Shuji Yonekura

The japanese multicenter open randomized trial of ursodeoxycholic acid prophylaxis for hepatic veno-occlusive disease after stem cell transplantation

Hepatic veno‐occlusive disease (VOD) is a common transplant‐related complication of stem cell transplantation. There is no safe and proven therapy for established VOD, and attempts have focused on its prevention. Limited studies have suggested that prophylactic use of ursodeoxycholic acid (UDCA) reduced the incidence of VOD. To confirm the preventive effect of UDCA on VOD, we conducted a prospective, unblinded randomized, multicenter study of UDCA involving 132 patients who underwent stem cell transplantation for a variety of disorders. Sixty‐seven patients were assigned to the UDCA‐treated group, and 65 patients were assigned to the control group. The clinical characteristics of the two groups were similar with respect to primary diagnosis, age, sex, and baseline organ function. The preparative regimen and GVHD prophylaxis did not differ significantly between the two groups. UDCA was highly effective in preventing VOD, which occurred in only 3.0% in the UDCA‐treated group, as opposed to 18.5% in the control group (P = 0.0043). There were no adverse effects attributable to UDCA. The initial promising report of a prophylactic effect of UDCA on VOD after stem cell transplantation was confirmed in this prospective study. Am. J. Hematol. 64:32–38, 2000.

Increased growth and collagen synthesis of bone marrow fibroblasts from patients with chronic myelocytic leukaemia

Summary. Growth and collagen synthesis were measured in human bone marrow fibroblasts derived from patients with chronic myelocytic leukaemia (CML) and normal individuals. The 3H‐thymidine uptake, growth rate and collagen synthesis of fibroblasts from patients with CML were significantly greater than those from normal subjects. Thus, there is increased proliferation and collagen synthesis of fibroblasts in patients with CML. These findings show that CML fibroblasts may display a greater sensitivity to stimulator contained in the fetal calf serum used for the cultures, and they are relevant to the myelofibrosis by bone marrow fibroblasts in this disease.

Clinical significance of LEA-1 expression in adult acute myeloid leukemia

In this study, we examined expressions of several adhesion molecules (AdMs), i.e. leukocyte function antigen-1 (LFA-1: CD11a/CD18), Hermes homing receptor (CD44) and intercellular adhesion molecule-1 (ICAM-1: CD54), on leukemia cells from 51 adult patients with newly diagnosed acute myeloid leukemias (AMLs) to elucidate clinical significance of these AdM expressions. Those expressions in lymphoid malignancies have been correlated with tumor evolutions, but CD44 was detected in all the AML cases examined and CD54 expression did not associate with their clinical characteristics or outcomes. However, we found that LFA-1 expressions significantly correlated with splenomegaly, resistance to induction chemotherapies and short survival periods in AML patients.

Analysis of intramedullary cell density by MRI using the multiple spin-echo technique

Analysis of the intramedullary cell distribution by magnetic resonance imaging (MRI) using conventional techniques involves subjectively interpreting images and estimating the cell distribution on the basis of signal intensity characteristics. In recent years, attempts have been made to achieve more precise analysis by new techniques, including chemical shift imaging. The multiple spin‐echo (MSE) technique offers some advantages over conventional MRI. Since it allows measurement of the transverse magnetization decay curve at 32 or more points, it is capable of separating several tissue components with different relaxation times. In addition, this technique can be used with MRI instruments having a static magnetic field as low as 1.0 Tesla. In the present study, the intramedullary cell density was assessed by MRI using the MSE technique in 4 patients with aplastic anemia (AA), 4 patients with myelodysplastic syndrome (MDS), and 5 normal subjects. The water component of the marrow (with a short relaxation time) and the fat component (with a long relaxation time) were separated from each other by analyzing MR images obtained using the MSE technique, and the signal intensity ratio of the 2 components was calculated. The ratio was significantly higher in the AA group than in the other groups (AA vs. MDS, P = 0.0209, AA vs. normal controls, P = 0.0143). The present technique appears promising for quantitative assessment of the intramedullary cell density. Am. J. Hematol. 55:134–138, 1997.

A Novel Variant of B-Lymphoid Leukemia Expressing Kappa/Lambda Light Chains

We studied a patient with an indolent leukemia which behaved similarly to chronic lymphocytic leukemia (CLL). Leukemic cells, however, showed larger cell diameters and lower nuclear/cytoplasmic ratios than typical CLL cells, and contained numerous cytoplasmic vacuoles. The cells also demonstrated some morphologic characteristics of hairy cell leukemia. Furthermore, flow-cytometric analysis demonstrated a distinct population of κ/λ double-positive tumor cells, as well as κ single and λ single populations. Southern blot analysis confirmed rearranged bands for both light chains with a monoclonal heavy chain rearrangement. Despite a decision not to treat this asymptomatic patient, disease progression was not observed. This case may represent a unique variant of B lymphoid leukemia. Possible mechanisms of abnormal light chain expression are discussed.

Hematologic response in patients with aplastic anemia after long-term administration of recombinant human granulocyte colony—stimulating factor and erythropoietin

Twenty patients with aplastic anemia underwent long-term administration (10 weeks) of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in doses from 50 to 800 micrograms/m2 per day by intravenous infusion or 50 to 100 micrograms/m2 per day by subcutaneous injection and re-combinant human erythropoietin (rhEPO) in doses ranging from 2000 to 8000 IU/m2 per day by intravenous injection three times a week for at least 4 weeks. The goal was to evaluate whether therapy ameliorated pancytopenia in these patients as well as to determine its safety. All assessable patients showed a substantial increase in absolute neutrophil count, with a recovery of myeloid components (granulocyte series) in the bone marrow, after 2 to 10 weeks of treatment. An increase > 1.5 g/dL in hemoglobin (Hb) concentration was observed in 2 patients (10%). A decrease > 50% in red cell transfusion requirement was observed in 2 patients (10%). Seven patients showed recovery of neutropenia, anemia, and platelet count. In addition, there was no serious infection before or during therapy, and side effects were mild. Of the 20 patients, 3 showed a dramatic improvement in severe anemia after 10 weeks of treatment accompanying a recovery of erythroid components in the bone marrow. They no longer require red cell transfusions and have had normal Hb concentrations and normal ferrokinetics. These results indicate that long-term administration of rhG-CSF and rhEPO may benefit some patients with aplastic anemia. Further studies will be necessary to elucidate the mechanism by which rhGCSF and rhEPO stimulate hematopoiesis and improve hematologic abnormalities in these patients.

Plasma noradrenaline as an indicator of functional state in hearts with mitral stenosis: the influence of acutely reduced left atrial pressure by balloon mitral commissurotomy

SummaryTo investigate the mechanism in which plasma noradrenaline concentration (pNA) is elevated in heart failure, the effect of balloon mitral valvulo-plasty was used as a model of acute manipulation of the left atrial pressure reduction in ten patients with mitral stenosis. Gorlin mitral valve area and pNA were correlated with New York Heart Association functional class and found to have a significant exponential inverse relationship with each other ([pNA, pg/ml] = 198.9 × [mitral valve area, cm2]−0.696;P = 0.003). Elevated pNA could be partially explained by a reduced cardiac index (CI) ([pNA, pg/ml] = 403.4 × [CI, l/min/m2]−0.889;P = 0.027;r = 0.495), especially in severely failed hearts, but not by pulmonary capillary wedge pressure (PCWP). However, the percent changes (%Δ) of variables early after balloon valvulo-plasty exhibited aparadoxical contrast; %Δ pNA showing a clear negative exponential correlation with %Δ PCWP ([%Δ pNA] = 436.0 × [%Δ PCWP + 80]−0.679 − 80;P = 0.021), but not with %Δ CI. These results suggest that pNA should be considered an indicator of cardiac functional class in mitral stenosis. PNA is modulated by both cardiac index and pulmonary capillary pressure, but in different ways.

Scintigraphic imaging of a case of congenitally corrected transposition of the great vessels and an adult case of single atrium and single ventricle

We report on the clinical utility of radionuclide angiography and gated blood pool single emission computed tomography (gated blood pool SPECT) in two patients having congenital heart disease. Both conventional equilibrium radionuclide angiography and gated blood pool SPECT demonstrated the connection of the great vessels with both ventricles in a 15-year-old male patient with a congenitally corrected transposition of the great vessels. In particular, the latter procedure could provide very useful information about the ventricular morphology and inversion which is important for diagnosing this disorder. The second case is an extremely rare 42-year-old female patient with a single atrium and single ventricle. She underwent first-pass and multiple gated blood pool angiography from the anterior, right and left oblique views. The combination of these scintigraphic techniques revealed an insufficiency in anatomical correlations among the single atrium, atrioventricular valve, single ventricle and the great vessels in addition to the connection of superior vena cava with the single atrium, and the atrioventricular valve. Thus, conventional equilibrated angiography from multiple views and gated blood pool SPECT seems to be very reliable not only for anatomical evaluation but also for clinical course observation in patients with complicated congenital heart disease.

Clinical significance of granulocyte colony-stimulating factor (G-CSF) receptor expression in acute myeloid leukemia.

We examined granulocyte colony-stimulating factor (G-CSF) receptor (GR) expression on leukemic cells from 44 adults with newly-diagnosed acute myeloid leukemia (AML). GR expression was higher in female patients. G-CSF was administered to AML patients after initial induction therapy without significant acceleration of leukemia, irrespective of GR expression level. G-CSF administration after initial chemotherapy did not adversely influence clinical outcome of GR-positive patients. However, at first relapse, leukemia regrowth was accelerated in 3 of 15 GR-positive patients who received G-CSF after re-induction. It remains to be determined whether leukemia acceleration due to G-CSF contributes to re-induction failure and if G-CSF therapy is a significant risk in relapsed, GR-positive AML patients.

Granulocyte colony‐stimulating factor production by human bone marrow fibroblasts stimulated with interleukins

Granulocyte colony‐stimulating factor (G‐CSF) is a cytokine that mediates the clonal proliferation and differentiation of progenitor cells into mature granulocytes. The kinetics of G‐CSF production by human bone marrow fibroblasts (BMF) were investigated by quantitative immunoassays. The spontaneous production of G‐CSF by BMF was below the detectable level. Interleukin‐1 (IL‐1) induced a dose‐dependent production of G‐CSF, and the production reached a plateau at 50 U/ml of IL‐1. G‐CSF production by BMF stimulated with IL‐1 was cell concentration dependent. Detectable G‐CSF was produced by 5 × 102 BMF in a 35 × 10‐mm plastic dish. The optimal range was 1 × 104−5 × 104 BMF. Production of newly synthesized G‐CSF was detectable 6 hr after stimulation and continued for approximately 48 hr. A 6‐hr pulse exposure to IL‐1 was necessary to induce production of G‐CSF, and after 48 hr, the adherent BMF could not be restimulated. IL‐2, IL‐3, IL‐4, IL‐5, and IL‐6 were unable to induce G‐CSF production. However, IL‐4 promoted G‐CSF production after stimulation with IL‐1. These results provide useful data with regard to the mechanism of G‐CSF production by human BMF.