Six-coordinate Pt(IV)-complexes are prominent prodrug candidates for the treatment of various cancers where, upon two-electron reduction and loss of two axial ligands, they form more familiar, pharmacologically active four-coordinate Pt(II) drugs. A series of electrochemical experiments coupled with extensive density functional calculations has been employed to elucidate the mechanism for the two-electron reduction of Pt(IV)(NH3)2Cl2L2 to Pt(II)(NH3)2Cl2 (L = CH3COO(-), 1; L = CHCl2COO(-), 2; L = Cl(-), 3). A reliable estimate for the normal reduction potential E(o) is derived for the electrochemically irreversible Pt(IV) reduction and is compared directly to the quantum chemically calculated reduction potentials. The process of electron transfer and Pt-L bond cleavage is found to occur in a stepwise fashion, suggesting that a metastable six-coordinate Pt(III) intermediate is formed upon addition of a single electron, and the loss of both axial ligands is associated with the second electron transfer. The quantum chemically calculated reduction potentials are in excellent agreement with experimentally determined values that are notably more positive than peak potentials reported previously for 1-3.

Background Hyperglycemia is a complication of induction chemotherapy in 10%‐50% of pediatric patients with acute lymphoblastic leukemia (ALL). Though hyperglycemia in ALL patients is usually transient, it may be associated with adverse health outcomes. However, the risk factors for and consequences of hyperglycemia are poorly understood. We hypothesized that hyperglycemia significant enough to require insulin therapy during induction chemotherapy would be associated with increased morbidity and mortality in pediatric ALL patients during induction chemotherapy and in subsequent care. Methods We abstracted clinical and resource utilization data from the Pediatric Health Information System (PHIS) database utilizing ICD‐9 codes and medication charges. We used logistic regression analysis to predict the development of hyperglycemia. The effects of hyperglycemia on binary and count adverse outcomes following induction chemotherapy were modeled using mixed‐effect regression models. Results An increased risk of hyperglycemia requiring insulin was associated with older age, female sex, higher risk group and trisomy 21. Patients on insulin for hyperglycemia had increased mortality following induction chemotherapy. These patients were more likely to have subsequent infectious complications, need for bone marrow transplant, and risk of disease relapse. They also had greater length of inpatient stay, higher cost of care, and were more likely to require intensive care unit admission during induction chemotherapy. Conclusions Hyperglycemia requiring insulin during induction chemotherapy in pediatric ALL is associated with an increased risk of short‐term and long‐term complications. Prospective studies are needed to analyze formal screening, preventive measures, and optimal management practices for hyperglycemia during ALL induction chemotherapy.

Renal disease is a common complication experienced by patients with sickle cell disease (SCD), though the epidemiology of acute kidney injury (AKI) in paediatric patients and its impact on long-term renal outcomes is unclear. We utilized the Pediatric Health Information System (PHIS) to identify inpatient encounters of paediatric patients with SCD admitted for vaso-occlusive pain crisis (VOC). Overall, 1Á4% of patients experienced at least one episode of AKI and 2Á5% of admissions were complicated by AKI.Patients with at least one episode of AKI were more likely to be adolescents or young adults at the time of their initial admission, had increased rates of admission to the ICU, longer lengths of stay, increased costs of hospitalization, increased risk of readmission and increased rates of SCD-related comorbidities. Generalized estimating equation modelling demonstrated that increasing age, history of hypertension, history of haematuria and history of chronic kidney disease were associated with increased odds of developing AKI, though hydroxycarbamide use (OR 0Á64, 95% CI 0Á44-0Á94) was protective. Episodes of AKI during hospitalization in children with SCD are associated with increased morbidity and utilization of hospital resources. Increasing the use of hydroxycarbamide may decrease the likelihood of this complication.

Background Infections are the leading cause of therapy‐related mortality in pediatric patients with acute myeloid leukemia (AML). Although effectiveness of levofloxacin antibacterial prophylaxis in oncology patients is recognized, its cost‐effectiveness is unknown. This study evaluated epidemiologic data regarding levofloxacin use and the cost‐effectiveness of this strategy as the cost per bacteremia episode, intensive care unit (ICU) admission, and death avoided in children with AML. Procedure A retrospective cohort study using the Pediatric Health Information System (PHIS) database compared demographic and clinical characteristics and receipt of levofloxacin prophylaxis in children with AML admitted for chemotherapy from January 1, 2014, through December 31, 2018. We then developed a decision analysis model in this population that compared costs associated with bacteremia, ICU admission, or death secondary to bacteremia to levofloxacin prophylaxis cost from a healthcare perspective. Time horizon is one chemotherapy cycle. Probabilistic and one‐way sensitivity analyses evaluated model uncertainty. Results Prophylaxis cost $8491 per bacteremia episode prevented compared with an average added hospital cost of $119 478. Prophylaxis cost $81 609 per ICU admission avoided, compared with an average added hospital cost of $94 181. Prophylaxis cost $220 457 per death avoided. In sensitivity analysis, at a willingness‐to‐pay threshold of $100 000 per bacteremia episode avoided, prophylaxis remained cost‐effective in 94.6% of simulations. Prophylaxis use was more common in recent years in patients with relapsed disease and with chemotherapy regimens considered more intensive. Conclusion Prophylaxis is cost‐effective in preventing bacterial infections in patients with AML. Findings support increased use in patients considered at high risk of bacterial infection secondary to myelosuppression.

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Background: PEG-asparaginase is critical in pediatric acute lymphoblastic leukemia (ALL) therapy but is highly immunogenic. Severe allergic reactions lead to substitution of further PEG-asparaginase with Erwinia. Erwinia is associated with more frequent dosing, increased expense, and limited availability. Premedication may reduce rates of allergic reactions.Procedures: This Markov model evaluated the cost-effectiveness of three strategies: premedication plus therapeutic drug monitoring (TDM), TDM alone, and no premedication or TDM. We modeled two scenarios: a standard-risk (SR) B-ALL patient receiving two asparaginase doses and a high-risk (HR) patient receiving seven asparaginase doses. The model incorporated costs of asparaginase, premedication, TDM and clinic visits, and lost parental wages associated with each additional Erwinia dose. We incorporated a five-year time horizon with a societal perspective. Outcomes were Erwinia substitutions avoided and differences in quality-adjusted life years (QALYs). Probabilistic and one-way sensitivity analyses evaluated model uncertainty. Results:In both scenarios, premedication was the least costly strategy. In SR and HR scenarios, premedication with monitoring resulted in 8% and 7% fewer changes to Erwinia compared with monitoring alone and 3% and 2% fewer changes compared with no premedication/monitoring, respectively. Premedication resulted in the most QALYs gained in the SR patients. Individual variation of model inputs did not change premedication/monitoring favorability for either scenario. In probabilistic sensitivity analyses, premedication/monitoring was favored in >87% of iterations in both scenarios. Conclusion:Compared with other strategies, premedication use and asparaginase level monitoring in children with B-ALL is potentially cost-saving.

This paper is dedicated to Professor Malcolm Chisholm on the occasion of his 70 th birthday and in celebration of his many contributions to organometallic chemistry.

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