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PURPOSE To evaluate long-term morbidity and mortality among unilateral, nonsyndromic Wilms tumor (WT) survivors according to conventional treatment regimens. METHODS Cumulative incidence of late mortality (≥ 5 years from diagnosis) and chronic health conditions (CHCs) were evaluated in WT survivors from the Childhood Cancer Survivor Study. Outcomes were evaluated by treatment, including nephrectomy combined with vincristine and actinomycin D (VA), VA + doxorubicin + abdominal radiotherapy (VAD + ART), VAD + ART + whole lung radiotherapy, or receipt of ≥ 4 chemotherapy agents. RESULTS Among 2,008 unilateral WT survivors, 142 deaths occurred (standardized mortality ratio, 2.9, 95% CI, 2.5 to 3.5; 35-year cumulative incidence of death, 7.8%, 95% CI, 6.3 to 9.2). The 35-year cumulative incidence of any grade 3-5 CHC was 34.1% (95% CI, 30.7 to 37.5; rate ratio [RR] compared with siblings 3.0, 95% CI, 2.6 to 3.5). Survivors treated with VA alone had comparable risk for all-cause late mortality relative to the general population (standardized mortality ratio, 1.0; 95% CI, 0.5 to 1.7) and modestly increased risk for grade 3-5 CHCs compared with siblings (RR, 1.5; 95% CI, 1.1 to 2.0), but remained at increased risk for intestinal obstruction (RR, 9.4; 95% CI, 3.9 to 22.2) and kidney failure (RR, 11.9; 95% CI, 4.2 to 33.6). Magnitudes of risk for grade 3-5 CHCs, including intestinal obstruction, kidney failure, premature ovarian insufficiency, and heart failure, increased by treatment group intensity. CONCLUSION With approximately 40% of patients with newly diagnosed WT currently treated with VA alone, the burden of late mortality/morbidity in future decades is projected to be lower than that for survivors from earlier eras. Nevertheless, the risk of late effects such as intestinal obstruction and kidney failure was elevated across all treatment groups, and there was a dose-dependent increase in risk for all grade 3-5 CHCs by treatment group intensity.

PURPOSE Kidney failure is a rare but serious late effect following treatment for childhood cancer. We developed a model using demographic and treatment characteristics to predict individual risk of kidney failure among 5-year survivors of childhood cancer. METHODS Five-year survivors from the Childhood Cancer Survivor Study (CCSS) without history of kidney failure (n = 25,483) were assessed for subsequent kidney failure (ie, dialysis, kidney transplantation, or kidney-related death) by age 40 years. Outcomes were identified by self-report and linkage with the Organ Procurement and Transplantation Network and the National Death Index. A sibling cohort (n = 5,045) served as a comparator. Piecewise exponential models accounting for race/ethnicity, age at diagnosis, nephrectomy, chemotherapy, radiotherapy, congenital genitourinary anomalies, and early-onset hypertension estimated the relationships between potential predictors and kidney failure, using area under the curve (AUC) and concordance (C) statistic to evaluate predictive power. Regression coefficient estimates were converted to integer risk scores. The St Jude Lifetime Cohort Study and the National Wilms Tumor Study served as validation cohorts. RESULTS Among CCSS survivors, 204 developed late kidney failure. Prediction models achieved an AUC of 0.65-0.67 and a C-statistic of 0.68-0.69 for kidney failure by age 40 years. Validation cohort AUC and C-statistics were 0.88/0.88 for the St Jude Lifetime Cohort Study (n = 8) and 0.67/0.64 for the National Wilms Tumor Study (n = 91). Risk scores were collapsed to form statistically distinct low- (n = 17,762), moderate- (n = 3,784), and high-risk (n = 716) groups, corresponding to cumulative incidences in CCSS of kidney failure by age 40 years of 0.6% (95% CI, 0.4 to 0.7), 2.1% (95% CI, 1.5 to 2.9), and 7.5% (95% CI, 4.3 to 11.6), respectively, compared with 0.2% (95% CI, 0.1 to 0.5) among siblings. CONCLUSION Prediction models accurately identify childhood cancer survivors at low, moderate, and high risk for late kidney failure and may inform screening and interventional strategies.

PURPOSE To describe the risk of late mortality, subsequent malignant neoplasms (SMNs), and chronic health conditions (CHCs) in survivors of neuroblastoma diagnosed in infancy by treatment era and exposures. METHODS Among 5-year survivors of neuroblastoma in the Childhood Cancer Survivor Study diagnosed age < 1 year between 1970 and 1999, we examined the cumulative incidence of late (> 5 years from diagnosis) mortality, SMN, and CHCs (grades 2-5 and 3-5). Multivariable Cox regression models estimated hazard ratios (HRs) and 95% CIs by decade and treatment (surgery-alone v chemotherapy with or without surgery [C ± S] v radiation with or without chemotherapy ± surgery [R ± C ± S]) among survivors and between survivors and 5,051 siblings. RESULTS Among 1,397 eligible survivors, the 25-year cumulative incidence of late mortality was 2.1% (95% CI, 1.3 to 3.9) with no difference by treatment era. Among 990 participants who completed a baseline survey, fewer survivors received radiation in more recent eras (51.2% 1970s, 20.4% 1980s, and 10.1% 1990s; P < .001). Risk of SMN was elevated only among individuals treated with radiation-containing regimens compared with surgery alone (HR[C ± S], 3.2 [95% CI, 0.9 to 11.6]; HR[R ± C ± S], 5.7 [95% CI, 1.2 to 28.1]). In adjusted models, there was a 50% reduction in risk of grade 3-5 CHCs in the 1990s versus 1970s (HR, 0.5 [95% CI, 0.3 to 0.9]; P = .01); individuals treated with radiation had a 3.6-fold risk for grade 3-5 CHCs (95% CI, 2.1 to 6.2) versus those treated with surgery alone. When compared with siblings, risk of grade 3-5 CHCs for survivors was lowest in the most recent era (HR[1970s], 4.7 [95% CI, 3.4 to 6.5]; HR[1980s], 4.6 [95% CI, 3.3 to 6.4]; HR[1990s], 2.5 [95% CI, 1.7 to 3.9]). CONCLUSION Neuroblastoma survivors treated during infancy have a relatively low absolute burden of late mortality and SMN. Encouragingly, risk of CHCs has declined in more recent eras with reduced exposure to radiation therapy.

Although pediatric lower extremity sarcoma once was routinely treated with amputation, multiagent chemotherapy as well as the evolution of tumor resection and reconstruction techniques have enabled the wide adoption of limb salvage surgery (LSS). Even though infection and tumor recurrence are established risk factors for early amputation (5 years) after LSS, the frequency of and factors associated with late amputation (≥ 5 years from diagnosis) in children with sarcomas are not known. Additionally, the resulting psychosocial and physical outcomes of these patients compared with those treated with primary amputation or LSS that was not complicated by subsequent amputation are not well studied. Studying these outcomes is critical to enhancing the quality of life of patients with sarcomas.(1) How have treatments changed over time in patients with lower extremity sarcoma who are included in the Childhood Cancer Survivor Study (CCSS), and did primary treatment with amputation or LSS affect overall survival at 25 years among patients who had survived at least 5 years from diagnosis? (2) What is the cumulative incidence of amputation after LSS for patients diagnosed with pediatric lower extremity sarcomas 25 years after diagnosis? (3) What are the factors associated with time to late amputation (≥ 5 years after diagnosis) in patients initially treated with LSS for lower extremity sarcomas in the CCSS? (4) What are the comparative social, physical, and emotional health-related quality of life (HRQOL) outcomes among patients with sarcoma treated with primary amputation, LSS without amputation, or LSS complicated by late amputation, as assessed by CCSS follow-up questionnaires, the SF-36, and the Brief Symptom Inventory-18 at 20 years after cancer diagnosis?The CCSS is a long-term follow-up study that began in 1994 and is coordinated through St. Jude Children's Research Hospital. It is a retrospective study with longitudinal follow-up of more than 38,000 participants treated for childhood cancer when younger than 21 years at one of 31 collaborating institutions between 1970 and 1999 in the United States and Canada. Participants were eligible for enrollment in the CCSS after they had survived 5 years from diagnosis. Within the CCSS cohort, we included participants who had a diagnosis of lower extremity sarcoma treated with primary amputation (547 patients with a mean age at diagnosis of 13 ± 4 years) or primary LSS (510 patients with a mean age 14 ± 4 years). The LSS cohort was subdivided into LSS without amputation, defined as primary LSS without amputation at the time of latest follow-up; LSS with early amputation, defined as LSS complicated by amputation occurring less than 5 years from diagnosis; or LSS with late amputation, defined as primary LSS in study patients who subsequently underwent amputation 5 years or more from cancer diagnosis. The cumulative incidence of late amputation after primary LSS was estimated. Cox proportional hazards regression with time-varying covariates identified factors associated with late amputation. Modified Poisson regression models were used to compare psychosocial, physical, and HRQOL outcomes among patients treated with primary amputation, LSS without amputation, or LSS complicated by late amputation using validated surveys.More study participants were treated with LSS than with primary amputation in more recent decades. The overall survival at 25 years in this population who survived 5 years from diagnosis was not different between those treated with primary amputation (87% [95% confidence interval [CI] 82% to 91%]) compared with LSS (88% [95% CI 85% to 91%]; p = 0.31). The cumulative incidence of amputation at 25 years after cancer diagnosis and primary LSS was 18% (95% CI 14% to 21%). With the numbers available, the cumulative incidence of late amputation was not different among study patients treated in the 1970s (27% [95% CI 15% to 38%]) versus the 1980s and 1990s (19% [95% CI 13% to 25%] and 15% [95% CI 10% to 19%], respectively; p = 0.15). After controlling for gender, medical and surgical treatment variables, cancer recurrence, and chronic health conditions, gender (hazard ratio [HR] 2.02 [95% CI 1.07 to 3.82]; p = 0.03) and history of prosthetic joint reconstruction (HR 2.58 [95% CI 1.37 to 4.84]; p = 0.003) were associated with an increased likelihood of late amputation. Study patients treated with a primary amputation (relative risk [RR] 2.04 [95% CI 1.15 to 3.64]) and LSS complicated by late amputation (relative risk [RR] 3.85 [95% CI 1.66 to 8.92]) were more likely to be unemployed or unable to attend school than patients treated with LSS without amputation to date. The CCSS cohort treated with primary amputation and those with LSS complicated by late amputation reported worse physical health scores than those without amputation to date, although mental and emotional health outcomes did not differ between the groups.There is a substantial risk of late amputation after LSS, and both primary and late amputation status are associated with decreased physical HRQOL outcomes. Children treated for sarcoma who survive into adulthood after primary amputation and those who undergo late amputation after LSS may benefit from interventions focused on improving physical function and reaching educational and employment milestones. Efforts to improve the physical function of people who have undergone amputation either through prosthetic design or integration into the residuum should be supported. Understanding factors associated with late amputation in the setting of more modern surgical approaches and implants will help surgeons more effectively manage patient expectations and adjust practice to mitigate these risks over the life of the patient.Level III, therapeutic study.

The integration of genomic testing into clinical care enables the use of individualized approaches to the management of rare diseases. We describe the use of belzutifan, a potent and selective small-molecule inhibitor of the protein hypoxia-inducible factor 2α (HIF2α), in a patient with polycythemia and multiple paragangliomas (the Pacak-Zhuang syndrome). The syndrome was caused in this patient by somatic mosaicism for an activating mutation in EPAS1. Treatment with belzutifan led to a rapid and sustained tumor response along with resolution of hypertension, headaches, and long-standing polycythemia. This case shows the application of a targeted therapy for the treatment of a patient with a rare tumor-predisposition syndrome. (Funded by the Morin Family Fund for Pediatric Cancer and Alex's Lemonade Stand Foundation.).

Germ cell tumors arise from primordial germ cells. Most develop in the gonads or along midline structures of the body. Genetic aberrations leading to disruption in the molecular signaling responsible for primordial germ cell migration early in development may provide rationale for why germ cell tumors originate in extragonadal locations. Establishing best practices for treating pediatric germ cell tumors remains an area of active investigation. Recent advances focused on limiting toxicities of therapy, identifying new therapies for relapsed and refractory tumors, defining best practices for surgical staging and resection, and developing novel methods to monitor for disease relapse.

Germ cell tumors (GCTs) comprise a wide spectrum of benign and malignant tumors. Neonatal GCTs are predominantly teratomas (mature or immature), which are typically cured with surgery alone. Relapses are infrequent even in the setting of microscopic residual disease; therefore, negative surgical margins at the cost of significant morbidity are not recommended. In neonates with metastatic malignant disease or malignant disease for which upfront surgical resection is not feasible without significant morbidity, an initial biopsy followed by neoadjuvant chemotherapy and delayed surgical resection is recommended. Carboplatin-based regimens should be considered when chemotherapy is indicated.

We sought to estimate the prevalence, incidence, and timing of surgery for elective and non-elective hernia repairs. We performed a retrospective cohort study, abstracting data on children 3 million dependents of U.S. Armed Services members. Our primary outcome was initial hernia repair (inguinal, umbilical, ventral, or femoral), stratified by elective versus non-elective repair and by age. We calculated prevalence, incidence rate, and time from diagnosis to repair. 19,398 children underwent hernia repair (12,220 inguinal, 5761 umbilical, 1373 ventral, 44 femoral). Prevalence of non-elective repairs ranged from 6% (umbilical) to 22% (ventral). Incidence rates of elective repairs ranged from 0.03 [95% CI: 0.02–0.04] (femoral) to 8.92 [95% CI: 8.76–9.09] (inguinal) per 10,000 person-years, while incidence rates of non-elective repairs ranged from 0.005 [95% CI: 0.002–0.01] (femoral) to 0.68 [95% CI: 0.64–0.73] (inguinal) per 10,000 person-years. Inguinal (median = 20, interquartile range [IQR] = 0–46 days), ventral (median = 23, IQR = 5–62 days), and femoral hernias (median = 0, IQR = 0–12 days) were repaired more promptly and with less variation than umbilical hernias (median = 66, IQR = 23–422 days). These data describe the burden of hernia repair in the U.S. The large variation in time between diagnosis and repair by hernia type identifies an important area of research to understand mechanisms underlying such heterogeneity and determine the ideal timing for repair. Prognosis study II.

We sought to analyze biologic, clinical, and prognostic differences according to pattern of failure at the time of first relapse in neuroblastoma.Children21 years diagnosed with neuroblastoma between 1989 and 2017 with known site of first relapse (isolated local vs. distant only vs. combined local and distant sites) were identified from the International Neuroblastoma Risk Group (INRG) database. Data were compared between sites of relapse according to clinical features, biologic features, initial treatment, time to first relapse, and overall survival (OS) from time of first relapse.Pattern of first relapse among 1833 children was 19% isolated local; 65% distant only; and 16% combined sites. All evaluated clinical and biologic variables with exception of tumor diagnosis differed statistically by relapse pattern, with patients with isolated local failure having more favorable prognostic features. Patients with stage 3 disease were more likely to have isolated local failure compared to all other stages (49% vs. 16%; p .001). OS significantly differed by relapse pattern (5-year OS ± SE): isolated local: 64% ± 3%; distant only: 23% ± 2%; and combined: 26% ± 4% (p .001). After controlling for age, stage, and MYCN status, patients with isolated local failure (adjusted hazard ratio [HR] = 0.46; 95% confidence interval [CI]: 0.33-0.62; p .001) and distant-only failure (adjusted HR = 0.57; 95% CI: 0.45-0.71; p .001) remained at decreased risk for death as compared to patients with combined failure.Patients with distant-only and combined failures have a higher proportion of unfavorable clinical and biological features, and a lower survival than those with isolated local relapse.

Malignant ovarian neoplasms are uncommon in the pediatric and adolescent population. Imaging and tumor markers help to guide the preoperative risk/benefit analysis for planned surgical management, which is the mainstay of therapy. An interdisciplinary approach should be taken in the management of this vulnerable population from diagnosis through post-treatment surveillance. In this review, the initial evaluation, risk stratification, and management of various types of malignant ovarian masses will be addressed with a special focus on how to optimize an interdisciplinary approach to ovarian masses.

Long term central venous access is necessary for the treatment of several conditions affecting young children. Totally implantable access ports (ports) offer the advantage of containing no external components, thus simplifying their care and maintenance. However, there is no consensus on the safety of port placement in infants (birth to 1-year of age). The aim of this study was to describe complications associated with port placement in infants, including which specific factors may be associated with risk for developing complications among these patients, and thereby assess the safety of port placement in this young population.A two-institution, retrospective cohort study identified patients under 1-year old who underwent port placement. Intraoperative, early postoperative (within 30 days), and late postoperative (greater than 30 days) complications were recorded. Multivariate logistic regression models were employed to assess factors associated with port-related complications.Among 121 patients who received a port, 36 (30%) experienced a complication with a median time to complication of 299.5 days [IQR 67.5-440.75]. Of those, 26 required unplanned port removal. Only 3 patients (2.5%) experienced an intraoperative complication, and 3 patients (2.5%) experienced a complication within 30 days of port placement. A diagnosis of cancer was found to be protective against early catheter malfunction (OR=0.31, p = 0.03). A non-statistically significant trend associated with increased complications for large caliber devices (6.0Fr) and weight7-kg (OR 2.20, p = 0.06 and OR=2.26, p = 0.11 respectively) was observed.Port placement appears to be safe for most infants with low or acceptable rates of intra- or post-operative complications. Smaller patient size (7 kg) and larger-sized catheters (6.0Fr) may be associated with an increased risk for complications among this population.III.

Hematopoietic stem cell transplantation (HSCT) in the pediatric population is associated with pulmonary complications in 25% of recipients. The role of surgical lung biopsy (SLB) remains unclear because of concerns about both the therapeutic impact and morbidity associated with the procedure. A retrospective review of consecutive allogeneic HSCT recipients at Dana-Farber and Boston Children's Hospital Cancer and Blood Disorders Center between 2006 and 2016 was performed. All recipients who underwent SLB during the study period were identified and charts reviewed for perioperative complications, histopathologic findings, and changes in therapy delivered. Pearson's chi-square test and Student's t-test (or appropriate nonparametric test) were used to evaluate the associations between perioperative complication and categorical and continuous variables, respectively. Five hundred fifty-five HSCTs were included, among which 48 SLBs (8.6%) were identified. Median follow-up time was 24 months (range, 0 to 139). Thirty-day postoperative morbidity was 16.7% and 30-day postoperative mortality 10.4% (n = 5). The overall 30-day postoperative complication rate (including mortality) was 20.8% (n = 10). No mortalities were directly attributable to SLB. Definitive diagnoses were identified in 70.8% of SLBs (n = 34), and therapeutic changes occurred in 79.2% (n = 38). Overall, 83.3% of SLBs (n = 40) either provided a diagnosis or led to a change in therapy. SLB has an acceptable risk of perioperative complications in this medically complicated and often severely ill population. In most HSCT patients, SLB aids in defining the etiology of pulmonary infiltrates and can inform therapeutic decisions in patients where noninvasive diagnostic modalities have failed to provide a definitive diagnosis.

This article reviews of the current evidence-based treatment standards for children with Wilms tumor. In this article, a summary of recently completed clinical trials by the Children’s Oncology Group are provided, the current diagnostic evaluation and surgical standards are discussed, and the surgical impact on current risk stratification for patients with Wilms tumor is highlighted. LEVEL OF EVIDENCE: This is a review article of previously published and referenced LEVEL 1 studies, but also includes expert opinion LEVEL V, represented by the American Pediatric Surgical Association Cancer Committee.

Germ cell tumors (GCTs) comprise a wide spectrum of benign and malignant tumors. Neonatal GCTs are predominantly teratomas (mature or immature), which are typically cured with surgery alone. Relapses are infrequent even in the setting of microscopic residual disease; therefore, negative surgical margins at the cost of significant morbidity are not recommended. In neonates with metastatic malignant disease or malignant disease for which upfront surgical resection is not feasible without significant morbidity, an initial biopsy followed by neoadjuvant chemotherapy and delayed surgical resection is recommended. Carboplatin-based regimens should be considered when chemotherapy is indicated.

Long-term survival following hematopoietic stem cell transplant (HSCT) in childhood continues to improve, and patients are thus increasingly faced with the late effects of treatment. Infertility is very common for both males and females following HSCT and is one of the most distressing sequelae. Adoption and surrogate egg or sperm donation are possibilities for some patients, but post-HSCT reversal of gonadal failure is not possible. We have recently initiated an oncofertility program with a dedicated practitioner with specific expertise in this area. Our practice is for her to meet with all families and age-appropriate patients during the pre-HSCT evaluation period. This allows patients and families to be accurately informed about the expected treatment-related infertility risk and the available options for fertility preservation. Sperm banking and egg or embryo cryopreservation are established approaches but are not achievable for many children and adolescents. Recently, the harvesting and cryopreservation of ovarian and testicular tissue represents a novel surgical option that allows for the possibility of fertility preservation to be extended to children of all ages. The purpose of this investigation is to evaluate the safety of these procedures proximal to conditioning therapy and HSCT. This is a retrospective report on a consecutive cohort of all patients aged 0 to 25 years who, after discussion with our oncofertility specialist, chose to undergo surgical fertility preservation (laparoscopic unilateral oophorectomy or testicular biopsy) at our institution between March 2018 and April 2020. These procedures occurred under general anesthesia at the time of central line placement prior to the initiation of HSCT conditioning. We assess the safety of the procedures in terms of postoperative complications and impact on HSCT course. Twenty-two patients underwent fertility preservation surgical procedures. Thirteen patients (59%) were female, median age 13 years (1 to 22 years), and 9 (41%) were male, median age 8 years (5 to 12 years). Fourteen (63%) were prepubertal and 8 (36%) pubertal. HSCT indications were hematologic malignancies/solid tumor (40%) and nonmalignant diseases (60%). Most received an allogenic graft (68%) and 81% had myeloablative conditioning. All patients became neutropenic at a median of 10 days (0 to 51 days) from the surgical procedure; 1 was neutropenic at the time of testicular tissue cryopreservation (TTC). The mean duration for the procedures performed, including ovarian tissue cryopreservation (OTC) or TTC, was 98 minutes (49 to 260 minutes) and 97 minutes (56 to 178 minutes), respectively. Estimated blood loss was minimal and no postoperative site infections occurred. One postprocedure, blood culture-negative fever was reported without an identifiable source; the patient completed 48 hours of antibiotics with resolution of fever. Sixty-two percent of females and 56% of males started conditioning within 24 hours of OTC/TTC (15 hours to 113 days; median, 1 day). The median time to engraftment was 22 days (9 to 33 days) in females and 17 days (11 to 67 days) in males, consistent with our institutional benchmarks. One patient with aplastic anemia had primary graft failure, attributed to low cell dose. This patient engrafted after a second transplant from an alternative donor but ultimately died of multiorgan failure. He was neutropenic for over 60 days and never experienced surgical site infection. There were no procedure-related delays to start of conditioning or to discharge. Children of all ages can now be offered the possibility of fertility preservation following HSCT for benign and malignant conditions. Our review suggests that these procedure for both females and males can be performed close to the start of conditioning, which allows for coupling with central access placement. These procedures appear to be safe and do not add to transplant-related morbidity.

e22023 Background: Survivors of childhood cancer with history of radiation therapy (RT) to the head/neck/chest are at increased risk for stroke. Children’s Oncology Group Guidelines recommend carotid ultrasound (CU) when clinically indicated or 10 years after RT ≥ 40Gy to the neck. Yet, the use of CU has not been previously described. Methods: 8,693 survivors of childhood cancer (median age at diagnosis 8.0 years, range 0-20; median age at evaluation 37.4, range 18-65) diagnosed between 1970-1999 were asked if they had ever had a CU. Cardiovascular disease (CVD) was defined as any of the following: stroke, congestive heart failure, hypertension, myocardial infarction, coronary heart disease, or arrythmia. Prevalence ratios (PR) were calculated; age and sex-adjusted multivariable Poisson regression models evaluated factors associated with CU. Results: 4.9% (427) of survivors had a history of stroke and 28% (2,442) had a history of any CVD. Of these, 40.0% (171) with a history of stroke and 28.6% (748) with any CVD had CU. Comparatively, 14.6% (1,404) without a stroke and 11.1% (798) without any CVD had a CU (both p40Gy RT to the neck have never had a CU, suggesting that greater awareness of guidelines is needed.[Table: see text]

We sought to estimate the prevalence, incidence, and timing of surgery for elective and non-elective hernia repairs.We performed a retrospective cohort study, abstracting data on children 18 years from the 2005-2014 DoD Military Health System Data Repository, which includes 3 million dependents of U.S. Armed Services members. Our primary outcome was initial hernia repair (inguinal, umbilical, ventral, or femoral), stratified by elective versus non-elective repair and by age. We calculated prevalence, incidence rate, and time from diagnosis to repair.19,398 children underwent hernia repair (12,220 inguinal, 5761 umbilical, 1373 ventral, 44 femoral). Prevalence of non-elective repairs ranged from 6% (umbilical) to 22% (ventral). Incidence rates of elective repairs ranged from 0.03 [95% CI: 0.02-0.04] (femoral) to 8.92 [95% CI: 8.76-9.09] (inguinal) per 10,000 person-years, while incidence rates of non-elective repairs ranged from 0.005 [95% CI: 0.002-0.01] (femoral) to 0.68 [95% CI: 0.64-0.73] (inguinal) per 10,000 person-years. Inguinal (median = 20, interquartile range [IQR] = 0-46 days), ventral (median = 23, IQR = 5-62 days), and femoral hernias (median = 0, IQR = 0-12 days) were repaired more promptly and with less variation than umbilical hernias (median = 66, IQR = 23-422 days).These data describe the burden of hernia repair in the U.S. The large variation in time between diagnosis and repair by hernia type identifies an important area of research to understand mechanisms underlying such heterogeneity and determine the ideal timing for repair.Prognosis study II.

Background Desmoplastic small round cell tumor (DSRCT) is a rare aggressive sarcoma that affects children and young adults, and portends poor outcomes despite intensive multimodal treatment approaches. We report toxicity, response, and outcomes of patients with DSRCT treated with the addition of vincristine, irinotecan, and temozolomide (VIT) to interval-compressed chemotherapy as per Children's Oncology Group ARST08P1. Methods All newly diagnosed pediatric patients with DSRCT treated at Dana-Farber Cancer Institute and Boston Children's Hospital between 2014 and 2019 as per ARST08P1, Arm P2 with replacement of VAC cycles with VIT, were identified. Medical records were reviewed for clinical and disease characteristics, and treatment response and outcomes. Results Six patients were treated as per the above regimen. Median age at diagnosis was 15.1 years (range 3.2-16.4) and five patients were male. Five patients had abdominal primary tumors, of which one had exclusively intraabdominal and four had extraabdominal metastases. Two initial cycles of VIT were well tolerated with nausea, vomiting, diarrhea, and constipation as the most common adverse events. Overall response rate defined as partial or complete response after two initial cycles of VIT was 50%. For local control, all patients had surgical resection followed by radiotherapy, and two patients received hyperthermic intraperitoneal chemotherapy at the time of surgery. Of the four patients who have completed therapy to date, three remain disease-free with median follow-up time of 46.7 months. Conclusions The addition of VIT to interval-compressed chemotherapy is tolerable and active in DSRCT, with activity warranting additional investigation.

Background The purpose was to examine associations between treatment and chronic health conditions with neurocognitive impairment survivors of acute lymphoblastic leukemia (ALL) treated with chemotherapy only. Methods This cross-sectional study included 1207 ALL survivors (54.0% female; mean age 30.6 years) and 2273 siblings (56.9% female; mean age 47.6 years), who completed the Childhood Cancer Survivor Study Neurocognitive Questionnaire. Multivariable logistic regression compared prevalence of neurocognitive impairment between survivors and siblings by sex. Associations between neurocognitive impairment with treatment exposures and chronic conditions (graded according to Common Terminology Criteria for Adverse Events) were also examined. Statistical tests were 2-sided. Results Relative to same-sex siblings, male and female ALL survivors reported increased prevalence of impaired task efficiency (males: 11.7% vs 16.9%; adjusted odds ratio [OR] = 1.89, 95% confidence interval [CI] = 1.31 to 2.74; females: 12.5% vs 17.6%; OR = 1.50, 95% CI = 1.07 to 2.14), as well as impaired memory (males: 11.6% vs 19.9%, OR = 1.89, CI = 1.31 to 2.74; females: 14.78% vs 25.4%, OR = 1.96, 95% CI = 1.43 to 2.70, respectively). Among male survivors, impaired task efficiency was associated with 2-4 neurologic conditions (OR = 4.33, 95% CI = 1.76 to 10.68) and with pulmonary conditions (OR = 4.99, 95% CI = 1.51 to 16.50), and impaired memory was associated with increased cumulative dose of intrathecal methotrexate (OR = 1.68, 95% CI = 1.16 to 2.46) and with exposure to dexamethasone (OR = 2.44, 95% CI = 1.19 to 5.01). In female survivors, grade 2-4 endocrine conditions were associated with higher risk of impaired task efficiency (OR = 2.19, 95% CI = 1.20 to 3.97) and memory (OR = 2.26, 95% CI = 1.31 to 3.92). Conclusion Neurocognitive impairment is associated with methotrexate, dexamethasone, and chronic health conditions in a sex-specific manner, highlighting the need to investigate physiological mechanisms and monitor impact through survivorship.

Incremental improvements in the treatment of children and adolescents with cancer have led to 5-year survival rates reaching nearly 85%. In the past decade, impressive progress has been made in understanding the biology of many pediatric cancers. With that understanding, multiple new agents have become available that offer the promise of more-effective and less-toxic treatment. These include agents that target various cell surface antigens and engage the adaptive immune system, as well as those that interfere with key signaling pathways involved in tumor development and growth. For local control, surgery and radiation techniques also have evolved, becoming less invasive or featuring new techniques and particles that more precisely target the tumor and limit the dose to normal tissue. Nevertheless, targeted agents, like conventional chemotherapy, radiotherapy, and surgery, may have off-target effects and deserve long-term follow-up of their safety and efficacy. These include injury to the endocrine, cardiovascular, and immunologic systems. New radiation and surgical techniques that theoretically reduce morbidity and improve long-term quality of life must also be validated with actual patient outcomes. Finally, with advances in genomics, information on host susceptibility to late effects is beginning to emerge. Such knowledge, coupled with improved metrics that better describe the spectrum of potential late effects across the entire lifespan, can lead to the development of decision models that project the potential long-term health outcomes associated with various treatment and follow-up strategies. These developments will help extend the current focus on precision medicine to precision survivorship, where clinicians, patients, and families will have a better grasp of the potential risks, benefits, and tradeoffs associated with the growing number of cancer treatment options.

Purpose Outcomes associated with primary laparoscopic gastrojejunal (GJ) tube placement in the pediatric population were evaluated. Methods A single-institution, retrospective review examined patients undergoing laparoscopic GJ tube placement between June 2011 and December 2014. Outcomes included gastric feeding tolerance, subsequent fundoplication, complications, and mortality. Results Ninety laparoscopic GJ tubes were placed. Median follow-up was 342days (interquartile range [IQR]=141–561days). Median patient age was 5months (IQR=3–11months) and weight was 5.2kg (IQR=4–8.4kg). The most common indications for placement were gastroesophageal reflux (n=85, 94.4%) and/or aspiration (n=40, 44.4%). Most common comorbidities included cardiac (n=34, 37.8%) and respiratory (n=29, 32.2%) diseases. The complication rate was 17.8%, including one case of intestinal perforation. Thirty-four (37.7%) patients transitioned to gastric feeding within 1year; time to conversion was 156days (IQR=117–210days); of those, 18.9% patients transitioned to oral feedings. A fundoplication was later performed in 4 children for persistent reflux. Mortality was 23.3% with no procedural-related deaths. Conclusion Primary laparoscopically placed GJ tubes are a reliable means of enteral access for pediatric patients with gastric feeding intolerance. Many of these children are successfully transitioned to gastric and/or oral feedings over time. Further studies are needed to characterize which patients are best served with a GJ tube versus alternatives such as fundoplication. Level of evidence III (treatment) Type of study Retrospective

The role of thymectomy in the treatment of juvenile myasthenia gravis (JMG) is poorly defined. The objective of this systematic review was to evaluate the effect of thymectomy on survival, disease severity, and peri-operative complications for patients with JMG. A search of MEDLINE, EMBASE, and the Cochrane Library (1/1/2000–3/1/2016) identified all English language, human studies of thymectomy for JMG. The population was patients with JMG age ≤18 years who underwent thymectomy (comparator group was unexposed to thymectomy). Outcomes included survival, disease severity, and post-operative complications. Data extraction was performed by independent reviewers. Sixteen retrospective studies included 1131 participants with JMG and 488 (43%) underwent thymectomy. Post-operative improvement in JMG severity occurred for 77% (n = 376/488). Comparisons of thymectomy to non-operative management were mixed. Post-operative complications were poorly recorded. Power to compare surgical approaches was limited. Outcomes specific to antibodies, surgical pathology findings, severity of JMG, and timing of thymectomy were sparse. Existing data regarding thymectomy for JMG are limited and entirely retrospective. The majority of patients who underwent thymectomy had improvement in disease severity and post-operative complications were rare. Prospective, multicenter study of thymectomy for JMG is warranted.

Background Given the rarity of pediatric surgical disease, it is important to consider available large-scale data resources as a means to better study and understand relevant disease-processes and their treatments. The Military Health System Data Repository (MDR) includes claims-based information for > 3 million pediatric patients who are dependents of members and retirees of the United States Armed Services, but has not been externally validated. We hypothesized that demographics and selected outcome metrics would be similar between MDR and the previously validated American College of Surgeons National Surgical Quality Improvement Program-Pediatric (NSQIP-P) for several common pediatric surgical operations. Methods We selected five commonly performed pediatric surgical operations: appendectomy, pyeloplasty, pyloromyotomy, spinal arthrodesis for scoliosis, and facial reconstruction for cleft palate. Among children who underwent these operations, we compared demographics (age, sex, and race) and clinical outcomes (length of hospital stay [LOS] and mortality) in the MDR and NSQIP-P, including all available overlapping years (2012–2014). Results Age, sex, and race were generally similar between the NSQIP-P and MDR. Specifically, these demographics were generally similar between the resources for appendectomy (NSQIP-P, n = 20,602 vs. MDR, n = 4363; median age 11 vs. 12 years; female 40% vs. 41%; white 75% vs. 84%), pyeloplasty (NSQIP-P, n = 786 vs. MDR, n = 112; median age 0.9 vs. 2 years; female 28% vs. 28%; white 71% vs. 80%), pyloromyotomy, (NSQIP-P, n = 3827 vs. MDR, n = 227; median age 34 vs. n = 5743 vs. MDR, n = 95; median age 14.2 vs. 14 years; female 75% vs. 67%; white 72% vs. 75%), and cleft lip/palate repair (NSQIP-P, n = 6202 vs. MDR, n = 749; median age, 1 vs. 1 year; female 42% vs. 45%; white 69% vs. 84%). Length of stay and 30-day mortality were similar between resources. LOS and 30-day mortality were also similar between datasets. Conclusion For the selected common pediatric surgical operations, patients included in the MDR were comparable to those included in the validated NSQIP-P. The MDR may comprise a valuable clinical outcomes research resource, especially for studying infrequent diseases with follow-up beyond the 30-day peri-operative period.

Background The prevalence and associated psychosocial morbidity of late-onset anorectal disease after surgery and radiotherapy for the treatment of childhood cancer are not known. Methods A total of 25,530 survivors diagnosed between 1970 and 1999 (median age at cancer diagnosis, 6.1 years; age at survey, 30.2 years) and 5036 siblings were evaluated for late-onset anorectal disease, which was defined as a self-reported fistula-in-ano, self-reported anorectal stricture, or pathology- or medical record-confirmed anorectal subsequent malignant neoplasm (SMN) 5 or more years after the primary cancer diagnosis. Piecewise exponential models compared the survivors and siblings and examined associations between cancer treatments and late-onset anorectal disease. Multiple logistic regression with generalized estimating equations was used to evaluate associations between late-onset anorectal disease and emotional distress, as defined by the Brief Symptom Inventory 18 (BSI-18), and health-related quality of life, as defined by the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36). Results By 45 years after the diagnosis, 394 survivors (fistula, n = 291; stricture, n = 116; anorectal SMN, n = 26) and 84 siblings (fistula, n = 73; stricture, n = 23; anorectal neoplasm, n = 1) had developed late-onset anorectal disease (adjusted rate ratio [RR] for survivors vs siblings, 1.2; 95% confidence interval [CI], 1.0-1.5). Among survivors, pelvic radiotherapy with ≥30 Gy within 5 years of the cancer diagnosis was associated with late-onset anorectal disease (adjusted RR for 30-49.9 Gy vs none, 1.6; 95% CI, 1.1-2.3; adjusted RR for ≥50 Gy vs none, 5.4; 95% CI, 3.1-9.2). Late-onset anorectal disease was associated with psychosocial impairment in all BSI-18 and SF-36 domains. Conclusions Late-onset anorectal disease was more common among childhood cancer survivors who received higher doses of pelvic radiotherapy and was associated with substantial psychosocial morbidity.

To describe variability in and consequences of opioid prescriptions following pediatric laparoscopic appendectomy.Postoperative opioid prescribing patterns may contribute to persistent opioid use in both adults and children.We included children18 years enrolled as dependents in the Military Health System Data Repository who underwent uncomplicated laparoscopic appendectomy (2006-2014). For the primary outcome of days of opioids prescribed, we evaluated associations with discharging service, standardized to the distribution of baseline covariates. Secondary outcomes included refill, Emergency Department (ED) visit for constipation, and ED visit for pain.Among 6732 children, 68% were prescribed opioids (range = 1-65 d, median = 4 d, IQR = 3-5 d). Patients discharged by general surgery services were prescribed 1.23 (95% CI = 1.06-1.42) excess days of opioids, compared with those discharged by pediatric surgery services. Risk of ED visit for constipation (n = 61, 1%) was increased with opioid prescription [1-3 d, risk ratio (RR) = 2.46, 95% CI = 1.31-5.78; 4-6 d, RR = 1.89, 95% CI = 0.83-4.67; 7-14 d, RR = 3.75, 95% CI = 1.38-9.44;14 d, RR = 6.27, 95% CI = 1.23-19.68], compared with no opioid prescription. There was similar or increased risk of ED visit for pain (n = 319, 5%) with opioid prescription [1-3 d, RR = 1.00, 95% confidence interval (CI) = 0.74-1.32; 4-6 d, RR = 1.31, 95% CI = 0.99-1.73; 7-14 d, RR = 1.52, 95% CI = 1.00-2.18], compared with no opioid prescription. Likewise, need for refill (n = 157, 3%) was not associated with initial days of opioid prescribed (reference 1-3 d; 4-6 d, RR = 0.96, 95% CI = 0.68-1.35; 7-14 d, RR = 0.91, 95% CI = 0.49-1.46; and14 d, RR = 1.22, 95% CI = 0.59-2.07).There was substantial variation in opioid prescribing patterns. Opioid prescription duration increased risk of ED visits for constipation, but not for pain or refill.

10047 Background: Kidney failure (need for dialysis or kidney transplantation, or death due to kidney disease) is a rare but serious late effect for survivors of childhood cancer. We aimed to develop a model using demographic and treatment characteristics to predict individual risk of kidney failure among five-year survivors of childhood cancer. Methods: CCSS survivors without kidney failure at five years after cancer diagnosis (n = 25,483) were assessed for subsequent kidney failure by age 40. Outcomes were self-reported and corroborated by the Organ Procurement and Transplantation Network and the National Death Index. A sibling cohort (n = 5045) served as a comparator. Piecewise exponential models with backward selection estimated the relationships between potential predictors and kidney failure and were converted to integer risk scores. Additional results from the St. Jude Lifetime Cohort Study (SJLIFE, n = 2490) and the National Wilms Tumor Study (NWTS, n = 6760) validated the models. Results: Among CCSS survivors, 204 developed late kidney failure. We developed a model with sex, race/ethnicity, age at cancer diagnosis, nephrectomy, exposure to specific chemotherapy, any abdominal radiation, presence of genitourinary anomalies, and early-onset hypertension (Table). Risk scores achieved an area under the curve (AUC) and concordance (C) statistic of 0.65 and 0.68 for kidney failure by age 40. Validation cohort AUC and C statistics were 0.83/0.86 for SJLIFE (8 cases) and 0.61/0.63 for NWTS (91 cases). An alternative model with specific chemotherapy doses and kidney-specific radiation dosimetry had similar AUC and C statistic (0.67/0.70). Integer risk scores were collapsed to form statistically distinct low (score

Purpose The current emphasis on fiscally responsible health spending in the era of the Affordable Care Act and other health care reform necessitates cost-conscious delivery of care. "Value" in health care is defined as the quality of care divided by the cost. As such, health systems optimize value by providing the most cost-effective care possible without sacrificing safety or outcomes. Elective, minimal risk surgical procedures in children may be value-enhanced by moving from an operating room (OR) to a more cost-efficient setting. The purpose of this study was to assess the safety and cost of performing the removal of implantable central venous access devices ("ports") in locations other than the main OR. Methods We compared port removal at three sites: 1. Main OR, 2. Satellite OR, and 3. Clinic Procedure Room. This was a mixed-methods study including a retrospective review of medical records and prospective observation/interviewing. To calculate cost without the inherent biases of hospital charges, costs, and payments, we utilized the methodology of time-driven activity based costing. Specifically, we recorded time spent by the patient in hospital facilities and with health care personnel. This duration was then weighted with the hourly cost of each health care professional and hospital space. The Mann–Whitney U test compared time and cost across the three sites. Overall cost at each site was divided by overall cost at the referent site (Main OR) to obtain a ratio of cost savings. Results A total of 120 patients (40 per site) were included in the analysis. Demographic and clinical factors were not significantly different between sites. No complication occurred with port removal at any site. Time of the entire care episode was significantly decreased in the Clinic (median 161min, 95% confidence interval [CI] 134–188min), compared to the Main OR (median 235min, 95% confidence interval [CI] 209–251min) or Satellite OR (median 228min, 95% confidence interval [CI] 211–245min). Overall cost was decreased by 25% (95% CI: 13–34%) at the Clinic and by 6% (95% CI: −2–11%) at the Satellite OR, compared to the Main OR (referent, P Conclusion In our study, port removal in the Clinic Procedure Room was not associated with increased risk of negative outcomes. Shifting port removal from the Main OR to the Clinic may result in substantial cost savings.

10553 Background: Refinement in risk stratification has led to intensification of therapy for Wilms tumor (WT) patients with adverse prognostic factors. Chronic health conditions (CHCs) including cardiac conditions, subsequent malignant neoplasms (SMNs), and late mortality are known risks for WT survivors, however the impact of specific treatment regimens on these outcomes is largely unknown. Methods: Late mortality (all-cause and non-recurrence death > 5 years from diagnosis), SMNs, and severity-graded CHCs (2 = moderate, 3 = severe, 4 = life-threatening, 5 = fatal) were assessed in 5-year WT survivors in the Childhood Cancer Survivor Study diagnosed from 1970-99. Survivors were categorized according to therapy received (Table). Cumulative incidence of mortality and standard mortality ratios (SMR) were estimated. Piecewise exponential models estimated rate ratios (RR) with 95% confidence intervals (CI). Results: Among 1507 survivors (median age at follow-up 26 yrs; range 6-55), 35-year cumulative incidence of all-cause mortality was 7.9% (SMR 2.9, CI 2.3-3.6) and 5.1% (SMR 1.9, CI 1.4-2.4) for non-recurrence mortality. RRs for developing any grade 2-5 CHC, grade 3-5 SMN, and grade 2-5 cardiac CHCs were higher for survivors compared to sibling controls (2.0, CI 1.8-2.3; 7.4, CI 5.0-10.8; 2.6, CI 2.2-3.1, respectively). Compared with VA and no RT, RR for non-recurrence late mortality and CHCs among survivors were higher for VAD + any RT, and for ≥ 4 drugs + any RT (Table). Conclusions: Administering increased-intensity therapy for WT is associated with increased late health consequences and non-recurrence late mortality, necessitating strategies to monitor and improve long-term health among survivors. [Table: see text]

Purpose To estimate the incidence of late-occurring venous thromboembolism (VTE) among survivors of childhood cancer and to identify risk factors for VTE to facilitate diagnosis and prevention. Methods The Childhood Cancer Survivor Study is a multi-institutional cohort of 24,355 5-year childhood cancer survivors (diagnosed between 1970 and 1999; median age at last follow-up, 28.7 years [range, 5.6 to 58.9 years]; median follow-up since diagnosis, 21.3 years [range, 5.0 to 39.2 years]) and 5,051 sibling participants. The primary end point was self-reported late (≥ 5 years after cancer diagnosis) VTE. Rate ratios (RRs) were estimated with multivariable piecewise exponential models. Results Late VTE incidence among survivors and siblings was 1.1 and 0.5 events per 1,000 person-years, respectively (RR, 2.2; 95% CI, 1.7 to 2.8), with 2.5 excess events per 100 survivors over 35 years. Among survivors, risk factors for VTE were female sex (RR, 1.3; 95% CI, 1.1 to 1.6), cisplatin (reference none; 1 to 199 mg/m2: RR, 3.0 [95% CI, 1.4 to 6.5]; 200 to 399 mg/m2: RR, 1.9 [95% CI, 1.0 to 3.6]; ≥ 400 mg/m2: RR, 2.0 [95% CI, 1.2 to 3.3]), l-asparaginase (RR, 1.3; 95% CI, 1.0 to 1.7), obesity or underweight (reference body mass index [BMI] 18.5 to 24.9 kg/m2; BMI ≥ 30.0 kg/m2: RR, 1.6 [95% CI, 1.2 to 2.0]; BMI < 18.5 kg/m2: RR, 2.4 [95% CI, 1.7 to 3.4]), and late cancer recurrence or subsequent malignant neoplasm (RR, 4.6; 95% CI, 3.6 to 5.8). Among lower-extremity osteosarcoma survivors, limb salvage (reference amputation; RR, 3.1; 95% CI, 1.2 to 7.5) and cisplatin 200 to 399 or ≥ 400 mg/m2 (reference none; RR, 4.0 [95% CI, 1.1 to 14.6] and 2.9 [95% CI, 1.1 to 8.0], respectively) were independently associated with late VTE. VTE was associated with increased risk for nonexternal cause late mortality (RR, 1.9; 95% CI, 1.6 to 2.3). Conclusion Childhood cancer survivors are at increased risk for VTE across their lifespan and a diagnosis of VTE increases mortality risk. Interventions that target potentially modifiable comorbidities, such as obesity, warrant consideration, with prophylaxis for high-risk survivors, including those treated with cisplatin and limb-sparing approaches.

The purpose of this study was to develop a pre-operative risk assessment tool for childhood and adolescent ovarian malignancy, in order to guide operative management of pediatric ovarian masses.We conducted a retrospective analysis of patients18 years old who underwent ovarian surgery at two quaternary care pediatric centers over 4 years (1/1/13-12/31/16). Probability of malignancy was estimated based on imaging characteristics (simple cyst, heterogeneous, or solid), maximal diameter, and tumor markers (α-fetoprotein, β-human chorionic gonadotropin).Among 188 children with ovarian masses, 11% had malignancies. For simple cysts, there were no malignancies (0/24, 95% CI = 0-17%). Among solid lesions, 44% (15/34, 95% CI = 28-62%) were malignant. Among marker-elevated heterogeneous masses, 40% (2/5, 95% CI = 12-77%) were malignant. Conversely, small (≤10 cm) and large (10 cm) marker-negative heterogeneous lesions had malignancy proportions of 0% (0/39, 95% CI = 0-11%) and 5% (2/40, 95% CI = 1-18%), respectively.Given the malignancy estimates identified from these multi-institutional data, we recommend an attempt at ovarian-sparing resection for simple cysts or tumor marker-negative heterogeneous lesions ≤10 cm. Oophorectomy is recommended for solid masses or heterogeneous lesions with elevated markers. Finally, large (10 cm) heterogeneous masses with non-elevated markers warrant a careful discussion of ovarian-sparing techniques. Complete surgical staging is mandatory regardless of operative procedure.Study of Diagnostic Test.Level I.

Neuroblastoma is an embryonic cancer arising from neural crest stem cells. This cancer is the most common malignancy in infants and the most common extracranial solid tumor in children. The clinical course may be highly variable with the possibility of spontaneous regression in the youngest patients and increased risk of aggressive disease in older children. Clinical heterogeneity is a consequence of the diverse biologic characteristics that determine patient risk and survival. This review will focus on current progress in neuroblastoma staging, risk stratification, and treatment strategies based on advancing knowledge in tumor biology and genetic characterization. TYPE OF STUDY: Review article. LEVEL OF EVIDENCE: Level II.

Background Children who have undergone splenectomy may develop impaired immunologic function and heightened risk of overwhelming postsplenectomy infection. We sought to define the long-term rate of and risk factors for postsplenectomy sepsis. Methods We leveraged the Military Health System Data Repository, a nationally representative claims database including > 3 million children registered as dependents of members of the United States Armed Services (2005–2014). Inclusion criterion was splenectomy at age 18 years or prior. The primary outcome was hospitalization for sepsis. Results Among 195 children who underwent splenectomy, 7% (n = 13) were hospitalized with sepsis, with an incidence of 1.8 (95% CI = 1.0-3.1) events per 100 person-years. The median time to sepsis was 224 days (IQR = 109–606) and 38% (5/13) of events occurred within the first postsplenectomy year. The postsplenectomy mortality rate was 1% (n = 3). After adjusting for underlying diagnosis, older age at splenectomy (HR = 0.90 per year, 95% CI = 0.81–0.99) was associated with decreased hazard of sepsis. Conclusions In a contemporary national cohort, the prevalence of postsplenectomy sepsis was 7% (1.8 events per 100 person-years). Although most presented during the first year after splenectomy, many (62%) sepsis events occurred later, suggesting that postsplenectomy immunologic dysfunction persists beyond one year. The immunologic consequences of asplenia must continue to be acknowledged, as postsplenectomy sepsis remains a serious concern. Type of Study Prognosis study. Level of Evidence Level III.

We sought to determine the incidence and timing of testicular atrophy following inguinal hernia repair in children. We used the TRICARE database, which tracks care delivered to active and retired members of the US Armed Forces and their dependents, including > 3 million children. We abstracted data on male children

We aimed to describe the incidence, timing, and predictors of recurrence following inguinal hernia repair (IHR) in children.We used the TRICARE claims database, a national cohort of3 million child dependents of members of the U.S. Armed Forces. We abstracted data on children12y who underwent IHR (2005-2014). Our primary outcome was recurrence (ICD9-CM diagnosis codes). We calculated incidence rates for the population and stratified by age, time from repair to recurrence, and multivariable logistic regression to determine predictors.Nine thousand nine hundred ninety-three children met inclusion criteria. Age at time of IHR was ≤1y in 37%, 2-3y in 23%, 4-5y in 16%, and 5-12y in 24%. Median follow-up time was 3.5y (IQR:1.6-6.1). 137 patients recurred (1.4%), with an incidence of 3.46 per 1000 person-years. Over half occurred in children 0-1y at repair (60%). The majority occurred within a year following repair (median 209 days [IQR:79-486]). Children 0-1y had 2.53 times greater odds of recurrence (compared to5y). Children with multiple comorbidities had 5.45 times greater odds compared to those with no comorbidities.The incidence of recurrence following IHR is 3.46 per 1000 person-years. The majority occurred within a year of repair. Children ≤1y and those with multiple comorbidities were at increased risk.Prognosis Study, Level II.

Autoamputation of the appendix has previously been reported in the literature, but it is likely an unusual event. We report a 2-year-old male child who had previously undergone laparotomy and bowel resection for necrotizing enterocolitis. Two years later a calcified intra-abdominal mass was identified on abdominal radiography and ultrasonography. Eventual laparotomy revealed a densely calcified mass within the transverse mesocolon. The mass was uneventfully resected. Pathologic evaluation showed appendiceal tissue, consistent with prior autoamputation of the vermiform appendix. Autoamputation of the appendix has not to our knowledge previously been associated with a calcified mass nor been associated with a history of necrotizing enterocolitis, and these factors distinguish this case as noteworthy.

e21525 Background: Cholecystectomy (CCY) is among the most common operations performed in the developed world and is offered as a cure for symptomatic gallbladder disease. Whether survivors of childhood cancer undergo CCY at a higher rate than the general population is unknown. Methods: We identified 5-year survivors diagnosed between 1970 and 1999 who self-reported late (> 5 years after cancer diagnosis) CCY. Rates of CCY were determined among the entire cohort and in association with various risk factors and treatment exposures. Adjusted rate ratios (ARR) were estimated with multivariable piecewise exponential models. Results: Among 24,248 survivors (median follow-up 22.3, interquartile range [IQR] 16.2-30.1 years) and 5,038 siblings (median follow-up 26.4, IQR 19.3-33.7 years), the unadjusted cumulative incidence of CCY at age 50 was 7.2% (n = 757) in survivors and 6.5% (n = 168) in siblings. After adjusting for age, sex and race/ethnicity, survivors underwent CCY at higher rates compared to siblings (ARR = 1.3, 95% CI = 1.1-1.5). Relative to siblings, acute lymphoblastic leukemia survivors underwent CCY at a higher rate (ARR = 1.6, 95% CI = 1.3-2.0), all other diagnoses were not independently associated with higher rates of CCY. Among survivors, risk factors for late CCY included female sex, increasing body mass index (BMI) class, exposure to platinum agents and total body irradiation (TBI) (Table). Conclusions: CCY is performed more commonly among childhood cancer survivors relative to siblings. In addition to known risk factors for gallbladder disease, cancer treatment exposures may further enhance risk for CCY. Awareness and education regarding this observation may ensure timely diagnosis and treatment of symptomatic disease. [Table: see text]

Background Neonatal mesenchymal stem cells exhibit less cardioprotective potential than their adult counterparts. Transforming growth factor-α (TGF-α) has been shown to stimulate adult stem cell VEGF production, however, it remains unknown whether it may augment neonatal stem cell paracrine function. We hypothesized that TGF-α would equalize adult and neonatal stem cell paracrine function and cardioprotection during acute ischemia/reperfusion. Materials and Methods Bone marrow mesenchymal stem cells isolated from adult and 2.5 wk-old mice were treated with TGF-α (250 ng/mL) for 24 h. VEGF, HGF, IGF-1, IL-1β, and IL-6 production were measure in vitro , and cells were infused via an intracoronary route using a model of isolated heart perfusion. Results TGF-α equalized adult and neonatal stem cell VEGF production but did not affect production of HGF, IGF-1, IL-1β, or IL-6. ERK, p38 MAPK, and JNK phosphorylation were greater in adult cells in response to TGF-α. Whereas infusion of adult but not neonatal stem cells was associated with improved myocardial functional recovery during reperfusion, infusions of either TGF-α-pretreated cell group were associated with the greatest functional recovery. TGF-α equalizes adult and neonatal mesenchymal stem cell VEGF production and cardioprotection in association with differential regulation of ERK, p38 MAPK, and JNK phosphorylation.

Background Mesenchymal stem cells (MSCs) improve postischemic myocardial function in part through their secretion of growth factors such as vascular endothelial growth factor (VEGF). Pretreating MSCs with various cytokines or small molecules can improve VEGF secretion and MSC-mediated cardioprotection. However, whether 1 cytokine can potentiate the effect of another cytokine in MSC pretreatment to achieve a synergistic effect on VEGF production and cardioprotection is poorly studied. Methods MSCs were treated with interleukin (IL)-1β and/or transforming growth factor (TGF)-β1 for 24 hours before experiments. VEGF production was determined by enzyme-linked immunosorbent assay. Isolated hearts from adult male Sprague-Dawley rats were subjected to 15 minutes of equilibration, 25 minutes of ischemia, and 40 minutes reperfusion. Hearts ( n = 5–7 per group) were randomly infused with vehicle, untreated MSCs, or MSCs pretreated with IL-1β and/or TGF-β1. Specific inhibitors were used to delineate the roles of p38 mitogen-activated protein kinase (MAPK) and SMAD3 in IL-1β– and TGF-β1–mediated stimulation of MSCs. Results MSCs cotreated with IL-1β and TGF-β1 exhibited synergistically increased VEGF secretion, and they greatly improved postischemic myocardial functional recovery. Ablation of p38 MAPK and SMAD3 activation with specific inhibitors negated both IL-1β– and TGF-β1–mediated VEGF production in MSCs and the ability of these pretreated MSCs to improve myocardial recovery after ischemia. Conclusion Pretreating MSCs with 2 cytokines may be useful to fully realize the potential of cell-based therapies for ischemic tissues.

Background Many but not all studies suggest that a favorable response to preoperative steroid therapy predicts a successful outcome after splenectomy in children with immune thrombocytopenic purpura (ITP). The purpose of this study is to further examine the relationship between steroid response and outcome after splenectomy in children. Methods After institutional review board approval, records of children undergoing splenectomy for ITP were reviewed. Patients’ responses were determined by platelet counts and grouped by complete response (CR; ≥150,000/μL), partial response (PR; 149,999– ≥50,000/μL), or no response (NR; Results Thirty-seven children were identified. After steroid therapy, 20 patients (54%) had CR, 9 (24%) had PR, and 8 (22%) had NR. After splenectomy, 31 patients (84%) had CR, 6 (16%) had PR, and 0 had NR. Of the 20 patients that had a CR to steroid therapy, 18 (80%) had CR and 2 (20%) had PR to splenectomy. Of the 9 patients that had PR to steroids, 7 (78%) had CR to splenectomy and 2 (22%) had PR. Of the 8 patients that had NR to steroids, 6 (75%) had CR and 2 (25%) had PR to splenectomy. Response to splenectomy was not associated with response to steroids ( P = .59). Conclusion These data suggest that response to splenectomy in children with ITP is unrelated to previous response to steroids.

Background Cardiac surgery induces the release of inflammatory mediators that can prolong cardiac dysfunction after operative intervention. Interleukin-10 (IL-10), a potent inhibitor of myocardial inflammation, is a known factor in myocardial protection after ischemia/reperfusion (I/R) injury. We hypothesized that IL-10 activity during initial reperfusion is mediated through the signal transducer and activator of transcription 3 (STAT3) pathway. Methods Adult rat hearts were isolated and perfused via Langendorff protocol and subjected to global I/R. After determining the effective IL-10 dose, hearts were administered vehicle, IL-10, or IL-10 + Stattic (specific STAT3 inhibitor) 1 min prior to ischemia. After reperfusion, hearts were sectioned and assessed for levels of myocardial inflammatory cytokines and protein. Results The IL-10 minimum effective dose was 1 μg. IL-10-treated hearts had improved markedly myocardial function after global I/R compared to both vehicle and IL-10 + Stattic groups. In addition, IL-10 treatment was associated with a significant decrease in myocardial interleukin-1β (IL-1β) and interleukin-6 (IL-6) and increase in myocardial IL-10. Myocardial STAT3 was elevated markedly in IL-10 treated hearts. Conclusion IL-10 improves myocardial function after acute global I/R and suppresses inflammation through the STAT3 pathway. The administration of anti-inflammatory agents may have potential therapeutic applications in cardiac surgery.

Mesenchymal stem cells (MSCs) protect ischemic tissues in part through paracrine growth factor production. IL-6, which is upregulated in the heart during ischemia, has been shown to enhance stem cell proliferation and migration. The effect of IL-6 on MSC paracrine function, however, remains unknown. In addition, TGF-α increases MSC vascular endothelial growth factor (VEGF) production and may share downstream signaling pathways with IL-6 involving ERK, JNK, and PI3K. We hypothesize that cotreatment with IL-6 and TGF-α will result in greater MSC VEGF production than by either treatment alone via these signaling pathways. Murine MSCs were treated with IL-6 (0.05 ng/mL) with or without TGF-α (250 ng/mL) and in combination with inhibitors of ERKI/II, JNK, and PI3K for 24 h. Vascular endothelial growth factor concentrations in the supernatants were measured using enzyme-linked immunosorbent assay. Phosphorylation of ERK, JNK, and PI3K was measured using Western blot analysis. IL-6 increased MSC VEGF production at a dose of 0.05 ng/mL, and the combination of IL-6 and TGF-α (250 ng/mL) increased VEGF production to a greater extent than IL-6 or TGF-α alone. IL-6 induced phosphorylation of ERK, JNK, and PI3K, and inhibition of each suppressed IL-6-induced VEGF production. TGF-α cotreatment overcame VEGF suppression after ERK2 inhibition but not ERK1, JNK, or PI3K. These data suggest that IL-6 stimulates MSC VEGF production alone and additively with TGF-α via ERK-, JNK-, and PI3K-mediated mechanisms. IL-6 and TGF-α cotreatment may be a useful strategy for enhancing MSC VEGF production and cardioprotection during myocardial ischemia.

Mesenchymal stem cells (MSCs) have been used experimentally and clinically in the treatment of a wide variety of pathologies. It is now clear that a number of different mechanisms contribute to the therapeutic effects exerted by these cells. The ability of MSCs to interact with and modulate the functions of a wide variety of immune cells has been recognized as one such mechanism. The implications that the immunomodulatory properties of MSCs may have for the treatment of solid organ rejection, the Systemic Inflammatory Response Syndrome, cancer, and Crohn’s disease are reviewed herein.

Background Stem cell-based therapies for myocardial ischemia have demonstrated promising early clinical results, but their benefits have been limited in duration due to impaired donor cell engraftment and function. Several strategies have emerged for enhancing stem cell function prior to their therapeutic use particularly with regard to stem cell homing, paracrine function, and survival. This review discusses current understandings of stem cell-mediated cardioprotection as well as methods of enhancing post-transplantation stem cell function and survival through hypoxic preconditioning, genetic manipulation, and pharmacologic pretreatment. Materials and Methods A literature search was performed using the MEDLINE and PubMed databases using the keywords “stem cell therapy,” “myocardial ischemia,” “hypoxic preconditioning,” “paracrine function,” and “stem cell pretreatment.” Studies published in English since January 1990 were selected. In addition, studies were identified from references cited in publications found using the search terms. Results All included studies utilized animal studies and/or in vitro techniques. Stem cell modifications generally targeted stem cell homing (SDF-1, CXCR4), paracrine function (VEGF, angiogenin, Ang-1, HGF, IL-18 binding protein, TNFR1/2), or survival (Akt, Bcl-2, Hsp20, HO-1, FGF-2). However, individual modifications commonly exhibited pleiotropic effects involving some or all of these general categories. Conclusion These strategies for optimizing stem cell-mediated cardioprotection present unique potential sets of advantages and disadvantages for clinical application. Additional questions remain including those that are most efficacious in terms of magnitude and duration of benefit as well as whether combinations may yield greater benefits in both the preclinical and clinical settings.

Toll-like receptors (TLRs) play a key role in innate immune defenses. After activation by foreign pathogens or host-derived molecules, TLRs signal via overlapping or distinct signaling cascades and eventually induce numerous genes involved in a variety of cellular responses. A growing body of evidence suggests that TLR signaling also plays an important role in cardiac ischemia/reperfusion injury. We review our current understanding of the TLR signaling pathways and their roles in the pathophysiology of cardiac ischemia/reperfusion injury, as well as discuss several mechanisms for TLR activation and regulation.