• Human cGVHD B cells have increased proximal BCR signaling protein expression and are more BCR responsive than non-cGVHD B cells.• Inhibiting Syk kinase activity abrogates the BCR-driven ex vivo proliferative and survival advantage of human chronic GVHD B cells.Although B cells have emerged as important contributors to chronic graft-versus-hostdisease (cGVHD) pathogenesis, the mechanisms responsible for their sustained activation remain unknown. We previously showed that patients with cGVHD have significantly increased B cell-activating factor (BAFF) levels and that their B cells are activated and resistant to apoptosis. Exogenous BAFF confers a state of immediate responsiveness to antigen stimulation in normal murine B cells. To address this in cGVHD, we studied B-cell receptor (BCR) responsiveness in 48 patients who were >1 year out from allogeneic hematopoietic stem cell transplantation (HSCT). We found that B cells from cGVHD patients had significantly increased proliferative responses to BCR stimulation along with elevated basal levels of the proximal BCR signaling components B cell linker protein (BLNK) and Syk. After initiation of BCR signaling, cGVHD B cells exhibited increased BLNK and Syk phosphorylation compared with B cells from patients without cGVHD. Blocking Syk kinase activity prevented relative post-HSCT BCR hyperresponsiveness of cGVHD B cells. These data suggest that a lowered BCR signaling threshold in cGVHD associates with increased B-cell proliferation and activation in response to antigen. We reveal a mechanism underpinning aberrant B-cell activation in cGVHD and suggest that therapeutic inhibition of the involved kinases may benefit these patients. (Blood. 2014;123(13):2108-2115

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Background Gastrostomy tube (G-tube) placement is a common intervention for newborns with severe feeding difficulties. Infants with congenital diaphragmatic hernia (CDH) are at high risk for feeding problems. Prevalence of G-tube placement and consequent nutritional outcomes of infants with CDH and G-tubes has not been described. Aims Determine factors associated with G-tube placement and growth in infants with congenital diaphragmatic hernia. Study design Retrospective cohort study of infants with CDH to evaluate the association of G-tube placement with risk factors using logistic regression. We also assessed the association between growth velocity and G-tube placement and other risk factors using linear regression. Subjects The subjects of the study were infants with CDH treated at Duke University Medical Center from1997 to 2013. Outcome measures Weight gain in infants with CDH that had G-tube placement compared to those infants with CDH that did not. Result Of the 123 infants with CDH, 85 (69%) survived and G-tubes were placed in 25/85 (29%) survivors. On adjusted analysis, extracorporeal membrane oxygenation (OR=11.26 [95% CI: 1.92–65.89]; P=0.01) and proton pump inhibitor use (OR=17.29 [3.98–75.14], P ≤0.001) were associated with G-tube placement. Infants without G-tubes had a growth velocity of 6.5 g/day (95% CI: 2.5–10.4) more than infants with G-tubes. Conclusion Survivors with more complex inpatient courses were more likely to receive G-tubes. Further investigation is needed to identify optimal feeding practices for infants with CDH.

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