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Background: Image-defined risk factors (IDRFs) were promulgated for predicting the feasibility and safety of complete primary tumor resection in children with neuroblastoma (NB). There is limited understanding of the impact of individual IDRFs on resectability of the primary tumor or patient outcomes. A multicenter database of patients with high-risk NB was interrogated to answer this question., Design/methods: Patients with high-risk NB (age <20 years) were eligible if cross-sectional imaging was performed at least twice prior to resection. IDRFs and primary tumor measurements were recorded for each imaging study. Extent of resection was determined from operative reports., Results: There were 211 of 229 patients with IDRFs at diagnosis, and 171 patients with IDRFs present pre-surgery. A ≥90% resection was significantly more likely in the absence of tumor invading or encasing the porta hepatis, hepatoduodenal ligament, superior mesenteric artery (SMA), renal pedicles, abdominal aorta/inferior vena cava (IVC), iliac vessels, and/or diaphragm at diagnosis or an overlapping subset of IDRFs (except diaphragm) at pre-surgery. There were no significant differences in event-free survival (EFS) and overall survival (OS) when patients were stratified by the presence versus absence of any IDRF either at diagnosis or pre-surgery., Conclusion: Two distinct but overlapping subsets of IDRFs present either at diagnosis or after induction chemotherapy significantly influence the probability of a complete resection in children with high-risk NB. The presence of IDRFs was not associated with significant differences in OS or EFS in this cohort., (© 2024 Wiley Periodicals LLC.)

Background: The International Neuroblastoma Risk Group (INRG) classifier utilizes a staging system based on pretreatment imaging criteria in which image-defined risk factors (IDRFs) are used to evaluate the extent of locoregional disease. Children's Oncology Group (COG) study ANBL0531 prospectively examined institutional determination of IDRF status and compared that to a standardized central review., Methods: Between 9/2009-6/2011, patients with intermediate-risk neuroblastoma were enrolled on ANBL0531 and had IDRF assessment at treating institutions. Paired COG pediatric surgeons and radiologists performed blinded central review of diagnostic imaging for the presence or absence of IDRFs. Second blinded review was performed in cases of discordance. Comparison of local and central review was performed using the Kappa coefficient to determine concordance in IDRF assessment., Results: 211 patients enrolled in ANBL0531 underwent IDRF assessment; 3 patients were excluded due to poor image quality. Central reviewer pairs agreed on the presence or absence of any IDRF in 170/208 (81.7%; κ = 0.48) cases. Thirteen (6.3%) cases could not be adjudicated after second blinded review. Radiologists were more likely to identify IRDFs as present than surgeons (p < 0.001). Local and central reviewers agreed on the presence or absence of any IDRF in only108/208 (51.9%; κ = 0.06) cases., Conclusions: Among experienced pediatric surgeons and radiologists participating in central review, concordance was moderate, with agreement in 81.7% of cases. On comparison of local and central assessment of IDRFs, concordance was poor. These data indicate that greater standardization, education, technology, and training are needed to improve the assessment of IDRFs in children with neuroblastoma., Level of Evidence: Treatment Study, Level III., Competing Interests: Conflict of interset Author AN serves on a data safety monitoring board for Novartis., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Neuroblastoma (NB) is the most common solid extracranial malignancy of childhood with an incidence of 1 per 100,000 in the United States compromising approximately 10 % of childhood cancer. Unfortunately, patients with high-risk NG continue to have long-term survival less than 50 %. Both Children's Oncology Group and the International Society of Paediatric Oncology have demonstrated the important role of surgery in the treatment of high-risk NB. Herein, we compose the results of an extensive literature review as well as expert opinion from leaders in pediatric surgical oncology, to present the critical elements of effective surgery for high-risk neuroblastoma., (Copyright © 2023. Published by Elsevier Inc.)

Background: Intercostal nerve cryoablation with the Nuss procedure has been shown to decrease opioid requirements and hospital length of stay; however, few studies have evaluated the impact on complications and hospital costs., Methods: A retrospective cohort study was performed for all Nuss procedures at our institution from 2016 through 2020. Outcomes were compared across 4 pain modalities: cryoablation with standardized pain regimen (n = 98), patient-controlled analgesia (PCA; n = 96), epidural (n = 36), and PCA with peripheral nerve block (PNB; n = 35). Outcomes collected included length of stay, opioid use, variable direct costs, and postoperative complications. Univariate and multivariate hierarchical regression analysis was used to compare outcomes between the pain modalities., Results: Cryoablation was associated with increased total hospital cost compared with PCA (cryoablation, $11 145; PCA, $8975; P < .01), but not when compared with epidural ($9678) or PCA with PNB ($10 303). The primary driver for increased costs was operating room supplies (PCA, $2741; epidural, $2767; PCA with PNB, $3157; and cryoablation, $5938; P < .01). With multivariate analysis, cryoablation was associated with decreased length of stay (-1.94; 95% CI, -2.30 to -1.57), opioid use during hospitalization (-3.54; 95% CI, -4.81 to -2.28), and urinary retention (0.13; 95% CI, 0.05-0.35)., Conclusions: Cryoablation significantly reduces opioid requirements and length of stay relative to alternative modalities, but it was associated with an increase in total hospital costs relative to PCA, but not epidural or PCA with PNB. Cryoablation was not associated with allodynia or slipped bars requiring reoperation., (Copyright © 2023 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: Wilms tumor therapy in low- and middle-income countries (LMICs) relies on treatment protocols adapted to resource limitations, but these protocols have rarely been evaluated in real-world settings. Such evaluations are necessary to identify high-impact research priorities for clinical and implementation trials in LMICs. The purpose of this study was to identify highest priority targets for future clinical and implementation trials in sub-Saharan Africa by assessing outcomes of a resource-adapted treatment protocol in Malawi., Methods: We conducted a retrospective cohort study of children treated for Wilms tumor with an adapted SIOP-backbone protocol in Lilongwe, Malawi between 2016 and 2021. Survival analysis assessed variables associated with poor outcome with high potential for future research and intervention., Results: We identified 136 patients, most commonly with stage III (n = 35; 25.7%) or IV disease (n = 35; 25.7%). Two-year event-free survival (EFS) was 54% for stage I/II, 51% for stage III, and 13% for stage IV. A single patient with stage V disease survived to 1 year. Treatment abandonment occurred in 36 (26.5%) patients. Radiotherapy was indicated for 55 (40.4%), among whom three received it. Of these 55 patients, 2-year EFS was 31%. Of 14 patients with persistent metastatic pulmonary disease at the time of nephrectomy, none survived to 2 years. Notable variables independently associated with survival were severe acute malnutrition (hazard ratio [HR]: 1.9), increasing tumor stage (HR: 1.5), and vena cava involvement (HR: 3.1)., Conclusion: High-impact targets for clinical and implementation trials in low-resource settings include treatment abandonment, late presentation, and approaches optimized for healthcare systems with persistently unavailable radiotherapy., (© 2023 Wiley Periodicals LLC.)

Purpose: Ganglioneuroma (GN) and ganglioneuroblastoma-intermixed (GNB-I) represent benign variants of neuroblastic tumors in children; however, differentiating from more aggressive histological variants of GNB including the nodular subtype (GNB-N) prior to resection can be challenging, even with biopsy. Currently, no standard treatment guidelines exist. The purpose of this study was to identify pre-operative characteristics of benign neuroblastic tumors and evaluate outcomes for patients who underwent surgical resection or observation., Methods: Retrospective chart review of children treated at a single institution between 2009 and 2019 for non-metastatic tumor with a tissue diagnosis of GN, GNB-N or GNB-I. Demographics, imaging, labs, operative details and outcomes were recorded and analyzed., Results: Of 53 patients, 45% were male. The most common tumor location was abdomen (49%), followed by thorax (34%). Forty-five percent had at least one image defined risk factor. Biopsy was performed in 32% (17/53) and upfront surgery in 68% (36/53). Three patients (3/53, 5.6%) with biopsy demonstrating GN tumors were observed due to high surgical risk. Pathology of resected specimens demonstrated GN in 52% (26/50) and GNB-I or GNB-N in 48% (24/50). The majority of GNB tumors (75% (18/24) were GNB-I and 25% (6/24) were GNB-N. Therefore, 88% of the resected tumors were benign spectrum neuroblastic tumors (GN & GNB-I). Seven (7/50, 14%) patients experienced perioperative complication (temporary paralysis, Horner's syndrome, chylothorax, vocal cord paralysis). Recurrence was noted in 1 patient with GN (1/50, 2%) and 3 with GNB-N (3/50, 6%). There were no tumor-related deaths. Patients with GN were older than those with GNB (8.8 years (IQR 6-11.25) vs 5.6 years for GN (IQR 3-7); p = 0.01). GNB tumors were also more likely to have calcifications on imaging (63% vs. 38%, p = .01) and more commonly had MIBG avidity (88% vs 66%, p = .04). There were no significant differences in tumor size or symptoms at presentation., Conclusions: In children with neuroblastic tumors, older age, CT without tumor calcifications, lack of MIBG avidity, and/or normal urine catecholamines may indicate benign GN. Close observation could be considered for asymptomatic patients meeting these criteria with biopsy-proven GN, with resection reserved for progressive growth or symptom development. However, larger, multicenter studies are needed for further validation., Level of Evidence: IV., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Up to a third of children undergoing partial hepatectomy for primary hepatic malignancies experience at least one perioperative complication, with a presumed deleterious effect on both short- and long-term outcomes. We implemented a multidisciplinary treatment protocol in the management of these patients in order to improve complication rates following partial hepatectomy., Methods: A retrospective chart review was completed for all patients < 18 years of age who underwent liver resection at our institution between 2002 and 2019 for primary hepatic cancer. Demographic, intraoperative, postoperative, pathologic, and outcome data were analyzed for perioperative complications using the CLASSIC and Clavien-Dindo (CD) scales, event-free survival (EFS) and overall survival (OS)., Results: A total of 73 patients were included in the analysis with 33 prior-to and 40 after dedicated provider protocol implementation. Perioperative complication rates decreased from 52% to 20% (p = 0.005) with major complications going from 18% to 10% (p = 0.31). On multivariable logistic regression, protocol implementation was associated with a reduction in any (OR 0.29 [95% CI 0.09 - 0.89]) but not major complications. On multivariate cox models, post protocol implementation was associated with improved event free survival (EFS) (HR 0.19 (0.036 - 0.195). Among patients with a diagnosis of hepatoblastoma (n = 62), the occurrence of a major perioperative complication was associated with a worse EFS (HR=5.45, p = 0.03) on multivariate analysis, however this did not translate into an impact on overall survival., Conclusions: Our results demonstrate that, for children with primary liver malignancies, a dedication of patients to high-volume surgeons can improve rates of complications of liver resections and may improve the oncological outcome of hepatoblastoma., Competing Interests: Declaration of Competing Interest None, (Copyright © 2021. Published by Elsevier Inc.)

Introduction:  The Nuss procedure is the most common and preferred operative correction of pectus excavatum. Surgeon preference and patient factors can result in variations in Nuss procedure technique. We hypothesize that certain techniques are associated with increased risk of complications., Materials and Methods:  We performed a single-center retrospective review of Nuss operations from 2016 to 2020. Variations in intraoperative techniques included sternal elevator (SE) use, number of bars placed, and usage of bilateral stabilizing sutures. Patient demographics, intraoperative data, and postoperative outcomes were reported as median with interquartile ranges or percentages. Statistical significance ( p  < 0.05) was determined with Wilcoxon's rank-sum and chi-square tests. Multivariate analysis was performed to control for introduction of intercostal nerve cryoablation and surgeon volume, and reported as odds ratio with 95% confidence interval., Results:  Two hundred and sixty-five patients were identified. Patients repaired with two bars were older with a larger Haller index (HI). Patient demographics were not significantly different for SE or stabilizing suture use. Placement of two bars was associated with significantly increased risk of readmission. Similarly, SE use was associated with increased risk of pleural effusion and readmission. Finally, the use of bilateral stabilizing sutures resulted in less frequent slipped bars without statistical significance., Conclusion:  Older patients with a larger HI were more likely to need two bars placed to repair pectus excavatum. Placement of multiple bars and SE use are associated with significantly higher odds of certain complications., Competing Interests: None declared., (Thieme. All rights reserved.)

Pancreatic angiosarcoma is an exceedingly rare malignancy accounting for <1% of pancreatic neoplasms. A very limited number of pancreatic angiosarcomas have been reported in the literature without any cases described in children. We present the case of a 17-year-old female diagnosed with angiosarcoma of the pancreas following pancreaticoduodenectomy for a pancreatic mass, initially presumed to be a solid pseudopapillary neoplasm of the pancreas. The angiosarcoma was found to have a novel activating internal tandem duplication in the KDR gene (KDR-internal tandem duplication). We discuss the current literature on this disease process. This is the first reported case of pancreatic angiosarcoma in a pediatric patient and the first with an activating KDR-internal tandem duplication., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To create the first structured surgical report form for NBL with international consensus, to permit standardized documentation of all NBL-related surgical procedures and their outcomes., Summary of Background Data: NBL, the most common extracranial solid malignant tumor in children, covers a wide spectrum of tumors with significant differences in anatomical localization, organ or vessel involvement, and tumor biology. Complete surgical resection of the primary tumor is an important part of NBL treatment, but maybe hazardous, prone to complications and its role in high-risk disease remains debated. Various surgical guidelines exist within the protocols of the different cooperative groups, although there is no standardized operative report form to document the surgical treatment of NBL., Methods: After analyzing the treatment protocols of the SIOP Europe International Neuroblastoma Study Group, Children's Oncology Group, and Gesellschaft fuer Paediatrische Onkologie und Haematologie - German Association of Pediatric Oncology and Haematology pediatric cooperative groups, important variables were defined to completely describe surgical biopsy and resection of NBL and their outcomes. All variables were discussed within the Surgical Committees of SIOP Europe International Neuroblastoma Study Group, Children's Oncology Group, and Gesellschaft fuer Paediatrische Onkologie und Haematologie - German Association of Pediatric Oncology and Haematology. Thereafter, joint meetings were organized to obtain intercontinental consensus., Results: The "International Neuroblastoma Surgical Report Form" provides a structured reporting tool for all NBL surgery, in every anatomical region, documenting all Image Defined Risk Factors and structures involved, with obligatory reporting of intraoperative and 30 day-postoperative complications., Conclusion: The International Neuroblastoma Surgical Report Form is the first universal form for the structured and uniform reporting of NBL-related surgical procedures and their outcomes, aiming to facilitate the postoperative communication, treatment planning and analysis of surgical treatment of NBL., Competing Interests: The authors declare no conflicts of interest and received no funding., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: We aim to assess the healthcare value achieved from a shared savings program for pediatric appendectomy., Methods: All appendectomy patients covered by our health plan were included. Quality targets were 15% reduction in time to surgery, length of stay, readmission rate, and patient satisfaction. Quality targets and costs for an appendectomy episode in two 6-month performance periods (PP1, PP2) were compared to baseline., Results: 640 patients were included (baseline:317, PP1:167, PP2:156). No quality targets were met in PP1. Two quality targets were met during PP2: readmission rate (-57%) and patient satisfaction. No savings were realized because the cost reduction threshold (-9%) was not met during PP1 (+1.7%) or PP2 (-0.4%)., Conclusions: Payer-provider partnerships can be a platform for testing value-based reimbursement models. Setting achievable targets, identifying affectable quality metrics, considering case mix index, and allowing sufficient time for interventions to generate cost savings should be considered in future programs., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Thoracic inlet (TI) tumors are rare, and can be particularly challenging to resect due to proximity to mediastinal vessels and nerves. Traditional resection is typically performed through "trapdoor" or sternoclavicular incisions. The purpose of our study was to evaluate the feasibility and effectiveness of thoracoscopic resection of this group of tumors. Methods: We performed a single-center retrospective chart review for children who presented with TI neuroblastic tumors between 2011 and 2020. Demographics, tumor characteristics, treatment, operative complications, and outcomes were collected and analyzed. Results: Eight patients were identified. The median age at diagnosis was 13 months (interquartile range [IQR] 6-32) with median tumor size at diagnosis of 4.1 cm (IQR 3.6-4.4). Neoadjuvant chemotherapy was given in 50% (4/8) with 38% (3/8) undergoing upfront surgery; 1 patient was observed without chemotherapy or surgery. Ultimately, 6 patients had thoracoscopic resection. For thoracoscopic resections, median intraoperative estimated blood loss was 15 mL (IQR 10-28), median operative room time was 199 minutes (IQR 152-259), and median hospital length of stay was 2 days (IQR 2-3). There were two complications: one recurrent laryngeal nerve injury and one new-onset Horner's syndrome. Complete gross total resection was achieved for all children and there were no recurrences or mortalities with a median follow-up of 3 years. Conclusion: Thoracoscopic resection for TI neuroblastic tumors is feasible with minimal morbidity and can lead to adequate oncological resection.

Background/purpose: Pediatric oncology patients often undergo open operations for tumor resection, and epidural catheters are commonly utilized for pain control. Our purpose was to evaluate whether a subcutaneous analgesic system (SAS) provides equivalent post-operative pain control., Methods: An IRB approved, retrospective chart review of children age <18 undergoing open abdominal, pelvic or thoracic surgery for tumor resection between 2017 and 2019 who received either epidural or SAS for post-operative pain control was performed. Comparisons of morphine milligram equivalents (MME), pain scores, and post-operative course were made using parametric and non-parametric analyses., Results: Of 101 patients, median age was 7 years (2 months-17.9 years). There were 65 epidural and 36 SAS patients. Transverse laparotomy was the most common incision (41%), followed by thoracotomy (29%). Pain scores, MME, urinary catheter days, and post-operative length of stay (LOS) were similar between the two groups. Urinary catheter use was more common in epidural patients (70% vs 30%, p = <0.001). SAS patients had faster time to ambulation and time to regular diet by 1 day (p = 0.02). Epidural patients more commonly had a complication with the pain device (20% vs 3%, p = 0.02) and were more likely to be discharged with narcotics (60% vs. 40%, p = 0.04). Charges associated with the hospital stay were similar between the two groups., Conclusion: In pediatric oncology patients undergoing open abdominal, pelvic, and thoracic surgery, SAS may provide similar pain control to epidural, but with faster post-operative recovery, fewer complications, and less discharge narcotic use. A prospective study is needed to validate these results., Type of Study: Retrospective Comparative LEVEL OF EVIDENCE: Level III., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background/objectives: Standard supportive care during induction therapy for high-risk neuroblastoma (HR-NBL) includes primary prophylactic granulocyte colony-stimulating factor (G-CSF) aimed at limiting duration of neutropenia, reducing infection risk, and minimizing treatment delays. Preclinical models suggest that G-CSF promotes maintenance of neuroblastoma cancer stem cells and may reduce the efficacy of chemotherapy. This study's objective was to determine the safety and feasibility of administering induction chemotherapy without routine use of prophylactic G-CSF., Design/methods: Children with newly diagnosed HR-NBL received six-cycle induction chemotherapy regimen without prophylactic G-CSF in four cycles. G-CSF was administered for stem cell mobilization after cycle 3 and granulocyte-monocyte colony-stimulating factor after cycle 5 prior to surgical resection of primary disease. The primary outcome measure was the incidence of grade 3 or higher infection. We hypothesized that the per patient infection rate would be comparable to our institutional baseline rate of 58% in patients with HR-NBL receiving induction chemotherapy with prophylactic growth factor support. The trial used an A'Hern single-stage design., Results: Twelve patients with HR-NBL received 58 cycles of chemotherapy on study. Three patients completed the entire six-cycle regimen with no infections. Nine patients experienced grade 3 infections (bacteremia four, urinary tract infection two, skin/soft tissue infection three). No patients experienced grade 4 infections or required intensive care treatment for infection., Conclusion: A greater than expected number of serious bacterial infections were observed during administration of induction chemotherapy for HR-NBL without primary prophylactic G-CSF. These results support continued prophylactic administration growth factor during induction chemotherapy., (© 2020 Wiley Periodicals, Inc.)

Patients with pulmonary Langerhans cell histiocytosis (LCH) typically have a benign course but may have extensive cystic lung disease with rare life-threatening complications including multiple and recurrent pneumothoraces and respiratory failure. We report seven severely affected pediatric patients treated with chemotherapy, aggressive chest tube management, and pleurodesis of whom five survived. Patients with extraordinary amounts of pulmonary cystic disease and multiple pneumothoraces due to LCH can have remarkable, curative outcomes with early recognition, optimal LCH-directed therapy, and supportive care., (© 2020 Wiley Periodicals LLC.)

Background: Wilms tumor accounts for more than 90% of all malignant kidney neoplasms in children. Survival after diagnosis and treatment is excellent in most high-income countries. Low- and middle-income countries (LMICs) continue to struggle with Wilms tumor detection and treatment. The purpose of this study was to compare the global incidence and outcomes of Wilms tumor., Material and Methods: Wilms tumor incidence data from the World Health Organization (WHO), International Incidence of Childhood Cancer, Volume III, was analyzed according to world region and country socioeconomic status using descriptive statistics and independent-sample Kruskal-Wallis Test. A literature review was also performed to assess outcomes and identify common themes., Results: Wilms tumor was most common in children aged 0-4 y (median incidence 15.1 [IQR 11.8-18.7] ASR/million). High-income countries reported significantly higher median incidence than middle-income countries (8.6 [7.4-9.3] versus 6.1 [4.9-8.7] ASR/million; P < 0.01), although low-income countries reported the highest median incidence overall (9.8 [6.2-16.4] ASR/million). Low-income countries had the fewest countries with registries (n = 6). Overall survival ranged from 70% to 97% in high-income countries, 61%-94% in upper-middle-income countries, 0%-85% in lower-middle-income countries, and 25%-53% in low-income countries. Delay in diagnosis, lack of available treatment, and inadequate follow up contributed to the large variations in outcomes., Conclusions: Reported Wilms tumor incidence is highest in low-income countries, and these are also the countries that have the lowest survival. Lack of significance may reflect incomplete and absent data reporting from lower income countries. Accurate and comprehensive registries are the first steps to appropriate resource allocation in order to improve outcomes for this highly curable childhood malignancy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Pancreatic islet cell tumors are rare in adolescents, and most studies published to date focus on older patients. We utilized a national database to describe the histology and clinical pattern of pancreatic islet cell tumors in adolescent and young adult (AYA) patients, and to compare AYAs to older adults. We hypothesized that AYAs with pancreatic islet cell tumors would have better overall survival., Methods: The National Cancer Data Base (NCDB, 1998-2012) was queried for AYA patients (15-39 years) with a pancreatic islet cell tumor diagnosis. Demographics, tumor characteristics, treatment modalities, and outcomes were abstracted and compared to adults (≥40 years)., Results: 383 patients (56.4% female, 65% non-Hispanic Whites) were identified, with a median age of 27 (IQR 16-34) years. Islet cell carcinoma was the most common histology. Of patients with known stage of disease, 49% presented with early stage (I or II). Seventy percent of patients underwent surgical resection, including local excision 44%, Whipple procedure 37.5%, or total pancreatectomy 19%. Chemotherapy was utilized in 27% and radiotherapy in 7%. All-cause mortality was 36%. AYA patients underwent more extensive resections (p = 0.001) and had lower mortality rates (p < 0.001), with no differences in tumor stage or use of adjuvant therapies, when compared to adults., Conclusions: AYA patients with pancreatic islet cell tumors had comparable utilization of adjuvant therapies but underwent more extensive resections and demonstrated a higher overall survival rate than adult counterparts. Further investigation into approaches to earlier diagnosis and tailoring of multimodality therapy of these neoplasms in the AYA population is needed., Levels of Evidence: Prognostic Study, Level II - retrospective study., (Copyright © 2019. Published by Elsevier Inc.)

Background/purpose: Elective ambulatory surgical care traditionally involves three independent visits. Single-Visit Surgery (SVS) is an alternative surgical model that consolidates care into one visit. Evaluation of the effect of this novel program on hospital operations is limited. The objective of this study was to analyze SVS from an institutional perspective., Methods: We retrospectively reviewed patients scheduled for SVS at a freestanding children's hospital between January 2016 and August 2017. Data collected included clinic "no show" rates, operating room (OR) utilization, reimbursement rates, and postoperative visits., Results: There were 89 patients scheduled for SVS, of which 63% (n=56) were male, and the median age was 6 years [IQR, 4-9]. The SVS clinic "no show" rate was 2% (n=2) compared to the pediatric surgery clinic "no show" rate of 11% (p=0.01). The SVS OR block utilization rate was 90%. Payment was received from third-party payors for 92% of consultations and 100% of operative procedures without securing prior authorization. Postoperatively 25% (n=17) of patients presented to clinic for follow-up, and one child presented to the emergency department for vomiting. There were no hospital admissions., Conclusion: Single-Visit Surgery is an alternative model of ambulatory surgical care that improves institutional efficiency while also enhancing the patient experience., Type of Study: Retrospective cohort review LEVEL OF EVIDENCE: III., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Neuroblastoma is the most common extracranial malignant solid tumor in children, and drug resistance is a major reason for poor outcomes. Elevated proteasome activity plays an important role in neuroblastoma tumor development and resistance to conventional chemotherapy. Ubiquitin-specific protease 14 (USP14), one of three deubiquitinases associated with the regulatory subunit of the proteasome, is emerging as a potential therapeutic target in multiple tumor types. However, the role of USP14 in neuroblastoma is yet to be elucidated. We found that USP14 inhibition in neuroblastoma via knockdown or a specific inhibitor such as b-AP15 suppressed cell proliferation by inducing cell apoptosis. Furthermore, b-AP15 significantly inhibited neuroblastoma tumor growth in NGP and SH-SY5Y xenograft mouse models. For combination treatment, b-AP15 plus conventional chemotherapeutic agents such as doxorubicin or VP-16 resulted in synergistic antitumor effects on neuroblastoma. Our study demonstrates that USP14 is required for cell viability and is a novel therapeutic target in neuroblastoma. Moreover, USP14 inhibition may add value in combination therapy due to its powerful synergistic effects in treating neuroblastoma., (©2019 American Association for Cancer Research.)

Purpose: We sought to compare the presentation, management, and outcomes in gastric adenocarcinoma cancer for pediatric and adult patients., Methods: Using the 2004 to 2014 National Cancer Database (NCDB), patients ≤21 years (pediatric) were retrospectively compared to >21 years (adult). Chi-squared tests were used to compare categorical variables, and Cox regression was used to estimate hazard ratios (HR) for survival differences., Results: Of the 129,024 gastric adenocarcinoma cases identified, 129 (0.10%) occurred in pediatric patients. Pediatric cases presented with more advanced disease, including poorly differentiated tumors (81% vs 65%, p = 0.006) and stage 4 disease (56% vs 41%, p = 0.002). Signet ring adenocarcinoma comprised 45% of cases in the pediatric group as compared to 20% of cases in the adults (P < 0.001). Similar proportions in both groups underwent surgery. However, near-total gastrectomy was more common in the pediatric group (16% vs 6%, p < 0.001). The proportions of patients with negative margins, nodal examination, and presence of positive nodes were similar. There was no overall survival difference between the two age groups (HR 0.92, 95% Confidence interval 0.73-1.15)., Conclusion: While gastric adenocarcinoma in pediatric patients present with a more advanced stage and poorly differentiated tumors compared to adults, survival appears to be comparable., Type of Study: Retrospective cohort study., Level of Evidence: III., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: In patients requiring gastrostomies, ventriculoperitoneal (VP) shunts are a frequently encountered comorbidity. The objective of this study is to evaluate the postoperative management of children with VP shunts that undergo laparoscopic gastrostomy placement and determine their incidence of complications., Materials and Methods: Children 18 y old or younger who underwent laparoscopic gastrostomy placement at a freestanding academic children's hospital between January 2014 and October 2016 were reviewed. Data collected included demographics, management, and outcomes. Patients were compared based on their presence of a VP shunt before laparoscopic gastrostomy. Statistical analysis was performed using chi square, Fisher's exact, and Wilcoxon rank-sum tests., Results: We reviewed the medical records of 270 children that underwent laparoscopic gastrostomy placement by 15 pediatric surgeons. Of these, 9% (25) had a previously placed VP shunt. In comparing patients with a VP shunt with those without a VP shunt, there was no significant difference in median age (4 versus 3 y, P = 0.92), gender (48% versus 51% males, P = 0.80), body mass index (15 versus 16, P = 0.69), preoperative diet (48% versus 47% nasogastric tube dependent, P = 0.60), or procedure time (43 versus 42 min, P = 0.37). The postoperative management of these children was similar: day of initiation of postoperative feeds (84% versus 73% on postoperative day #1, P = 0.70), method of initiation of feeds (60% versus 55% continuous, P = 0.25), and type of initial feeds (83% versus 71% Pedialyte, P = 0.24). Similarly, there was no difference in hospital length of stay, return to the emergency department, or postoperative complications within 90 d (P > 0.05)., Conclusions: Children with ventriculoperitoneal shunts do not have a higher rate of immediate complications after laparoscopic gastrostomy placement and may be managed similar to other children in the postoperative period., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background/purpose: Pediatric testicular tumors are rare, constituting only 1% of all pediatric solid tumors. Single-institution studies addressing pediatric testicular tumors published to date have been limited in the number of patients., Methods: We utilized the National Cancer Data Base (1998-2012) to review all prepubescent patients (≤12 years old) with testicular neoplasms. Demographics, tumor characteristics, treatment modalities, and outcomes were abstracted., Results: A total of 479 patients were identified, with a median age of 3 years (IQR 0-4) at diagnosis. 67% of cases were diagnosed by 3 years of age. Yolk sac tumors were the most common histology (202 patients, 42.2%). Most tumors were diagnosed at a low stage. Resection was performed in 465 boys, with 75% having undergone radical orchiectomies. Chemotherapy was utilized in 28% of cases and radiotherapy in 7%. With mean follow-up of 5.6 years, mortality rate was 3%. No difference in mortality was noted based on histology or extent of surgical resection., Conclusions: This series of prepubertal testicular tumors is the largest yet reported and highlights the patient demographics, tumor characteristics, treatment modalities and outcomes for these tumors., Type of Study: Prognosis study LEVEL OF EVIDENCE: II., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: In many cancers, racial and socioeconomic disparities exist regarding the extent of surgery. For ovarian dysgerminoma, fertility-sparing (FS) surgery is recommended whenever possible. The aim of this study was to investigate rates of FS versus non-fertility-sparing (NFS) procedures for stage I ovarian dysgerminoma in adolescents and young adults (AYAs) by ethnicity/race and socioeconomic status., Materials and Methods: The National Cancer Data Base was queried for patients with ovarian dysgerminoma from 1998 to 2012. After selecting patients aged 15-39 y with stage I disease, a multivariate regression analysis was performed, and rates of FS and NFS procedures were compared, first according to ethnicity/race, and then by socioeconomic surrogate variables., Results: Among the 687 AYAs with stage I ovarian dysgerminoma, there was no significant difference in rates of FS and NFS procedures based on ethnicity/race alone (P = 0.17), but there was a significant difference in procedure type for all three socioeconomic surrogates. The uninsured had higher NFS rates (30%) than those with government (21%) or private (19%) insurance (P = 0.036). Those in the poorest ZIP codes had almost twice the rate of NFS procedures (31%) compared with those in the most affluent ZIP codes (17%). For those in the least-educated regions, 24% underwent NFS procedures compared to 14% in the most-educated areas (P = 0.027)., Conclusions: AYAs with stage I ovarian dysgerminoma in lower socioeconomic groups were more likely to undergo NFS procedures than those in higher socioeconomic groups, but there was no difference in rates of FS versus NFS procedures by ethnicity/race. Approaches aimed at reducing socioeconomic disparities require further examination., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Standard of care for unilateral nephroblastoma includes total nephrectomy (TN) with nodal sampling. We sought to compare the outcomes of TN and partial nephrectomy (PN). We performed a retrospective cohort study of TN and PN for nephroblastoma using the National Cancer Data Base. The outcomes included nodal sampling frequency, margin status, and survival. Categorical and continuous data were evaluated with χ2 and t tests, respectively (P < 0.05). Generalized linear models evaluated nodal sampling and margin status. Cox regression compared survival. In total, 235 patients underwent PN and 3572 had TN. TN patients were 50 per cent more likely to undergo nodal sampling (RR: 1.47, 95% CI 1.30-1.66). There was no difference in margin status (RR: 0.91, 95% CI 0.65-1.28) or overall survival (HR 1.57; 95% CI 0.78-3.19). This study reports the largest review of patients with PN for unilateral nephroblastoma. PN patients had less nodal sampling but similar margin involvement and overall survival.

Background: Malignant ovarian germ cell tumors (MOGCTs) are a rare form of ovarian malignancy. Socioeconomic status (SES) has been shown to affect survival in several gynecologic cancers. We examined whether SES impacted survival in adolescent and young adults (AYAs) with MOGCT., Materials and Methods: The National Cancer Data Base was used to identify AYAs (aged 15-39 years) with MOGCT from 1998 to 2012. Three SES surrogate variables identified were as follows: insurance type, income quartile, and education quartile. Pooled variance t-tests and chi-square tests were used to compare tumor characteristics, the time from diagnosis to staging/treatment, and clinical outcome variables for each SES surrogate variable, while controlling for age and race/ethnicity in a multivariate model. Kaplan-Meier survival estimates were calculated using the log-rank test., Results: A total of 3125 AYAs with MOGCT were identified. Subjects with lower SES measures had higher overall stage and T-stage MOGCTs at presentation. There was no significant difference in the time to staging/treatment, extent of surgery, or use of chemotherapy by SES. Subjects from a lower education background, from a lower income quartile, and without insurance had decreased survival (P ≤ 0.02 for all). Controlling for overall stage and T-stage, the difference in survival was no longer significant., Conclusions: AYAs with MOGCT from lower SES backgrounds presented with more advanced stage disease. Further studies that focus on the underlying reasons for this difference are needed to address these disparities., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To determine the impact of surgery and/or radiation therapy on distant metastatic sites (DMS) in children with stage IV rhabdomyosarcoma (RMS)., Methods: A retrospective chart review was conducted on all patients with stage IV RMS at Texas Children's Hospital from 1992 to 2012. Data analyzed included age, gender, primary site, histologic subtype, number and sites of metastases, treatment including local therapy to DMS, and Oberlin score., Results: The 5-year progression-free survival (PFS) and overall survival (OS) rates were 20% and 25%. The 5-year PFS in patients receiving local therapy to all DMS (n = 16) and to less than all DMS (n = 19) was 31.3% versus 0% (P = 0.002), whereas the 5-year OS was 37.3% versus 0% (P < 0.001), respectively. The 5-year PFS in patients with isolated lung metastasis versus other types of metastasis was 29% versus 7% (P = n.s.), whereas the 5-year OS was 43% versus 10% (P = 0.01). The 5-year pulmonary local control was improved by the use of whole lung irradiation (WLI; 56% vs. 10%, P = 0.03)., Conclusions: Local treatment to all metastatic sites was associated with improved PFS and OS at 5 years. The use of WLI improved pulmonary control in patients with lung metastasis. We recommend an aggressive approach including local therapy to DMS in children with stage IV RMS., (© 2017 Wiley Periodicals, Inc.)

Background: Multimodal therapy is the standard treatment for pediatric rhabdomyosarcoma, but for adolescents and young adults (AYAs: ages 15-39) and older adults with rhabdomyosarcoma, the use of adjuvant therapy is variable, and survival is greatly decreased compared with younger patients., Methods: All patients with rhabdomyosarcoma who had a curative operative were identified from the 1998-2012 National Cancer Database. Regression analyses identified independent factors relating to receipt of multimodal therapy (resection + chemotherapy + radiation) and the influence of multimodal therapy on 5-year overall survival., Results: Of 2,312 patients, 44% were pediatric (age < 15 years), 22% AYA (ages 15-39), and 34% adult (age ≥ 40 years). Adults received multimodal therapy least often (pediatric: 62%, AYA: 46%, adults: 24%; P < .001), even after controlling for demographic characteristics, tumor features, and stage. In the entire cohort, multimodal therapy was associated with a decreased risk of death within 5 years (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.62-0.84), with similar findings after stratification by age (pediatric: HR 0.64, 95% CI 0.48-0.85; AYA: HR 0.72, 95% CI 0.55-0.95; adult: HR 0.74, 95% CI 0.58-0.93). In AYAs only, black and Hispanic patients had an increased risk of death within 5 years (black patients: HR 1.64, 95% CI 1.14-2.37; Hispanic patients: HR 1.62, 95% CI 1.11-2.36)., Conclusion: This first large national study suggests that multimodal therapy is independently associated with improved survival for both AYAs and adults with rhabdomyosarcoma, similar to pediatric patients, but multimodal therapy is appreciably underused. Implementation of multimodal therapy for all patients could potentially improve overall outcomes of patients with rhabdomyosarcoma., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Treatment failure in high risk neuroblastoma (NB) is largely due to the development of chemotherapy resistance. We analyzed the gene expression changes associated with exposure to chemotherapy in six high risk NB tumors with the aid of the Connectivity Map bioinformatics platform. Ten therapeutic agents were predicted to have a high probability of reversing the transcriptome changes associated with neoadjuvant chemotherapy treatment. Among these agents, initial screening showed the EWS-FLI1 and RNA helicase A interaction inhibitor YK-4-279, had obvious cytotoxic effects on NB cell lines. Using a panel of NB cell lines, including MYCN nonamplified (SK-N-AS, SH-SY5Y, and CHLA-255), and MYCN amplified (NB-19, NGP, and IMR-32) cell lines, we found that YK-4-279 had cytotoxic effects on all lines tested. In addition, YK-4-279 also inhibited cell proliferation and anchorage-independent growth and induced cell apoptosis of these cells. YK-4-279 enhanced the cytotoxic effect of doxorubicin (Dox). Moreover, YK-4-279 was able to overcome the established chemoresistance of LA-N-6 NB cells. In an orthotopic xenograft NB mouse model, YK-4-279 inhibited NB tumor growth and induced apoptosis in tumor cells through PARP and Caspase 3 cleavage in vivo . While EWS-FLI1 fusion protein is not frequently found in NB, using the R2 public database of neuroblastoma outcome and gene expression, we found that high expression of EWSR1 was associated with poor patient outcome. Knockdown of EWSR1 inhibited the oncogenic potential of neuroblastoma cell lines. Taken together, our results indicate that YK-4-279 might be a promising agent for treatment of NB that merits further exploration., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Purpose: Standardized clinical pathways for simple appendicitis decrease length of stay and result in cost savings. We performed a prospective cohort study to assess a same day discharge (SDD) protocol for children with simple appendicitis., Methods: All children undergoing laparoscopic appendectomy for simple appendicitis after protocol implementation (February 2016 to January 2017) were assessed. Length of stay (LOS), 30-day resource utilization (ED visits and hospital readmissions), patient satisfaction, and hospital accounting costs for SDD were compared to non-SDD patients., Results: Of 602 children treated at our institution, 185 (31%) were successfully discharged per protocol. SDD patients had longer median PACU duration (3.0 vs. 1.0h, p<0.001), but postoperative LOS (4.4 vs. 17.4h, p<0.001) and overall LOS (17.1 vs. 31.2h, p<0.001) were significantly shorter. Complication rates (1.6% vs. 3.1%), ED visits (4.3% vs. 6.0%), and readmissions (0.5% vs. 2.4%) were not significantly different for SDD compared to non-SDD patients. However, SDD decreases total cost of an appendectomy episode ($8073 vs $8424, p=0.002), and patients report high satisfaction with their hospital experience (mean 9.4 out of 10)., Conclusions: Safe and satisfactory outpatient management of pediatric simple appendicitis is achievable with appropriate patient selection. An SDD protocol can lead to significant generation of value to the healthcare system., Level of Evidence: Prognosis study, Level II., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Well-differentiated thyroid cancer is the most common endocrine malignancy in children. Adult literature has demonstrated socioeconomic disparities in patients undergoing thyroidectomy, but the effects of socioeconomic status on the management of pediatric well-differentiated thyroid cancer remains poorly understood., Methods: Patients ≤21 years of age with well-differentiated thyroid cancer remains were reviewed from the National Cancer Data Base. Three socioeconomic surrogate variables were identified: insurance type, median income, and educational quartile. Tumor characteristics, diagnostic intervals, and clinical outcomes were compared within each socioeconomic surrogate variable., Results: A total of 9,585 children with well-differentiated thyroid cancer remains were reviewed. In multivariate analysis, lower income, lower educational quartile, and insurance status were associated with higher stage at diagnosis. Furthermore, lower income quartile was associated with a longer time from diagnosis to treatment (P < .002). Similarly, uninsured children had a longer time from diagnosis to treatment (28 days) compared with those with government (19 days) or private (18 days) insurance (P < .001). Despite being diagnosed at a higher stage and having a longer time interval between diagnosis and treatment, there was no significant difference in either overall survival or rates of unplanned readmissions based on any of the socioeconomic surrogate variables., Conclusion: Children from lower income families and those lacking insurance experienced a longer period from diagnosis to treatment of their well-differentiated thyroid cancer remains. These patients also presented with higher stage disease. These data suggest a delay in care for children from low-income families. Although these findings did not translate into worse outcomes for well-differentiated thyroid cancer remains, future efforts should focus on reducing these differences., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose More than two decades ago, an international working group established the International Neuroblastoma Response Criteria (INRC) to assess treatment response in children with neuroblastoma. However, this system requires modification to incorporate modern imaging techniques and new methods for quantifying bone marrow disease that were not previously widely available. The National Cancer Institute sponsored a clinical trials planning meeting in 2012 to update and refine response criteria for patients with neuroblastoma. Methods Multidisciplinary investigators from 13 countries reviewed data from published trials performed through cooperative groups, consortia, and single institutions. Data from both prospective and retrospective trials were used to refine the INRC. Monthly international conference calls were held from 2011 to 2015, and consensus was reached through review by working group leadership and the National Cancer Institute Clinical Trials Planning Meeting leadership council. Results Overall response in the revised INRC will integrate tumor response in the primary tumor, soft tissue and bone metastases, and bone marrow. Primary and metastatic soft tissue sites will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) and iodine-123 ( 123 I) -metaiodobenzylguanidine (MIBG) scans or [ 18 F]fluorodeoxyglucose-positron emission tomography scans if the tumor is MIBG nonavid. 123 I-MIBG scans, or [ 18 F]fluorodeoxyglucose-positron emission tomography scans for MIBG-nonavid disease, replace technetium-99m diphosphonate bone scintigraphy for osteomedullary metastasis assessment. Bone marrow will be assessed by histology or immunohistochemistry and cytology or immunocytology. Bone marrow with ≤ 5% tumor involvement will be classified as minimal disease. Urinary catecholamine levels will not be included in response assessment. Overall response will be defined as complete response, partial response, minor response, stable disease, or progressive disease. Conclusion These revised criteria will provide a uniform assessment of disease response, improve the interpretability of clinical trial results, and facilitate collaborative trial designs.

Purpose: Pediatric breast malignancies are rare, and descriptions in the literature are limited. The purpose of our study was to compare pediatric and adult breast malignancy., Methods: We performed a retrospective cohort study using the National Cancer Data Base comparing patients ≤21 years to those >21 years at diagnosis (1998-2012). Generalized linear models estimated differences in demographic, tumor, and treatment characteristics. Cox regression was used to compare overall survival., Results: Of 1,999,181 cases of invasive breast malignancies, 477 (0.02%) occurred in patients ≤21 years. Ninety-nine percent of adult patients had invasive carcinoma compared with 64.8% of pediatric patients with the remaining patients having sarcoma, malignant phyllodes, or malignancy not otherwise specified (p < 0.001). Pediatric patients were twice as likely to have an undifferentiated malignancy [relative risk (RR) 2.19; 95% confidence interval (CI) 1.72-3.79]. Half of adults presented with Stage I disease compared with only 22.7% of pediatric patients (p < 0.001). Pediatric patients were 40% more likely to have positive axillary nodes (RR 1.42; 95% CI 1.10-1.84). Among patients with invasive carcinoma, pediatric patients were more than four times as likely to receive a bilateral than a unilateral mastectomy compared with adults (RR 4.56; 95% CI 3.19-6.53). There was no difference in overall survival between children and adults., Conclusions: Pediatric breast malignancies are more advanced at presentation, and there is variability in treatment practices. Adult and pediatric patients with invasive carcinoma have similar overall survival.

Objectives: Healthcare reform policies are emphasizing value-based healthcare delivery. We hypothesize that time-driven activity-based costing (TDABC) can be used to appraise healthcare interventions in pediatric appendicitis., Methods: Triage-based standing delegation orders, surgical advanced practice providers, and a same-day discharge protocol were implemented to target deficiencies identified in our initial TDABC model. Post-intervention process maps for a hospital episode were created using electronic time stamp data for simple appendicitis cases during February to March 2016. Total personnel and consumable costs were determined using TDABC methodology., Results: The post-intervention TDABC model featured 6 phases of care, 33 processes, and 19 personnel types. Our interventions reduced duration and costs in the emergency department (-41min, -$23) and pre-operative floor (-57min, -$18). While post-anesthesia care unit duration and costs increased (+224min, +$41), the same-day discharge protocol eliminated post-operative floor costs (-$306). Our model incorporating all three interventions reduced total direct costs by 11% ($2753.39 to $2447.68) and duration of hospitalization by 51% (1984min to 966min)., Conclusion: Time-driven activity-based costing can dynamically model changes in our healthcare delivery as a result of process improvement interventions. It is an effective tool to continuously assess the impact of these interventions on the value of appendicitis care., Level of Evidence: II, Type of study: Economic Analysis., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To examine patient characteristics and outcomes in children with undifferentiated embryonal sarcoma of the liver (UESL) using a multi-institutional database., Summary Background Data: UESL is a rare disease (incidence is one per million). Therefore, the current literature is mostly limited to small case series., Methods: The National Cancer Database was queried for primary UESL diagnosed between 1998 and 2012., Results: A total of 103 patients (<18 years) were identified. The 5-year overall survival of the entire group was 86%. The best outcomes were seen in children who had tumors smaller than 15 cm and were able to undergo surgical resection with or without chemotherapy. Margin status did not appear to significantly affect survival. The most common type of resection was hemihepatectomy (37%), followed by sectionectomy (10%) and trisectionectomy (10%). Orthotopic liver transplant was performed in 10 children, all of whom survived to 5 years., Conclusion: Surgical resection with or without chemotherapy should be the mainstay of treatment in children with UESL, and is associated with very favorable outcomes. Negative surgical margins were not associated with improved survival. Orthotopic liver transplantation may be a viable method of attaining local control in tumors, which would otherwise be unresectable., (© 2016 The Authors. Pediatric Blood & Cancer Published by Wiley Periodicals, Inc.)

Neuroendocrine tumor (NET) of the appendix is the most common gastrointestinal epithelial tumor in children. The utility of serum markers or the indication for hemicolectomy has not been established in children. In 45 children diagnosed with appendiceal NET, 89% NETs were incidentally found following appendectomy performed for suspected acute appendicitis. The median age was 12 years, and 56% patients were female. Postoperative somatostatin scan (n=5), serum chromogranin A (n=4), and urine 5-HIAA (n=9) were all within normal limits. Pathology slides of 35 patients showed mesoappendiceal invasion in 29% patients, and vascular invasion in 6% patients. Seven patients (16%) underwent hemicolectomy for invasion of mesoappendix (n=5), tumor near the resection margin (n=1), and tumor size 1.5 cm with vascular invasion (n=1). Only 2 hemicolectomy specimens showed disease: one in the appendiceal stump and the other as a micrometastasis in a mesenteric lymph node. There were no recurrences and all patients were alive and without evidence of disease at last follow-up. Pediatric appendiceal NET tends to have a benign clinical course with excellent prognosis. In the absence of carcinoid syndrome, postoperative scans and serum biomarkers do not seem to be useful. With completely resected tumors, the indication for hemicolectomy is unclear.

Neuroblastoma (NB) is the most common extracranial solid tumor in children. Aberrant activation of the non-receptor tyrosine kinases Src and c-Abl contributes to the progression of NB. Thus, targeting these kinases could be a promising strategy for NB therapy. In this paper, we report that the potent dual Src/Abl inhibitor bosutinib exerts anti-tumor effects on NB. Bosutinib inhibited NB cell proliferation in a dose-dependent manner and suppressed colony formation ability of NB cells. Mechanistically, bosutinib effectively decreased the activity of Src/Abl and PI3K/AKT/mTOR, MAPK/ERK, and JAK/STAT3 signaling pathways. In addition, bosutinib enhanced doxorubicin (Dox)- and etoposide (VP-16)-induced cytotoxicity in NB cells. Furthermore, bosutinib demonstrated anti-tumor efficacy in an orthotopic xenograft NB mouse model in a similar mechanism as of that in vitro. In summary, our results reveal that Src and c-Abl are potential therapeutic targets in NB and that the novel Src/Abl inhibitor bosutinib alone or in combination with other chemotherapeutic agents may be a valuable therapeutic option for NB patients.

Neuroblastoma (NB) is the most common extracranial tumor in children. Unlike in most adult tumors, tumor suppressor protein 53 (p53) mutations occur with a relatively low frequency in NB and the downstream function of p53 is intact in NB cell lines. Wip1 is a negative regulator of p53 and hindrance of Wip1 activity by novel inhibitor GSK2830371 is a potential strategy to activate p53's tumor suppressing function in NB. Yet, the in vivo efficacy and the possible mechanisms of GSK2830371 in NB have not yet been elucidated. Here we report that novel Wip1 inhibitor GSK2830371 induced Chk2/p53-mediated apoptosis in NB cells in a p53-dependent manner. In addition, GSK2830371 suppressed the colony-formation potential of p53 wild-type NB cell lines. Furthermore, GSK2830371 enhanced doxorubicin- (Dox) and etoposide- (VP-16) induced cytotoxicity in a subset of NB cell lines, including the chemoresistant LA-N-6 cell line. More importantly, GSK2830371 significantly inhibited tumor growth in an orthotopic xenograft NB mouse model by inducing Chk2/p53-mediated apoptosis in vivo. Taken together, this study suggests that GSK2830371 induces Chk2/p53-mediated apoptosis both in vitro and in vivo in a p53 dependent manner.

Neuroblastoma (NB), which accounts for about 15% of cancer-related mortality in children, is the most common childhood extracranial malignant tumor. In NB, somatic mutations of the tumor suppressor, p53, are exceedingly rare. Unlike in adult tumors, the majority of p53 downstream functions are still intact in NB cells with wild-type p53. Thus, restoring p53 function by blocking its interaction with p53 suppressors such as MDM2 is a viable therapeutic strategy for NB treatment. Herein, we show that MDM2 inhibitor SAR405838 is a potent therapeutic drug for NB. SAR405838 caused significantly decreased cell viability of p53 wild-type NB cells and induced p53-mediated apoptosis, as well as augmenting the cytotoxic effects of doxorubicin (Dox). In an in vivo orthotopic NB mouse model, SAR405838 induced apoptosis in NB tumor cells. In summary, our data strongly suggest that MDM2-specific inhibitors like SAR405838 may serve not only as a stand-alone therapy, but also as an effective adjunct to current chemotherapeutic regimens for treating NB with an intact MDM2-p53 axis.

Purpose: As reimbursement programs shift to value-based payment models emphasizing quality and efficient healthcare delivery, there exists a need to better understand process management to unearth true costs of patient care. We sought to identify cost-reduction opportunities in simple appendicitis management by applying a time-driven activity-based costing (TDABC) methodology to this high-volume surgical condition., Methods: Process maps were created using medical record time stamps. Labor capacity cost rates were calculated using national median physician salaries, weighted nurse-patient ratios, and hospital cost data. Consumable costs for supplies, pharmacy, laboratory, and food were derived from the hospital general ledger., Results: Time-driven activity-based costing resulted in precise per-minute calculation of personnel costs. Highest costs were in the operating room ($747.07), hospital floor ($388.20), and emergency department ($296.21). Major contributors to length of stay were emergency department evaluation (270min), operating room availability (395min), and post-operative monitoring (1128min). The TDABC model led to $1712.16 in personnel costs and $1041.23 in consumable costs for a total appendicitis cost of $2753.39., Conclusion: Inefficiencies in healthcare delivery can be identified through TDABC. Triage-based standing delegation orders, advanced practice providers, and same day discharge protocols are proposed cost-reducing interventions to optimize value-based care for simple appendicitis., Level of Evidence: II., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: While most high-risk neuroblastoma (HRNB) patients are enrolled in cooperative group or institutional protocols, variability exists within these protocols as to when surgical resection of the primary tumor should be performed after neoadjuvant induction chemotherapy. We sought to determine if the number of chemotherapy cycles prior to surgery affects surgical or survival outcomes in HRNB patients., Methods: We performed a retrospective review of all HRNB patients <18years of age from 2000 to 2010, at Texas Children's Hospital. Patients were stratified based on the number of neoadjuvant induction chemotherapy cycles prior to surgical resection. Pre and post- chemotherapy tumor size, MYCN status, iodine-131-metaiodobenzylguanidine (MIBG) score at diagnosis, extent of surgical resection, estimated surgical blood loss, post-operative outcomes, and event free (EFS) and overall survival (OS) were evaluated. Data were analyzed using Wilcoxon rank-sum test, Kruskal-Wallis test, Fisher's exact test, Kaplan-Meier analyses, and Cox regression analyses. P-value <0.05 was considered significant., Results: Data from 50 patients with HRNB were analyzed. Patients were stratified by the number of cycles of chemotherapy received prior to surgery. Six patients received 2cycles of chemotherapy (12%), 20 patients received 3cycles (40%), 13 patients received 4cycles (26%), and 11 patients received 5cycles (22%) prior to surgical resection of the primary tumor. The 5-year OS was 33%, 45%, 83% and 36% in patients who received 2, 3, 4 and 5cycles of chemotherapy prior to surgery, respectively (p=0.07). Multivariate analysis revealed that patients who received 4cycles of chemotherapy had a significantly lower mortality (HR: 0.11, 95% CI: 0.01-0.87, p=0.04) compared to those with 2cycles of chemotherapy. Among the different cohorts, there were no differences with respect to MYCN status, MIBG score at diagnosis, incidence of bone marrow metastasis, extent of surgical resection, estimated blood loss, incidence of post-operative complications, or length of stay., Conclusion: HRNB patients who receive 4cycles of chemotherapy prior to surgical resection have a superior OS than patients who receive 2. Based on the superior survival of patients who received 4cycles of chemotherapy prior to surgery, further studies are warranted to elucidate these differences., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Neuroblastoma is an embryonic cancer of neural crest cell lineage, accounting for up to 10% of all pediatric cancer. The clinical course is heterogeneous ranging from spontaneous regression in neonates to life-threatening metastatic disease in older children. Much of this clinical variance is thought to result from distinct pathologic characteristics that predict patient outcomes. Consequently, many research efforts have been focused on identifying the underlying biologic and genetic features of neuroblastoma tumors in order to more clearly define prognostic subgroups for treatment stratification. Recent technological advances have placed emphasis on the integration of genetic alterations and predictive biologic variables into targeted treatment approaches to improve patient survival outcomes. This review will focus on these recent advances and the implications they have on the diagnostic, staging, and treatment approaches in modern neuroblastoma clinical management., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Pediatric colorectal cancer (CRC) is rare. Comparison with adult CRC tumors, management, and outcomes may identify opportunities for improvement in pediatric CRC care., Study Design: CRC patients in the National Cancer Data Base from 1998 to 2011, were grouped into Pediatric (≤21years), early onset adult (22-50) and older adult (>50) patients. Groups were compared with χ(2) and survival analysis., Results: A total of 918 pediatric (Ped), 157,779 early onset adult (EA), and 1,304,085 older adults (OA) were identified (p<0.01 for all comparisons). Patients ≤50 presented more frequently with stage 3 and 4 disease (Ped: 62.0%, EA: 49.7%, OA: 37.3%) and rectal cancer (Ped: 23.6%, EA: 27.5%, OA: 19.2%). Pediatric histology was more likely signet ring, mucinous, and poorly differentiated. Initial treatment was usually surgery, but patients ≤50 were more likely to have radiation (Ped: 15.1%, EA: 18.6%, and OA: 9.2%) and chemotherapy (Ped: 42.0%, EA: 38.2%, and OA: 22.7%). Children and older adults showed poorer overall survival at 5years when compared to early onset adults. Adjusting for covariates, age ≤21 was a significant predictor of mortality for colon and rectal cancers (colon HR: 1.22, rectal HR: 1.69)., Conclusions: This is the largest cohort of pediatric CRC patients, revealing more aggressive tumor histology and behavior in children, particularly in rectal cancer. Despite standard oncologic treatment, age ≤21 was a significant predictor of mortality. This is likely owing to worse tumor biology rather than treatment disparities and may signal the need for different therapeutic strategies., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Importance: Whole-exome sequencing (WES) has the potential to reveal tumor and germline mutations of clinical relevance, but the diagnostic yield for pediatric patients with solid tumors is unknown., Objective: To characterize the diagnostic yield of combined tumor and germline WES for children with solid tumors., Design: Unselected children with newly diagnosed and previously untreated central nervous system (CNS) and non-CNS solid tumors were prospectively enrolled in the BASIC3 study at a large academic children's hospital during a 23-month period from August 2012 through June 2014. Blood and tumor samples underwent WES in a certified clinical laboratory with genetic results categorized on the basis of perceived clinical relevance and entered in the electronic health record., Main Outcomes and Measures: Clinical categorization of somatic mutations; frequencies of deleterious germline mutations related to patient phenotype and incidental medically-actionable mutations., Results: Of the first 150 participants (80 boys and 70 girls, mean age, 7.4 years), tumor samples adequate for WES were available from 121 patients (81%). Somatic mutations of established clinical utility (category I) were reported in 4 (3%) of 121 patients, with mutations of potential utility (category II) detected in an additional 29 (24%) of 121 patients. CTNNB1 was the gene most frequently mutated, with recurrent mutations in KIT, TSC2, and MAPK pathway genes (BRAF, KRAS, and NRAS) also identified. Mutations in consensus cancer genes (category III) were found in an additional 24 (20%) of 121 tumors. Fewer than half of somatic mutations identified were in genes known to be recurrently mutated in the tumor type tested. Diagnostic germline findings related to patient phenotype were discovered in 15 (10%) of 150 cases: 13 pathogenic or likely pathogenic dominant mutations in adult and pediatric cancer susceptibility genes (including 2 each in TP53, VHL, and BRCA1), 1 recessive liver disorder with hepatocellular carcinoma (TJP2), and 1 renal diagnosis (CLCN5). Incidental findings were reported in 8 (5%) of 150 patients. Most patients harbored germline uncertain variants in cancer genes (98%), pharmacogenetic variants (89%), and recessive carrier mutations (85%)., Conclusions and Relevance: Tumor and germline WES revealed mutations in a broad spectrum of genes previously implicated in both adult and pediatric cancers. Combined reporting of tumor and germline WES identified diagnostic and/or potentially actionable findings in nearly 40% of newly diagnosed pediatric patients with solid tumors.

Background: The purpose of this study was to review surgical outcomes after elective placement of peritoneal dialysis (PD) catheters in children with end-stage renal disease., Methods: Children with PD catheters placed between February 2002 and July 2014 were retrospectively reviewed. Outcomes were catheter life, late (>30days post-op) complications (catheter malfunction, catheter malposition, infection), and re-operation rates. Comparison groups included laparoscopic versus open placement, age<2, and weight<10kg. Univariate and multivariate analysis were performed., Results: One hundred sixteen patients had 173 catheters placed (122 open, 51 laparoscopic) with an average patient age of 9.7±6.3years. Mean catheter life was similar in the laparoscopic and open groups (581±539days versus 574±487days, p=0.938). The late complication rate was higher for open procedures (57% versus 37%, p=0.013). Children age<2 or weight<10kg had higher re-operation rates (64% versus 42%, p=0.014 and 73% versus 40%, p=0.001, respectively). Adjusted for age and weight, open technique remained a risk factor for late complications (OR 2.44, 95% CI 1.20-4.95) but not re-operation., Discussion: Laparoscopic placement appears to reduce the rate of late complications in children who require PD dialysis catheters. Children <2years age or <10kg remain at risk for complications regardless of technique., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: A pilot rounding surgeon of the week (SOW) program was implemented in our institution on July 2013 to improve patient care through focused attending rounds. The purpose of this study was to assess the impact of the SOW., Methods: We performed a descriptive retrospective study from a single, large-volume academic center. Data were collected from July to December 2013 (post-SOW) and compared to July to December 2012 (pre-SOW). Outcomes included patient safety (safety reports) and team productivity (billing data). We also evaluated nursing satisfaction through a 10-point Likert scale survey., Results: The total number of patient safety complaints decreased after the SOW (37 pre-SOW versus 27 post-SOW). Work relative value units (wRVUs) increased by 8% while nonoperative billing increased by 15%. Twenty of the daytime nursing staff completed the survey and overall satisfaction with the SOW was 8.3. Twelve were employed prior to the SOW and, when analyzed independently, the proportion of employees satisfied with nursing to physician communication was higher after the SOW (55% pre-SOW vs. 83% post-SOW, p=0.13) as was perception of parental satisfaction (33% vs. 75%, p=0.04)., Conclusions: The SOW program appears to improve patient safety as evidenced by a decrease in patient safety events. Additionally, the SOW program led to higher ancillary staffing satisfaction and perceived parental satisfaction without decreasing revenue. This study suggests that the SOW may be a beneficial program that could be considered at other large-volume institutions., (Copyright © 2015 Elsevier Inc. All rights reserved.)