Immune expression in children with Wilms tumor: a pilot study.

BACKGROUND: Given improvements in multimodality therapy, survival among children with Wilms tumor (WT) exceeds 90%. However, 15% of children with favorable histology and 50% of children with anaplastic WT experience recurrence or progression. Of patients with advanced disease, only 50% survive to adulthood. In adult malignancies (including renal tumors), patient survival has improved with the advent of immunotherapy. However, little is known about the immune microenvironment of WT, making the potential role of immunotherapy unclear. OBJECTIVE: The objective of the study is to perform an exploratory, descriptive analysis of the immune milieu in WT. STUDY DESIGN: Between 2016 and 2017, all pediatric patients with WT, some of whom received neoadjuvant chemotherapy, underwent ex vivo wedge biopsy at the time of nephrectomy. The fresh tumor tissue and peripheral blood samples were analyzed for infiltrating immune infiltrate and effector cells using flow cytometry. Immunohistochemistry was performed for CD4, CD8, and PD-L1 expression. Matched blood samples were obtained for each patient, and circulating immune cells were analyzed by flow cytometry. RESULTS: A total of six patients were enrolled. One patient with neuroblastoma was excluded. The remaining five patients included the following: two with unilateral WT (resected before chemotherapy), two with bilateral WT (resected after neoadjuvant chemotherapy), and one with Denys-Drash syndrome, end-stage renal disease, and history of WT in the contralateral kidney. Immune analysis showed that WT were infiltrated by immune cells regardless of chemotherapy status. CD8 and CD4 T cells were present in the tumor tissue and exhibited an activated phenotype. Elevated levels of natural killer (NK) cells were observed in the tumors (Figure). Immune checkpoint PD-L1 was also found expressed in one of the tumors stained. DISCUSSION: In this pilot study, it was found that WTs were infiltrated by immune cells (CD45+) both before and after chemotherapy. Elevated levels of NK cells infiltrating the tumor specimens, which were quantitatively increased compared with levels of NK cells circulating in the blood, were noted. T cells, particularly CD4+ and CD8+ T cells, were present in tumor specimens. Tumor-infiltrating CD4 and CD8 T cells displayed an activated phenotype as defined by increased expression of human leukocyte antigen-DR isotype (HLA-DR), programmed cell death protein 1 (PD1), and CD57. Together, these findings suggest that WT microenvironment is immune engaged and may be susceptible to immunotherapy similar to other malignancies. CONCLUSIONS: These pilot data suggest an immune-engaged tumor microenvironment is present within WT. This implies that WT may be susceptible to immunotherapy similar to adult renal tumors and other adult malignancies. Follow-up studies are currently underway.

Assessment of pediatric bowel and bladder dysfunction: a critical appraisal of the literature.

OBJECTIVE: Bowel and bladder dysfunction (BBD) is a clinical syndrome defined by the coexistence of constipation and lower urinary tract symptoms. Although BBD is a common condition in pediatric urology and can cause significant stress to patients/parents, clinical diagnosis of BBD has not been standardized. Bowel and bladder dysfunction instruments have gained popularity over the past decade to aid in diagnosis. In this review, the currently published BBD symptom questionnaires were summarized and an analysis on their psychometric validation process was provided. SUBJECTS/PATIENTS: PubMed was searched for articles on BBD symptom questionnaires/instruments/surveys since 2000. Two investigators (R.Y.J. & M.S.K.) conducted the search in duplicate. The search was limited to English language. The included search terms were 'dysfunctional elimination syndrome', 'bowel and bladder dysfunction', 'dysfunctional voiding', 'voiding dysfunction symptom score', and 'dysfunctional voiding symptom scale'. Reference lists of included studies were screened for missed studies. Unpublished abstracts presented at the following scientific meetings were also manually searched for: the American Urological Association, the Society for Pediatric Urology, and the American Academy of Pediatrics Section on Urology. Exclusion criteria included articles in languages other than English, articles not related to BBD questionnaires, and articles not pertaining to pediatric patients. RESULTS: After initial search, a total of 54 articles were obtained. Of the seven questionnaires reviewed, only one did not measure sensitivity or specificity. Almost all questionnaires showed excellent discriminative property with an Area under the curve (AUC) >0.85. Criterion validity was not reported in any of the questionnaires. Known-group validation was used as a common method to evaluate construct validity. Internal consistency was reported in 2 studies, and only 1 study measured questionnaire responsiveness during initial validation. CONCLUSIONS: Although BBD is a common pediatric urology condition; a large amount of heterogeneity exists in the questionnaires' psychometric testing and validation process. To further improve the diagnosis and management of BBD in pediatric patients, there is a need for consensus on the gold standard questionnaire measure.

Increased pediatric sub-specialization is associated with decreased surgical complication rates for inpatient pediatric urology procedures.

INTRODUCTION: Increased case volumes and training are associated with better surgical outcomes. However, the impact of pediatric urology sub-specialization on perioperative complication rates is unknown. OBJECTIVES: To determine the presence and magnitude of difference in rates of common postoperative complications for elective pediatric urology procedures between specialization levels of urologic surgeons. The Nationwide Inpatient Sample (NIS), a nationally representative administrative database, was used. STUDY DESIGN: The NIS (1998-2009) was retrospectively reviewed for pediatric (≤18 years) admissions, using ICD-9-CM codes to identify urologic surgeries and National Surgical Quality Improvement Program (NSQIP) inpatient postoperative complications. Degree of pediatric sub-specialization was calculated using a Pediatric Proportion Index (PPI), defined as the ratio of children to total patients operated on by each provider. The providers were grouped into PPI quartiles: Q1, 0-25% specialization; Q2, 25-50%; Q3, 50-75%; Q4, 75-100%. Weighted multivariate analysis was performed to test for associations between PPI and surgical complications. RESULTS: A total of 71,479 weighted inpatient admissions were identified. Patient age decreased with increasing specialization: Q1, 7.9 vs Q2, 4.8 vs Q3, 4.8 vs Q4, 4.6 years, P < 0.01). Specialization was not associated with race (P > 0.20), gender (P > 0.50), or comorbidity scores (P = 0.10). Mortality (1.5% vs 0.2% vs 0.3% vs 0.4%, P < 0.01) and complication rates (15.5% vs 11.7% vs 9.6% vs 10.9%, P < 0.0001) both decreased with increasing specialization. Patients treated by more highly specialized surgeons incurred slightly higher costs (Q2, +4%; Q3, +1%; Q4 + 2%) but experienced shorter length of hospital stay (Q2, -5%; Q3, -10%; Q4, -3%) compared with the least specialized providers. A greater proportion of patients treated by Q1 and Q3 specialized urologists had CCS ≥2 than those seen by Q2 or Q4 urologists (12.5% and 12.2%, respectively vs 8.4% and 10.9%, respectively, P = 0.04). Adjusting for confounding effects, increased pediatric specialization was associated with decreased postoperative complications: Q2 OR 0.78, CI 0.58-1.05; Q3 OR 0.60, CI 0.44-0.84; Q4 OR 0.70, CI 0.58-0.84; P < 0.01. DISCUSSION: Providers with proportionally higher volumes of pediatric patients achieved better postoperative outcomes than their less sub-specialized counterparts. This may have arisen from increased exposure to pediatric anatomy and physiology, and greater familiarity with pediatric techniques. LIMITATION: The NIS admission-based retrospective design did not enable assessment of long-term outcomes, repeated admissions, or to track a particular patient across time. The study was similarly limited in evaluating the effect of pre-surgical referral patterns on patient distributions. CONCLUSIONS: Increased pediatric sub-specialization among urologists was associated with a decreased risk of mortality and surgical complications in children undergoing inpatient urologic procedures.

Evaluation of the contralateral inguinal ring in clinically unilateral inguinal hernia: a systematic review and meta-analysis.

PURPOSE: The management of the contralateral inguinal canal in children with clinical unilateral inguinal hernia is controversial. Our objective was to systematically review the literature regarding management of the contralateral inguinal canal. METHODS: We searched MEDLINE, EMBASE, and Cochrane databases (1940-2011) using 'hernia' and 'inguinal' and either 'pediatric,' 'infant,' or 'child,' to identify studies of pediatric (age ≤21 years) patients with inguinal hernia. Among clinical unilateral hernia patients, we assessed the number of cases with contralateral patent processus (CPP) and incidence of subsequent clinical metachronous contralateral hernia (MCH). We evaluated three strategies for contralateral management: expectant management, laparoscopic evaluation or pre-operative ultrasound. Pooled estimates of MCH or CPP were generated with random effects by study when heterogeneity was found (I(2) > 50 %, or Cochrane's Q p ≥ 0.10). RESULTS: We identified 2,477 non-duplicated studies, 129 of which met our inclusion criteria and had sufficient information for quantitative analysis. The pooled incidence of MCH after open unilateral repair was 7.3 % (95 % CI 6.5-8.1 %). Laparoscopic examination identified CPP in 30 % (95 % CI 26-34 %). Lower age was associated with higher incidence of CPP (p < 0.01). The incidence of MCH after a negative laparoscopic evaluation was 0.9 % (95 % CI 0.5-1.3 %). Significant heterogeneity was found in studies and pooled estimates should be interpreted with caution. CONCLUSIONS: The literature suggests that laparoscopically identified CPP is a poor indicator of future contralateral hernia. Almost a third of patients will have a CPP, while less than one in 10 will develop MCH when managed expectantly. Performing contralateral hernia repair in patients with CPP results in overtreatment in roughly 2 out of 3 patients.

Evaluation of the United States pediatric urology workforce and fellowships: a series of surveys performed in 2006-2010.

OBJECTIVE: In the US, there has been an evolution in the practice of pediatric urology from a primary academic sub-specialty focused on reconstruction of major congenital genitorurinary abnormalities to a mixed academic and private practice that serves as the primary care giver for all pediatric urologic concerns. The estimated manpower needs were unable to be resolved, due to our inability to determine the impact of sub-specialty certification on referral patterns, along with the failure to embrace the use of physician extenders. Here, we review a series of surveys performed in 2006-2010 regarding the sub-specialty of pediatric urology. MATERIALS AND METHODS: The four surveys focused on workforce needs, appraised the financial impact of educational debt on the pediatric urology community, and evaluated concerns of the current fellows in training. RESULTS: The median financial income for a pediatric urologist, the resident's educational debt load, and a desire of the fellows to have an open dialog with the urologic community regarding the merits of the research year are revealed. CONCLUSION: We have identified that the ability to recruit fellows into our field is dependent upon a combination of factors: interest in the field, job availability in relationship to geographic locations, mentoring, concerns regarding financial/familial hardships encountered during a 2-year fellowship, and the lack of increased financial reimbursement for the extra training required.

Lung transplantation for cystic fibrosis patients with Burkholderia cepacia complex. Survival linked to genomovar type.

The number of cystic fibrosis (CF) patients undergoing lung transplant has risen over the past decade, because of a clear-cut survival benefit. However, patients with Burkholderia cepacia complex are often excluded from transplantation because of increased mortality. To determine the influence of B. cepacia complex genomovar type on transplant outcome, we undertook a retrospective study in 121 CF patients transplanted at UNC. Twenty-one and three patients, respectively, were infected pre- or postoperatively with B. cepacia complex. All posttransplant acquisitions were successfully treated. However, excess mortality occurred over the first 6 postoperative months in those infected preoperatively with B. cepacia complex compared with those not infected (33% versus 12%, p = 0.01). The 1-, 3-, and 5-yr survival were significantly lower in the B. cepacia complex cohort. Of the patients infected preoperatively, genomovar III patients were at the highest risk of B. cepacia complex-related mortality (5 of 12 versus 0 of 8, one isolate not typed; p = 0.035). Each of the B. cepacia complex-related deaths was caused by a unique genotype as determined by pulsed-field gel electrophoresis. All isolates were negative for the cable pilin gene. These results warrant a multicenter analysis of B. cepacia complex-infected patients with genomovar-typing to confirm that genomovar III patients are at highest risk for post-transplant complications.