Pierre W. Wijermans

Changes in the expression of N-acetylglucosaminyltransferase III, IV, V associated with the differentiation of HL-60 cells.

By use of a new assay method based on HPLC, GlcNAc‐transferase III, IV and V activities were determined in HL‐60 cells, differentiated HL‐60 cells and normal myeloid cells. Differentiation along the monocytic lineage with 1α,25‐dihydroxyvitamin D3 resulted in increased GlcNAc‐transferase IV and decreased GlcNAc‐transferase III activity. Differentiation along the myeloid lineage with retinoic acid resulted in a decrease in GlcNAc‐transferase III activity. Although differentiated HL‐60 cells show a changed GlcNAc‐transferase pattern, they do not resemble normal myeloid cells. Macrophages and granulocytes are characterized by a very low level of GlcNAc‐transferase III activity whereas differentiated HL‐60 cells still contain this activity. This is the first demonstration of GlcNAc‐transferase IV and V activity in a human cell.

Autologous stem-cell transplantation in patients with mantle cell lymphoma beyond 65 years of age: a study from the European Group for Blood and Marrow Transplantation (EBMT)

BACKGROUNDnLimited experience is available on the feasibility and efficacy of autologous stem-cell transplantation (ASCT) in patients with mantle cell lymphoma (MCL) beyond 65 years.nnnDESIGN AND METHODSnWe analysed 712 patients with MCL treated with ASCT from 2000 to 2007 and reported to the European Group for Blood and Marrow Transplantation registry. Patients >65 years were compared with patients <65 years for the end points non-relapse mortality (NRM), relapse incidence, progression-free survival (PFS), and overall survival (OS).nnnRESULTSnSeventy-nine patients were ≥65 years old. Median time from diagnosis to ASCT was longer in the elderly patients (11 versus 9 months, P=0.005); they had more commonly received at least two treatment lines (62.0% versus 47.9%, P=0.02) and were less commonly in first complete remission at ASCT (35.4% versus 51.2%, P=0.002). Median follow-up after ASCT was 19 and 25 months, respectively. NRM was comparable at 3 months (3.8% versus 2.5%) and at 5 years (5.6% versus 5.0%). There were no differences in relapse rate (66% versus 55% at 5 years), PFS (29% versus 40%) and OS (61% versus 67%) between both populations of patients.nnnCONCLUSIONSnASCT beyond 65 years of age is feasible in selected patients with MCL and results in similar disease control and survival as in younger patients.BACKGROUNDnLimited experience is available on the feasibility and efficacy of autologous stem-cell transplantation (ASCT) in patients with mantle cell lymphoma (MCL) beyond 65 years.nnnDESIGN AND METHODSnWe analysed 712 patients with MCL treated with ASCT from 2000 to 2007 and reported to the European Group for Blood and Marrow Transplantation registry. Patients>65 years were compared with patients<65 years for the end points non-relapse mortality (NRM), relapse incidence, progression-free survival (PFS), and overall survival (OS).nnnRESULTSnSeventy-nine patients were ≥65 years old. Median time from diagnosis to ASCT was longer in the elderly patients (11 versus 9 months, P=0.005); they had more commonly received at least two treatment lines (62.0% versus 47.9%, P=0.02) and were less commonly in first complete remission at ASCT (35.4% versus 51.2%, P=0.002). Median follow-up after ASCT was 19 and 25 months, respectively. NRM was comparable at 3 months (3.8% versus 2.5%) and at 5 years (5.6% versus 5.0%). There were no differences in relapse rate (66% versus 55% at 5 years), PFS (29% versus 40%) and OS (61% versus 67%) between both populations of patients.nnnCONCLUSIONnASCT beyond 65 years of age is feasible in selected patients with MCL and results in similar disease control and survival as in younger patients.

Monocytic differentiation induction of HL-60 cells by MC 903, a novel vitamin D analogue.

1.25 (OH)2D3 is a potent inducer of differentiation of leukaemic cells into a monocytic direction. However, therapeutic application is difficult because of the development of hypercalcaemia. We examined a novel vitamin D analogue, MC 903, which is at least 100 times less effective on calcium metabolism in rats than 1.25 (OH)2D3. Using the HL-60 cell line, differentiation was measured with a comprehensive panel of qualitative and quantitative parameters. Development of monocytic cells was shown morphologically, immunophenotypically and functionally by increased capability of reducing NBT (vs cultures without MC 903, p less than 0.0001) and by qualitatively and quantitatively increased non-specific esterase activity. Furthermore, a concomitant decreased activity of myeloperoxidase and lactate dehydrogenase was noticed. In conclusion, MC 903 is a potent inducer of monocytic differentiation, comparable with 1.25 (OH)2D3 and will therefore be an interesting and potential therapeutic agent for studies in human acute leukaemia.

Differentiation induction of HL60 cells in a long-term bone marrow culture of acute myeloid leukemia.

Bone marrow stromal cells are critical for the proliferation and differentiation of hemopoietic stem cells. The hemopoietic microenvironment is reproduced in long term bone marrow culture (LTBMC). Normal LTBMC versus leukemic LTBMC and their stroma conditioned medium were compared with respect to their proliferative and differentiation-inducing capacities. Myeloid leukemic cells (HL60) were layered onto LTBMCs derived from normal volunteers and patients with AML. Differentiation was measured with a comprehensive panel of maturation parameters, i.e. morphology, cytochemistry, quantitative enzyme determination, NBT test and immunophenotyping. Inhibition of proliferation occurred in all cocultures. Clear maturation in monocytic direction was obvious in one culture of HL60 cells layered onto a leukemic stroma. As stroma-derived conditioned medium has no effect, a cellular interaction seems involved. These observations support not only the concept that normal stroma influences leukemic cell growth but also that leukemic stroma can modulate cell growth and maturation.

Graft-Versus-Leukemia Effect of Allogeneic Stem-Cell Transplantation and Minimal Residual Disease in Patients With Acute Myeloid Leukemia in First Complete Remission

PurposeThe detection of minimal residual disease (MRD) in patients with acute myeloid leukemia (AML) may improve future risk-adapted treatment strategies. We assessed whether MRD-positive and MRD-negative patients with AML benefit differently from the graft-versus-leukemia effect of allogeneic hematopoietic stem-cell transplantation (alloHSCT).MethodsA total of 1,511 patients were treated in subsequent Dutch-Belgian Hemato-Oncology Cooperative Group and the Swiss Group for Clinical Cancer Research AML trials, of whom 547 obtained a first complete remission, received postremission treatment (PRT), and had available flow cytometric MRD before PRT. MRD positivity was defined as more than 0.1% cells with a leukemia-associated immunophenotype within the WBC compartment. PRT consisted of alloHSCT (n = 282), conventional PRT by a third cycle of chemotherapy (n = 160), or autologous hematopoietic stem-cell transplantation (n = 105).ResultsMRD was positive in 129 patients (24%) after induction chemotherapy before ...

Coexistence of myelofibrosis and focal osteolysis with clusters of megakaryocytes and necrosis in a patient with trilineage myelodysplastic syndrome

shivering. Morphine and fentanyl have no effect (4). The meperidine effect is associated with a decrease in oxygen consumption and carbon dioxide production (5) . Meperidine is also useful in the symptomatic treatment of shaking chills and fever following amphotericin B infusion and granulocyte transfusions (6, 7). Meperidine, however, is also very effective in rapidly reducing and stopping shaking chills and fever after transfusion of red blood cells and platelets containing enough leukocytes to start such a febrile, non-hemolytic transfusion reaction. It is my experience that this treatment is not known to all hematologists. At present, meperidine (pethidine, 25-50 rng) is used as the drug of choice in our department to suppress these transfusion reactions. Disadvantages of meperidine include nausea and respiratory depression when used in larger doses. The dose of meperidine used to treat shivering (2550 mg) does not cause respiratory distress, nausea or vomiting (4, 5). The mechanism of action of meperidine is uncertain. Meperidine, but not morphine, produces a lethal hyperthermic reaction when given in combination with monoamino oxidase inhibitors (8). This effect was not antagonized by nalorphine (9). The effect of morphine and other opiate and opioid agonists on body temperature has been studied in mice. Meperidine was found to be a far more potent hypothermic agent than morphine at 20°C and 25°C and did not cause hyperthermia at 30°C like the other opiates (10). In rats, the thermoregulatory setpoint was altered by opioid agonists, also suggesting a role of endogenous opioids in thermoregulatory control (2). References