, consistent with the recognized proangiogenic function of PSMA. Relative to PSMA-positive tumors, tumors lacking PSMA had less than half the abundance of type 1 insulin-like growth factor receptor (IGF-1R), less activity in the survival pathway mediated by PI3K-AKT signaling, and more activity in the proliferative pathway mediated by MAPK-ERK1/2 signaling. Biochemically, PSMA interacted with the scaffolding protein RACK1, disrupting signaling between the ß1 integrin and IGF-1R complex to the MAPK pathway, enabling activation of the AKT pathway instead. Manipulation of PSMA abundance in PCa cell lines recapitulated this signaling pathway switch. Analysis of published databases indicated that IGF-1R abundance, cell proliferation, and expression of transcripts for antiapoptotic markers positively correlated with PSMA abundance in patients, suggesting that this switch may be relevant to human PCa. Our findings suggest that increase in PSMA in prostate tumors contributes to progression by altering normal signal transduction pathways to drive PCa progression and that enhanced signaling through the IGF-1R/ß1 integrin axis may occur in other tumors.

Patterns of Performance of Oncologic Surgery by North American Pediatric Urologists: A Report from the Pediatric Urologic Oncology Working Group of the Society for Pediatric Urology.

PURPOSE: Objective data on patterns of oncology practice among pediatric urologists are lacking. We reviewed surgical case logs submitted to the American Board of Urology by those self-reporting as pediatric urologists. We hypothesized that logs would reveal a low oncology volume (fewer than 5 cases) and identify orchiectomy as the most common oncology cases, and that less than 25% of logs would show nephrectomy for renal tumor. MATERIALS AND METHODS: Case logs submitted for American Board of Urology certification, recertification or pediatric subspecialty certification were reviewed and standardized to represent 12-month practice. Data were collected on pediatric oncologic surgeries as noted by procedure codes linked with oncologic diagnosis codes for patients up to age 30 years. RESULTS: We identified 281 case logs meeting study criteria. A total of 364 oncology cases were logged and 131 logs (46.6%) listed at least 1 oncology case, while 150 (53.4%) contained no oncology cases. The 75th, 90th and 95th percentiles of oncology volume were represented by reporting 2, 3 and 4 cases, respectively. A total of 13 logs (4.6%) accounted for more than a third of all oncology cases (35.9%). The most frequent oncology case logged was orchiectomy, which was documented in 83 logs (29.5%). On Poisson regression surgeon variables associated with higher oncology volume included male gender (IRR 2.8, 95% CI 2.1-3.9), 2010 log year (IRR 2.4, 95% CI 1.3-4.4), 2015 log year (IRR 3.7, 95% CI 2.1-6.4) and nonpediatric subspecialty certification log (IRR 1.6, 95% CI 1.2-2.3). CONCLUSIONS: Few pediatric urologists perform a high volume of oncologic surgeries based on surgical case logs submitted to the American Board of Urology. A small cohort of pediatric urologists logged the majority of such cases.

A Society for Pediatric Urology Workforce Survey on the Current Perceptions of Oncology Care by Pediatric Urologists: A Report from the Pediatric Urologic Oncology Working Group of the Society for Pediatric Urology.

PURPOSE: Data are lacking on the current perception of oncology care among pediatric urologists. Thus, we developed, pilot tested and administered a survey on this topic to SPU (Society for Pediatric Urology) members. MATERIALS AND METHODS: Approval for this proposal was granted by SPU leadership prior to developing or distributing the survey instrument. The survey was developed and pilot tested by the PUOWG (Pediatric Urologic Oncology Working Group). Response data were collected and descriptive statistics were used for analysis. Logistic regression analysis was performed to correlate surgeon reported factors with higher volumes of reported oncology surgery. RESULTS: A total of 426 surveys were distributed via email to SPU members and 212 individual surveys (49.8%) were returned with the background/introduction section completed. Of these surveys 200 (94.3%) were completed by practicing pediatric urologists. Overall, 155 respondents (77.5%) reported performing 5 or fewer oncology related surgeries per year and 74.9% reported that less than 25% of renal tumor surgery at their institution was performed through the pediatric urology service. On multivariate analysis the self-reported factors significantly associated with increased oncology surgical volume (more than 5 cases per year) were greater than 50% attendance at institutional tumor board meetings (OR 4.8, 95% CI 1.4-16.9) and practicing at a hospital with a higher volume of renal tumor surgery (OR 2.6, 95% CI 1.2-5.8). CONCLUSIONS: Few surveyed pediatric urologists reported performing a high volume of oncology surgery. Respondents expressed interest in ways to increase pediatric urology involvement in oncology care, including opportunities for increased education. Self-reported factors that correlated with higher volume were regular attendance at the institutional pediatric tumor board and practice at a higher volume institution.

Clinical Outcome and Biological Predictors of Relapse After Nephrectomy Only for Very Low-risk Wilms Tumor: A Report From Children's Oncology Group AREN0532.

OBJECTIVE: To determine if observation alone after nephrectomy in very low-risk Wilms tumor (defined as stage I favorable histology Wilms tumors with nephrectomy weight <550g and age at diagnosis <2 years) results in satisfactory event-free survival and overall survival, and to correlate relapse with biomarkers. PATIENTS AND METHODS: The AREN0532 study enrolled patients with very low-risk Wilms tumor confirmed by central review of pathology, diagnostic imaging, and surgical reports. After nephrectomy, patients were followed without adjuvant chemotherapy. Evaluable tumors were analyzed for WT1mutation, 1p and 16q copy loss, 1q copy gain, and 11p15 imprinting. The study was powered to detect a reduction in 4-year EFS from 87% to 75% and overall survival from 95% to 88%. RESULTS: A total of 116 eligible patients enrolled with a median follow up of 80 months (range: 5-97 months). Twelve patients relapsed. Estimated 4-year event-free survival was 89.7% (95% confidence interval 84.1-95.2%) and overall survival was 100%. First sites of relapse were lung (n = 5), tumor bed (n = 4), and abdomen (n = 2), with one metachronous tumor in the contralateral kidney (n = 1) at a median time of 4.3 months for those who relapsed (range 2.3-44 months). The presence of intralobar (P = 0.46) or perilobar rests (P = 1.0) were not associated with relapse (P = 0.16). 1q gain, 1p and 16q loss, and WT1 mutation status were not associated with relapse. 11p15 methylation status was associated relapse (20% relapse with loss of heterozygosity, 25% with loss of imprinting, and 3.3% relapse with retention of the normal imprinting (P = 0.011)). CONCLUSIONS: Most patients meeting very low-risk criteria can be safely managed by nephrectomy alone with resultant reduced exposure to chemotherapy. Expansion of an observation alone strategy for low-risk Wilms tumor incorporating both clinical features and biomarkers should be considered.

Proximal tubule proteins are significantly elevated in bladder urine of patients with ureteropelvic junction obstruction and may represent novel biomarkers: A pilot study.

PURPOSE: Ureteropelvic junction obstruction (UPJO) is the major cause of hydronephrosis in children and may lead to renal injury and early renal dysfunction. However, diagnosis of the degree of obstruction and severity of renal injury relies on invasive and often inconclusive renal scans. Biomarkers from voided urine that detect early renal injury are highly desirable because of their noninvasive collection and their potential to assist in earlier and more reliable diagnosis of the severity of obstruction. Early in response to UPJO, increased intrarenal pressure directly impacts the proximal tubule brush border. We hypothesize that single-pass, apically expressed proximal tubule brush border proteins will be shed into the urine early and rapidly and will be reliable noninvasive urinary biomarkers, providing the tools for a more reliable stratification of UPJO patients. MATERIALS AND METHODS: We performed a prospective cohort study at Connecticut Children's Medical Center. Bladder urine samples from 12 UPJO patients were obtained prior to surgical intervention. Control urine samples were collected from healthy pediatric patients presenting with primary nocturnal enuresis. We determined levels of NGAL, KIM-1 (previously identified biomarkers), CD10, CD13, and CD26 (potentially novel biomarkers) by ELISA in control and experimental urine samples. Urinary creatinine levels were used to normalize the urinary protein levels measured by ELISA. RESULTS: Each of the proximal tubule proteins outperformed the previously published biomarkers. No differences in urinary NGAL and KIM-1 levels were observed between control and obstructed patients (p = 0.932 and p = 0.799, respectively). However, levels of CD10, CD13, and CD26 were significantly higher in the voided urine of obstructed individuals when compared with controls (p = 0.002, p = 0.024, and p = 0.007, respectively) (Figure). CONCLUSIONS: Targeted identification of reliable, noninvasive biomarkers of renal injury is critical to aid in diagnosing patients at risk, guiding therapeutic decisions and monitoring treatment efficacy. Proximal tubule brush border proteins are reliably detected in the urine of obstructed patients and may be more effective at predicting UPJO.

Future directions in risk stratification and therapy for advanced pediatric genitourinary rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) represents the most common soft tissue sarcoma in infants and children and the third most common pediatric solid tumor, accounting for 5% to 15% of all childhood solid tumors. Of these, 15% to 20% arise from the genitourinary tract, with the most common sites originating from the prostate, bladder, and paratesticular regions, followed by the vagina and uterus. Although upfront radical surgery was used at the initiation of Intergroup RMS Study-I (1972-1978), the treatment paradigm has shifted to include initial biopsy with the goal of organ preservation, systemic chemotherapy for all patients, and local control involving surgical resection with or without radiation therapy for most patients. Collaborative group clinical trials have led to dramatic improvement in survival rates from 1960 to 1996 among patients with low- or intermediate-risk disease; however, outcomes appear to have plateaued in more recent years, and the prognosis for patients with metastatic or relapsed/refractory disease remains poor. Current management goals include minimizing toxicity while maintaining the excellent outcomes in low-risk disease, as well as improving outcomes in patients with intermediate- and high-risk disease. Advances in genetic analysis have allowed further refinement in risk stratification of patients. Perhaps the most significant recent development in RMS research was the discovery of an association of alveolar RMS (ARMS) with translocations t(2;13) and t(1;13). Translocation fusion-positive tumors comprise 80% of ARMS and are more aggressive. Fusion-negative ARMS may have a clinical course similar to embryonal RMS. Future Children's Oncology Group sarcoma studies will likely incorporate fusion status into risk stratification and treatment allocation. Newer radiotherapy modalities hold promise for providing local control of disease while minimizing morbidity. The addition of traditional cytotoxic chemotherapeutic agents does not seem to improve outcomes in high-risk patients. Ultimately, the most substantial progress may arise from further elucidation of genetic and molecular pathways involved in RMS tumor formation in an effort to identify novel, targeted therapeutic approaches.

Feasibility of using CT volume as a predictor of specimen weight in a subgroup of patients with low risk Wilms tumors registered on COG Study AREN03B2: implications for central venous catheter placement.

OBJECTIVE: Patients with stage I Wilms tumor, age ≤ 2 years, tumor ≤ 550 g may not require therapy beyond nephrectomy. This study's aims were to determine: (1) if a linear relationship exists between tumor weight and computed tomography (CT) estimated volume; (2) describe the accuracy of a slope-intercept equation in estimating weight; and (3) determine the potential impact of weight estimation on port placement decisions. MATERIALS AND METHODS: Tumor weight and port placement information were abstracted from 105 patients, age ≤ 2 years, with tumors ± 550 g, enrolled in COG AREN03B2. One radiologist estimated tumor size from CT scan. Prolate ellipse volume (PEV) was calculated, linear regression performed, slope-intercept equation calculated, equation estimated weight determined, and potential impact of the on port placement evaluated. RESULTS: A strong relationship exists between PEV and weight (R(2) = 0.87). The slope-intercept equation for weight was: weight = 1.04(PEV) + 58.75. Overall median relative error for the equation was 0.9%, and -3% in tumors weighing 350-750 g. Fifty-five ports were placed, 29 in patients with tumor weight ≤ 550 g, and six not placed in patients with tumor weight > 550 g. CONCLUSIONS: The relationship between PEV and weight produced a reliable weight prediction equation. Preoperative consideration of specimen weight may diminish the number of ports placed in this population.