A comprehensive assessment of the prolonged febrile neutropenia evaluation in pediatric oncology patients.

BACKGROUND: Pediatric oncology patients with prolonged (≥96 hours) febrile neutropenia (absolute neutrophil count < 500/µL) often undergo an evaluation for invasive fungal disease (IFD) and other infections. Current literature suggests that beta-D-glucan (BDG), galactomannan, bronchoalveolar lavage (BAL), and computed tomography (CT) scans (sinus, chest, and abdomen/pelvis) may help determine a diagnosis in this population. METHODS: In a retrospective cohort study of all cancer/stem cell transplant patients (diagnosed 2005-2019) from one pediatric hospital, all episodes with prolonged febrile neutropenia or IFD evaluations (defined as sending a fungal biomarker or performing a CT scan to assess for infection) were identified. RESULTS: In total, 503 episodes met inclusion criteria and 64% underwent IFD evaluations. In total, 36.4% of episodes documented an infection after initiation of prolonged febrile evaluation, most commonly Clostridioides difficile colitis (6.4%) followed by a true bacterial bloodstream infection (BSI) (5.2%), proven/probable IFD (4.8%), and positive respiratory pathogen panel (3.6%). There was no difference in sinus CTs showing sinusitis (74% vs 63%, p = 0.46), whereas 32% of abdomen/pelvis CTs led to a non-IFD diagnosis, and 25% of chest CTs showed possible pneumonia. On chest CT, the positive predictive value (PPV) for IFD was 19% for nodules and 14% for tree and bud lesions. BDG had a PPV of 25% for IFD and GM 50%. BAL diagnosed IFD once and pneumocystis jirovecii pneumonia twice. CONCLUSIONS: Chest CTs and abdomen/pelvis CTs provide clinically relevant information during the prolonged febrile neutropenia evaluation, whereas BDG, galactomannan, BAL, and sinus CTs have less certain utility.

Ultrasound and Microbubble-targeted Delivery of a microRNA Inhibitor to the Heart Suppresses Cardiac Hypertrophy and Preserves Cardiac Function.

MicroRNAs (miRs) are dysregulated in pathological left ventricular hypertrophy. AntimiR inhibition of miR-23a suppressed hypertension-induced cardiac hypertrophy in preclinical models, but clinical translation is limited by a lack of cardiac-targeted delivery systems. Ultrasound-targeted microbubble cavitation (UTMC) utilizes microbubbles as nucleic acid carriers to target delivery of molecular therapeutics to the heart. The objective of this study was to evaluate the efficacy of UTMC targeted delivery of antimiR-23a to the hearts of mice for suppression of hypertension-induced cardiac hypertrophy. Methods: Cationic lipid microbubbles were loaded with 300 pmol negative control antimiR (NC) or antimiR-23a. Mice received continuous phenylephrine infusion via implanted osmotic minipumps, then UTMC treatments with intravenously injected antimiR-loaded microbubbles 0, 3, and 7 days later. At 2 weeks, hearts were harvested and miR-23a levels were measured. Left ventricular (LV) mass and function were assessed with echocardiography. Results: UTMC treatment with antimiR-23a decreased cardiac miR-23a levels by 41 ± 8% compared to UTMC + antimiR-NC controls (p < 0.01). Furthermore, LV mass after 1 week of phenylephrine treatment was 17 ± 10% lower following UTMC + antimiR-23a treatment compared to UTMC + antimiR-NC controls (p = 0.02). At 2 weeks, fractional shortening was 23% higher in the UTMC + antimiR-23a mice compared to UTMC + antimiR-NC controls (p < 0.01). Conclusions: UTMC is an effective technique for targeted functional delivery of antimiRs to the heart causing suppression of cardiac hypertrophy and preservation of systolic function. This approach could represent a revolutionary therapy for patients suffering from pathological cardiac hypertrophy and other cardiovascular conditions.