High lymphoid enhancer-binding factor-1 expression is associated with disease progression and poor prognosis in chronic lymphocytic leukemia

We determined lymphoid enhancer-binding factor-1 (LEF1) mRNA expression in 112 chronic lymphocytic leukemia (CLL) samples and assessed correlations with the prognostic markers ZAP70 and CD38, Binet stages, the percentage of lymphocytes in the peripheral blood, and fibromodulin (FMOD) transcripts. The mean LEF1 relative expression ratios (RER) were 53.72 and 37.10 in ZAP70-positive and ZAP70-negative patients, respectively (P=0.004). However, we did not observe a significant difference in LEF1 expression between CD38-positive and CD38-negative patients. Moreover, patients requiring treatment showed a mean LEF1 RER of 85.61 whereas patients in recently diagnosed Binet A stage had a mean of only 22.01 (P<0.001). We also found significant correlations of LEF1 with the percentage of lymphocytes and FMOD expression. Our results suggest that high LEF1 expression is associated with poor prognosis and disease progression. Thus, LEF1 might be involved in the process of disease progression and possibly can serve as a molecular parameter for risk assessment and/or monitoring of CLL

Natural killer cell dysfunction is a distinguishing feature of systemic onset juvenile rheumatoid arthritis and macrophage activation syndrome

Macrophage activation syndrome (MAS) has been reported in association with many rheumatic diseases, most commonly in systemic juvenile rheumatoid arthritis (sJRA). Clinically, MAS is similar to hemophagocytic lymphohistiocytosis (HLH), a genetic disorder with absent or depressed natural killer (NK) function. We have previously reported that, as in HLH, patients with MAS have profoundly decreased NK activity, suggesting that this abnormality might be relevant to the pathogenesis of the syndrome. Here we examined the extent of NK dysfunction across the spectrum of diseases that comprise juvenile rheumatoid arthritis (JRA). Peripheral blood mononuclear cells (PBMC) were collected from patients with pauciarticular (n = 4), polyarticular (n = 16), and systemic (n = 20) forms of JRA. NK cytolytic activity was measured after co-incubation of PBMC with the NK-sensitive K562 cell line. NK cells (CD56(+)/T cell receptor [TCR]-αβ(-)), NK T cells (CD56(+)/TCR-αβ(+)), and CD8(+ )T cells were also assessed for perforin and granzyme B expression by flow cytometry. Overall, NK cytolytic activity was significantly lower in patients with sJRA than in other JRA patients and controls. In a subgroup of patients with predominantly sJRA, NK cell activity was profoundly decreased: in 10 of 20 patients with sJRA and in only 1 of 20 patients with other JRA, levels of NK activity were below two standard deviations of pediatric controls (P = 0.002). Some decrease in perforin expression in NK cells and cytotoxic T lymphocytes was seen in patients within each of the JRA groups with no statistically significant differences. There was a profound decrease in the proportion of circulating CD56(bright )NK cells in three sJRA patients, a pattern similar to that previously observed in MAS and HLH. In conclusion, a subgroup of patients with JRA who have not yet had an episode of MAS showed decreased NK function and an absence of circulating CD56(bright )population, similar to the abnormalities observed in patients with MAS and HLH. This phenomenon was particularly common in the systemic form of JRA, a clinical entity strongly associated with MAS

Alternate-Day Micafungin Antifungal Prophylaxis in Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation: A Pharmacokinetic Study

Disseminated fungal infection is a major cause of morbidity and mortality in children undergoing hematopoietic stem cell transplantation (HSCT). Prophylaxis with amphotericin B can be limited by renal toxicity. Oral triazoles can be limited by poor absorption, large interindividual pharmacokinetic (PK) variability, and hepatic toxicity, leading to interruptions in therapy and breakthrough infections. Intravenous (i.v.) micafungin has potential advantages, because of its better safety profile, specifically in terms of hepatic and renal toxicity, and lack of drug-drug interactions with common medications used in the HSCT setting. We hypothesized that higher dose micafungin (3 mg/kg) every other day will provide drug exposure similar to standard dosing (1 mg/kg) given daily, and improve patient compliance in very young children in whom oral medications can be challenging, at reduced administration costs. Both animal and adult patient data support the use of this approach. Fifteen children (M/F = 11/4, aged ≤10 years; mean: 3.9 years, range: 0.6-10 years) with various hematologic, metabolic, and immune deficiency disorders undergoing HSCT received a single dose of micafungin (3 mg/kg) i.v. over 1 hour. Dose selection was based on published PK data in pediatric patients, and exploration of different dosing regimens using Monte Carlo PK/PD simulation. Blood samples were drawn around this dose and PK analysis was conducted using standard noncompartmental methods. Micafungin at 3 mg/kg dose was well tolerated in all patients. Measurable plasma concentrations were present in all cases at 48 hours. Half-life and clearance observed were comparable to previous pediatric PK data, with clearance being higher than adults as expected. Volume of distribution was higher in our patients compared to published pediatric data, likely because of a larger proportion of very young children in our study cohort. After correction for protein binding, concentrations at the end of the dosing interval during maintenance treatment remain above the minimum inhibitory concentration (MIC) of highly susceptible fungal pathogens. These data suggest that alternate day micafungin dosing, as described here, may provide an attractive alternative for antifungal prophylaxis in HSCT patients and merits further evaluation

Sustained elevation of serum interleukin-18 and its association with hemophagocytic lymphohistiocytosis in XIAP deficiency

X-linked lymphoproliferative syndrome (XLP) is a rare primary immunodeficiency characterized by increased vulnerability to Epstein-Barr virus infection. XLP type 1 is caused by mutations in SH2D1A, whereas X-linked inhibitor of apoptosis (XIAP) encoded by XIAP/BIRC4 is mutated in XLP type 2. In XIAP deficiency, hemophagocytic lymphohistiocytosis (HLH) occurs more frequently and recurrence is common. However, the underlying mechanisms remain mostly unknown. We describe the characteristics of the cytokine profiles of serum samples from 10 XIAP-deficient patients. The concentration of interleukin (IL)-18 was strikingly elevated in the patients presented with HLH, and remained high after the recovery from HLH although levels of other pro-inflammatory cytokines approached the normal range. Longitudinal examination of two patients demonstrated marked exacerbation of IL-18 levels during every occasion of HLH. These findings may suggest the association between HLH susceptibility and high serum IL-18 levels in XIAP deficiency. © 2013 Elsevier Ltd. All rights reserved

Hemophagocytosis causes a consumptive anemia of inflammation

IFN-γ stimulates blood-eating macrophages (hemophagocytes) by acting directly on macrophages to promote phagocytosis and uptake of blood cells

Ancillary Therapy and Supportive Care of Chronic Graft-versus-Host Disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: V. Ancillary Therapy and Supportive Care Working Group Report

AbstractThe Ancillary Therapy and Supportive Care Working Group had 3 goals: (1) to establish guidelines for ancillary therapy and supportive care in chronic graft-versus-host disease (GVHD), including treatment for symptoms and recommendations for patient education, preventive measures, and appropriate follow-up; (2) to provide guidelines for the prevention and management of infections and other common complications of treatment for chronic GVHD; and (3) to highlight the areas with the greatest need for clinical research. The definition of “ancillary therapy and supportive care” embraces the most frequent immunosuppressive or anti-inflammatory interventions used with topical intent and any other interventions directed at organ-specific control of symptoms or complications resulting from GVHD and its therapy. Also included in the definition are educational, preventive, and psychosocial interventions with this same objective. Recommendations are organized according to the strength and quality of evidence supporting them and cover the most commonly involved organs, including the skin, mouth, female genital tract, eyes, gastrointestinal tract, and lungs. Recommendations are provided for prevention of infections, osteoporosis, and steroid myopathy and management of neurocognitive and psychosocial adverse effects related to chronic GVHD. Optimal care of patients with chronic GVHD often requires a multidisciplinary approach