Vancomycin-Resistant Enterococcus Colonization and Bacteremia and Hematopoietic Stem Cell Transplantation Outcomes.

The association between pre-hematopoietic stem cell transplantation (HSCT) vancomycin-resistant Enterococcus (VRE) colonization, HSCT-associated VRE bacteremia, and HSCT mortality is disputed. We studied 161 consecutive patients with acute leukemia who underwent HSCT at our hospital between 2006 and 2014, of whom 109 also received leukemia induction/consolidation on our unit. All inpatients had weekly VRE stool surveillance. Pre-HSCT colonization was not associated with increases in HSCT mortality but did identify a subgroup of HSCT recipients with a higher risk for VRE bacteremia and possibly bacteremia from other organisms. The major risk factor for pre-HSCT colonization was the number of hospital inpatient days between initial admission for leukemia and HSCT. One-third of evaluable patients colonized before HSCT were VRE-culture negative on admission for HSCT; these patients had an increased risk for subsequent VRE stool surveillance positivity but not VRE bacteremia. Molecular typing of VRE isolates obtained before and after HSCT showed that VRE strains frequently change. Postengraftment VRE bacteremia was associated with a much higher mortality than pre-engraftment VRE bacteremia. Pre-engraftment bacteremia from any organism was associated with an alternative donor and resulted in an increase in hospital length of stay and cost. Mortality was similar for pre-engraftment VRE bacteremia and pre-engraftment bacteremia due to other organisms, but mortality associated with post-engraftment VRE bacteremia was higher and largely explained by associated severe graft-versus-host disease and relapsed leukemia. These data emphasize the importance of distinguishing between VRE colonization before HSCT and at HSCT, between pre-engraftment and postengraftment VRE bacteremia, and between VRE bacteremia and bacteremia from other organisms.

Vitamin C promotes maturation of T-cells.

AIMS: Vitamin C (ascorbic acid) is thought to enhance immune function, but the mechanisms involved are obscure. We utilized an in vitro model of T-cell maturation to evaluate the role of ascorbic acid in lymphocyte development. RESULTS: Ascorbic acid was essential for the developmental progression of mouse bone marrow-derived progenitor cells to functional T-lymphocytes in vitro and also played a role in vivo. Ascorbate-mediated enhancement of T-cell development was lymphoid cell-intrinsic and independent of T-cell receptor (TCR) rearrangement. Analysis of TCR rearrangements demonstrated that ascorbic acid enhanced the selection of functional TCRαß after the stage of ß-selection. Genes encoding the coreceptor CD8 as well as the kinase ZAP70 were upregulated by ascorbic acid. Pharmacologic inhibition of methylation marks on DNA and histones enhanced ascorbate-mediated differentiation, suggesting an epigenetic mechanism of Cd8 gene regulation via active demethylation by ascorbate-dependent Fe(2+) and 2-oxoglutarate-dependent dioxygenases. INNOVATION: We speculate that one aspect of gene regulation mediated by ascorbate occurs at the level of chromatin demethylation, mediated by Jumonji C (JmjC) domain enzymes that are known to be reliant upon ascorbate as a cofactor. JmjC domain enzymes are also known to regulate transcription factor activity. These two mechanisms are likely to play key roles in the modulation of immune development and function by ascorbic acid. CONCLUSION: Our results provide strong experimental evidence supporting a role for ascorbic acid in T-cell maturation as well as insight into the mechanism of ascorbate-mediated enhancement of immune function.

Techniques for risk stratification of newly diagnosed patients with chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by BCR-ABL, a constitutively active tyrosine kinase generated as a result of the t(9;22)(q34;q11). The natural history of CML is progression from a relatively benign chronic phase to an acute leukemia termed blast crisis. Imatinib, an inhibitor of BCR-ABL tyrosine kinase activity, has a dramatic effect on the natural history of the disease. Despite the favorable outcomes with imatinib, a subset of patients have primary refractory disease, or experience relapse after an initial response. Recently identified molecular predictors of drug response might help predict outcome with tyrosine kinase inhibitor therapy more accurately than clinical prognostication scores, but have not yet been introduced into clinical routine. These techniques include analysis of drug transport proteins, in vitro drug assays, measurement of imatinib plasma levels, BCR-ABL activity monitoring, and gene expression profiling. In this article we review the current status of these technologies, which may ultimately allow us to tailor therapy to a specific patient.