Recent advances in the treatment of childhood cancers.

PURPOSE OF REVIEW: Although cancer remains the leading nonaccidental cause of mortality in children, substantial advances in care have led to 5-year overall survival exceeding 85%. However, improvements in outcomes have not been uniform across malignancies or strata of social determinants of health. The current review highlights recent areas of advancement and anticipated directions for future progress. RECENT FINDINGS: Incorporation of rational targeted agents into upfront treatment regimens has led to incremental improvements in event-free survival for many children, sometimes with potential reductions in late effects. For rare or challenging-to-treat cancers, the increasing feasibility of molecular profiling has provided specific treatment options to patients with some of the greatest needs. Simultaneously, increased focus is being given to patient-reported outcomes and social determinants of health, the importance ofwhich are becoming readily recognized in providing equitable, quality care. Finally, as survival from malignant diseases improves, breakthroughs in the prevention and management of adverse late effects will promote long-term quality of life. SUMMARY: Multi-institutional collaboration and risk-adapted approaches have been crucial to recent advancements in the care of children with cancer and inform potential directions for future investigation.

An Unusual Case of Extranodal Marginal Zone Lymphoma Mimicking Abdominal Cocoon Syndrome in an Adolescent Patient.

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is an indolent non-Hodgkin lymphoma rarely seen in pediatric patients. MALT lymphoma most commonly involves the gastrointestinal tract or peri-orbital tissues, potentially as sequela of chronic antigenic stimulation or immune dysregulation. Rare cases of MALT lymphoma arising from the gynecologic tract have been reported in older adult patients. We present the unique case of a 16-year-old postpubescent female with MALT lymphoma localized to the gynecologic tract, who initially presented with abdominal fullness, abnormal uterine bleeding, and obstructive acute kidney injury secondary to urinary outflow obstruction. Intraoperatively, dense fibrosis of the uterus and left fallopian tube was noted which mimicked abdominal cocoon syndrome. She was treated with 6 cycles of bendamustine and rituximab with complete anatomic and metabolic remission. In this report we highlight a very unusual presentation of a rare malignancy in the pediatric population as well as unique treatment considerations given this patient's young age and tumor location.

Financial hardship among siblings of long-term survivors of childhood cancer: A Childhood Cancer Survivor Study report.

BACKGROUND: Siblings of children with cancer may experience adverse household economic consequences, but their financial outcomes in adulthood are unknown. METHODS: A total of 880 siblings (aged 18-64 years) of adult-aged childhood cancer survivors were surveyed to estimate the prevalence of financial hardship by three established domains (behavioral, material, and psychological). For individual financial hardship items matching the contemporaneous National Health Interview Survey or Behavioral Risk Factor Surveillance System, siblings were compared with the general population by calculating adjusted prevalence odds ratios (ORs) to sample-weighted responses. Multivariable logistic regression models examined associations between sibling characteristics and each hardship domain and between sibling hardship and survivors' cancer/treatment characteristics. RESULTS: Behavioral, material, and psychological hardship was reported by 24%, 35%, and 28%, respectively. Compared with national survey respondents, siblings were more likely to report worries about medical bills (OR, 1.14; 95% confidence interval [CI], 1.06-1.22), difficulty affording nutritious foods (OR, 1.79; 95% CI, 1.54-2.07), and forgoing needed medical care (OR, 1.38; 95% CI, 1.10-1.73), prescription medications (OR, 2.52; 95% CI, 1.99-3.20), and dental care (OR, 1.34; 95% CI, 1.15-1.57) because of cost. Sibling characteristics associated with reporting financial hardship in one or more domains included female sex, older age, chronic health conditions, lower income, not having health insurance, high out-of-pocket medical expenditures, and nonmedical/nonhome debt. No survivor cancer/treatment characteristics were associated with sibling financial hardship. CONCLUSIONS: Adult siblings of childhood cancer survivors were more likely to experience financial hardship compared with the general population. Childhood cancer may adversely affect entire households, with potentially lasting implications.

Primary Care Utilization and Cardiovascular Screening in Adult Survivors of Childhood Cancer.

Importance: Cardiovascular disease is the leading noncancer cause of premature death among survivors of childhood cancer. Adult survivors of childhood cancer are largely managed by primary care practitioners (PCPs), and health care utilization patterns related to cardiovascular screening are not well described. Objective: To examine screening and health care utilization among survivors of childhood cancer at high risk for cardiovascular complications. Design, Setting, and Participants: This multicenter cross-sectional study included participants enrolled in a randomized clinical trial from 2017 to 2021. Abstracted documentation of participants' cancer history, cardiotoxic treatment exposures, and survivorship care plans were obtained from participants' PCPs spanning 2 years preceding trial enrollment. Participants were members of the Childhood Cancer Survivor Study cohort at elevated risk for ischemic heart disease or heart failure, enrolled in a randomized trial focused on improving cardiovascular risk factor control. Data were analyzed from November 2022 to July 2023. Main Outcomes and Measures: Outcomes of interest were numbers of PCP and specialist visits, cardiovascular risk factors (hypertension, dyslipidemia, and diabetes), risk factor screening, and cardiac testing. Multivariable logistic regression assessed characteristics associated with up-to-date cardiac testing at enrollment. Results: Of 347 enrolled participants, 293 (84.4%) had evaluable medical records (median [range] age, 39.9 [21.5-65.0] years; 149 [50.9%] male) and were included in analyses. At baseline, 238 participants (81.2%) had a documented PCP encounter; 241 participants (82.3%) had undergone blood pressure screening, 179 participants (61.1%) had undergone lipid testing, and 193 participants (65.9%) had undergone diabetes screening. A total of 63 participants (21.5%) had echocardiography completed or planned. Only 198 participants (67.6%) had records referencing a cancer history. PCP documentation of prior cardiotoxic exposures was low compared with known exposures, including radiation therapy (103 participants [35.2%] vs 203 participants [69.3%]; P < .001) and anthracycline chemotherapy (27 participants [9.2%] vs 222 participants [75.8%]; P = .008). Few records referenced a need for cancer-related late effects surveillance (95 records [32.4%]). Independent factors associated with cardiac screening included documentation of increased cardiovascular disease risk (odds ratio [OR], 11.94; 95% CI, 3.37-42.31), a late-effects surveillance plan (OR, 3.92; 95% CI, 1.69-9.11), and existing cardiovascular risk factors (OR per each additional factor, 2.09; 95% CI, 1.32-3.31). Conclusions and Relevance: This cross-sectional study of adult survivors of childhood cancer at increased risk of cardiovascular disease found low adherence to recommended cardiac testing and documentation of risk for these individuals. Improving accuracy of reporting of survivors' exposures and risks within the medical record may improve screening.

CD43-positive, EWSR1::FLI1 -rearranged Soft Tissue Sarcoma in a Pediatric Patient With History of B-Cell Acute Lymphoblastic Leukemia.

Ewing sarcoma is a small round blue cell tumor typically characterized by an EWSR1 rearrangement and expression of CD99 and NKX2.2, without expression of hematopoietic markers such as CD45. CD43 is an alternative hematopoietic immunohistochemical marker often utilized in the workup of these tumors and its expression typically argues against Ewing sarcoma. We report a 10-year-old with history of B-cell acute lymphoblastic leukemia presenting with an unusual malignant shoulder mass with variable CD43 positivity, but with an EWSR1::FLI1 fusion detected by RNA sequencing. Her challenging workup highlights the utility of next-generation DNA-based and RNA-based sequencing methods in cases with unclear or conflicting immunohistochemical results.

Congenital pleuropulmonary blastoma in a newborn with a variant of uncertain significance in DICER1 evaluated by RNA-sequencing.

BACKGROUND: Pleuropulmonary blastoma (PPB) is a rare mesenchymal malignancy of the lung and is the most common pulmonary malignancy in infants and children. Cystic PPB, the earliest form of PPB occurring from birth to approximately two years of age, is often mistaken for a congenital pulmonary airway malformation, as the two entities can be difficult to distinguish on imaging and pathology. Diagnosis of PPB should prompt workup for DICER1 syndrome, an autosomal dominant tumor predisposition syndrome. We report a newborn with a congenital PPB presenting with tachypnea and hypoxia, who was found to have variant of uncertain clinical significance (VUS) in DICER1. CASE PRESENTATION: A term female infant developed respiratory distress shortly after birth. Initial imaging was concerning for a congenital pulmonary airway malformation versus congenital diaphragmatic hernia, and she was transferred to a quaternary neonatal intensive care unit for management and workup. Chest CT angiography demonstrated a macrocytic multicystic lesion within the right lower lobe without systemic arterial supply. The pediatric surgery team was consulted, and the neonate underwent right lower lobectomy. Pathology revealed a type I PPB. Oncology and genetics consultants recommended observation without chemotherapy and single gene sequencing of DICER1, which identified a germline VUS in DICER1 predicted to alter splicing. RNA-sequencing from blood demonstrated that the variant resulted in an in-frame deletion of 29 amino acids in a majority of transcripts from the affected allele. Due to the patient's young age at presentation and high clinical suspicion for DICER1 syndrome, tumor surveillance was initiated. Renal and pelvic ultrasonography were unremarkable. CONCLUSION: We present the case of a term neonate with respiratory distress and cystic lung mass, found to have a type I PPB with a germline VUS in DICER1 that likely increased her risk of DICER1-related tumors. Nearly 70% of patients with PPB demonstrate germline mutations in DICER1. Review of RNA sequencing data demonstrates the difficulty in classifying splice variants such as this. Penetrance is low, and many patients with pathogenic DICER1 variants do not develop a malignancy. Best practice surgical and oncologic recommendations include an individualized approach and tumor board discussion. This case highlights the importance of a multidisciplinary team approach and the utility of international registries for patients with rare diagnoses.

Population-Based Impact of Rurality and Neighborhood-Level Socioeconomic Disadvantage on Pediatric Cancer Mortality in Washington State.

BACKGROUND: Childhood cancer-related mortality differs by socioeconomic factors, but the impact of residential location, including rurality and neighborhood-level socioeconomic disadvantage, is not well-characterized. METHODS: This retrospective cohort study linked Washington State cancer registry data (1992-2013) to state birth (1974-2013) and death records (1992-2013) to identify residents <20 years diagnosed with cancer (n = 4,306). Census-based rural-urban commuting area codes and Area Deprivation Index (ADI) defined rural residence and neighborhood socioeconomic disadvantage at time of cancer diagnosis, respectively. Neighborhoods in the highest state ADI quintile were classified as the most disadvantaged. Kaplan-Meier estimates and Cox hazards models, adjusted for key characteristics, were used to compare mortality by rural and ADI classification. RESULTS: Five-year overall survival for children from non-rural low ADI neighborhoods (referent) was 80.9%±0.8%, versus 66.4%±2.9% from non-rural high ADI neighborhoods, 69.4%±3.8% from rural low ADI neighborhoods, and 66.9%±3.8% from rural high ADI neighborhoods (P < 0.01 for each comparison versus referent). Compared with the referent group, children from comparator neighborhoods had a greater mortality risk: Rural low ADI [hazard ratio (HR), 1.50; 95% confidence interval (CI), 1.12-2.02], rural high ADI (HR, 1.53; 95% CI, 1.16-2.01), and non-rural high ADI (HR, 1.64; 95% CI, 1.32-2.04). Associations of ADI and rurality with mortality varied in sub-analyses by cancer type. CONCLUSIONS: Children with cancer living in rural and/or socioeconomically disadvantaged neighborhoods at diagnosis experienced greater mortality relative to those without either factor. IMPACT: Future investigation is needed to examine how rurality and poverty potentially impact healthcare utilization and health-related outcomes in pediatric oncology.

Nine Seasons of a Bronchiolitis Observation Unit and Home Oxygen Therapy Protocol.

BACKGROUND: We implemented an observation unit and home oxygen therapy (OU-HOT) protocol at our children's hospital during the 2010-2011 winter season to facilitate earlier discharge of children hospitalized with bronchiolitis. An earlier study demonstrated substantial reductions in inpatient length of stay and costs in the first year after implementation. OBJECTIVE: Evaluate long-term reductions in length of stay and cost. DESIGN, SETTING, AND PARTICIPANTS: Interrupted time-series analysis, adjusting for patient demographic factors and disease severity. Participants were children aged 3 to 24 months and hospitalized with bronchiolitis from 2007 to 2019. INTERVENTION: OU-HOT protocol implementation. MAIN OUTCOME AND MEASURES: Hospital length of stay. Process measures were the percentage of patients discharged from the OU; percentage of patients discharged with HOT. Balancing measures were 7-day hospital revisit rates; annual per-population bronchiolitis admission rates. Secondary outcomes were inflation-adjusted cost per episode of care and discharges within 24 hours. RESULTS: A total of 7,116 patients met inclusion criteria. The OU-HOT protocol was associated with immediate decreases in mean length of stay (-30.6 hours; 95% CI, -37.1 to -24.2 hours) and mean cost per episode of care (-$4,181; 95% CI, -$4,829 to -$3,533). These findings were sustained for 9 years after implementation. Hospital revisit rates did not increase immediately (-1.1% immediate change; 95% CI, -1.8% to -0.4%), but a small increase in revisits was observed over time (change in slope 0.4% per season, 95% CI, 0.1%-0.8%). CONCLUSION: The OU-HOT protocol was associated with sustained reductions in length of stay and cost, representing a promising strategy to reduce the inpatient burden of bronchiolitis.