Stein A. Evensen

Cellular cooperation in endothelial cell thromboplastin synthesis

Summary. Endothelial cells from human umbilical veins produce a procoagulant identified as thromboplastin (tissue factor, factor III) when stimulated with the phorbol ester 12‐0‐tetradecanoyl‐phorbol‐13‐acetate (TPA), phytohaemagglutinin (PHA) or endotoxin. Inducible thromboplastin synthesis (i.e. synthesis of the protein component of thromboplastin, apoprotein III) was totally inhibited by cycloheximide and actinomycin D, indicating that de novo protein and RNA syntheses are necessary. Serum enhanced the induced apoprotein synthesis.

LDL-induced cytotoxicity and its inhibition by anti-oxidant treatment in cultured human endothelial cells and fibroblast

Low density lipoproteins (LDL) isolated by ultracentrifugation induce cytotoxic changes in cultured human endothelial cells (EC) and fibroblasts if the ratio between LDL cholesterol and the final protein concentration of the culture medium exceeds 0.10-0.12 mmol/g protein. In order to investigate if reactive oxygen species could contribute to the cytotoxicity, LDL were prepared in the presence of the antioxidants butylated hydroxytoluene (BHT) or superoxide dismutase (SOD), while routinely prepared LDL from the same donors served as control (N-LDL). A radiochromium release assay was used to evaluate cellular injury. BHT treatment of the LDL fraction virtually abolished LDL-induced cytotoxicity in cultured human EC and fibroblasts. SOD-LDL offered partial protection against LDL cytotoxicity. A positive correlation between the cytotoxicity of the various fractions and their content of malondialdehyde (MDA) further supports our conclusion that lipid peroxides in the LDL fractions mediate the cytotoxic effect on cultured cells.

Health-related quality of life 1 year after allogeneic or autologous stem-cell transplantation: A prospective study

PURPOSE To evaluate health-related quality of life (HRQOL) in adults treated with high-dose chemotherapy followed by allogeneic (SCT) and autologous (ASCT) stem-cell transplantation 1 year after transplantation, using data from concurrent lymphoma patients receiving combination chemotherapy (CT) as a reference. MATERIALS AND METHODS Forty-one leukemia patients (SCT group), 51 lymphoma patients (ASCT group), and 85 CT patients completed the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire at baseline and after 1 year. RESULTS The SCT group (median age, 36 years) had better functioning scores and less symptomatology at baseline compared with the ASCT (median age, 41 years) and CT (median age, 37 years) groups. Statistically significant differences of 10 or more points on the 0 to 100 scales were found for 10 of 15 scales and items (P< or =.01) between the SCT and ASCT groups. Global quality of life (79 v 58, P<.0001), role function (83 v 65, P = .001), sleep disturbances (6 v 28, P<.0001), and fatigue (25 v 44, P = .0001) deviated most. The differences were 10 or more points for seven of 15 scales and items comparing the SCT and CT groups, with sleep disturbances (6 v 35, P<.0001) and pain (11 v 29, P<.01) deviating most. Differences across groups were smaller after 1 year; cognitive function was the only scale with a statistically significant difference (ASCT 80 v CT 89; P = .002). Patterns of change in HRQOL scores were different between groups during follow-up. A great improvement was found in the ASCT group (P<.01 for emotional and role function, fatigue, appetite, and constipation), whereas no significant changes were observed for the SCT group. CONCLUSION Prospective studies with extended follow-up periods are necessary to separate a slow recovery process from more permanently reduced HRQOL after transplantation and to examine the late side effects from previous treatment.

Subcutaneous injections of 2-chlorodeoxyadenosine for symptomatic hairy cell leukemia.

PURPOSE To evaluate the clinical efficacy and safety of 2-chlorodeoxyadenosine (CdA) when administered by subcutaneous injection to patients with symptomatic hairy cell leukemia (HCL), and to evaluate predictive factors for response. PATIENTS AND METHODS Seventy-three patients were given CdA as a subcutaneous injection once daily for 7 days. Complete remission (CR) required normalized blood counts and the absence of B-ly 7-positive bone marrow cells by flow cytometry. CdA concentrations in plasma following the first injection were analyzed by high-pressure liquid chromatography. RESULTS Fifty-nine patients (81%) achieved a durable CR after one (n = 55) or two courses, and 10 had a partial remission (PR). With a median follow-up duration of 20 months, no patient had a clinical relapse. Neutropenic fever that required intravenous antibiotics occurred in 28 patients (38%). No toxicity at injection sites was observed. Incomplete response was predicted by an elevated lymphocyte count and serum beta 2-microglobulin level, and by a high percentage of hairy cells in the bone marrow. Plasma CdA levels were similar to those achieved from intravenous administration. CONCLUSION Subcutaneous injection of CdA is safe and as effective as continuous infusion without problems associated with the mode of administration. Our schedule simplifies CdA treatment and can be generally recommended.

Do patients who are treated with stem cell transplantation have a health-related quality of life comparable to the general population after 1 year?

Health-related quality of life (HRQOL) in leukemia and lymphoma patients treated with high-dose chemotherapy followed by allogeneic (SCT) and autologous (ASCT) stem cell transplantation or receiving combination chemotherapy (CT) was prospectively assessed by the EORTC QLQ-C30 and compared with reference data from a general population sample. One year after transplant, the SCT group had functional scores which were close to population values except for lower social (P < 0.0001) and role function (P = 0.0004). More symptoms and problems were reported, especially appetite loss (P = 0.001) and financial difficulties (P = 0.0001). The ASCT patients reported a less than optimal HRQOL relative to the population 1 year post transplant. Cognitive, physical, role, and social function, dyspnoea, financial difficulties and global quality of life were most impaired (P < 0.001). in the ct group, physical, role and social function, dyspnoea and financial difficulties were impaired 1 year after start of chemotherapy, compared with the general population (P < 0.001). the eortc qlq-c30 was supplemented by a high-dose chemotherapy module, the hdc-19, at the 1-year assessment, but no consistent differences were found across groups. fifteen to 34% of the patients expressed fears of relapse and worries about future health, while 24–30% indicated no participation in sexual activities.

The course of anxiety and depression during the first year after allogeneic or autologous stem cell transplantation.

Psychological distress is frequently reported in transplant survivors. We prospectively assessed anxiety and depression before transplant, in the isolation period and during a follow-up period of 1 year. The Hospital Anxiety and Depression Scale (HADS) was administered to 131 cancer patients treated with high-dose chemotherapy followed by allogeneic (SCT) or autologous (ASCT) stem cell transplantation, and a concurrent group of 123 lymphoma patients receiving standard chemotherapy (CT) who served as a reference group. Relatively low levels of anxiety and depression were found. The level of anxiety slightly declined from baseline during follow-up (mean scores SCT: from 5.3 to 3.6, CT: from 6.0 to 4.2) or remained fairly stable (ASCT: from 5.4 to 4.8). The level of depression peaked when the transplant patients were in protective isolation or shortly thereafter (SCT: 6.1, ASCT: 6.4), but stabilized at baseline levels after 4 months. The highest level of depression in the CT group was reported 4 months after start of chemotherapy (3.4). Elevated levels of anxiety and depression at baseline predicted more anxiety and depression at the later assessments (P values <0.0001). the asct group had higher levels of anxiety after 1 year (mean 4.8) than those found in the other two groups (sct: 3.6, ct: 4.2), although they were not statistically significant. this study revealed lower than expected levels of anxiety and depression after intensive chemotherapy followed by sct or asct. there was a decline in psychological distress during the 1-year follow-up period.

European results of matched unrelated donor bone marrow transplantation for chronic myeloid leukemia. Impact of HLA class II matching

We have retrospectively analyzed the impact of prognostic factors on the outcome of serologically HLA-matched unrelated donor (UD) BMT for CML. For this purpose, we have studied a cohort of 366 patients transplanted in Europe between January 1985 and December 1994. The median age of the 211 males and 155 females was 34 years; 238 patients were transplanted in first chronic phase and 116 in advanced phases. The median interval from diagnosis to BMT was 827 days. GVHD prophylaxis consisted of CsA and MTX in 202 patients or of ex vivo or in vivo T cell depletion (TCD) in 129. Recently, DNA-based methods of HLA-class II typing have been used to improve donor selection. We obtained complete data on 300 donor/recipient (D/R) pairs. Among them, we have identified three groups of patients, according to specific HLA-DRB1 D/R compatibility. Two hundred and ten patients received marrow from donors identical for HLA-DRB1 (group 1). Thirty-one patients received BMT from a donor who was HLA-DRB1 mismatched (group 2) and 59 from a donor in whom specific HLA-DRB1 typing was not performed (group 3). The overall survival was 37 ± 3% at 2 years and leukemia-free survival (LFS) was 31 ± 3%. In univariate analysis, five variables had a favorable effect on LFS: transplant in first chronic phase (P = 0.0001), time interval from diagnosis to BMT shorter than the median (P = 0.01), prophylaxis of GVHD without TCD (P = 0.001), acute GVHD <grade III (P = 0.0009) and HLA-DRB1 D/R matching (P = 0.0001). Transplant-related mortality (TRM) was 49 ± 4% in group 1, 79 ± 8% in group 2 and 80 ± 6% in group 3 (P = 0.0001). Multivariate analysis confirmed that HLA-DRB1 matching was the most significant factor influencing survival (P = 0.04), LFS (P = 0.013) and TRM (P = 0.0049). From these results, we have defined a ‘good risk’ group, ie patients transplanted in first chronic phase, from an HLA-DRB1 matched donor, without TCD as prophylaxis against GVHD. The 2 year LFS, TRM and relapse incidence for this group were 51 ± 5%, 47 ± 5% and 2 ± 2%, respectively. This suggests that the long-term outcome of patients with favorable prognostic features can approach that of patients transplanted from geno-identical siblings. In contrast, the TRM for patients transplanted for advanced disease from non HLA-DRB1-identical donors was 94%. Such a high TRM clearly indicates that UD BMT is not justifiable for these individuals.

A phase I/II study of the MDR modulator Valspodar (PSC 833) combined with daunorubicin and cytarabine in patients with relapsed and primary refractory acute myeloid leukemia

The cyclosporine analog Valspodar (PSC 833, Novartis Pharma) is a strong inhibitor of the mdr1 gene product p-glycoprotein (pgp). A phase I/II study was conducted in order to evaluate if addition of Valspodar to treatment with daunorubicin and cytarabine, given to patients with primary refractory or relapsed acute myeloid leukemia, could increase the complete remission rate.Fifty-three patients were treated in cohorts of three to six patients. Twelve patients reached a complete remission in bone marrow, five of whom also normalized their peripheral blood values. Three patients experienced treatment-related deaths from pneumonia, liver failure and cerebral hemorrhage, respectively. It is concluded that Valspodar 10 mg/kg per 24 h in combination with daunorubicin 45 mg/m(2) for 3 days and cytarabine 1 g/m(2) twice daily for 4 days is tolerable in this heavily pre-treated group of patients. Due to the moderate treatment results, the phase II part of the study was ended prematurely. The modulation of only pgp did not give an obvious improvement of the treatment results in this group of patients.

Platelets and the Triggering Mechanism of Intravascular Coagulation

Summary The ability of platelets to trigger intravascular coagulation was studied by infusing a suspension of frozen‐thawn homologous platelets into rabbits pretreated with either saline or Thorotrast. Each animal received during a period of 30 min an amount of platelets at least equivalent to the number of circulating platelets in a normal animal of the same weight. The infusion of platelet material did not trigger fibrinogen consumption in saline‐pretreated animals. In Thorotrast‐pretreated animals, however, the platelet suspension produced significantly increased disappearance of [125I]fibrinogen, moderate decreases in the fibrinogen level, significant falls in factors V and VIII, but no increase in fibrinolytic split products. None of the animals developed the generalized Shwartzman reaction. We conclude that platelets contain weak procoagulant activity which was effectively cleared by the reticuloendothelial system in the normal animal. Depression of the phagocytic capacity by Thorotrast prior to the infusion unmasked moderate intravascular coagulation.

Donation of stem cells from blood or bone marrow: results of a randomised study of safety and complaints

Biological consequences and physical complaints were compared for donors randomly assigned either to blood stem cell (BSC) or bone marrow (BM) donation. In the period 1994–1999, 61 consecutive donors were included. The BSC donors were given G-CSF 10 μg/kg s.c., daily during 5 days before the first leukapheresis. Nineteen donors had one leukapheresis, 10 required two and one donor needed three leukaphereses in order to reach the target cell number of 2 × 106 CD34+ cells/kg bw of the recipient. A median platelet nadir of 102 × 109/l was reached shortly after the last leukapheresis. Three weeks post harvest, 17 of 30 BSC donors had a mild leukopenia. Six had a leukopenia lasting more than a year before returning to normal values. Both groups were monitored prospectively through a standardised questionnaire completed by the donors. BSC donation was significantly less burdensome than BM donation and was preferred by the donors. The short-term risks of BSC mobilisation and harvest seem negligible. The potential long-term effects of G-CSF are unresolved and the donors must be followed closely.Bone Marrow Transplantation (2002) 29, 479–486. doi:10.1038/sj.bmt.1703418