Pediatric Bladder Tumors: A Ten-Year Retrospective Analysis.

OBJECTIVE: To present our experience in a single pediatric urology practice over a 10-year period with bladder tumors in the pediatric population in an effort to add to the relatively small amount of existing data. We hope to expand the community's knowledge of presentations, management and natural history of pediatric bladder tumors. METHODS: We retrospectively queried our electronic medical records for International Classification of Diseases, Tenth Revision (ICD-10) and Current Procedural Terminology (CPT) codes relevant for bladder tumors. Patients with underlying bladder pathology, such as neurogenic bladder, history of bladder exstrophy, and history of bladder augmentation, were excluded. RESULTS: We identified 30 patients with bladder tumors from 2011 to 2021. There were 21 males and 9 females. Age at diagnosis ranged from 16 months to 19 years. Tumors identified were: 11 of various inflammatory subtypes; 4 papillomas; 4 rhabdomyosarcomas; 3 papillary urothelial neoplasms of low malignant potential and 8 of other types. Treatment included transurethral resection of bladder tumor, chemoradiation and laparoscopic partial cystectomy. Twenty nine patients had disease limited to the bladder and 1 had disease outside the bladder. Follow-up ranged from 2 weeks to 13 years (median 19 months). All patients had no evidence of disease at most recent follow-up. CONCLUSION: Pediatric bladder tumors range from aggressive rhabdomyosarcomas to more benign urothelial lesions. Fortunately, the latter type of tumor is the more prevalent lesion. Knowledge of the treatment options and natural history of these tumors will hopefully be of benefit to clinicians and parents alike.

Focusing on organ preservation and function: paradigm shifts in the treatment of pediatric genitourinary rhabdomyosarcoma.

OBJECTIVE: Pediatric genitourinary rhabdomyosarcoma (RMS) accounts for 25 % of all pediatric soft tissue sarcomas. The treatment of these tumors has shifted over time from debilitating radical exenteration to organ-sparing techniques using multimodal therapy. Our review aims to summarize recent relevant literature regarding the current treatment practices of pediatric genitourinary RMS and how these practices have shifted over time. METHODS: PubMed database search was utilized to identify relevant literature from 1997 to 2015 relating to the treatment of pediatric genitourinary RMS with emphasis on organ preservation and maintaining organ function. RESULTS: A total of 31 articles from 1997 through 2015 were identified relating to current management concepts in pediatric genitourinary sarcomas. Relevant articles were reviewed in detail and discussed. CONCLUSION: The treatment of pediatric genitourinary RMS has shifted from debilitating pelvic exenteration to a multimodal treatment approach involving surgery, chemotherapy, and radiation therapy in an effort to preserve genitourinary organs and reduce treatment morbidity. Continued research is required to improve post-treatment organ function. Further studies utilizing objective urodynamic evaluation are necessary to better characterize bladder function after treatment for RMS. Exciting recent developments in RMS research of fusion proteins that induce cell transformation and inhibit apoptosis and myogenic differentiation may result in future management changes to treatment protocols.

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.

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.

Practice patterns in the surgical approach for adolescent varicocelectomy.

OBJECTIVE: To describe practice patterns in the choice of surgical approach for adolescent varicocelectomy using the Pediatric Health Information System (PHIS) database. METHODS: Hospitals enrolled in the PHIS database that reported all outpatient surgeries by CPT code from 2003 to 2012 were included. Patients at least 10 years of age whose records contained both the ICD-9 code for varicocele (456.4) and a CPT code for varicocelectomy [55550 (laparoscopic), 55530 (open inguinal), 55535 (open abdominal)] were identified. Microsurgical approach was identified by the add-on CPT code 69990. Comparisons among surgical approaches were made using one-way ANOVA, and time trend was evaluated with linear regression. RESULTS: A total cohort of 2528 patients was identified from 38 hospitals. Laparoscopic approach was utilized in 53.6 % of patients. (n = 1354) Microsurgical approach was reported in only 2 % (n = 23) of open varicocelectomies. A subgroup analysis was performed including only those hospitals that reported varicocelectomies in every year of the study period. (n = 587) In this subgroup, 57 % of cases were performed laparoscopically (n = 333), and the trend in laparoscopic cases within this subgroup remained stable over the study period (r(2) = 0.00, p = 0.97). CONCLUSIONS: Laparoscopic varicocelectomy was the most commonly reported surgical approach in this cohort, and the distribution of surgical approaches appeared to remain stable between 2003 and 2012. While subinguinal microsurgical repair has become the gold standard for management of varicocele in adults with infertility, this technique does not appear to be widely adopted in adolescents, though use of an operating microscope is likely underreported in the PHIS database.

Antitumor Activity of a Novel Sphingosine-1-Phosphate 2 Antagonist, AB1, in Neuroblastoma.

The bioactive lipid sphingosine-1-phosphate (S1P) and its receptors (S1P1-5) play critical roles in many pathologic processes, including cancer. The S1P axis has become a bona fide therapeutic target in cancer. JTE-013 [N-​(2,​6-​dichloro-​4-​pyridinyl)-​2-​[1,​3-​dimethyl-​4-​(1-​methylethyl)-​1H-​pyrazolo[3,​4-​b]pyridin-​6-​yl]-​hydrazinecarboxamide], a known S1P2 antagonist, suffers from instability in vivo. Structurally modified, more potent, and stable S1P2 inhibitors would be desirable pharmacological tools. One of the JTE-013 derivatives, AB1 [N-(1H-4-isopropyl-1-allyl-3-methylpyrazolo[3,4-b]pyridine-6-yl)-amino-N'-(2,6-dichloropyridine-4-yl) urea], exhibited improved S1P2 antagonism compared with JTE-013. Intravenous pharmacokinetics indicated enhanced stability or slower clearance of AB1 in vivo. Migration assays in glioblastoma showed that AB1 was slightly more effective than JTE-013 in blocking S1P2-mediated inhibition of cell migration. Functional studies in the neuroblastoma (NB) cell line SK-N-AS showed that AB1 displayed potency at least equivalent to JTE-013 in affecting signaling molecules downstream of S1P2. Similarly, AB1 inhibition of the growth of SK-N-AS tumor xenografts was improved compared with JTE-013. Cell viability assays excluded that this enhanced AB1 effect is caused by inhibition of cancer cell survival. Both JTE-013 and AB1 trended to inhibit (C-C motif) ligand 2 expression and were able to significantly inhibit subsequent tumor-associated macrophage infiltration in NB xenografts. Interestingly, AB1 was more effective than JTE-013 in inhibiting the expression of the profibrotic mediator connective tissue growth factor. The terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling assay and cleaved caspase-3 detection further demonstrated that apoptosis was increased in AB1-treated NB xenografts compared with JTE-013. Overall, the modification of JTE-013 to produce the AB1 compound improved potency, intravenous pharmacokinetics, cellular activity, and antitumor activity in NB and may have enhanced clinical and experimental applicability.

Impact of warm versus cold ischemia on renal function following partial nephrectomy.

INTRODUCTION: We evaluated renal function following partial nephrectomy with cold ischemia (CI) versus warm ischemia (WI). METHODS: Data were collected from 1,396 patients at six institutions who underwent partial nephrectomy for a renal mass with normal contralateral kidney to evaluate percent change in glomerular filtration rate (GFR) at 3-18 months. A multivariate linear regression model tested the association of percent change GFR with clinical, operative, and pathologic factors. RESULTS: A total of 874 patients (63 %) underwent PN with CI and 522 (37 %) with WI. All patients undergoing laparoscopic and robotic-assisted partial nephrectomy (n = 443) had WI, whereas 92 % of open partial nephrectomy patients (n = 953) had CI. The CI group had a lower mean baseline GFR (72 vs. 80 ml/min/1.73 m(2)), longer median ischemia time (33 vs. 29 min), and larger mean tumor size (3.2 vs. 2.9 cm) with more advanced pathologic stage (T1b-T3: 25 vs. 16 %) (all p values <0.001). Patients with CI and WI demonstrated 12.3 and 10.1 % reductions in renal function from baseline, respectively (p = 0.067). Increasing age, female gender, and increasing tumor size were associated with reduction in renal function (all p values <0.001). Neither renal hypothermia nor operative technique independently predicted reduced renal function. Sensitivity analyses limited to ischemia time >30 min, baseline estimated glomerular filtration rate <60 ml/min/1.73 m(2), or tumors >4 cm did not significantly alter the findings. CONCLUSIONS: Increasing age, female gender, and larger tumor size independently predict a decrease in renal function following partial nephrectomy with a normal contralateral kidney. Within the limitations of a non-randomized comparison, including lack of parenchymal preservation percentage, neither surgical approach (open or laparoscopic) nor presence of hypothermia appears to be associated with long-term renal function.

Induction of chemokine (C-C motif) ligand 2 by sphingosine-1-phosphate signaling in neuroblastoma.

BACKGROUND/PURPOSE: Neuroblastoma (NB) is the most common extracranial solid tumor of childhood. Preliminary data derived from a human angiogenesis array in NB showed that the bioactive lipid sphingosine-1-phosphate (S1P) induced the secretion of several angiogenesis-related proteins including the important inflammatory factor chemokine (C-C motif) ligand 2 (CCL2). In the present study, we investigated the mechanism of S1P-induced CCL2 expression in NB. METHODS: Quantitative real-time PCR and CCL2 ELISA were conducted to detect the mRNA expression and protein secretion of CCL2 in NB cells. Gain and loss of function studies were performed by using specific S1PR antagonists, adenoviral transduction and siRNA transfection. Macrophage F4/80 receptor in NB xenografts was detected by quantitative real-time PCR and immunohistochemistry staining. RESULTS: S1P induced CCL2 mRNA expression and protein secretion in a time- and concentration-dependent manner in NB cells. Blockade of S1P2 signaling using the selective S1P2 antagonist JTE-013 inhibited S1P-induced CCL2 expression. Overexpression of S1P2 by adenoviral transduction increased CCL2 secretion while knockdown of S1P2 by siRNA transfection decreased S1P-induced CCL2 secretion in NB cells. Macrophage infiltration, as detected by F4/80 staining, was significantly decreased in JTE-013-treated NB xenografts. CONCLUSIONS: Taken together, our data for the first time demonstrate that S1P induced the macrophage-recruiting factor CCL2 expression in NB cells via S1P2, providing new insights into the complicated functions of S1P2 in cancer.

Paratesticular inflammatory myofibroblastic tumor in a pediatric patient.

Although rare, paratesticular inflammatory myofibroblastic tumor (IMT) represents the second most common paratesticular mass after adenomatoid tumor and comprises roughly 6% of such lesions. Only approximately four cases have been reported in patients younger than 18 years of age. We report an incidentally discovered paratesticular IMT in a 17-year-old male successfully treated with wide excision and testis sparing. To our knowledge, no recurrence has been reported after complete excision of paratesticular IMT; however, continued follow-up is recommended.

Oncology: the role of partial nephrectomy in Wilms tumor.

Wilms tumor represents the most common pediatric renal malignancy and the fourth most common childhood cancer overall. Overall survival from Wilms tumor has increased to over 90 % secondary to multidisciplinary therapy and multi-institutional cooperative group trials. Recent therapeutic focus has shifted to reduction in treatment morbidity and renal preservation while maintaining the high survival rates. Partial nephrectomy is an integral component of the multimodal treatment protocols for Wilms tumor patients with bilateral disease, solitary kidney, or predisposing syndromes. Recent consideration has been given to utilization of nephron sparing surgery (NSS) in carefully selected patients with nonsyndromic unilateral Wilms tumor. While long-term, prospective data in this subgroup of patients is not yet available, case series demonstrate comparable oncologic outcomes after partial versus radical nephrectomy. The relative rarity of Wilms tumor, especially those amenable to upfront partial nephrectomy, presents a challenge to conducting controlled trials.

Characterization of overactive bladder in women in a primary care setting.

BACKGROUND: Overactive bladder (OAB) represents a disorder with overall increasing prevalence in the American population. However, gender-specific characteristics of OAB and how it relates to the general practitioner are not well described. We sought to determine the distribution and characteristics of OAB in women in a primary care setting. METHODS: Self-administered questionnaires were distributed to patients visiting a family medicine outpatient center. The modified questionnaire included eight questions on evidence of lower urinary tract symptoms (LUTS, OAB-validated 8-question screener [OAB-V8]), two questions on stress urinary incontinence, and one question on incomplete emptying. The questionnaire included demographic characteristics and relevant medical and surgical history. Body mass index was calculated based on weight and height. Chi-square test and risk ratio analysis were used to analyze the relationship between OAB and other independent variables. RESULTS: Of 1025 questionnaires administered, 386 were completed. Patients ranged from 16 to 97 years, the majority were African American (78.2%), and 49.7% were premenopausal while 50.3% were postmenopausal. OAB was present in 46.4% of premenopausal women and 41.7% of postmenopausal women. OAB was significantly associated with overweight status (body mass index 25.0-29.9, P = 0.042) and obesity (body mass index ≥30, P < 0.001). Overall, obese women were twice as likely to have OAB (relative risk = 1.99, 1.31-3.04) than women with normal weight. OAB was not shown to correlate with race, cigarette use, history of hysterectomy, or parity. CONCLUSION: OAB was evident in 44% of all female patients surveyed, which is much higher than previously reported estimates. In addition, overweight women were more likely to have OAB. Increased awareness of OAB in the primary care setting should be considered for women's general health.

Pest management programmes in vineyards using male mating disruption.

Israeli vine growers have been reluctant to adopt the mating disruption technique for control of the European vine moth, Lobesia botrana Den. & Schiff. Since the chemically controlled honeydew moth, Cryptoblabes gnidiella Mill., coexists with the European vine moth, growers have maintained that the use of mating disruption would fail to bring about a significant reduction in pesticide use. In this study, the efficacy of mating disruption techniques against C. gnidiella was tested, as well as the effect of these methods on pesticide use and damage to clusters when the method was employed against both of the pests in wine grapes. Comparisons were made between plots treated with (1) L. botrana mating disruption pheromone, (2) L. botrana and C. gnidiella mating disruption pheromones and (3) control plots. A significant difference in the number of clusters infested with the developmental stages of the moths was seen between pheromone-treated plots and controls, while no such difference was observed between plots treated with one versus two pheromones. A similar pattern was observed in the number of insecticide applications; the greatest number of applications was used in control plots, followed by plots treated with L. botrana mating disruption pheromone and by plots treated with pheromones against both pests, in which no pesticides were applied.

Mating disruption of Lobesia botrana (Lepidoptera: Tortricidae): effect of pheromone formulations and concentrations.

The reluctance of Israeli vine growers to adopt the mating disruption technique to control the moth Lobesia botrana Den. & Schiff. has been attributed to the high cost of this method compared with that of traditional insecticide control. In this study, we tested the possibility of reducing the cost, first by testing different pheromone formulations (and thus open the market for competition) and second by reducing the pheromone concentration used in vineyards. Comparisons were made between two pheromone formulations--Shin-Etsu (Tokyo, Japan) at 165 g/ha and Concep (Sutera, Bend, OR) at 150 g/ha--and between two concentrations of Shin-Etsu, 165 and 110 g/ha. Pheromone dispensers were placed at the onset of the second moth generation. Comparison of the numbers of clusters infested with eggs and larvae of L. botrana showed no significant differences in the performance, either between the two formulations, or between the two tested concentrations. The results suggest that 1) the two formulations are equally effective, and 2) a low pheromone concentration is sufficient to maintain good control of small populations of L. botrana. However, when the population is high, pest control efficacy is not improved by increasing the pheromone concentration. Therefore, in the interest of reducing the relatively high cost of mating disruption, we emphasize that increasing the pheromone concentration does not provide improved control of high populations of L. botrana. The cost of mating disruption can be diminished by reducing the applied pheromone concentration and by using the least expensive pheromone formulations