OUTCOMES OF PEDIATRIC FLUID-REFRACTORY SEPTIC SHOCK ACCORDING TO DIFFERENT VASOACTIVE STRATEGIES: A SYSTEMATIC REVIEW AND META-ANALYSIS.

ABSTRACT: Background: Hemodynamic support using vasoactive agents is a mainstay in the management of patients with pediatric fluid-refractory septic shock (FRSS). However, evidence supporting the appropriate choice of vasoactive agent is limited. This study aimed to perform a systematic review and meta-analysis on the effect of different first-line vasoactive strategies on mortality in pediatric FRSS. Methods: MEDLINE, Embase, Scopus, CINAHL, Web of Science, the Cochrane Library, ClinicalTrials.gov , and the ISRCTN registry were searched up until December 2023. Randomized controlled trials and observational cohort studies reporting vasoactive agent-specific outcomes of children with FRSS were included. Mortality was assessed as primary outcome in studies on patients receiving dopamine, epinephrine, or norepinephrine as first-line. Random-effects meta-analyses were conducted. Prevalence ratio (PR) estimates were calculated between two drugs when was available in the same study. Findings: Of the 26,284 identified articles, 13 were included, for a total of 997 children. Twelve studies included 748 patients receiving a single vasoactive agent. Of these, 361 received dopamine, 271 epinephrine, and 116 norepinephrine. Overall pooled mortality for patients receiving a single vasoactive was 12% (95% CI 6%-21%) of which 11% (95% CI 3%-36%) for patients receiving dopamine, 17% (95% CI 6%-37%) for epinephrine, and 7% (95% CI 1%-48%) for norepinephrine. Four first-line dopamine (176 patients) and first-line epinephrine (142 patients): dopamine showed a tendency toward higher mortality (PR 1.38, 95% CI 0.81-2.38) and a significant higher need for mechanical ventilation (PR 1.12, 95% CI 1.02-1.22). Interpretation: Among children with FRSS receiving a single vasoactive agent, norepinephrine was associated with the lowest mortality rate. Comparing dopamine and epinephrine, patients receiving epinephrine needed less mechanical ventilation and showed a trend for lower mortality rate. Further research is needed to better delineate the first-line vasoactive agent in this population.

NPM1 Mutational Status Underlines Different Biological Features in Pediatric AML.

Nucleophosmin (NPM1) is a nucleocytoplasmic shuttling protein, predominantly located in the nucleolus, that regulates a multiplicity of different biological processes. NPM1 localization in the cell is finely tuned by specific signal motifs, with two tryptophan residues (Trp) being essential for the nucleolar localization. In acute myeloid leukemia (AML), several NPM1 mutations have been reported, all resulting in cytoplasmic delocalization, but the putative biological and clinical significance of different variants are still debated. We explored HOXA and HOXB gene expression profile in AML patients and found a differential expression between NPM1 mutations inducing the loss of two (A-like) Trp residues and those determining the loss of one Trp residue (non-A-like). We thus expressed NPM1 A-like- or non-A-like-mutated vectors in AML cell lines finding that NPM1 partially remained in the nucleolus in the non-A-like NPM1-mutated cells. As a result, only in A-like-mutated cells we detected HOXA5, HOXA10, and HOXB5 hyper-expression and p14ARF/p21/p53 pathway deregulation, leading to reduced sensitivity to the treatment with either chemotherapy or Venetoclax, as compared to non-A-like cells. Overall, we identified that the NPM1 mutational status mediates crucial biological characteristics of AML cells, providing the basis for further sub-classification and, potentially, management of this subgroup of patients.