St. Jude Children's Research Hospital, founded in 1962, is a pediatric treatment and research facility focused on children's catastrophic diseases, particularly leukemia and other cancers. The hospital costs about US$2.8 million a day to run, but patients are not charged for their care. It is located in Memphis, Tennessee, and is a nonprofit medical corporation designated as a 501(c)(3) tax-exempt organization by the Internal Revenue Service. St. Jude treats infants, children, teenagers, and young adults up to the age of 21, and in some cases, up to the age of 25.
Abstract Transgenic mouse models expressing predefined T-cell receptors (TCRs) have been instrumental in advancing our understanding of T-cell biology. However, these traditional models rely on random genomic insertion of large constructs, require labor-intensive embryo manipulation, and frequently result in aberrant TCR expression and phenotypes. These limitations render traditional models insufficient to meet the mounting demands for rapid and precise model systems to evaluate TCR specificities. In this study, we developed a streamlined method that uses adeno-associated virus (AAV) and CRISPR/Cas9-mediated genome editing to precisely integrate pre-rearranged TCRα/β sequences into the mouse TCRβ (Trb) locus, enabling the rapid generation of TCR knock-in mice with physiological TCR expression and functional T-cell differentiation upon antigenic challenge. This approach bypasses the need for screening multiple founders for faithful TCR expression, enhancing the versatility and utility of monoclonal TCR mice in basic immunology and preclinical research, such as in the fields of cancer immunotherapy and vaccine development.
Survivors of pediatric acute lymphoblastic leukemia (ALL) face long-term health challenges partially explained by treatment-related and cancer-related systemic inflammation. Beyond these effects, biobehavioral frameworks for understanding morbidity among survivors posit that other modifiable factors (e.g., emotional distress) influence systemic inflammation. These frameworks have not been explored within pediatric populations and do not consider potential caregiver impact. This study aimed to examine associations of caregiver factors and biobehavioral domains with systemic inflammation in survivors of pediatric ALL. Survivors of ALL (n = 48), > 5 years from diagnosis, provided blood samples to assess C-reactive protein (CRP), a biomarker of inflammation. Caregivers completed measures of caregiver strain, caregiver distress, and survivor internalizing symptoms. Multivariable models examined associations between survivor internalizing symptoms, caregiver strain, and caregiver emotional distress on CRP. Interaction effects between predictor variables and age were tested in each model. Post hoc analyses assessed the relationships at the 16th (pre-adolescent), 50th (adolescent), and 84th (older adolescent) percentiles for participant age. Internalizing symptoms (β = .10, p = 0.01) and caregiver emotional distress (β = .08, p = 0.06) were associated with CRP levels in older adolescent survivors. Caregiver strain was associated with CRP levels among younger (β = .06, p = 0.01) and older adolescent survivors (β = .12, p = .002). These findings suggest that developmental stage may moderate the impact of emotional and environmental stressors on systemic inflammation. These findings demonstrate the importance of follow-up care for caregivers and survivors during survivorship to support better physical and mental health outcomes.
PURPOSE:The Children's Oncology Group (COG) protocol AALL0434 evaluated the safety and efficacy of multi-agent chemotherapy with Capizzi-based methotrexate/pegaspargase (C-MTX) in patients with newly diagnosed pediatric T-cell lymphoblastic lymphoma (T-LL) and gained preliminary data using nelarabine in high-risk patients. PATIENTS AND METHODS:The trial enrolled 299 patients, age 1-31 years. High-risk (HR) patients had ≥ 1% minimal detectable disease (MDD) in the bone marrow at diagnosis or received prior steroid treatment. Induction failure was defined as failure to achieve a partial response (PR) by the end of the 4-week induction. All patients received the augmented Berlin-Frankfurt-Muenster (ABFM) C-MTX regimen. HR patients were randomly assigned to receive or not receive 6 5-day courses of nelarabine incorporated into ABFM. Patients with induction failure were nonrandomly assigned to ABFM C-MTX plus nelarabine. No patients received prophylactic cranial radiation; however, patients with CNS3 disease (CSF WBC ≥ 5/μL with blasts or cranial nerve palsies, brain/eye involvement, or hypothalamic syndrome) were ineligible. RESULTS:At end-induction, 98.8% of evaluable participants had at least a PR. The 4-year event-free survival (EFS) and overall survival (OS) were 84.7% ± 2.3% and 89.0% ± 2.0%. The 4-year disease-free survival (DFS) from end-induction was 85.9% ± 2.6%. There was no difference in DFS observed between the HR and standard-risk groups (P = .29) or by treatment regimen (P = .55). Disease stage, tumor response, and MDD at diagnosis did not demonstrate thresholds that resulted in differences in EFS. Nelarabine did not show an advantage for HR patients. CNS relapse occurred in only 4 patients. CONCLUSION:COG AALL0434 produced excellent outcomes in one of the largest trials ever conducted for patients with newly diagnosed T-LL. The COG ABFM regimen with C-MTX provided excellent EFS and OS without cranial radiation.
The prospective pediatric Continuous Renal Replacement Therapy (ppCRRT) registry identified the degree of fluid accumulation (FA) at continuous kidney replacement therapy (CKRT) initiation as a predictor of adverse outcomes in children. These predate major advancements in CKRT technology and fluid stewardship. We aimed to describe the epidemiology of FA at CKRT initiation and associated outcomes in a contemporary paediatric cohort. Secondary analysis of Worldwide Exploration of Renal Replacement Outcomes Collaborative in Kidney Disease (WE-ROCK), a retrospective, multicenter study (35 centers, 9 countries) of patients ≤ 25 years treated with CKRT from 2015 to 2021. Primary Outcome: survival to ICU discharge. Secondary outcomes: ventilator-free and ICU-free days. A total of 1027 patients were included in this analysis. Survival to ICU discharge was 64.5
Implementation strategies are adapted to improve fit of evidence-based practices for resource-limited settings, yet how they are adapted is poorly understood. We described the adaptation of a resource-adapted multilevel strategy to implement Pediatric Early Warning Scores in centers caring for children with cancer in Latin America for pilot predominantly in Sub-Saharan Africa. This exploratory, sequential mixed-methods study identified strategy adaptations through content analysis of (1) focus group discussions, (2) informal interviews, and (3) adaptation process documents. An external investigator developed a preliminary matrix of adaptations and then applied the Framework for Reporting Adaptations and Modifications to Evidence-based Implementation Strategies. The implementation team iteratively reviewed and reached consensus through focus group discussions. The final matrix had 24 adaptations; most were proactively planned by the implementation team (67
