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Objective The aim of this study was to investigate the relation of QT dispersion to left ventricular (LV) systolic and diastolic function in patients undergoing anthracycline therapy. Methods We used echocardiography to evaluate LV systolic and diastolic function and electrocardiography to evaluate QT dispersion and corrected QT dispersion (QTcD) in patients with hematological diseases, who received anthracycline therapy. Patients Seventy-two patients with hematological diseases who were receiving anthracycline treatment were enrolled in the present study. Results LV end-diastolic diameter or LV end-systolic diameter had a significant positive correlation to QTcD (r=0.35, p

A prospective study was conducted in 71 evaluable patients who received myeloablative hematopoietic stem cell transplantation (HSCT) at our facility from 1995 to 2002, to find a sensitive marker for post-transplant heart failure, including echocardiographic systolic and diastolic markers and QTc interval. QTc was found to be an independent and significant risk factor for acute heart failure (AHF) on multivariate logistic regression analysis (OR 1.5, P=0.01, 95% confidence interval (CI) 1.1-2.0), while no significant differences between patients with AHF and those without AHF were found in age, sex, treatment history, type of conditioning regimen, and echocardiographic systolic and diastolic markers. On further analysis, post-transplant risk of AHF appeared to be increased as QTc was prolonged. The post-transplant risk of AHF in the group with longest QTc on multivariate logistic regression analysis was found to be 9.8 times that in the group with shortest QTc (P=0.04, 95% CI 1.0-100). These results suggest that echocardiographic markers are less valuable predictors of post-transplant AHF, but that prolongation of the QTc, an ECG marker, before HSCT is strongly associated with onset of AHF after HSCT.

A 38-year-old man was diagnosed with acute lymphoblastic leukemia. We performed myeloablative bone marrow transplantation from an unrelated donor during the patient's first complete remission. After engraftment, he developed acute graft-versus-host disease involving the gastrointestinal tract on day 32. Steroids and mycophenolate mofetil were initiated from day 39. His symptoms improved and the dose of immunosuppressants was tapered and then discontinued on day 421. On day 491, he developed nephrotic syndrome (NS). Based on renal biopsy, membranous nephropathy was diagnosed. There were no apparent symptoms or abnormal laboratory data suggestive of chronic graft-versus-host disease (cGVHD). Steroid therapy was initiated from day 518 and proteinuria improved significantly. NS is very rare following allogeneic hematopoietic stem cell transplantation (allo-HSCT). When there is no concomitant cGVHD, as in this case, allo-HSCT-associated NS is difficult to distinguish from idiopathic NS.

A 64-year-old man was diagnosed as having acute myeloid leukemia. We performed sequential treatment with chemotherapy and reduced-intensity stem cell transplantation from an unrelated donor while the patient was in partial remission. After engraftment, he developed acute graft-versus-host disease of the gut on day 42 and steroid therapy was started. Despite transient aggravation of diarrhea, his symptoms slowly improved and the dose of steroid was tapered. On day 159, he complained of acute left lower abdominal pain. A CT scan showed perforation of the digestive tract and ileectomy was performed. At surgery, multiple ulcers of the intestine were found and one of the ulcers was perforated. Pathologically, transmural and diffuse proliferation of atypical cells in the ulcer were confirmed. Since these cells were positive for CD20 and Epstein-Barr-virus (EBV) encoded RNA, we made a diagnosis of EBV-associated post-transplant lymphoproliferative disorder (PTLD). Reduction in the dose of immunosuppressive agents and rituximab led to complete remission of PTLD. PTLD after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is relatively rare, and the development of gastrointestinal perforation after allo-HSCT is very rare.

We have recently demonstrated that granulocyte-colony stimulating factor (G-CSF) delays human neutrophil apoptosis via up-regulation of cellular inhibitor of apoptosis 2 (cIAP2), which is dependent on activation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3). Here, we show that type I and type II interferons (IFNs), which bind to the distinct receptors, exert the antiapoptotic effect on human neutrophils through the similar mechanism. IFN-α (type I IFN) and IFN-γ (type II IFN), like G-CSF, delayed human neutrophil apoptosis through the protein synthesis-dependent mechanism. Stimulation of neutrophils with IFN-α or IFN-γ resulted in tyrosine phosphorylation of STAT1 and STAT3 but not phosphorylation of STAT5, Akt, extracellular signal-regulated kinase, and p38 mitogen-activated protein kinase. IFN-α and IFN-γ induced the expression of transcripts of cIAP2 and suppressor of cytokine signaling 1 and 3, but not cIAP1, Mcl-1, and A1. IFN-α- and IFN-γ-induced up-regulation of cIAP2 mRNA and protein, phosphorylation of STAT3, and antiapoptotic effect were inhibited significantly by pretreatment of cells with AG490, a specific inhibitor of JAK2. These findings suggest that cIAP2 expression is up-regulated by IFN-α and IFN-γ through, at least in part, activation of the JAK2-STAT3 pathway, and increased expression of the cIAP2 protein may contribute to an IFN-α- and IFN-γ-mediated antiapoptotic effect on human neutrophils.

The aim of our study was to evaluate whether corrected QT dispersion (QTc dispersion), an electrocardiographic marker, is a good predictor of the development of acute heart failure after high-dose chemotherapy followed by autologous or allogeneic hematopoietic stem cell transplantation. We enrolled 50 consecutive patients, from age 15 to 63 years, with hematopoietic diseases scheduled to undergo autologous or allogeneic hematopoietic stem cell transplantation, and compared QTc dispersion with other markers before transplantation conditioning. In univariate logistic analysis, QTc dispersion was a significant factor for acute heart failure after hematopoietic stem cell transplantation (odds ratio, 3.7 per 10 msec; confidence interval, 1.6-8.5; P = 0.002). There were no significant differences as age, sex, systolic or diastolic echocardiographic function markers, cumulative anthracycline dose, or QTc before transplantation between patients with and without acute heart failure. After multiple adjustments for left ventricular ejection fraction, cumulative anthracycline dose, cyclophosphamide conditioning dose, QTc dispersion was a significant and independent factor for acute heart failure after hematopoietic stem cell transplantation (odds ratio, 48.0 per 10 msec; confidence interval, 1.4-1666.3; P = 0.03). This study demonstrated that QTc dispersion could be used as a powerful noninvasive predictor of the development of acute heart failure after hematopoietic stem cell transplantation.

Spontaneous neutrophil apoptosis during culture was delayed by granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), or dibutyryl-cyclic adenosine monophosphate (cAMP), whereas apoptosis was accelerated by cycloheximide or actinomycin D. G-CSF-mediated antiapoptosis was completely abolished by cycloheximide or actinomycin D, whereas GM-CSF-mediated antiapoptosis was not completely abolished by these inhibitors. Antiapoptosis induced by dibutyryl-cAMP was highly resistant to cycloheximide, and that induced by benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone was unaffected by cycloheximide. G-CSF- and GM-CSF-mediated antiapoptosis and phosphorylation of signal transducer and activator of transcription 3 (STAT3) and STAT5 were inhibited by AG490, an inhibitor of Janus kinase. The level of Mcl-1 protein was not associated with neutrophil apoptosis. The results suggest that (a) neutrophil survival in the resting state is primarily regulated by the constitutive synthesis of antiapoptotic proteins; (b) the prevention of spontaneous apoptosis is mediated through the protein synthesis-dependent and/or protein synthesis-independent mechanisms according to the stimuli used; and (c) the Janus kinase-STAT pathway is involved in G-CSF- and GM-CSF-mediated antiapoptosis.

Peripheral blood stem cell harvest (PBSCH) has been widely performed for rescue following high-dose chemotherapy or as an alternative to BMT for allogeneic stem cell transplantation. However, severe complications, which caused sudden death, were reported in PBSCH from healthy donors. Recent cumulative evidence shows that decrease in cardiovascular signal variability of the R-R period (heart rate variability, HRV) is strongly associated with sudden death and/or cardiac event after a myocardial infarction. Furthermore, usefulness of HRV as a clinical tool has been explored in numerous conditions such as hypertrophic cardiomyopathy, obstructive sleep apnea, diabetic neuropathy, and various neurological alterations. Two types, time domain and frequency domain, are included in HRV analysis. In this study, we investigated HRV during and after apheresis for PBSCH in 23 cases [8 autologous transplant patients, 15 allogeneic transplant donors; 8 men, 15 women; median age 47 years (27–55)]. Date from 24-hour ambulatory ECG recordings were analyzed with R-R data analysis software (MemCalc/CHIRAM version 1, Suwatrust, Tokyo, Japan). Acknowledged simple markers in time domain analysis are the standard deviation of all normal beats (SDNN) and the square root of the mean of the sum of squared differences between adjacent normal-to-normal intervals (r-MSSD). On the other hand, markers in frequency domain analysis include LH, low frequency power (0.04–0.15Hz); HF, high frequency power (0.15–0.4 Hz); LH/HF ratio; VLF, very low frequency power (0.003–0.04 Hz); and ULF, ultra low frequency power (