T-cell depleted allogeneic hematopoietic stem cell transplant for the treatment of Fanconi anemia and MDS/AML.

The only curative approach for myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) arising in patients with Fanconi anemia (FA) is allogeneic hematopoietic stem cell transplantation (HCT); however, HCT approaches are inconsistent and limited data on outcomes exist. We retrospectively evaluated outcomes of thirty patients with FA and MDS/AML who underwent first allogeneic HCT with a T-cell depleted (TCD) graft at our institution. Patients were transplanted on successive protocols with stepwise changes in cytoreduction and GVHD prophylaxis. All but two patients (93%) experienced durable hematopoietic engraftment. With median follow-up of 8.7 years, 5-year OS was 66.8% and DFS 53.8%. No significant differences in survival were found in patients with high-risk prognostic features (age ≥20 years, AML diagnosis, alternative donor graft) or when stratified by conditioning regimen. The 5-year cumulative incidences of relapse and NRM were 24.3% and 21.9%, respectively. NRM was higher in patients ≥20 years at HCT but did not otherwise differ. We herein demonstrate promising outcomes following allogeneic HCT for patients with FA and MDS/AML using TCD grafts, particularly in a cohort of high-risk patients with 50% ≥20 years and a majority receiving mismatched grafts. Future prospective studies are needed to compare this approach with other HCT platforms.

Too many white cells-TAM, JMML, or something else?

Leukocytosis is a common finding in pediatric patients, and the differential diagnosis can be broad, including benign reactive leukocytosis and malignant myeloproliferative disorders. Transient abnormal myelopoiesis is a myeloproliferative disorder that occurs in young infants with constitutional trisomy 21 and somatic GATA1 mutations. Most patients are observed, but outcomes span the spectrum from spontaneous resolution to life-threatening complications. Juvenile myelomonocytic leukemia is a highly aggressive myeloproliferative disorder associated with altered RAS-pathway signaling that occurs in infants and young children. Treatment typically involves hematopoietic stem cell transplantation, but certain patients can be observed. Early recognition of these and other myeloproliferative disorders is important and requires a clinician to be aware of these diagnoses and have a clear understanding of their presentations. This paper discusses the presentation and evaluation of leukocytosis when myeloproliferative disorders are part of the differential and reviews different concepts regarding treatment strategies.

Expression of ENaC subunits in epithelia.

The epithelial Na+ channel (ENaC) is a heterotrimeric protein whose assembly, trafficking, and function are highly regulated. To better understand the biogenesis and activation of the channel, we quantified the expression of individual subunits of ENaC in rat kidneys and colon using calibrated Western blots. The estimated abundance for the three subunits differed by an order of magnitude with the order γENaC ∼ ßENaC ≫ αENaC in both organs. Transcript abundance in the kidney, measured with digital-drop PCR and RNAseq, was similar for the three subunits. In both organs, the calculated protein expression of all subunits was much larger than that required to account for maximal Na+ currents measured in these cells, implying a large excess of subunit protein. Whole-kidney biotinylation indicated that at least 5% of ß and γ subunits in the kidney and 3% in the colon were expressed on the surface under conditions of salt restriction, which maximizes ENaC-dependent Na+ transport. This indicates a 10- to 100-fold excess of ßENaC and γENaC subunits at the surface relative to the requirement for channel activity. We conclude that these epithelia make much more ENaC protein than is required for the physiological function of the channel. This could facilitate rapid regulation of the channels at the cell surface by insuring a large population of inactive, recruitable subunits.

Factorial Analysis Quantifies the Effects of Pediatric Discharge Bundle on Hospital Readmission.

BACKGROUND AND OBJECTIVES: Factorial design of a natural experiment was used to quantify the benefit of individual and combined bundle elements from a 4-element discharge transition bundle (checklist, teach-back, handoff to outpatient providers, and postdischarge phone call) on 30-day readmission rates (RRs). METHODS: A 24 factorial design matrix of 4 bundle element combinations was developed by using patient data (N = 7725) collected from January 2014 to December 2017 from 4 hospitals. Patients were classified into 3 clinical risk groups (CRGs): no chronic disease (CRG1), single chronic condition (CRG2), and complex chronic condition (CRG3). Estimated main effects of each bundle element and their interactions were evaluated by using Study-It software. Because of variation in subgroup size, important effects from the factorial analysis were determined by using weighted effect estimates. RESULTS: RR in CRG1 was 3.5% (n = 4003), 4.1% in CRG2 (n = 1936), and 17.6% in CRG3 (n = 1786). Across the 3 CRGs, the number of subjects in the factorial groupings ranged from 16 to 674. The single most effective element in reducing RR was the checklist in CRG1 and CRG2 (reducing RR by 1.3% and 3.0%) and teach-back in CRG3 (by 4.7%) The combination of teach-back plus a checklist had the greatest effect on reducing RR in CRG3 by 5.3%. CONCLUSIONS: The effect of bundle elements varied across risk groups, indicating that transition needs may vary on the basis of population. The combined use of teach-back plus a checklist had the greatest impact on reducing RR for medically complex patients.