Factors that contribute to disparities in time to acute leukemia diagnosis in young people: an in depth qualitative interview study.

BACKGROUND: Racial and ethnic disparities in outcomes for Black and Hispanic children with acute leukemia have been well documented, however little is known about the determinants of diagnostic delays in pediatric leukemia in the United States. The primary objective of this study is to identify factors contributing to delays preceding a pediatric leukemia diagnosis. METHODS: This qualitative study utilized in-depth semi-structured interviews. Parents and/or patients within two years of receiving a new acute leukemia diagnosis were asked to reflect upon their family's experiences preceding the patient's diagnosis. Subjects were purposively sampled for maximum variation in race, ethnicity, income, and language. Interviews were analyzed using inductive theory-building and the constant comparative method to understand the process of diagnosis. Chart review was conducted to complement qualitative data. RESULTS: Thirty-two interviews were conducted with a diverse population of English and Spanish speaking participants from two tertiary care pediatric cancer centers. Parents reported feeling frustrated when their intuition conflicted with providers' management decisions. Many felt laboratory testing was not performed soon enough. Additional contributors to delays included misattribution of vague symptoms to more common diagnoses, difficulties in obtaining appointments, and financial disincentives to seek urgent or emergent care. Reports of difficulty obtaining timely appointments and financial concerns were disproportionately raised among low-income Black and Hispanic participants. Comparatively, parents with prior healthcare experiences felt better able to navigate the system and advocate for additional testing at symptom onset. CONCLUSIONS: While there are disease-related factors contributing to delays in diagnosis, it is important to recognize there are multiple non-disease-related factors that also contribute to delays. Evidence-based approaches to reduce outcome disparities in pediatric cancer likely need to start in the primary care setting where timeliness of diagnosis can be addressed.

Hospital-Based Pediatric Quality Improvement Interventions and Health Disparities: A Scoping Review of the Literature.

BACKGROUND AND OBJECTIVES: Quality improvement (QI) has the potential to reduce health disparities through multiple mechanisms, including by standardizing care and addressing social barriers to health. National organizations require that hospital systems integrate equity into quality efforts, but effective approaches remain unclear. We aimed to examine the association of hospital-based pediatric QI interventions and racial and ethnic, language, and socioeconomic disparities in health outcomes. METHODS: Quantitative studies from January 1, 2000 to December 11, 2023 reporting the effects of pediatric hospital-based QI were selected from PubMed and Embase. Studies were excluded if outcomes were not stratified by race and ethnicity, language, or socioeconomic status. Studies were reviewed in duplicate for inclusion and by 1 author for data extraction. RESULTS: A total of 22 studies were included. Most studies (n = 19, 86%) revealed preexisting disparities, and 68% of those (n = 13) found disparities reductions post-intervention. Studies with disparity-focused objectives or interventions more commonly found reduced disparities than studies of general QI (85% vs 33%). Hospital-based process standardization was associated with reduced disparities in provider practices. Most interventions associated with reduced disparities in patient-facing outcomes involved community/ambulatory partnership. Limitations included potential exclusion of relevant studies, topic heterogenity, and risk of bias. CONCLUSIONS: Although the authors of few published hospital-based QI initiatives assessed their equity effect, intentionally designed QI studies were associated with reduced disparities. Interventions focused on care standardization may reduce disparities in care quality, although multilevel interventions are likely needed to affect the health care structures that influence more significant patient outcomes.

Characterization of Birth Hospitalizations in the United States.

OBJECTIVES: A broad understanding of the scope of birth hospitalizations in the United States is lacking. We aimed to describe the demographics and location of birth hospitalizations in the United States and rank the most common and costly conditions documented during birth hospitalizations. METHODS: We conducted a cross-sectional analysis of the 2019 Kids' Inpatient Database, a nationally-representative administrative database of pediatric discharges. All hospitalizations with the indicator "in-hospital birth" and any categorized by the Pediatric Clinical Classification System as "liveborn" were included. Discharge-level survey weights were used to generate nationally-representative estimates. Primary and secondary conditions coded during birth hospitalizations were categorized using the Pediatric Clinical Classification System, rank-ordered by total prevalence and total marginal costs (calculated using design-adjusted lognormal regression). RESULTS: In 2019, there were an estimated 5 299 557 pediatric hospitalizations in the US and 67% (n = 3 551 253) were for births, totaling $18.1 billion in cost. Most occurred in private, nonprofit hospitals (n = 2 646 685; 74.5%). Prevalent conditions associated with birth admissions included specified conditions originating in the perinatal period (eg, pregnancy complications, complex births) (n = 1 021 099; 28.8%), neonatal hyperbilirubinemia (n = 540 112; 15.2%), screening or risk for infectious disease (n = 417 421; 11.8%), and preterm newborn (n = 314 288; 8.9%). Conditions with the highest total marginal costs included specified conditions originating in perinatal period ($168.7 million) and neonatal jaundice with preterm delivery ($136.1 million). CONCLUSIONS: Our study details common and costly areas of focus for future quality improvement and research efforts to improve care during term and preterm infant birth hospitalizations. These include hyperbilirubinemia, infectious disease screening, and perinatal complications.

ATP-Competitive Inhibitors Midostaurin and Avapritinib Have Distinct Resistance Profiles in Exon 17-Mutant KIT.

KIT is a type-3 receptor tyrosine kinase that is frequently mutated at exon 11 or 17 in a variety of cancers. First-generation KIT tyrosine kinase inhibitors (TKI) are ineffective against KIT exon 17 mutations, which favor an active conformation that prevents these TKIs from binding. The ATP-competitive inhibitors, midostaurin and avapritinib, which target the active kinase conformation, were developed to inhibit exon 17-mutant KIT. Because secondary kinase domain mutations are a common mechanism of TKI resistance and guide ensuing TKI design, we sought to define problematic KIT kinase domain mutations for these emerging therapeutics. Midostaurin and avapritinib displayed different vulnerabilities to secondary kinase domain substitutions, with the T670I gatekeeper mutation being selectively problematic for avapritinib. Although gatekeeper mutations often directly disrupt inhibitor binding, we provide evidence that T670I confers avapritinib resistance indirectly by inducing distant conformational changes in the phosphate-binding loop. These findings suggest combining midostaurin and avapritinib may forestall acquired resistance mediated by secondary kinase domain mutations. SIGNIFICANCE: This study identifies potential problematic kinase domain mutations for next-generation KIT inhibitors midostaurin and avapritinib.

Rational Design, Synthesis and Biological Evaluation of Pyrimidine-4,6-diamine derivatives as Type-II inhibitors of FLT3 Selective Against c-KIT.

FMS-like Tyrosine Kinase 3 (FLT3) is a clinically validated target for acute myeloid leukemia (AML). Inhibitors targeting FLT3 have been evaluated in clinical studies and have exhibited potential to treat FLT3-driven AML. A frequent, clinical limitation is FLT3 selectivity, as concomitant inhibition of FLT3 and c-KIT is thought to cause dose-limiting myelosuppression. Through a rational design approach, novel FLT3 inhibitors were synthesized employing a pyridine/pyrimidine warhead. The most potent compound identified from the studies is compound 13a, which exhibited an IC50 value of 13.9 ± 6.5 nM against the FLT3 kinase with high selectivity over c-KIT. Mechanism of action studies suggested that 13a is a Type-II kinase inhibitor, which was also supported through computer aided drug discovery (CADD) efforts. Cell-based assays identified that 13a was potent on a variety of FLT3-driven cell lines with clinical relevance. We report herein the discovery and therapeutic evaluation of 4,6-diamino pyrimidine-based Type-II FLT3 inhibitors, which can serve as a FLT3-selective scaffold for further clinical development.

GSTP1 Is a Driver of Triple-Negative Breast Cancer Cell Metabolism and Pathogenicity.

Breast cancers possess fundamentally altered metabolism that fuels their pathogenicity. While many metabolic drivers of breast cancers have been identified, the metabolic pathways that mediate breast cancer malignancy and poor prognosis are less well understood. Here, we used a reactivity-based chemoproteomic platform to profile metabolic enzymes that are enriched in breast cancer cell types linked to poor prognosis, including triple-negative breast cancer (TNBC) cells and breast cancer cells that have undergone an epithelial-mesenchymal transition-like state of heightened malignancy. We identified glutathione S-transferase Pi 1 (GSTP1) as a novel TNBC target that controls cancer pathogenicity by regulating glycolytic and lipid metabolism, energetics, and oncogenic signaling pathways through a protein interaction that activates glyceraldehyde-3-phosphate dehydrogenase activity. We show that genetic or pharmacological inactivation of GSTP1 impairs cell survival and tumorigenesis in TNBC cells. We put forth GSTP1 inhibitors as a novel therapeutic strategy for combatting TNBCs through impairing key cancer metabolism and signaling pathways.