Fumarate hydratase (FH) is an enzyme of the tricarboxylic acid cycle (TCA cycle) that catalyses the hydration of fumarate into malate. Germline mutations of FH are responsible for hereditary ...leiomyomatosis and renal-cell cancer (HLRCC). It has previously been demonstrated that the absence of FH leads to the accumulation of fumarate, which activates hypoxia-inducible factors (HIFs) at normal oxygen tensions. However, so far no mechanism that explains the ability of cells to survive without a functional TCA cycle has been provided. Here we use newly characterized genetically modified kidney mouse cells in which Fh1 has been deleted, and apply a newly developed computer model of the metabolism of these cells to predict and experimentally validate a linear metabolic pathway beginning with glutamine uptake and ending with bilirubin excretion from Fh1-deficient cells. This pathway, which involves the biosynthesis and degradation of haem, enables Fh1-deficient cells to use the accumulated TCA cycle metabolites and permits partial mitochondrial NADH production. We predicted and confirmed that targeting this pathway would render Fh1-deficient cells non-viable, while sparing wild-type Fh1-containing cells. This work goes beyond identifying a metabolic pathway that is induced in Fh1-deficient cells to demonstrate that inhibition of haem oxygenation is synthetically lethal when combined with Fh1 deficiency, providing a new potential target for treating HLRCC patients.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
IntroductionApproximately 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 analysisThis 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 disseminationThe 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.
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.
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.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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.
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.
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.
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.
To investigate the temporal trends and factors associated with outpatient rehabilitation utilization and costs for pediatric acute lymphoblastic leukemia (ALL).
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.
Outpatient rehabilitation.
1000 Patients aged 1-30 years with a new diagnosis of ALL between 1993 and 2017 and continuous insurance coverage (N=1000).
Not applicable.
Outpatient rehabilitation service utilization and cost based on reimbursed charge codes, summarized over 36 months after cancer diagnosis.
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.
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.
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.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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