Gonadal dysgenesis is associated with worse outcomes in patients with ovarian nondysgerminomatous tumors: A report of the Children's Oncology Group AGCT 0132 study.

PURPOSE: In this report, we characterize the timing and behavior of malignant ovarian germ cell tumors (GCTs) in pediatric patients with dysgenetic gonads compared to those with normal gonadal development. PATIENTS AND METHODS: Patients from the Children's Oncology Group AGCT0132 with malignant ovarian GCTs were included. Within this population, we sought to identify patients with gonadoblastoma, streak ovaries, or other evidence of gonadal dysgenesis (GD). Patients with malignant GCTs containing one or more of the following histologies-yolk sac tumor, embryonal carcinoma, or choriocarcinoma-were included. Patients were compared with respect to event-free survival (EFS) and overall survival (OS). RESULTS: Nine patients with GD, including seven with gonadoblastoma (mean age, 9.3 years), were compared to 100 non-GD patients (mean age, 12.1 years). The estimated 3-year EFS for patients with GD was 66.7% (95% CI 28.2-87.8%) and for non-GD patients was 88.8% (95% CI 80.2-93.8%). The estimated 3-year OS for patients with GD was 87.5% (95% CI 38.7-98.1%) and for non-GD patients was 97.6% (95% CI of 90.6-99.4%). CONCLUSION: Patients presenting with nongerminomatous malignant ovarian GCTs in the context of GD have a higher rate of events and death than counterparts with normal gonads. These findings emphasize the importance of noting a contralateral streak ovary or gonadoblastoma at histology for any ovarian GCT and support the recommendation for early bilateral gonadectomy in patients known to have GD with Y chromosome material. In contrast to those with pure dysgerminoma, these patients may represent a high-risk group that requires a more aggressive chemotherapy regimen.

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.

Matrix metalloproteinase-8 expression in periodontal tissues surgically removed from diabetic and non-diabetic patients with periodontal disease.

BACKGROUND: Although it is known that periodontal matrix metalloproteinase-8 (MMP-8) expression is associated with periodontal disease, the information concerning the periodontal MMP-8 expression in diabetic patients with periodontal disease is insufficient. MATERIALS AND METHODS: Periodontal tissue specimens were collected from seven patients without periodontal disease and diabetes (Group 1), 15 patients with periodontal disease alone (Group 2) and 10 patients with both periodontal disease and diabetes (Group 3). The frozen sections were prepared and MMP-8 protein expression was detected using immunohistochemistry and quantified. For in vitro study, human U937 mononuclear cells were pre-exposed to normal or high glucose and then treated with lipopolysaccharide (LPS). RESULTS: The nonparametric Kruskal-Wallis test showed that the difference in MMP-8 protein levels among the three groups were statistically significant (p = 0.003). Nonparametric analysis using Jonckheere-Terpstra test showed a tendency of increase in periodontal MMP-8 levels across Group 1 to Group 2 to Group 3 (p = 0.0002). In vitro studies showed that high glucose and LPS had a synergistic effect on MMP-8 expression. CONCLUSION: Our current study showed an increasing trend in MMP-8 protein expression levels across patients without both periodontal disease and diabetes, patients with periodontal disease alone and patients with both diseases.

The monetary costs of pediatric upper urinary tract stone disease: Analysis in a contemporary United States cohort.

INTRODUCTION: The prevalence of upper urinary tract stone disease (USD) in the United States is rising among both adults and children. Studies on the contemporary economic burden of USD management in the pediatric population are lacking. OBJECTIVE: To comprehensively analyze the economic impact of USD in a contemporary United States pediatric cohort, and to evaluate drivers of cost. STUDY DESIGN: A retrospective cohort study of pediatric patients (aged 0-17), diagnosed with USD between 2011 and 2018 were identified from PearlDiver-Mariner, an all-payer claims database containing diagnostic, treatment and prescription data provided in all treatment settings. Relevant International Classification of Disease (ICD-9 and ICD-10) and Current Procedural Terminology (CPT) codes were used for identification, and only patients with claims recorded for at least one year before and after entry of a diagnosis code for USD were selected (N = 10,045). Patients were stratified into those undergoing operative vs. non-operative management and for each patient, total 1-year healthcare costs following USD diagnosis, including same day and non-same day encounters, were analyzed. Factors associated with increased spending, as well as economic trends were analyzed. RESULTS: Overall, 8498 (85%) patients were managed non-operatively, while 1547 (15%) underwent a total of 1880 procedural interventions. Total overall cost was $117.1 million, while median annual expenditure was $15.8 million. Proportion of spending for outpatient, inpatient and prescription services was 52%, 32% and 16%, respectively (Table). Outpatient management accounted for 67% of overall spending. The proportion of patients managed non-operatively increased significantly over time, in parallel with spending for non-operative care. Comorbidity burden, treatment year and geographic region were among predictors of costs. DISCUSSION: Our study is the first to report actual insurance reimbursements for pediatric USD management using actual reimbursement data, examined across all treatment settings. We found that majority of the costs were for outpatient services and for non-operative management, with a rising tendency toward non-operative management over time. Regional variation in expenditures was evident. Specific reasons underlying these observed patterns could not directly be discerned from our dataset, but merit further investigation. CONCLUSION: Non-operative and outpatient management for pediatric USD are increasingly common, resulting in parallel shifts in spending. Notably, 52% of overall spending was for outpatient care. These insights into the contemporary economic burden of pediatric USD could provide value in shaping future healthcare policy.

The Cleveland Clinic experience with adult hypospadias patients undergoing repair: their presentation and a new classification system.

OBJECTIVE: • To characterize and categorize adults with hypospadias who presented to our clinic with urethral stricture and fistula to better clarify the presentation, history and intraoperative findings in this heterogeneous group and to better describe the natural history of this anomaly in adulthood. PATIENT AND METHODS: • A retrospective chart review was performed on adults with hypospadias who underwent urethroplasty for urethral stricture, urethrocutaneous fistula, and/or hypospadias repair at Cleveland Clinic between 1993 and 2009. All procedures were performed by a single staff surgeon (K.W.A.). • The charts were reviewed for site of hypospadias, presenting complaint, overall symptoms, history of repair and type of surgery performed. RESULTS: • Fifty-five adult patients were identified. Median age was 37 years (range: 18-72). About half of the patients had distal (glanular/subcoronal or pendulous) hypospadias (56.4%) and the others had more proximal (bulbar) hypospadias (43.6%). • Voiding symptoms (such as dysuria, weak stream, spraying, urgency, frequency) were the most common presenting complaint (50.9%) and overall symptom (81.8%). About half of patients underwent a two-stage urethroplasty (52.7%). • Based on their history of repair, patients were divided into three categories: I, patients who have undergone continuous multiple surgeries for repair with significant scarring and tissue loss; II, delayed complications after an initially successful childhood repair; and III, no previous repair. Most patients were category I (58.2%); however, seven patients (12.7%) were category III. Balanitis xerotica obliterans (BXO) was more common in this subgroup compared with other categories (42.9% vs 8.3%, respectively, P= 0.037). In two of the three patients in category III with BXO, the stricture length was longer than 7 cm. CONCLUSIONS: • Adults with hypospadias represent a heterogeneous group. More than half of adults with complications related to hypospadias have had multiple operations (category I) representing one of the most difficult challenges to the reconstructive urologist. • Roughly 30% of patients undergo an initially successful repair in childhood with recurrent problems in adulthood (category II), suggesting that the outcomes of repair may not be as durable as estimated by studies with shorter-term follow-up. • Finally, BXO is over-represented in men with hypospadias who have not previously undergone repair, which contradicts the previous suggestion that the risk of BXO is related to the use of skin grafts/flaps from previous repairs and suggests that there may be an increased risk of severe stricture disease in patients who have never undergone corrective surgery for this anomaly.

Partial orchiectomy vs. radical orchiectomy for pediatric testis tumors.

While radical orchiectomy remains the gold standard for testicular cancer, partial orchiectomy has become a well-accepted organ-sparing approach for benign testicular tumors in pre-pubertal patients. The aims of testicular-sparing surgery include prevention of over-treatment, preservation of future hormonal and reproductive function, and provision of a durable cure. For pre-pubertal patients, who have a high likelihood of benign lesions, partial orchiectomy provides effective treatment, owing to the high reliability of scrotal ultrasound (US) and intraoperative frozen section. In adolescent and young adult patients, who are more likely to harbor malignant pathology, the role of partial orchiectomy is less clear. Testis-sparing surgery is being reported with greater frequency in the adult literature for small testicular masses and for situations in which radical orchiectomy would result in an anorchia. More recently, a testis-sparing approach has also been described for carefully-selected post-pubertal pediatric patients. This review will highlight the role of partial orchiectomy in pediatric patients (<18 years old).

Timing of the presentation of urethrocutaneous fistulas after hypospadias repair in pediatric patients.

PURPOSE: We evaluated the timing of the presentation of urethrocutaneous fistulas after hypospadias repair and the development of recurrent urethrocutaneous fistulas after prior fistula repair. MATERIALS AND METHODS: We reviewed the charts of all patients with urethrocutaneous fistulas following hypospadias repair who were seen from 1995 to 2005. Age at hypospadias repair, hypospadias level, hypospadias repair type, time when the parent/patient noted the fistula, date/type of fistula repair, time when fistula recurrence was noticed, date/type of secondary repair and date of last followup were documented. RESULTS: A total of 26 patients with urethrocutaneous fistula were seen, of whom 15 had undergone at least 1 prior operation elsewhere. Of the patients 58% and 61% with fistulas following hypospadias repair and recurrent fistulas following the initial fistula, respectively, presented in the immediate postoperative period. Of the patients 23% with initial fistulas presented more than 2 years after hypospadias repair (up to 17 years later), while only 5.5% with recurrent fistulas presented more than 1 year after fistula repair. Age at presentation with initial fistulas after hypospadias repair was 0 to 12 months in 5 patients, 12 to 24 in 6, 24 to 36 in 6, 36 to 48 in 2 and more than 48 in 7. Mean followup was 5.5 months (range 0 to 69). CONCLUSIONS: While many urethrocutaneous fistulas develop immediately following hypospadias repair, almost a quarter present well beyond the typical followup of many urologists. These findings suggest that reported rates of urethrocutaneous fistula may be underestimated and longer followup may be warranted. Late recurrence of urethrocutaneous fistula is rare with 5.2% seen at more than 1 year, suggesting that more limited followup may be appropriate in these patients.

Reduced and Compressed Cisplatin-Based Chemotherapy in Children and Adolescents With Intermediate-Risk Extracranial Malignant Germ Cell Tumors: A Report From the Children's Oncology Group.

Purpose To investigate whether event-free survival (EFS) can be maintained among children and adolescents with intermediate-risk (IR) malignant germ cell tumors (MGCT) if the administration of cisplatin, etoposide, and bleomycin (PEb) is reduced from four to three cycles and compressed from 5 to 3 days per cycle. Patients and Methods In a phase 3, single-arm trial, patients with IR MGCT (stage II-IV testicular, II-III ovarian, I-II extragonadal, or stage I gonadal tumors with subsequent recurrence) received three cycles of PEb. A parametric comparator model specified that the observed EFS rate should not be significantly < 92%. As recommended for trials that test a reduction of therapy, a one-sided P value ≤ .10 was used to indicate statistical significance. In a post hoc analysis, we also compared results to the EFS rate of comparable patients treated with four cycles of PEb in two prior studies. Results Among 210 eligible patients enrolled from 2003 to 2011, 4-year EFS (EFS4) rate was 89% (95% confidence interval, 83% to 92%), which was significantly lower than the 92% threshold of the comparison model ( P = .08). Among 181 newly diagnosed patients, the EFS4 rate was 87%, compared with 92% for 92 comparable children in the historical cohort ( P = .15). The EFS4 rate was significantly associated with stage (stage I, 100%; stage II, 92%; stage III, 85%; and stage IV, 54%; P < .001). Conclusion The EFS rate for children with IR MGCT observed after three cycles of PEb was less than that of a prespecified parametric model, particularly for patients with higher-stage tumors. These data do not support a reduction in the number of cycles of PEb from four to three. However, further investigation of a reduction in the number of cycles for patients with lower-stage tumors is warranted.

The role of urologists in the care of children with cancer.

At most institutions, pediatric urologists play a limited role in the care of children with cancer. Pediatric urologists have a unique experience and skill set to contribute to the care of these patients. Interested pediatric urologists should become experts in pediatric urologic oncology and demonstrate this interest by participating in tumor board and relevant academic activities. They should advocate for a collaborative approach with pediatric general surgeons in the surgical management of children with genitourinary as such an approach benefits patient care, contributes to professional development of all parties, and develops relationships that contribute to programmatic development for the institution in oncology and other areas.

The role of testis-sparing surgery in children and adolescents with testicular tumors.

Organ-sparing approaches have been applied to the treatment of a variety of urologic tumors in both the realms of adult and pediatric urology, with the goals of minimizing overtreatment of benign lesions, preserving function, and providing durable cure. The predominance of benign tumors in prepubertal patients and the reliability of both ultrasound and intraoperative frozen sections have resulted in a marked shift toward testis-sparing approaches over the last few decades. The role of testis sparing in the adolescent population is presently unclear, although there have been increasing reports of successful organ-sparing surgery for testis tumors in the adult literature. This review presents recent trends in testis-sparing approaches for both pediatric and adolescent patients, the operative technique, and some of the controversies related to testis-sparing surgery.

Secondary or Transient Pseudohypoaldosteronism Associated With Urinary Tract Anomaly and Urinary Infection: A Case Report.

Hyponatremia with hyperkalemia in infancy is a rare presentation, but may be due to aldosterone deficiency or end organ resistance to its action. There are few cases associating this condition with urinary tract infections or anatomic abnormalities that predispose to infection. Clinicians should have a high index of suspicion in diagnosing secondary pseudohypoaldosteronism (PHA) due to its often atypical presentation. We describe ten month-old infant who presented with this condition and was found to have urinary tract infection complicating unilateral urinary tract anomaly, which may have strong association with renal tubular resistance to aldosterone.

Impact of central surgical review in a study of malignant germ cell tumors.

BACKGROUND: Verification of surgical staging has received little attention in clinical oncology trials. Central surgical review was undertaken during a study of malignant pediatric germ cell tumors. METHODS: Children's Oncology Group study AGCT0132 included central surgical review during the study. Completeness of submitted data and confirmation of assigned stage were assessed. Review responses were: assigned status confirmed, assignment withheld pending review of additional information requested, or institutional assignment of stage disputed with explanation given. Changes in stage assignment were at the discretion of the enrolling institution. RESULTS: A total of 206 patients underwent central review. Failure to submit required data elements or need for clarification was noted in 40%. Disagreement with stage assignment occurred in 10% with 17/21 discordant patients reassigned to stage recommended by central review. Four ovarian tumor patients not meeting review criteria for Stage I remained in that stratum by institutional decision. Two-year event free survival in Stage I ovarian patients was 25% for discordant patients compared to 57% for those meeting Stage I criteria by central review. CONCLUSIONS: Central review of stage assignment improved complete data collection and assignment of correct tumor stage at study entry, and allowed for prompt initiation of chemotherapy in patients determined not to have Stage I disease.

Surveillance after initial surgery for Stage I pediatric and adolescent boys with malignant testicular germ cell tumors: Report from the Children's Oncology Group.

PURPOSE: The purpose of this study was to determine prognostic factors correlating with outcome in boys with Stage I malignant testicular germ cell tumors (MTGCT) initially managed with surveillance after surgical resection. METHODS: Between November 2003 and July 2011, 80 boys 0-15 years with Stage I MTGCT were enrolled in Children's Oncology Group Study AGCT0132. Those with residual or recurrent disease were treated with chemotherapy. RESULTS: Characteristics include: age (65, 0-5 years and 15, 11+years), pure YST (93.9%, 0-5 years and 0%, 11+years); and lymphovascular invasion (LVI) (50.6% present vs. 49.4% absent). At median follow-up of 4.94 years, 19 had persistent or recurrent disease, all detected by elevated AFP at a median of 87 days after study enrollment. The outcome from enrollment was 4-year EFS 74% (95% CI: 63%-83%) and 4-year OS 100%. 4-year EFS was improved with younger age (<11 years, 80% vs. 11+years, 48%, p<0.01); pure YST vs. mixed histology (81% vs. 45%, p<0.01), and lack of LVI (84% vs. 62%, p=0.03). CONCLUSIONS: Boys with Stage I MTGCT have excellent overall survival when treated with surgery alone. Age greater than 10 years, mixed histology and presence of LVI are each associated with relapse and may allow identification of high risk boys at time of enrollment.

Laparoendoscopic single-site nephrectomy: initial clinical experience in children.

OBJECTIVE: To present the initial clinical experience in children undergoing unilateral and bilateral laparoendoscopic single-site nephrectomy. PATIENTS AND METHODS: We reviewed our experience with pediatric patients who had undergone single-port nephrectomy (SPN) at our institution since August of 2009. Access was obtained by using the Hassan technique to place a 2-cm SILS™ Port (Covidien Surgical Devices, Norwalk, CT), which contains a gas insufflation channel and three individual cannulas that can readily accommodate laparoscopic instruments up to 12 mm in diameter. Nephrectomy was performed using a standard set of laparoscopic instruments and a rigid 5 mm 30 degree laparoscope (Karl Storz, Tuttlingen, Germany) with an end-on light source. Patient demographics, operative details, and postoperative treatment parameters were collected and recorded. RESULTS: SPN was successfully performed in three consecutive pediatric patients (one female and two male patients: aged 11, 10, and 13 years, respectively) without placement of additional trocars or conversion to open surgery. The operative time for the unilateral SPN was 188 minutes, whereas bilateral SPNs required 214 and 300 minutes, respectively. Estimated blood loss for the unilateral and bilateral SPNs was 25, 20, and 30 mL; whereas patients were discharged on postoperative days 1, 3, and 12, respectively. The prolonged hospital stay was secondary to fever and pseudomembranous colitis in a patient with dialysis who also required a blood transfusion. CONCLUSIONS: Laparoendoscopic single-site simple nephrectomy is a technically demanding yet feasible procedure in children. Further studies are necessary to define the indications, advantages, and limitations of this technique as compared with standard laparoscopy.

Sexual development and fertility of Loxl1-/- male mice.

Our objective was to investigate the genitourinary defects and fertility of the male lysyl oxidase-like 1 gene (Loxl1) knockout (Loxl1(-/-)) mouse, with particular attention to fecundity and testicular, epididymal, gubernacular, and penile histopathology, which may lead us to a better understanding of the role of the elastin-homeostasis gene, LOXL1, in male sexual development. Genital morphometric evaluation of 6- to 9-month-old male Loxl1(-/-) mice (n = 26) was compared with C57Bl/6 controls (n = 24). Measurements included: body weight, scrotal development, evidence of feminization (nipples or vaginal pouch), penile malformations, anogenital distance, and absence/presence and size of perineal bulge. Sperm production was estimated using a standardized technique. A breeding program was conducted to determine how much of the infertility observed in Loxl1(-/-) pairs was due to the male factor. Finally, we performed histopathologic comparison of the genitourinary organs of Loxl1(-/-) and control mice. Loxl1(-/-) mice weighed less than their age-matched C57Bl/6 counterparts (P < .001). Size-adjusted perineal bulge was larger (P < .001), and resting location of the gonads was higher intra-abdominally (P = .048) in the Loxl1(-/-) mice. Estimates of daily sperm counts revealed that the Loxl1(-/-) mice had lower sperm production (P = .048). Loxl1(-/-) males bred with control females demonstrated relative fecundity values intermediate between Loxl1(-/-) pairs (lowest fecundity) and control pairs (highest fecundity), suggesting a component of male-factor infertility. No histologic differences were noted using hematoxylin-eosin or specialized elastin staining of the gonads, gubernaculum, and penis. Although further studies are warranted, these findings suggest a subtle and likely multifactorial role of the LOXL1 protein in male sexual development and fertility.