Correlative studies investigating effects of PI3K inhibition on peripheral leukocytes in metastatic breast cancer: potential implications for immunotherapy.

PURPOSE: Patients with localized breast cancer have a 5-year survival rate > 99% compared to patients with metastatic breast cancer (MBC) that have a 5-year survival rate of ~ 27%. Unregulated PI3K/AKT signaling is a common characteristic of MBC, making it a desirable therapeutic target for tumors with activating mutations in this pathway. Interestingly, inhibition of the PI3K/AKT pathway can affect signaling in immune cells, which could potentially alter the immune phenotype of patients undergoing therapy with these drugs. The purpose of this study is to evaluate how PI3K inhibition affects the immune cells of MBC patients during treatment. METHODS: We investigated the effects of PI3K inhibition on the immune cell populations in peripheral blood of MBC patients enrolled in 4 different clinical trials utilizing PI3K inhibitors. Peripheral blood was drawn at different points in patient treatment cycles to record immune cell fluctuations in response to therapy. RESULTS: MBC patients who responded to treatment with a positive fold-change in cytotoxic T cell population, had an average duration of treatment response of 31.4 months. In contrast, MBC patients who responded to treatment with a negative fold-change in cytotoxic T-cell population, had an average duration of therapeutic response of 5 months. These data suggest that patients with a more robust, initial anti-tumor T cell response may have a longer therapeutic response compared to patients who do not have a robust, initial anti-tumor T cell response. CONCLUSIONS: These results highlight the potential for PI3K inhibition to sensitize tumors to immune checkpoint inhibitors, thus providing additional therapeutic options for patients with MBC.

Intravenous antibiotics for urinary tract infections in children with neurologic impairment.

BACKGROUND: Children with high-intensity neurologic impairment (HINI) have an increased risk of urinary tract infection (UTI) and prolonged intravenous (IV) antibiotic exposure. OBJECTIVE: To determine the association between short (≤3 days) and long (>3 days) IV antibiotic courses and UTI treatment failure in hospitalized children with HINI. METHODS: We performed a retrospective cohort study examining UTI hospitalizations at 49 hospitals in the Pediatric Health Information System from 2016 to 2021 for children (1-18 years) with HINI. The primary outcome was UTI readmission within 30 days. Our secondary outcome was the association of hospital-level variation in short IV antibiotic course use with readmission. Readmission rates were compared between short and long courses using multivariable regression. RESULTS: Of 5612 hospitalizations, 3840 (68.4%) had short IV antibiotic courses. In our adjusted model, children with short IV courses were less likely than with long courses to have a 30-day UTI readmission (4.0%, 95% CI [3.6%, 4.5%] vs. 6.3%, 95% CI [5.1%, 7.8%]). Despite marked hospital-level variation in short IV course use (50.0%-87.5% of hospitalizations), there was no correlation with readmissions. CONCLUSIONS: Children with HINI hospitalized with UTI had low UTI readmission rates, but those who received long IV antibiotic courses were more likely to experience UTI readmission versus those receiving short courses. While residual confounding may influence our results, we did not find that short IV courses impacted readmission at the hospital level despite variation in use across institutions. Long IV antibiotic courses are associated with risks and may not confer benefit in this population.

Clinical prediction model: Multisystem inflammatory syndrome in children versus Kawasaki disease.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a rare but serious complication of severe acute respiratory syndrome coronavirus 2 infection. Features of MIS-C overlap with those of Kawasaki disease (KD). OBJECTIVE: The study objective was to develop a prediction model to assist with this diagnostic dilemma. METHODS: Data from a retrospective cohort of children hospitalized with KD before the coronavirus disease 2019 pandemic were compared to a prospective cohort of children hospitalized with MIS-C. A bootstrapped backwards selection process was used to develop a logistic regression model predicting the probability of MIS-C diagnosis. A nomogram was created for application to individual patients. RESULTS: Compared to children with incomplete and complete KD (N = 602), children with MIS-C (N = 105) were older and had longer hospitalizations; more frequent intensive care unit admissions and vasopressor use; lower white blood cell count, lymphocyte count, erythrocyte sedimentation rate, platelet count, sodium, and alanine aminotransferase; and higher hemoglobin and C-reactive protein (CRP) at admission. Left ventricular dysfunction was more frequent in patients with MIS-C, whereas coronary abnormalities were more common in those with KD. The final prediction model included age, sodium, platelet count, alanine aminotransferase, reduction in left ventricular ejection fraction, and CRP. The model exhibited good discrimination with AUC 0.96 (95% confidence interval: [0.94-0.98]) and was well calibrated (optimism-corrected intercept of -0.020 and slope of 0.99). CONCLUSIONS: A diagnostic prediction model utilizing admission information provides excellent discrimination between MIS-C and KD. This model may be useful for diagnosis of MIS-C but requires external validation.

Decreasing pre-procedural fasting times in hospitalized children.

OBJECTIVE: Prolonged pre-procedural fasting in children is associated with decreased patient and family satisfaction and increased patient hemodynamic instability. Practice guidelines recommend clear liquid fasting times of 2 h. We aimed to decrease pre-procedural clear liquid fasting time from 10 h 13 min to 5 h for pediatric hospital medicine (PHM) patients. METHODS: All children admitted to the PHM service at a quaternary care children's hospital with an NPO (nil per os) order associated with a procedure requiring general anesthesia or sedation from November 2, 2017 to September 19, 2021 were included. The primary outcome measure was the average time from clear liquid fasting end time to anesthesia start time. The process measure was the percent of NPO orders including a documented clear liquid fasting end time. Balancing measures were aspiration events and case delays/cancellations. Statistical process control charts were used to analyze outcomes. RESULTS: Shortly after implementation of a SmartPhrase in the NPO order, there was special cause variation resulting in a centerline shift from a mean of 10 h 13 min to 6 h 37 min and an increase in the process measure from a baseline of 2%-52%. Following implementation of a hospital-wide change to the NPO order format, another centerline shift to 6 h 7 min occurred which has been sustained for 6 months. No aspiration events and four NPO violations occurred during the intervention period. CONCLUSION: Quality improvement methodology and higher reliability interventions safely decreased the average pre-procedural fasting time in hospitalized children.