Hyperammonemia has been reported following asparaginase administration, consistent with the mechanisms of asparaginase, which catabolizes asparagine to aspartic acid and ammonia, and secondarily converts glutamine to glutamate and ammonia. However, there are only a few reports on the treatment of these patients, which varies widely from watchful waiting to treatment with lactulose, protein restriction, sodium benzoate, and phenylbutyrate to dialysis. While many patients with reported asparaginase-induced hyperammonemia (AIH) are asymptomatic, some have severe complications and even fatal outcomes despite medical intervention. Here, we present a cohort of five pediatric patients with symptomatic AIH, which occurred after switching patients from polyethylene glycolated (PEG)- asparaginase to recombinant Crisantaspase Pseudomonas fluorescens (4 patients) or Erwinia (1 patient) asparaginase, and discuss their subsequent management, metabolic workup, and genetic testing. We developed an institutional management plan, which gradually evolved based on our local experience and previous treatment modalities. Because of the significant reduction in glutamine levels after asparaginase administration, sodium benzoate should be used as a first-line ammonia scavenger for symptomatic AIH instead of sodium phenylacetate or phenylbutyrate. This approach facilitated continuation of asparaginase doses, which is known to improve cancer outcomes. We also discuss the potential contribution of genetic modifiers to AIH. Our data highlights the need for increased awareness of symptomatic AIH, especially when an asparaginase with higher glutaminase activity is used, and its prompt management. The utility and efficacy of this management approach should be systematically investigated in a larger cohort of patients.

BACKGROUND:Multiple stakeholders have advocated for minimum volume standards for complex surgical procedures. The Leapfrog Group recommends that patients with non-small cell lung cancer (NSCLC) receive surgical resection at hospitals that perform at least 40 lung resections annually. However, the cost-effectiveness of this paradigm is unknown. METHODS:A cost-effectiveness analysis was performed on 90-day and 5-year horizons for patients with clinical stage I NSCLC undergoing surgical resection at hospitals stratified by Leapfrog standard. Model inputs were derived from either the literature or a propensity score-matched cohort using the National Cancer Database. For the 5-year horizon, we simulated using a Markov model with 1-year cycle. Incremental cost-effectiveness ratio (ICER) was calculated to evaluate cost-effectiveness. RESULTS:For the 90-day horizon, resection at a Leapfrog hospital was more costly ($25 567 vs $25 530) but had greater utility (0.185 vs 0.181 quality-adjusted life-years), resulting in an ICER of 10 506. Similarly, for the 5-year horizon, resection at a Leapfrog hospital was more costly ($26 600 vs $26 495) but more effective (3.216 vs 3.122 quality-adjusted life-years), resulting in an ICER of 1108. When the costs for long-distance travel, lodging, and loss of productivity for caregivers were factored in, the ICER was 20 499 during the 5-year horizon for resection at Leapfrog hospitals. Using a willingness-to-pay threshold of $50 000, resection at a Leapfrog hospital remained cost-effective. CONCLUSIONS:Receiving surgery for clinical stage I NSCLC at hospitals that meet Leapfrog volume standards is cost-effective. Payers and policymakers should consider supporting patient and caregiver travel to higher volume institutions for lung cancer surgery.

PURPOSE:Biallelic CAD variants underlie CAD deficiency (or early infantile epileptic encephalopathy-50, [EIEE-50]), an error of pyrimidine de novo biosynthesis amenable to treatment via the uridine salvage pathway. We further define the genotype and phenotype with a focus on treatment.METHODS:Retrospective case series of 20 patients.RESULTS:Our study confirms CAD deficiency as a progressive EIEE with recurrent status epilepticus, loss of skills, and dyserythropoietic anemia. We further refine the phenotype by reporting a movement disorder as a frequent feature, and add that milder courses with isolated developmental delay/intellectual disability can occur as well as onset with neonatal seizures. With no biomarker available, the diagnosis relies on genetic testing and functional validation in patient-derived fibroblasts. Underlying pathogenic variants are often rated as variants of unknown significance, which could lead to underrecognition of this treatable disorder. Supplementation with uridine, uridine monophosphate, or uridine triacetate in ten patients was safe and led to significant clinical improvement in most patients.CONCLUSION:We advise a trial with uridine (monophosphate) in all patients with developmental delay/intellectual disability, epilepsy, and anemia; all patients with status epilepticus; and all patients with neonatal seizures until (genetically) proven otherwise or proven unsuccessful after 6 months. CAD deficiency might represent a condition for genetic newborn screening.