Clinical Outcomes of Intravenous Methylnaltrexone in Children: A Single-Arm Retrospective Cohort Study.

OBJECTIVES: Constipation is a common adverse event of opioid use that is often difficult to treat. Methylnaltrexone is a therapeutic option for opioid-induced constipation (OIC) approved for oral and subcutaneous use in adults. These administration routes are not always feasible in the pediatric population. The primary objective of this research was to quantify the response rate of methylnaltrexone in pediatric patients when it was administered via the intravenous (IV) route. METHODS: This retrospective study evaluated patients ages <18 years who received IV methylnaltrexone between January 1, 2013, and June 30, 2020, for OIC. Efficacy was evaluated through documentation of bowel evacuation within 4 hours of methylnaltrexone administration. Adverse events observed within 24 hours of administration were attributed to methylnaltrexone. RESULTS: Methylnaltrexone was administered to 134 unique patients during the study period. Of these, 46 met exclusion criteria, resulting in 88 patients being included in the study. Patients with an underlying hematology/oncology diagnosis consisted of 77% of the study population, and 23% of patients had an -underlying medical/surgical diagnosis. The response rate to IV methylnaltrexone was 25% (CI, 16-34). CONCLUSIONS: The results of this retrospective chart review demonstrate the potential role of IV methylnaltrexone in the pediatric population. Despite the overall lower response rate relative to that reported in adults, IV methylnaltrexone possesses a unique mechanism of action that may serve as an alternative treatment option for patients unable to use the oral and subcutaneous administration routes. There were no significant adverse events seen in the study.

Multicentre, retrospective cohort study protocol to identify racial and ethnic differences in acute kidney injuries in children and adolescents with diabetic ketoacidosis.

INTRODUCTION: Approximately 40% of children with diabetic ketoacidosis (DKA) develop acute kidney injury (AKI), which increases the risk of chronic kidney damage. At present, there is limited knowledge of racial or ethnic differences in diabetes-related kidney injury in children with diabetes. Understanding whether such differences exist will provide a foundation for addressing disparities in diabetes care that may continue into adulthood. Further, it is currently unclear which children are at risk to develop worsening or sustained DKA-related AKI. The primary aim is to determine whether race and ethnicity are associated with DKA-related AKI. The secondary aim is to determine factors associated with sustained AKI in children with DKA. METHODS AND ANALYSIS: This retrospective, multicentre, cross-sectional study of children with type 1 or type 2 diabetes with DKA will be conducted through the Paediatric Emergency Medicine Collaborative Research Committee. Children aged 2-18 years who were treated in a participating emergency department between 1 January 2020 and 31 December 2023 will be included. Children with non-ketotic hyperglycaemic-hyperosmolar state or who were transferred from an outside facility will be excluded. The relevant predictor is race and ethnicity. The primary outcome is the presence of AKI, defined by Kidney Disease: Improving Global Outcomes criteria. The secondary outcome is 'sustained' AKI, defined as having AKI ≥48 hours, unresolved AKI at last creatinine measurement or need for renal replacement therapy. Statistical inference of the associations between predictors (ie, race and ethnicity) and outcomes (ie, AKI and sustained AKI) will use random effects regression models, accounting for hospital variation and clustering. ETHICS AND DISSEMINATION: The Institutional Review Board of Children's Minnesota approved this study. 12 additional sites have obtained institutional review board approval, and all sites will obtain local approval prior to participation. Results will be presented at local or national conferences and for publication in peer-reviewed journals.

Anaplastic sarcoma of the kidney (DICER1-sarcoma of the kidney): A report from the International Pleuropulmonary Blastoma/DICER1 Registry.

BACKGROUND: Anaplastic sarcoma of the kidney (ASK) is a DICER1-related neoplasm first identified as a distinctive tumor type through the evaluation of unusual cases of putative anaplastic Wilms tumors. Subsequent case reports identified the presence of biallelic DICER1 variants as well as progression from cystic nephroma, a benign DICER1-related neoplasm. Despite increasing recognition of ASK as a distinct entity, the optimal treatment remains unclear. METHODS: Individuals with known or suspected DICER1-related tumors including ASK were enrolled in the International Pleuropulmonary Blastoma/DICER1 Registry. Additionally, a comprehensive review of reported cases of ASK was undertaken, and data were aggregated for analysis with the aim to identify prognostic factors and clinical characteristics to guide decisions regarding genetic testing, treatment, and surveillance. RESULTS: Ten cases of ASK were identified in the Registry along with 37 previously published cases. Staging data, per Children's Oncology Group guidelines, was available for 40 patients: 13 were stage I, 12 were stage II, 10 were stage III, and five were stage IV. Outcome data were available for 37 patients. Most (38 of 46) patients received upfront chemotherapy and 14 patients received upfront radiation. Two-year event-free survival (EFS) for stage I-II ASK was 81.8% (95% confidence interval [CI]: 67.2%-99.6%), compared with 46.6% EFS (95% CI: 24.7%-87.8%) for stage III-IV (p = .07). Two-year overall survival (OS) for stage I-II ASK was 88.9% (95% CI: 75.5%-100.0%), compared with 70.0% (95% CI: 46.7%-100.0%) for stage III-IV (p = .20). Chemotherapy was associated with improved EFS and OS with hazard ratios of 0.09 (95% CI: 0.02-0.31) and 0.08 (95% CI: 0.02-0.42), respectively. CONCLUSION: ASK is a rare DICER1-related renal neoplasm. In the current report, we identify clinical and treatment-related factors associated with outcome including the importance of chemotherapy in treating ASK. Ongoing data collection and genomic analysis are indicated to optimize outcomes for children and adults with these rare tumors.

Outcomes in ovarian Sertoli-Leydig cell tumor: A report from the International Pleuropulmonary Blastoma/DICER1 and Ovarian and Testicular Stromal Tumor Registries.

OBJECTIVE: Sertoli-Leydig cell tumors (SLCTs) are rare sex cord-stromal tumors, representing <0.5% of all ovarian tumors. We sought to describe prognostic factors, treatment and outcomes for individuals with ovarian SLCT. METHODS: Individuals with SLCT were enrolled in the International Pleuropulmonary Blastoma/DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Medical records were systematically abstracted, and pathology was centrally reviewed when available. RESULTS: In total, 191 participants with ovarian SLCT enrolled, with most (92%, 175/191) presenting with FIGO stage I disease. Germline DICER1 results were available for 156 patients; of these 58% had a pathogenic or likely pathogenic germline variant. Somatic (tumor) DICER1 testing showed RNase IIIb hotspot variants in 97% (88/91) of intermediately and poorly differentiated tumors. Adjuvant chemotherapy was administered in 40% (77/191) of cases, and among these, nearly all patients received platinum-based regimens (95%, 73/77), and 30% (23/77) received regimens that included an alkylating agent. Three-year recurrence-free survival for patients with stage IA tumors was 93.6% (95% CI: 88.2-99.3%) compared to 67.1% (95% CI: 55.2-81.6%) for all stage IC and 60.6% (95% CI: 40.3-91.0%) for stage II-IV (p < .001) tumors. Among patients with FIGO stage I tumors, those with mesenchymal heterologous elements treated with surgery alone were at higher risk for recurrence (HR: 74.18, 95% CI: 17.99-305.85). CONCLUSION: Most individuals with SLCT fare well, though specific risk factors such as mesenchymal heterologous elements are associated with poor prognosis. We also highlight the role of DICER1 surveillance in early detection of SLCT, facilitating stage IA resection.

Impact of the COVID-19 pandemic on utilization and cost for care of pediatric and young adult ALL.

OBJECTIVE: Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and among the most common malignancies in young adults and requires a unique pattern of healthcare utilization including an acute/emergent presentation and an intensive initial 8 months of therapy followed by two years of outpatient treatment. The COVID-19 pandemic caused massive global disruptions in healthcare use and delivery. This report aims to examine the effects of the COVID-19 pandemic on the presentation, diagnosis and continued management of childhood and young adult ALL in regard to utilization and cost of care among commercially insured individuals in the United States. RESULTS: Utilizing a commercial insurance claims database, 529 pediatric and young adult patients were identified who were diagnosed with ALL between January 2016 and March 2021. New diagnoses were evaluated by era and demographics. Utilization was measured by COVID-related era as number of inpatient and outpatient encounters, inpatient days, and cumulative cost during the initial 8 months of therapy. None of these cost or utilization factors changed significantly during or shortly after the pandemic. These findings reinforce that the necessary care for pediatric and young adult ALL was unwavering despite the massive shifts in the healthcare system caused by the COVID-19 pandemic. This provides a valuable benchmark as we further examine the factors that influence the pandemic's impact on health equity and access to care, especially in vulnerable pediatric and young adult populations. This is the first investigation of the effect of the COVID-19 pandemic on utilization and cost of care in pediatric and young adult cancer.

Prevalence of lung cysts in adolescents and adults with a germline DICER1 pathogenic/likely pathogenic variant: a report from the National Institutes of Health and International Pleuropulmonary Blastoma/DICER1 Registry.

BACKGROUND: Pleuropulmonary blastoma (PPB), the hallmark tumour associated with DICER1-related tumour predisposition, is characterised by an age-related progression from a cystic lesion (type I) to a high-grade sarcoma with mixed cystic and solid features (type II) or purely solid lesion (type III). Not all cystic PPBs progress; type Ir (regressed), hypothesised to represent regressed or non-progressed type I PPB, is an air-filled, cystic lesion lacking a primitive sarcomatous component. This study aims to evaluate the prevalence of non-progressed lung cysts detected by CT scan in adolescents and adults with germline DICER1 pathogenic/likely pathogenic (P/LP) variants. METHODS: Individuals were enrolled in the National Cancer Institute Natural History of DICER1 Syndrome study, the International PPB/DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Individuals with a germline DICER1 P/LP variant with first chest CT at 12 years of age or older were selected for this analysis. RESULTS: In the combined databases, 110 individuals with a germline DICER1 P/LP variant who underwent first chest CT at or after the age of 12 were identified. Cystic lung lesions were identified in 38% (42/110) with a total of 72 cystic lesions detected. No demographic differences were noted between those with lung cysts and those without lung cysts. Five cysts were resected with four centrally reviewed as type Ir PPB. CONCLUSION: Lung cysts are common in adolescents and adults with germline DICER1 variation. Further study is needed to understand the mechanism of non-progression or regression of lung cysts in childhood to guide judicious intervention.

Healthcare cost and utilization for chimeric antigen receptor (CAR) T-cell therapy in the treatment of pediatric acute lymphoblastic leukemia: A commercial insurance claims database analysis.

BACKGROUND: B-lineage acute lymphoblastic leukemia (B-ALL) is the most common malignancy of childhood. With the introduction of novel cellular therapies, cost of care is a critical component and the financial burden experienced by patients and society requires evaluation. AIMS: This study aims to assess the utilization and cost of care for chimeric antigen receptor T-cell (CAR-T) therapy for pediatric ALL patients with commercial insurance coverage in the United States. METHODS AND RESULTS: Using de-identified commercial insurance data from the OptumLabs® Data Warehouse, a cohort of 37 patients, aged 1-25 years, with B-ALL treated with CAR-T therapy between Oct 2016 and Dec 2021 in the United States was identified. Cost was evaluated for a 90 day period encompassing CAR-T infusion and by administration and complication characteristics. Among the 37 identified B-ALL patients that received a CAR-T product infusion, 14 patients were female, median age at administration was 13 years. The median 90-day total cost was $620,500 (Mean: $589,108). Inpatient cost accounted for approximately 71% of the total cost with an average of 28 inpatient days per patient. Although inpatient cost was slightly higher in the older age group (aged 10-25 years) and in patients with a code for cytokine release syndrome (CRS), these differences were not statistically significant. CONCLUSION: This real-world cost analysis shows for the first time the encompassing cost of CAR-T therapy for pediatric B-ALL patients in the US with commercial insurance. This study provides a valuable benchmark that can be used to analyze the financial implications of CAR-T therapy for pediatric B-ALL therapy on health systems.

Maternal smoking during pregnancy links to childhood blood pressure through birth weight and body mass index: NHANES 1999-2018.

Maternal smoking during pregnancy (MSDP) is associated with lower birth weight, childhood obesity, and elevated blood pressure (BP) in offspring. We aimed to examine whether birth weight and body mass index (BMI) mediate the effect of MSDP on BP in children. The study included 14,713 children aged 8 to 15 years from the National Health and Nutrition Examination Surveys from 1999 to 2018. General third-variable models were used to examine the mediating effects of birth weight and BMI on the association of MSDP with BP. A total of 1928 (13.1%) children were exposed to MSDP. MSDP was associated with reduced birth weight (p < 0.001), increased BMI (p < 0.001), and elevated systolic BP (p = 0.005). MSDP was not associated with systolic BP after adjustment for birth weight and BMI z-score (p = 0.875), with 95.0% of the effect of MSDP on BP mediated by birth weight (39.1%) and BMI (55.9%). In conclusion, lower birth weight and increased obesity measures mediate the adverse effects of MSDP on BP in children. These findings provide novel mechanistic insight into the adverse effect of MSDP on BP in children and have implications for preventing hypertension in later life.

Novel Metabolites Are Associated With Thrombosis After Cardiac Surgery in Children With Congenital Heart Disease.

BACKGROUND: Thrombosis is a major complication after cardiac surgery in children with congenital heart disease. The mechanisms underlying thrombosis development remain poorly understood. We aimed to identify novel circulating metabolites before cardiac surgery that are associated with thrombosis after surgery in children with congenital heart disease. METHODS: In this prospective cohort study, all blood samples were drawn right before surgical incision and after the induction of anesthesia, and plasma was separated immediately under 4 °C. Untargeted metabolomic data were measured by Metabolon in plasma from children (age range, 0 days-18 years) with congenital heart disease undergoing cardiac surgery. The primary outcome was thrombosis within 30 days of surgery or before discharge. Associations of individual metabolites with thrombosis were assessed with logistic regression with false discovery rate correction for multiple comparison and adjustment for clinical characteristics; elastic net regression was used to select a prediction model. RESULTS: Out of 1115 metabolites measured in samples from 203 children, 776 met the quality control criteria. In total, 25 children (12.3%) developed thrombosis. Among the 776 metabolites, 175 were significantly associated with thrombosis (false discovery rate Q<0.05). The top 3 metabolites showing the strongest associations with thrombosis were eicosapentaenoate, stearidonate, and andro steroid monosulfate C19H28O6S (false discovery rate, 0.01 for all). Pathway analysis showed that the pathways of nicotinate and nicotinamide metabolism and glycerophospholipid metabolism were enriched (false discovery rate, 0.003 for both) and had significant impact on the development of thrombosis. In elastic net regression analysis, the area under the receiver operating-characteristic curve of a prediction model for thrombosis was 0.969 in the training sample (70% of the total sample) and 0.833 in the testing sample (the remaining 30%). CONCLUSIONS: We have identified promising novel metabolites and metabolic pathways associated with thrombosis. Future studies are warranted to confirm these findings and examine the mechanistic pathways to thrombosis.

Impact of Clinical Guidelines on Hospital Utilization in Children With Croup.

OBJECTIVES: To assess the impact of croup guidelines on healthcare utilization and association between guideline-recommended racemic epinephrine (RE) treatments and admission. METHODS: Cross-sectional study of children ≥3 months to ≤8 years with croup diagnosis (International Classification of Diseases, 10th Revision) from 38 hospitals within the Pediatric Health Information System between January 1, 2019 and June 30, 2022. Guidelines were categorized by minimum number of RE treatments recommended before admission. Exclusion criteria included complex chronic or croup mimicking conditions, alternate respiratory diagnoses, and direct admissions or transfers. Primary outcomes were admission rates and standardized costs. Outcomes were compared by guideline availability and different admission thresholds. Mixed effects regression was adjusted for age, sex, race, payer, previous croup encounters, and year. RESULTS: Twenty hospitals (52.6%) had guidelines. Fourteen recommended 2 RE treatments and 3 recommended 3 RE treatment before admission. Among 121 284 croup encounters, overall mean admission rate was 5.7% (range 0.6% to 18.5%). Hospitals with guidelines demonstrated lower unadjusted admission rate (4.6% vs 6.6%; mean difference -2.0, 95% confidence interval -2.3 to -1.7) and higher costs ($704 vs $651; mean difference 53, 95% confidence interval 43 to 63) compared with hospitals without guidelines. Hospitals with guidelines recommending 3 RE treatments demonstrated similar unadjusted mean admission rate (5.1%) and lower costs ($658 vs $713) compared with hospitals with guidelines recommending 2 RE treatments. After adjustment, all above-mentioned differences were not statistically significant. CONCLUSIONS: Many children's hospitals lack guidelines for croup. Admission rates and costs were not significantly different between hospitals with or without guidelines after adjusting for confounders.

Variation in Organizational Clinical Practice Guidelines for Croup.

BACKGROUND: Croup is one of the most common respiratory complaints in pediatric emergency departments (EDs), yet little is known about clinical practice guidelines (CPGs) for this condition. OBJECTIVES: To describe variation in CPGs across US children's hospitals. METHODS: We describe the prevalence and features of CPGs among hospitals that submit data to the Pediatric Health Information System. Each hospital was contacted between January 10, 2022, and April 25, 2022, for their most recent croup CPG and any revisions. Characteristics reported were based on the most recent CPG revision. Characteristics included treatment recommendations, utilization measures, ED observation times, and admission criteria. Interrater reliability between reviewers was reported as percentage agreement. RESULTS: Thirty-eight hospitals (79.2%) responded to our query, of which 20 (52.6%) had croup CPGs. Interrater reliability was moderate-high for categorizing the indication for racemic epinephrine (RE) (19 of 20; 95%), the minimum number of RE doses recommended before admission (15 of 20; 75%), and ED observation time (19 of 20; 95%), and was 100% for all other characteristics. Three CPGs (15.0%) recommended 1 RE dose, 14 (70.0%) recommended 2 RE doses, and 3 (15.0%) recommended 3 RE doses before hospital admission. Thirteen (65%) CPGs recommended RE for stridor at rest, whereas 7 (30%) recommended RE for any degree of stridor. Fourteen (70%) CPGs recommended an ED observation time <2 hours, 3 (15%) recommended 2 to 4 hours, and 2 (10%) recommended >4 hours. Few CPGs (15%) recommended use of standardized croup clinical scores. CONCLUSIONS: Substantial variation exists among croup CPGs. Our results may inform future efforts to standardize croup CPGs across centers.

Survival-to-Hospital Discharge in Neonates With Congenital Heart Disease Supported With Prolonged Extracorporeal Membrane Oxygenation.

Factors that determine early outcomes in neonates with congenital heart disease (CHD) supported with prolonged venoarterial extracorporeal membrane oxygenation (ECMO) are not known and contemporary multicenter data are limited. This Extracorporeal Life Support Organization registry-based retrospective cohort study included all neonates (age ≤28 days) with CHD supported with venoarterial ECMO >7 days at 111 centers in the United States from January 2011 to December 2020. The primary outcome was survival-to-hospital discharge, and the secondary outcome was ECMO survival (successful decannulation before hospital discharge or death). Of the 2,155 total ECMO runs, 948 neonates received prolonged ECMO (gestational age [mean ± SD] 37.9 ± 1.8 weeks; birth weight 3.1 ± 0.6 kg; ECMO duration 13.6 ± 11.2 days). The ECMO survival rate was 51.6% (489 of 948), and the survival-to-hospital discharge rate was 23.9% (226 of 948). Body weight at ECMO (odds ratio [OR] 0.59, 95% confidence interval [CI] 0.44 to 0.78/kg), gestational age (OR 0.89, 95% CI 0.79 to 1.00 per week), risk-adjusted congenital heart surgery-1 score (OR 1.22, 95% CI 1.04 to 1.45), and pump flow at 24 hours (OR 1.11, 95% CI 1.04 to 1.18 per 10 ml/kg/min) were significantly associated with survival-to-hospital discharge. Pre-ECMO mechanical ventilation duration, time to extubation after ECMO decannulation, and length of stay were inversely associated with hospital survival. Patient-specific (higher body weight and gestational age) and CHD-related (lower risk-adjusted congenital heart surgery-1 score) attributes are associated with better outcomes in neonates who receive prolonged venoarterial ECMO. Further elucidation of the factors associated with reduced survival to discharge in ECMO survivors is needed.

Utilization and Cost of Outpatient Rehabilitation Services for Pediatric Patients Treated for Acute Lymphoblastic Leukemia Using a Commercial Claims Database.

OBJECTIVE: To investigate the temporal trends and factors associated with outpatient rehabilitation utilization and costs for pediatric acute lymphoblastic leukemia (ALL). DESIGN: Deidentified administrative claims data and longitudinal health information on patients representing a mixture of ages, ethnicities, and geographic regions across the United States were accessed using Optum Labs Data Warehouse. Regression models were constructed to assess associations of outpatient rehabilitation with age, sex, race and ethnicity, year of diagnosis, and region. SETTING: Outpatient rehabilitation. PARTICIPANTS: 1000 Patients aged 1-30 years with a new diagnosis of ALL between 1993 and 2017 and continuous insurance coverage (N=1000). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Outpatient rehabilitation service utilization and cost based on reimbursed charge codes, summarized over 36 months after cancer diagnosis. RESULTS: In 1000 patients, utilization of outpatient rehabilitation services increased from 20% in 1993-2002 to 55% in 2013-2017. In the earliest era examined, physical and/or occupational therapy was provided to 18% and increased to 54% in the latest years. Speech service utilization remained between 5%-8% across timepoints. Inflation-adjusted cost for provision of services did not change significantly across time and remained low, accounting for a median of 1.3% (Q1, Q3 0.3, 3.4) of total treatment cost in 1993-2002 and decreasing to a median 0.4% (Q1, Q3, 0.1, 1.0) in 2013-2017. Age 1 to 5 years at ALL diagnosis was associated with increased rehabilitation visit number and cost, and treatment in the Midwest was associated with increased likelihood of outpatient rehabilitation service utilization compared to other geographic regions. CONCLUSIONS: Outpatient rehabilitation services are being increasingly provided to patients with ALL at a relatively low cost per patient, yet geographic variability in care utilization is evident. These services do not add excessively to the overall cost of leukemia care and thus cost containment should not be an excuse to limit access.

Effect Modification of Racial Differences in Pediatric COVID-19 Inpatient Admissions in a Large Healthcare Database.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has been more severe in racial and ethnic minorities relative to non-Hispanic White populations. Here, we investigate how these disparities vary across effect modifiers in a pediatric population. METHODS: Using the TriNetX Dataworks Network from April 2020 to September 2021, we compared inpatient rates between non-Hispanic Black and non-Hispanic White patients among pediatric COVID-19 cases. Following propensity score matching, comparisons were performed within subgroups of 4 potential effect modifiers: age group (0-2, 3-5, 6-11 and 12-18 years), presence of complex comorbidities, quarter of the year (from 2020 Q2 to 2021 Q3) and geographic regions of the United States. RESULTS: The cohort included 47,487 COVID-19 cases, of which 13,130 were Black patients. Among most subgroups of effect modifiers, inpatient rates were higher among the Black patients. The largest variation in disparities was observed across age groups and the presence of complex comorbidities. Twelve to 18 years old Black children had a 1.7% point [confidence interval (CI): 0.8-2.4] higher inpatient rate than the matched White children, whereas 0-2 years old Black children had a 2.5% point (CI: 0.9-4.1) lower rate than the matched White children. Among children with complex comorbidities, inpatient rates for Black children was 6.2 (CI: 3.4-8.9) percentage points higher than the White children; however, among kids without complex comorbidities, inpatient rates were comparable. CONCLUSIONS: Among pediatric patients experiencing COVID-19, higher inpatient rates for Black compared with White patients were observed among older children and those with complex comorbidities. These findings can spur discussions of potential root causes of these disparities, including structural racism.

Health-related quality of life in children and adolescents with pleuropulmonary blastoma: A report from the International PPB/DICER1 Registry.

PURPOSE: Pleuropulmonary blastoma (PPB) is the most common lung cancer of infancy and early childhood and is associated with germline DICER1 variants. Type I and Ir PPB are cystic lesions treated surgically, with a subset of children with type I receiving chemotherapy. Type II and III are more aggressive lesions, treated with surgery, intensive chemotherapy and potentially radiation. We sought to assess health-related quality of life (HRQoL) in children with PPB and known germline DICER1 variants. METHODS: Children with a diagnosis of PPB or germline DICER1 pathogenic variant without history of PPB or other DICER1-related neoplasm (DICER1+ only) were enrolled in the International PPB/DICER1 Registry. Parent reports for participants aged 2-17 years for the PedsQL v.4 and PedsQL Multidimensional Fatigue Scale v.3 were collected. Fatigue, physical, and psychosocial function scores were compared. RESULTS: Analysis included 84 participants (PPB type Ir = 20, type I = 15, type II/III = 27, DICER1+ only = 22). Total fatigue scores of participants with type I and II/III PPB were lower compared to DICER1+ only, with effect size larger in type II/III (-0.82 vs. -0.40). Total psychosocial and physical functioning scores were lower in participants with type I and type II/III PPB compared to DICER1+ only, with larger effects noted in type II/III. Female sex was suggestive of worse HRQoL for both type I/Ir and type II/III cohorts. CONCLUSIONS: These data demonstrate the importance of regular HRQoL assessment in patients with a history of PPB as well as the importance and feasibility of studying HRQoL in children with rare tumors.

Type I and Ir pleuropulmonary blastoma (PPB): A report from the International PPB/DICER1 Registry.

BACKGROUND: Pleuropulmonary blastoma (PPB) is the most common lung cancer of infancy and early childhood. Type I PPB is a purely cystic lesion that has a microscopic population of primitive small cells with or without rhabdomyoblastic features and may progress to type II or III PPB, whereas type Ir lacks primitive small cells. METHODS: Children with suspected PPB were enrolled in the International PPB/DICER1 Registry. Pathology was centrally reviewed, and follow-up was ascertained annually. RESULTS: Between 2006 and 2022, 205 children had centrally reviewed type I or Ir PPB; 39% of children with type I and 5% of children with type Ir PPB received chemotherapy. Outcomes were favorable, although 11 children (nine with type I and two with type Ir PPB) experienced progression to type II/III (n = 8) or regrowth of type I PPB at the surgical site (n = 3), none of whom received chemotherapy before progression. Age and cyst size in combination were more suitable than either factor alone in predicting whether a particular lesion was type I or Ir PPB. CONCLUSIONS: For young children with type I PPB, outcomes are favorable, but complete resection is indicated because of the risk for progression. Chemotherapy may be useful in a subset of children at increased risk for recurrence/progression. Efforts to risk stratify children with type I PPB to optimize outcomes while reducing treatment-related side effects are underway.

Outcomes for Children With Type II and Type III Pleuropulmonary Blastoma Following Chemotherapy: A Report From the International PPB/DICER1 Registry.

PURPOSE: Pleuropulmonary blastoma (PPB) is the most common primary lung neoplasm of infancy and early childhood. Type II and type III PPB have historically been associated with a poor prognosis. METHODS: Patients with known or suspected PPB were enrolled in the International PPB/DICER1 Registry. Medical records were abstracted with follow-up ascertained annually. All PPB diagnoses were confirmed by central pathology review. Beginning in 2007, the IVADo regimen (ifosfamide, vincristine, actinomycin-D, and doxorubicin) was recommended as a potential treatment regimen for children with type II and type III PPB. This regimen was compared with a historical control cohort. RESULTS: From 1987 to 2021, 314 children with centrally confirmed type II and type III PPB who received upfront chemotherapy were enrolled; 132 children (75 with type II and 57 with type III) received IVADo chemotherapy. Adjusted analyses suggest improved overall survival for children treated with IVADo in comparison with historical controls with an estimated hazard ratio of 0.65 (95% CI, 0.39 to 1.08). Compared with localized disease, distant metastasis at diagnosis was associated with worse PPB event-free survival and overall survival with hazard ratio of 4.23 (95% CI, 2.42 to 7.38) and 4.69 (95% CI, 2.50 to 8.80), respectively. CONCLUSION: The use of IVADo in children with type II and type III PPB resulted in similar-to-improved outcomes compared with historical controls. Inferior outcomes with metastatic disease suggest the need for novel therapies. This large cohort of uniformly treated children with advanced PPB serves as a benchmark for future multicenter therapeutic studies for this rare pediatric tumor.

Impact of the COVID-19 Pandemic on Utilization and Cost for Care of Pediatric ALL.

Objective: Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and requires a unique pattern of healthcare utilization including an acute/emergent presentation and an intensive initial 8 months of therapy followed by two years of outpatient treatment. The COVID-19 pandemic caused massive global disruptions in healthcare use and delivery. This report aims to examine the effects of the COVID-19 pandemic on the presentation, diagnosis and continued management of childhood ALL in regard to utilization and cost of care. Results: Utilizing a commercial insurance claims database, 529 pediatric patients were identified who were diagnosed with ALL and completed their initial 8 months of treatment between January 2016 and December 2021. New diagnoses were evaluated by era and demographics. Utilization was measured by COVID-related era as number of inpatient and outpatient encounters, inpatient days, and cumulative cost. None of these cost or utilization factors changed significantly during or shortly after the pandemic. These findings reinforce that the necessary care for pediatric ALL is largely inflexible and was unwavering despite the massive shifts in the healthcare system caused by the COVID-19 pandemic. This provides a valuable benchmark as we further examine the factors that influence the pandemic's impact on health equity and access to care, especially in vulnerable pediatric populations. This is the first investigation of the effect of the COVID-19 pandemic on utilization and cost of care in pediatric cancer.

Real-World Cost of Pediatric Acute Lymphoblastic Leukemia Care Among Commercially Insured Individuals in the United States: Effect of Era and Age at Diagnosis.

PURPOSE: Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Five-year survival is approaching 90%. In efforts to further improve outcomes, it is critical to consider the cost of ALL care. MATERIALS AND METHODS: Commercial insurance data from OptumLabs Data Warehouse were used to identify patients with ALL, age 1-30 years, diagnosed in 1993-2017 in the United States, with 36 months of continuous insurance coverage. Patients treated with hematopoietic cell transplantation were excluded. Inpatient and outpatient utilization and cumulative reimbursements (inflation-adjusted to December 2020) were computed 8 and 36 months from diagnosis and stratified by age (1-9, 10-12, and ≥ 13 years) as proxies for National Cancer Institute risk groups. Regression models were constructed to assess associations with demographic and clinical characteristics. RESULTS: Among 927 patients (median age, 6 years; interquartile range, 3-12 years; 43% female), individuals age ≥ 10 years had 23-25 more inpatient days and 22 more outpatient encounters compared with younger patients. The 36-month median cost was $394,000 (USD) (interquartile range, $256,000-$695,000 [USD]), and 64% of the total cost was incurred during the initial 8 months. The 36-month cost was 1.5-fold higher for those age 10-12 years and 1.7-fold higher for those age ≥ 13 years compared with 1-9 years. The cost for those diagnosed in 2013-2017 was 70% higher compared with 1993-2002, and was not different on the basis of sex, race, or ethnicity. CONCLUSION: Older age was associated with higher utilization and cost, and the cost of treatment increased significantly over time. These data provide valuable benchmarks for future studies examining the cost-benefit of ALL therapy modifications.

Accuracy and Interrater Reliability of Point-of-Care Ultrasonography Image Interpretation for Intussusception.

OBJECTIVES: The aim of this study was to determine the accuracy and interrater reliability of (1) point-of-care ultrasound (POCUS) image interpretation for identification of intussusception and (2) reliability of secondary signs associated with intussusception among experts compared with novice POCUS reviewers. METHODS: We conducted a planned secondary analysis of a prospective, convenience sample of children aged 3 months to 6 years who were evaluated with POCUS for intussusception across 17 international pediatric emergency departments between October 2018 and December 2020. A random sample of 100 POCUS examinations was reviewed by novice and expert POCUS reviewers. The primary outcome was identification of the presence or absence of intussusception. Secondary outcomes included intussusception size and the presence of trapped free fluid or echogenic foci. Accuracy was summarized using sensitivity and specificity, which were estimated via generalized mixed effects logistic regression. Interrater reliability was summarized via Light's κ statistics with bootstrapped standard errors (SEs). Accuracy and reliability of expert and novice POCUS reviewers were compared. RESULTS: Eighteen expert and 16 novice POCUS reviewers completed the reviews. The average expert sensitivity was 94.5% (95% confidence interval [CI], 88.6-97.5), and the specificity was 94.3% (95% CI, 90.3-96.7), significantly higher than the average novice sensitivity of 84.7% (95% CI, 74.3-91.4) and specificity of 80.4% (95% CI, 72.4, 86.7). κ was significantly greater for expert (0.679, SE 0.039) compared with novice POCUS reviewers (0.424, SE 0.044; difference 0.256, SE 0.033). For our secondary outcome measure of intussusception size, κ was significantly greater for experts (0.661, SE 0.038) compared with novices (0.397, SE 0.041; difference 0.264, SE 0.029). Interrater reliability was weak for expert and minimal for novice reviewers regarding the detection of trapped free fluid and echogenic foci. CONCLUSIONS: Expert POCUS reviewers demonstrate high accuracy and moderate interrater reliability when identifying intussusception via image interpretation and perform better than novice reviewers.