Implications of Tumor Characteristics and Treatment Modality on Local Recurrence and Functional Outcomes in Children With Chest Wall Sarcoma: A Pediatric Surgical Oncology Research Collaborative Study.

OBJECTIVE: To determine the impact of tumor characteristics and treatment approach on (1) local recurrence, (2) scoliosis development, and (3) patient-reported quality of life in children with sarcoma of the chest wall. SUMMARY OF BACKGROUND DATA: Children with chest wall sarcoma require multimodal therapy including chemotherapy, surgery, and/or radiation. Despite aggressive therapy which places them at risk for functional impairment and scoliosis, these patients are also at significant risk for local recurrence. METHODS: A multi-institutional review of 175 children (median age 13 years) with chest wall sarcoma treated at seventeen Pediatric Surgical Oncology Research Collaborative institutions between 2008 and 2017 was performed. Patient-reported quality of life was assessed prospectively using PROMIS surveys. RESULTS: The most common diagnoses were Ewing sarcoma (67%) and osteosarcoma (9%). Surgical resection was performed in 85% and radiation in 55%. A median of 2 ribs were resected (interquartile range = 1-3), and number of ribs resected did not correlate with margin status ( P = 0.36). Local recurrence occurred in 23% and margin status was the only predictive factor(HR 2.24, P = 0.039). With a median follow-up of 5 years, 13% developed scoliosis (median Cobb angle 26) and 5% required corrective spine surgery. Scoliosis was associated with posteriorrib resection (HR 8.43; P= 0.003) and increased number of ribs resected (HR 1.78; P = 0.02). Overall, patient-reported quality of life is not impaired after chest wall tumor resection. CONCLUSIONS: Local recurrence occurs in one-quarter of children with chest wall sarcoma and is independent of tumor type. Scoliosis occurs in 13% of patients, but patient-reported quality of life is excellent.

Intestinal organoids: roadmap to the clinic.

Recent advances in intestinal organoid research, along with encouraging preclinical proof-of-concept studies, have revealed significant therapeutic potential for induced pluripotent stem cell (iPSC)-derived organoids in the healing and replacement of severely injured or diseased bowel (Finkbeiner et al. Biol Open 4: 1462-1472, 2015; Kitano et al. Nat Commun 8: 765, 2017; Cruz-Acuna et al. Nat Cell Biol 19: 1326-1335, 2017). To fully realize the tremendous promise of stem cell organoid-based therapies, careful planning aligned with significant resources and efforts must be devoted demonstrating their safety and efficacy to meet critical regulatory requirements. Early recognition of the inherent preclinical and clinical obstacles that occur with the novel use of pluripotent stem cell-derived products will accelerate their bench-to-bedside translation (Neofytou et al. J Clin Invest 125: 2551-2557, 2015; O'Brien et al. Stem Cell Res Ther 6: 146, 2015; Ouseph et al. Cytotherapy 17: 339-343, 2015). To overcome many of these hurdles, a close and effective collaboration is needed between experts from various disciplines, including basic and clinical research, product development and manufacturing, quality assurance and control, and regulatory affairs. Therefore, the purpose of this article is to outline the critical areas and challenges that must be addressed when transitioning laboratory-based discovery, through an investigational new drug (IND) application to first-in-human clinical trial, and to encourage investigators to consider the required regulatory steps from the earliest stage of the translational process. The ultimate goal is to provide readers with a draft roadmap that they could use while navigating this exciting cell therapy space.

Optimization of percutaneous biopsy for diagnosis and pretreatment risk assessment of neuroblastoma.

BACKGROUND: Image-guided percutaneous core needle biopsy (PCNB) is increasingly utilized to diagnose solid tumors. The objective of this study is to determine whether PCNB is adequate for modern biologic characterization of neuroblastoma. PROCEDURE: A multi-institutional retrospective study was performed by the Pediatric Surgical Oncology Research Collaborative on children with neuroblastoma at 12 institutions over a 3-year period. Data collected included demographics, clinical details, biopsy technique, complications, and adequacy of biopsies for cytogenetic markers utilized by the Children's Oncology Group for risk stratification. RESULTS: A total of 243 children were identified with a diagnosis of neuroblastoma: 79 (32.5%) tumor excision at diagnosis, 94 (38.7%) open incisional biopsy (IB), and 70 (28.8%) PCNB. Compared to IB, there was no significant difference in ability to accurately obtain a primary diagnosis by PCNB (95.7% vs 98.9%, P = .314) or determine MYCN copy number (92.4% vs 97.8%, P = .111). The yield for loss of heterozygosity and tumor ploidy was lower with PCNB versus IB (56.1% vs 90.9%, P < .05; and 58.0% vs. 88.5%, P < .05). Complications did not differ between groups (2.9 % vs 3.3%, P = 1.000), though the PCNB group had fewer blood transfusions and lower opioid usage. Efficacy of PCNB was improved for loss of heterozygosity when a pediatric pathologist evaluated the fresh specimen for adequacy. CONCLUSIONS: PCNB is a less invasive alternative to open biopsy for primary diagnosis and MYCN oncogene status in patients with neuroblastoma. Our data suggest that PCNB could be optimized for complete genetic analysis by standardized protocols and real-time pathology assessment of specimen quality.

Acid suppression duration does not alter anastomotic stricture rates after esophageal atresia with distal tracheoesophageal fistula repair: A prospective multi-institutional cohort study.

INTRODUCTION: Anastomotic stricture is the most common complication after esophageal atresia (EA) repair. We sought to determine if postoperative acid suppression is associated with reduced stricture formation. METHODS: A prospective, multi-institutional cohort study of infants undergoing primary EA repair from 2016 to 2020 was performed. Landmark analysis and multivariate Cox regression were used to explore if initial duration of acid suppression was associated with stricture formation at hospital discharge (DC), 3-, 6-, and 9-months postoperatively. RESULTS: Of 156 patients, 79 (51%) developed strictures and 60 (76%) strictures occurred within three months following repair. Acid suppression was used in 141 patients (90%). Landmark analysis showed acid suppression was not associated with reduction in initial stricture formation at DC, 3-, 6- and 9-months, respectively (p = 0.19-0.95). Multivariate regression demonstrated use of a transanastomotic tube was significantly associated with stricture formation at DC (Hazard Ratio (HR) = 2.21 (95% CI 1.24-3.95, p<0.01) and 3-months (HR 5.31, 95% CI 1.65-17.16, p<0.01). There was no association between acid suppression duration and stricture formation. CONCLUSION: No association between the duration of postoperative acid suppression and anastomotic stricture was observed. Transanastomotic tube use increased the risk of anastomotic strictures at hospital discharge and 3 months after repair.

Prospective quality of life outcomes in pediatric fecal incontinence following bowel management.

BACKGROUND: Severe fecal incontinence (FI) is common in patients both with and without anorectal malformations. Whether a formal bowel management program (BMP) has significant effects on FI, psychosocial development of the child, and caregiver stress is poorly understood. We hypothesize that BMP participation results in long-term clinical and quality of life (QOL) improvements for patients and caregivers. METHODS: Using a prospective cohort study over three years, 342 children (age 3-12 years) and caregivers were followed for one year after attending a week-long BMP, during which a regimen was tailored to promote daily stool evacuation.FI QOL was measured with the validated Cincinnati Fecal Incontinence Scale (CINCY-FIS), evaluating multiple subscales, including parental stress. Scores were obtained at multiple timepoints following BMP (baseline, 2 weeks, 3 months, 1 year). RESULTS: Within 2 weeks, BMP participation significantly improved FI with increased frequency of daily daytime voluntary bowel movements (20%-70%, p < 0.001) and decreased daily daytime and nighttimeinvoluntary bowel movements (60%-20%, p < 0.001; 30%-10%, p < 0.05). Marked improvements in CINCY-FIS were observed across multiple QOL subscales, with the greatest in parental stress, and sustained through one year. CONCLUSIONS: BMP results in significant and sustained improvement in FI and QOL for patients and caregivers.

Clinical outcomes following implementation of a management bundle for esophageal atresia with distal tracheoesophageal fistula.

BACKGROUND/PURPOSE: This study evaluated compliance with a multi-institutional quality improvement management protocol for Type-C esophageal atresia with distal tracheoesophageal fistula (EA/TEF). METHODS: Compliance and outcomes before and after implementation of a perioperative protocol bundle for infants undergoing Type-C EA/TEF repair were compared across 11 children's hospitals from 1/2016-1/2019. Bundle components included elimination of prosthetic material between tracheal and esophageal suture lines during repair, not leaving a transanastomotic tube at the conclusion of repair (NO-TUBE), obtaining an esophagram by postoperative-day-5, and discontinuing prophylactic antibiotics 24 h postoperatively. RESULTS: One-hundred seventy patients were included, 40% pre-protocol and 60% post-protocol. Bundle compliance increased 2.5-fold pre- to post-protocol from 17.6% to 44.1% (p < 0.001). After stratifying by institutional compliance with all bundle components, 43.5% of patients were treated at low-compliance centers (<20%), 43% at medium-compliance centers (20-80%), and 13.5% at high-compliance centers (>80%). Rates of esophageal leak, anastomotic stricture, and time to full feeds did not differ between pre- and post-protocol cohorts, though there was an inverse correlation between NO-TUBE compliance and stricture rate over time (ρ = -0.75, p = 0.029). CONCLUSIONS: Compliance with our multi-institutional management protocol increased 2.5-fold over the study period without compromising safety or time to feeds and does not support the use of transanastomotic tubes. LEVEL OF EVIDENCE: Level II. TYPE OF STUDY: Treatment Study.

A Quality Improvement Initiative to Decrease Time to Antibiotics for Children with Intestinal Failure, Fever, and a Central Line.

INTRODUCTION: Pediatric intestinal failure (IF) patients experience significant morbidity, including sepsis related to central line-associated bloodstream infections. Adult studies of sepsis demonstrate an association between time to antibiotic administration (TTA) and mortality. To overcome challenges in treating pediatric IF patients in an emergency department (ED), we appropriated an existing, reliable system for febrile immunocompromised oncology/bone marrow transplant children. We describe the translation of this process to febrile IF patients in the ED and steps toward sustained improvement. METHODS: We formed a multidisciplinary team and used the Model for Improvement to define aims and identify key drivers. The goal was to use an existing improvement process to increase the percentage of patients with IF who receive antibiotics within 60 minutes of arrival to the ED from 46% to 90%. Key drivers included pre- and postarrival processes, staff and family engagement, and a preoccupation with failure. We performed Plan-Do-Study-Act cycles targeting family engagement, prearrival efficiency, and postarrival consistency. RESULTS: Two hundred seventy-six encounters involving febrile IF patients between November 2012 and March 2017 were evaluated. There was a sustained reduction in the median time from arrival to antibiotic administration (71-45 minutes). We decreased TTA to less than 60 minutes for 77% of febrile IF patients. CONCLUSIONS: The basic tenets of process improvement for 1 high-risk population can be translated to another high-risk population but must be adjusted for variability in characteristics.

Pediatric trauma undertriage in Ohio.

BACKGROUND: Appropriate and timely triage is an essential component of a trauma system. In the state of Ohio, there are 6 verified pediatric trauma centers (PTCs) across 8 state regions. The purpose of this study was to better understand the pediatric undertriage rates in the state. METHODS: We used the Ohio Trauma Registry from 2007 to 2012, consisting of 14,045 records of children younger than 16 years admitted to a hospital for more than 48 hours or who sustained a traumatic death. Pediatric undertriage was defined as not being directly transported to a PTC when one was available within 30 minutes or not being transferred to a PTC within 2 hours of injury. RESULTS: The state pediatric undertriage rate was 52%, only decreasing to 35% when up to a 4-hour transfer time was allowed. Across state trauma regions, undertriage rates varied from 94% to 40%. More than 28% of injured children had access to a PTC within 30 minutes of their home. A trauma center (adult or pediatric) was within 30 minutes for 66% of the children, yet 32% of the children went to a nontrauma center first. Overall, 29% of children never made it to a PTC, and 4% of children remained at a nontrauma center, with regional variation from 5% to 0.5%. Statewide mortality was nearly 3%, with regional variations between 5% and 0.4%. Mortality rate within the appropriately triaged group was 5.3%, while mortality rate in the undertriage group was only 0.7%. Overall, 53% of transferred patients had a more than 2-hour transfer time. CONCLUSIONS: Despite the significant number of PTCs in Ohio, there remains a high undertriage rate with significant regional variations and long transfer times. Continued analysis will be useful in furthering trauma system development for the injured child. LEVEL OF EVIDENCE: Therapeutic/care management study, level IV; epidemiological, level IV.

Ethanol Lock Efficacy and Associated Complications in Children With Intestinal Failure.

BACKGROUND: Prophylactic ethanol lock therapy (ELT) reduces central line-associated bloodstream infections (CLA-BSIs) in children with intestinal failure (IF). However, the risk of associated complications is unclear. We aim to describe our experience with prophylactic ethanol locks in a cohort of patients with IF. MATERIALS AND METHODS: Thirty patients on ELT from 2010-2013 were identified by review of our intestinal rehabilitation registry. Patient demographics, CLA-BSI events, and line complications were extracted. Comparisons in infection and complication rates when on and off ELT were made using a Poisson mixed-effect regression model. RESULTS: CLA-BSIs when on and off ELT were 3.1 and 5.5 per 1000 catheter days, respectively (P <015). Overall complication rates were similar in both groups. In those patients who experienced a complication, the complication rates on ELT compared with time off ELT were significantly lower (P <003). Line perforation or breakage rates declined significantly when on ELT, from 1.8 to 1.53 per 1000 catheter days (P <006). Line occlusion rates also decreased on ELT, from 0.6 to 0.3 per 1000 catheter days (P =056). Infecting organisms were not different on and off ELT, and patients experienced a similar number of polymicrobial infections on or off therapy. Klebsiella pneumoniae was the most common infecting organism in both groups. CONCLUSIONS: Ethanol lock therapy use reduces both CLA-BSI and central line complication rates in children with IF. These results underscore the safety and efficacy of ELT use in this population.

Increased Anti-Flagellin and Anti-Lipopolysaccharide Immunoglobulins in Pediatric Intestinal Failure: Associations With Fever and Central Line-Associated Bloodstream Infections.

BACKGROUND: Central line-associated bloodstream infections (CLABSIs) pose a significant challenge in the lives of patients with intestinal failure (IF). We hypothesized that plasma immunoglobulins against flagellin (FLiC) and lipopolysaccharide (LPS) would be able to differentiate CLABSIs from nonbacterial febrile episodes and that levels would increase with infection and decline following appropriate antibiotic treatment. MATERIALS AND METHODS: Patients with IF, due to short bowel syndrome, between the ages of 3 months and 4 years of age, were recruited at Cincinnati Children's Hospital Medical Center. Anti-FLiC and anti-LPS plasma antibody levels were measured in 13 children with IF at baseline, during febrile events, and also following treatment with antibiotics. These were also measured in 11 healthy children without IF who were recruited as controls. RESULTS: Plasma anti-FLiC IgA levels increased during febrile episodes in all patients with IF (baseline mean of 1.10 vs febrile episode mean of 1.32 optical density units, respectively; P = .046). Neither plasma anti-FLiC nor anti-LPS IgA or IgG levels distinguished CLABSI from nonbacterial febrile episodes compared with baseline levels. Compared with controls, patients with IF had significantly higher plasma levels of anti-FLiC and anti-LPS IgA at baseline. CONCLUSION: Plasma anti-FLiC IgA antibody levels rise during febrile episodes but do not differentiate between nonbacterial febrile illnesses and CLABSIs in pediatric IF. However, the upregulation of these antibodies in IF suggests the baseline systemic presence of Gram-negative bacterial products.

Nonclinical evaluation of GMA161--an antihuman CD16 (FcγRIII) monoclonal antibody for treatment of autoimmune disorders in CD16 transgenic mice.

Fc receptors are a critical component of the innate immune system responsible for the recognition of cross-linked antibodies and the subsequent clearance of pathogens. However, in autoimmune diseases, these receptors play a role in the deleterious action of self-directed antibodies and as such are candidate targets for treatment. GMA161 is an aglycosyl, humanized version of the murine antibody 3G8 that targets the human low-affinity Fcγ receptor III (CD16). As CD16 expression and sequence have high species specificity, preclinical assessments were conducted in mice transgenic for both isoforms of human CD16, CD16A, and CD16B. This transgenic mouse model was useful in transitioning into phase I clinical trials, as it generated positive efficacy data in a relevant disease model and an acceptable single-dose safety profile. However, when GMA161 or its murine parent 3G8 were dosed repeatedly in transgenic mice having both human CD16 isoforms, severe reactions were observed that were not associated with significant cytokine release, nor were they alleviated by antihistamine administration. Prophylactic dosing with an inhibitor of platelet-activating factor (PAF), however, completely eliminated all signs of hypersensitivity. These findings suggest that (1) GMA161 elicits a reaction that is target dependent, (2) immunogenicity and similar adverse reactions were observed with a murine version of the antibody, and (3) the reaction is driven by the atypical hypersensitivity pathway mediated by PAF.

Immune depletion with cellular mobilization imparts immunoregulation and reverses autoimmune diabetes in nonobese diabetic mice.

OBJECTIVE: The autoimmune destruction of beta-cells in type 1 diabetes results in a loss of insulin production and glucose homeostasis. As such, an immense interest exists for the development of therapies capable of attenuating this destructive process through restoration of proper immune recognition. Therefore, we investigated the ability of the immune-depleting agent antithymocyte globulin (ATG), as well as the mobilization agent granulocyte colony-stimulating factor (GCSF), to reverse overt hyperglycemia in the nonobese diabetic (NOD) mouse model of type 1 diabetes. RESEARCH DESIGN AND METHODS: Effects of each therapy were tested in pre-diabetic and diabetic female NOD mice using measurements of glycemia, regulatory T-cell (CD4+CD25+Foxp3+) frequency, insulitis, and/or beta-cell area. RESULTS: Here, we show that combination therapy of murine ATG and GCSF was remarkably effective at reversing new-onset diabetes in NOD mice and more efficacious than either agent alone. This combination also afforded durable reversal from disease (>180 days postonset) in animals having pronounced hyperglycemia (i.e., up to 500 mg/dl). Additionally, glucose control improved over time in mice subject to remission from type 1 diabetes. Mechanistically, this combination therapy resulted in both immunological (increases in CD4-to-CD8 ratios and splenic regulatory T-cell frequencies) and physiological (increase in the pancreatic beta-cell area, attenuation of pancreatic inflammation) benefits. CONCLUSIONS: In addition to lending further credence to the notion that combination therapies can enhance efficacy in addressing autoimmune disease, these studies also support the concept for utilizing agents designed for other clinical applications as a means to expedite efforts involving therapeutic translation.