Preoperative platelet function predicts perioperative bleeding complications in ticagrelor-treated cardiac surgery patients: a prospective observational study.

BACKGROUND: Treatment with P2Y12 receptor antagonists increases the risk for perioperative bleeding, but there is individual variation in the antiplatelet effect and time to offset of this effect. We investigated whether preoperative platelet function predicts the risk of bleeding complications in ticagrelor-treated cardiac surgery patients. METHODS: Ninety patients with ticagrelor treatment within <5 days of surgery were included in a prospective observational study. Preoperative platelet aggregation was assessed with impedance aggregometry using adenosine diphosphate (ADP), arachidonic acid (AA), and thrombin receptor-activating peptide (TRAP) as initiators. Severe bleeding complications were registered using a new universal definition of perioperative bleeding. The accuracy of aggregability tests for predicting severe bleeding was assessed using receiver operating characteristic (ROC) curves, which also identified optimal cut-off values with respect to sensitivity and specificity, based on Youden's index. RESULTS: The median time from the last ticagrelor dose to surgery was 35 (range 4-108) h. The accuracy of platelet function tests to predict severe bleeding was highest for ADP [area under the ROC curve 0.73 (95% confidence interval 0.63-0.84, P<0.001); TRAP 0.61 (0.49-0.74); AA 0.53 (0.40-0.66)]. The optimal cut-off for ADP-induced aggregation was 22 U. In subjects with ADP-induced aggregation below the cut-off value, 24/38 (61%) developed severe bleeding compared with 8/52 (14%) when aggregation was at or above the cut-off value (P<0.001). The positive and negative predictive values for this cut-off value were 63 and 85%, respectively. CONCLUSIONS: Preoperative ADP-induced platelet aggregability predicts the risk for severe bleeding complications in ticagrelor-treated cardiac surgery patients.

Cell saver processing mitigates the negative effects of wound blood on platelet function.

BACKGROUND: Wound blood is highly activated and has poor haemostatic properties. Recent data suggest that retransfusion of unwashed wound blood may impair haemostasis. We hypothesized that cell saver processing of wound blood before retransfusion reduces the negative effects. METHODS: Wound blood was collected from 16 cardiac surgery patients during cardiopulmonary bypass. One portion of the wound blood was processed in a cell saver and one portion left unprocessed. Increasing amounts of unprocessed blood (10% and 20% of the systemic blood volume) or corresponding volumes of processed blood were added ex vivo to whole blood samples from the same patient. Clot formation was assessed by modified thromboelastometry (ROTEM(®) ) and platelet function with impedance aggregometry (Multiplate(®) ). RESULTS: Addition of unprocessed wound blood significantly impaired clot formation and platelet aggregability. Cell saver processing before addition did not influence clot formation but abolished completely the negative effects of wound blood on platelet aggregability tested with all agonists. Median adenosine diphosphate-induced platelet aggregation was 51 (25th and 75th percentiles 42-69) when 20% processed cardiotomy suction blood was added vs. 34 (24-52) U when 20% unprocessed blood was added, P < 0.001. The corresponding figures for arachidonic acid-, thrombin receptor activating peptide- and collagen-induced aggregation was 21 (17-51) vs. 13 (10-25) U, 112 (87-128) vs. 78 (65-103) U and 58 (50-73) vs. 33 (28-44) U, respectively, all P < 0.001). CONCLUSION: The results suggest that cell saver processing before retransfusion mitigates the negative effects of wound blood on platelet function despite that cell saver processing reduces platelet count.

Differentiation of canine adipose mesenchymal stem cells into insulin-producing cells: comparison of different culture medium compositions.

The aim of this study was to differentiate canine adipose-derived mesenchymal stem cells (ADMSCs) into insulin-producing cells by using culture media with different compositions to determine the most efficient media. Stem cells isolated from the fat tissues close to the bitch uterus were distributed into 6 groups: (1) Dulbecco's modified Eagle medium (DMEM)-high glucose (HG), ß-mercaptoethanol, and nicotinamide; (2) DMEM-HG, ß-mercaptoethanol, nicotinamide, and exendin-4; (3) DMEM-HG, ß-mercaptoethanol, nicotinamide, exendin-4, B27, nonessential amino acids, and l-glutamine; (4) DMEM-HG, ß-mercaptoethanol, and nicotinamide (for the initial 8-d period), and DMEM-HG, ß-mercaptoethanol, nicotinamide, exendin-4, B27, nonessential amino acids, l-glutamine, and basic fibroblast growth factor (for the remaining 8-d period); (5) DMEM-HG and fetal bovine serum; and (6) DMEM-low glucose and fetal bovine serum (standard control group). Adipose-derived mesenchymal stem cells from groups 1 to 5 gradually became round in shape and gathered in clusters. These changes differed between the groups. In group 3, the cell clusters were apparently more in numbers and gathered as bigger aggregates. Dithizone staining showed that groups 3 and 4 were similar in terms of the mean area of each aggregate stained for insulin. However, only in group 4, the number of insulin aggregates and the total area of aggregates stained were significantly bigger than in the other groups. The mRNA expression of PDX1, BETA2, MafA, and Insulin were also confirmed in all the groups. We conclude that by manipulating the composition of the culture medium it is possible to induce canine ADMSCs into insulin-producing cells, and the 2-staged protocol that was used promoted the best differentiation.

Site of intrauterine artificial insemination in the bitch does not affect sperm distribution within the uterus.

The aim of this study was to evaluate the distribution of frozen-thawed spermatozoa within the uterine lumen and oviducts following intrauterine laparoscopic deposition at two sites. Twelve bitches of unknown reproductive history were randomly distributed into two groups. Semen (3 ml containing 300 × 10(6) frozen-thawed spermatozoa) was infused at the uterine body (UB group) or at the cranial tip of the left uterine horn. A 22-G catheter was used to access the uterine lumen. Sperm cell distribution was evaluated after ovariohysterectomy performed 3 h after artificial insemination (AI). There was no difference between groups in mean time to perform AI. Spermatozoa were detected in all uterine segments, including the tip of both horns, but none was detected in the oviduct. The 22-G catheter facilitated deposition of semen in the uterine lumen, particularly at the UB site. Sperm cell distribution occurred evenly along both horns, independent of the site of semen deposition.

Repeated human papillomavirus DNA findings among female university students.

In a previous study, we found a high (33%) human papillomavirus (HPV) DNA prevalence among first year university students in the Helsinki metropolitan area. We have now performed HPV rescreening among first-round HPV-positive students using a liquid-based hybridization assay. A total of 212 students participated in rescreening, and 82 (38.7%) of 212 were found to be positive for HPV DNA. Low-risk (lr) HPV DNA was repeatedly found in 16.8% of the patients who had been lr positive in the first screening round. High-risk (hr) HPV DNA was repeatedly found in 33.3% of the patients. Although HPV typing in these samples has not been carried out yet, we conclude that repeatedly positive HPV DNA findings were strikingly common. hrHPV DNA was repeatedly found twice as often as lrHPV DNA. HPV DNA prevalence was higher among oral contraceptive users than among patients using other contraception.

Subcutaneous alemtuzumab vs ATG in adjusted conditioning for allogeneic transplantation: influence of Campath dose on lymphoid recovery, mixed chimerism and survival.

Sixty-nine consecutive patients (median age 54 years) were prospectively enrolled in a single-institution protocol for allogeneic transplantation with adjusted non-myeloablative fludarabine-melfalan-based conditioning including cyclosporin A and MMF, and one of three modes of serotherapy. Thirty-one donors (45%) were unrelated. The first cohort of 29 had ATG (Thymoglobulin 2 mg/kg x 3 days), the subsequent 26 had Campath 30 mg x 3 days subcutaneously, and the final cohort of 14 had 30 mg Campath once. The groups were similar as regards age, diagnosis and risk factors. Campath-patients had no acute toxicity, fewer days with fever and antibiotics, and required fewer transfusions than ATG-treated patients. 3-d-Campath patients showed lower lymphocyte counts from day +4, and CD4+, CD8+, CD19+ and NK cells recovered slower than in ATG-treated patients. More Campath patients developed mixed chimerism that required DLI. 3-d-Campath induced more serious and opportunistic infections than ATG, which resulted in a greater non-relapse mortality and an impaired overall survival despite a low tumor-related mortality. The change of the Campath dosing schedule to one dose abrogated the deleterious effect of 3-d-Campath on immune recovery, severe infections and survival. Subcutaneous Campath is simple and provides strong immune suppression with no early toxicity, but dose limitation to 30 mg once is recommended.

Expression of the transforming growth factor alpha protooncogene in differentiating human promyelocytic leukemia (HL-60) cells.

The process of myeloid differentiation in human promyelocytic leukemia cells (HL-60) is accompanied by the coordinate expression of numerous protooncogenes. To investigate the expression of transforming growth factor alpha (TGF-alpha) in myeloid differentiation, HL-60 cells were induced to differentiate into granulocytes with 1.25% dimethyl sulfoxide, 0.2 microM all-trans retinoic acid, or 500 microM N6,O2-dibutyryladenosine-3'5'-cyclic monophosphate or differentiated along the monocyte/macrophage pathway with 0.1 microM phorbol-12-myristate-13-acetate. Using Northern blot analyses, TGF-alpha transcripts were detected within 24 h of treatment in cells differentiating toward granulocytes; maximal levels of gene expression were reached after 3 days or later and remained essentially constant throughout the observation period. These cells released TGF-alpha protein, as demonstrated by analysis of the incubation medium. In contrast, no TGF-alpha RNA or protein was detectable in HL-60 cell cultures when induced with phorbol-12-myristate-13-acetate. Epidermal growth factor receptor transcripts could not be detected either in undifferentiated or in differentiated HL-60 cells; therefore it appears as if an autocrine loop involving TGF-alpha in HL-60 cells is unlikely. In conclusion, the results demonstrate, for the first time, the expression of TGF-alpha in human granulocyte precursor cells. Our findings may indicate novel regulatory pathways in hematopoiesis.

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.

Production of transforming growth factor alpha by normal human blood eosinophils.

Transforming growth factor alpha (TGF-alpha) is a pleiotropic factor mediating numerous cellular responses in normal and transformed cells. This includes differentiation, proliferation, migration, and formation of extracellular matrix. TGF-alpha has been demonstrated in circulating eosinophils from the idiopathic hypereosinophilic syndrome and in differentiating promyelocytic leukemia cells in vitro. Whether TGF-alpha production also occurs in normal human blood cells is not known. Northern blot analysis showed that normal human white blood cells consistently expressed the TGF-alpha gene in 47 out of 47 donors. Cell preparations enriched in mononucleated cells, and devoid of granulocytes, showed no TGF-alpha mRNA. In situ hybridization experiments assigned the TGF-alpha gene expression to the eosinophils; 100% of the eosinophils and no other cell types were specifically recognized by the complementary human TGF-alpha riboprobe. White blood cells, incubated at 37 degrees C for up to 6 hours, released immunoreactive TGF-alpha to the incubation medium, as determined by ELISA. In contrast, no TGF-alpha protein was detected in the incubation medium of mononuclear cells. It is concluded that TGF-alpha is constitutively produced and released by normal human blood eosinophils. TGF-alpha provided by eosinophils, may participate in the inflammatory reaction by interacting with mesenchymal and epithelial cells, thus promoting fibrosis or neovascularization.

Variant translocation t(3;15)(q21;q22) in a patient with acute promyelocytic leukemia.

Bone marrow cells from most patients with acute promyelocytic leukemia contain a highly specific cytogenetic rearrangement, a reciprocal translocation between the long arms of chromosomes 15 and 17. Several cases of variant translocations involving 17q but not 15q have been reported, leading to the suggestion that the break in 17q rather than the one in 15q is the crucial change in the regular t(15;17). We describe a hematologically typical case of acute promyelocytic leukemia with a t(3;15)(q21;q22). This is the first report in this leukemia subset of a variant translocation affecting 15q without involvement of 17q.

Production of transforming growth factor alpha by human leukemia cells (HL-60 and U-937) during monocytic differentiation.

We have previously demonstrated that human promyelocytic HL-60 cells express transforming growth factor-alpha (TGF-alpha) during granulocytic differentiation. The present experiments were carried out in order to determine whether cells differentiated towards monocytes/macrophages will analogously express the TGF-alpha proto-oncogene product. HL-60 cells were induced to differentiate with 1 microM 1,alpha 25-dihydroxycholecalciferol (vitamin D3), and the human monocytoid cell line, U-937, was induced with 1 microM retinoic acid (RA), 0.1 microM vitamin D3, or 0.16 microM phorbol-12-myristate-13-acetate (PMA), ie experimental protocols known to induce monocyte/macrophage differentiation in these cells. In HL-60 cells, lacking constitutive TGF-alpha mRNA, vitamin D3 caused expression of the TGF-alpha gene and protein as demonstrated by Northern blot analysis and enzyme-linked immunoabsorbant assay (ELISA). In U-937 cells, showing constitutive TGF-alpha expression, RA but not vitamin D3 or PMA, caused marked increase in TGF-alpha mRNA (approximately 5-fold) and protein (approximately 3-fold) levels. In both cell lines the increase in TGF-alpha mRNA was evident within 24 h and continued throughout the observation period. Thus, it is established that differentiation of human leukemia cells towards monocytes/macrophages may be accompanied by TGF-alpha gene and protein expression in vitro. This is in conformity with the observed ability of mature activated macrophages to produce TGF-alpha.

Transforming growth factor alpha expression in normal human blood eosinophils: differential regulation by granulocyte-macrophage colony-stimulating factor and interleukin-3.

We have previously demonstrated a constitutive expression of transforming growth factor alpha (TGF-alpha) in normal human blood eosinophils, both at the mRNA and protein level. This may indicate a novel function of the eosinophil, the regulation of which has not been clarified. Therefore human white blood cells (WBC) were treated with potential regulators of eosinophil function. Northern blot analysis demonstrated that human recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3) caused a time and dose-dependent 2- to 3-fold increase of TGF-alpha mRNA levels, in relation to incubation in the absence of cytokine; maximal response was attained within 4 h of incubation. In contrast, IL-5 failed to influence the expression of the TGF-alpha gene. In situ analysis of GM-CSF- or IL-3-stimulated cells showed that eosinophils remained the sole cell type expressing TGF-alpha mRNA. However, whereas GM-CSF significantly induced, within 1 h, release of immunoreactive TGF-alpha protein, IL-3 was insufficient in this respect. In conclusion, our findings indicate that expression of TGF-alpha gene and protein in normal blood eosinophils is differently regulated by GM-CSF and IL-3.

Deletion of chromosome arm 3p in hematologic malignancies.

Cytogenetic aberrations resulting in deletion of 3p are common in solid tumors, indicating the presence of tumor suppressor genes (TSG) on this chromosome arm. The present study was undertaken to investigate 3p loss in hematologic disorders. Ten acute myeloid leukemias (AML), two myelodysplastic syndromes (MDS), one Philadelphia chromosome-positive chronic myeloid leukemia (CML), three acute lymphoblastic leukemias (ALL), one chronic lymphoproliferative disorder (CLD), and three non-Hodgkin's lymphomas (NHL) with abnormalities leading to 3p deletions were identified, constituting 2.9% of AML, 0.7% of MDS, 1.0% of CML with changes in addition to t(9;22), 1.5% of ALL, 4.2% of CLD, and 1.1% of NHL with cytogenetic abnormalities analyzed at our Department. Among 19042 karyotypically aberrant published cases, 1.2% of 6260 AML, 1.3% of 2285 MDS, 0.8% of 840 chronic myeloproliferative disorders (CMD), 0.7% of 1894 CML with additional aberrations to t(9;22), 0.6% of 3589 ALL 2.4% of 1602 CLD, 4.5% of 178 Hodgkin disease (HD), and 3.1% of 2394 NHL displayed partial loss of 3p (0.6-4.5%; P < 0.001); the majority occurring together with other abnormalities. The frequencies of 3p loss did not differ significantly among the MDS, ALL, and CLD morphologic subgroups, between B and T cell ALL, CLD, and NHL, among low-, intermediate-, and high-grade NHL, or between therapy-related MDS and de novo MDS, whereas the incidence of 3p deletions was higher in treatment-associated AML (P < 0.001) than in de novo AML and varied among the AML FAB groups (P < 0.001). The most frequently deleted chromosome bands were 3p25 in AML, 3p26 in MDS, 3p14 in CMD, 3p25, 3p23, and 3p21 in CML, 3p26 and 3p25 in ALL, 3p26 and 3p25 in CLD, 3p26 in HD, and 3p26 in NHL. These deletion hot spots are more distal than those reported in most solid tumor types, suggesting that different TSG are involved in hematologic malignancies and solid neoplasms.

Clinical impact of breakpoint position within M-bcr in chronic myeloid leukemia.

We have analyzed the M-bcr breakpoint position in 133 Philadelphia-positive chronic myeloid leukemia patients and correlated the findings with clinical, hematologic, and cytogenetic data. We also investigated the splicing pattern of the BCR-ABL mRNA in 30 patients, using reverse transcriptase PCR. No statistically significant differences were found between breakpoint position within M-bcr and clinical parameters at diagnosis, the karyotypic evolution pattern, or the leukemic phenotype during blast crisis. Furthermore, the breakpoint position within M-bcr did not correlate with the duration of chronic phase or survival time. When the splicing pattern of the BCR-ABL mRNA was compared with the results of the genomic breakpoint mapping, it was found that approximately 60% (8/14) of the patients with a 5' break expressed b2a2 fusion mRNA, whereas all patients (10/10) with a 3' break expressed b3a2 BCR-ABL mRNA.

Trisomy 14 in atypical chronic myeloid leukemia.

Trisomy 14 was the sole karyotypic anomaly in three patients with Ph1-negative chronic myeloid leukemia, and the only abnormality in one of three clones in a fourth case. The hematologic features were partly myeloproliferative, partly myelodysplastic, and included myeloid hyperplasia, neutrophilia without basophilia, a relatively high number of immature granulocyte precursors in the peripheral blood, and monocytosis in three and dysgranulopoiesis in two of the patients. These data, in combination with the patients' high age at diagnosis, their short survival, and the lack of rearrangements of the major breakpoint cluster region (M-bcr) in the two cases where cells were available for molecular analysis, indicate that all four patients suffered from atypical chronic myeloid leukemia (aCML). We suggest that trisomy 14 may be a characteristic karyotypic abnormality in this hematologic disorder.

Ig-secreting cells pass the blood-brain barrier: studies on kappa and lambda light chain secreting cells in plasma cell dyscrasia.

To study if immunoglobulin (Ig)-secreting cells actively pass the blood-brain barrier (BBB), 15 patients with monoclonal gammopathy underwent bonemarrow (BM) iliac crest aspiration biopsy, peripheral blood (PB) sampling and cerebrospinal fluid (CSF) analysis. With an enzyme-linked immunospot assay we investigated the number and ratio of mononuclear cells secreting Ig with kappa and lambda light chains in the three different compartments. A statistically significant (P < 0.05) correlation between the ratio of Ig kappa/lambda-secreting cells in CSF, PB and BM was found. The frequency of kappa and lambda (i.e. Ig in total) secreting mononuclear cells, of the same Ig class as the paraprotein, per 10(4) mononuclear cells was higher in BM (median 2.16%, range 0.43-9.28%) compared to CSF (median 0.44%, range 0.05-9.25%) and in CSF compared to PB (median 0.12%, range 0.02-0.96%). The proportion of all mononuclear cells with Ig kappa and lambda light chain (i.e. Ig) secretion was on average 5-fold greater in CSF compared to PB and 11-fold greater in BM compared to PB. The present study indicates that paraprotein-secreting cells preferentially pass from PB to CSF.

Intensive treatment in order to minimize the Ph-positive clone in CML. Danish-Swedish CML Group.

With the rationale that a significant reduction of the malignant clone in CML might prolong time to metamorphosis, intensive treatment was given to patients < or = 55 years. Six months of hydroxyurea and high dose interferon-alpha (IFN-alpha) was followed by one to three courses of intensive chemotherapy. Patients who had a donor were allotransplanted and patients who became Ph-negative in bone marrow were autotransplanted. On 1 May 1995, 160 patients were registered in the study. Fifty-one percent of the patients who received six months IFN-alpha and hydroxyurea had a significant Ph-reduction and 5% became Ph-negative. The corresponding figures after two intensive chemotherapy courses were 47 and 28%, respectively. Twenty-seven of 30 autotransplanted patients have been analysed for Ph. Seventeen have relapsed cytogenetically, while ten are Ph-negative 1-64 + months after ABMT. BMT was performed in 59 patients. The actuarial 6-year survival from diagnosis of all 160 registered patients is 68%, which seems to be better than for age-matched historical controls.

Effects of eccentric exercise on the immune system in men.

The effects of eccentric exercise on changes in numbers of circulating leukocytes, cell activation, cell adhesion, and cellular memory function were investigated in 12 men, aged 22-35 yr. The immunologic effects of postexercise epidermal treatment with monochromatic, infrared light were also evaluated. Blood was drawn before and 6, 24, and 48 h after exercise for phenotyping and analysis of creatine kinase activity. There was an increase in leukocyte, monocyte, and neutrophil number, no change in the number of basophils, eosinophils, B cells, and T cells, and a decrease in natural killer cell number postexercise. Some markers of lymphocyte and monocyte activation remained unchanged or decreased, whereas the expression of adhesion molecules 62L and 11b increased on monocytes. It is concluded that eccentric exercise induced decreased activation, and increased cell adhesion capacity, of monocytes. Altered trafficking of cells between lymphoid tissue and blood, selective apoptosis, or attachment/detachment from the endothelial wall can explain the observed phenotypic changes. Treatment with monochromatic, infrared light did not significantly affect any of the investigated variables. Correlations between immunologic and physiological parameters indicate a role of the immune system in adaptation to physical exercise.

Trisomy 13 as a primary chromosome aberration in acute leukemia.

Four patients with acute leukemia displayed trisomy 13 as the primary chromosome abnormality. The two patients with acute nonlymphocytic leukemia FAB-type M1 (ANLL-M1) had the karyotypes 47,XY,+13/48,XY,+13,+13 and 47,XX,+13, a patient with the hypogranular form of ANLL M3 had 47,XX,+13, and the fourth patient, who had acute undifferentiated leukemia (AUL), had the karyotype 47,XY,+13/48,XY,+8,+13. Including these four cases, a total of 24 hematologic neoplasms with an extra chromosome 13 as the sole aberration have now been reported. Except for the AUL, all have been of myeloid origin--20 ANLL, one myelodysplastic syndrome, and two chronic myeloproliferative disorders. Trisomy 13 as the sole acquired karyotypic abnormality therefore seems to be strongly associated with myeloid differentiation of the neoplastic cells and with a differentiation block leading to acute leukemia.

Mitoxantrone and cytarabine versus daunorubicin and cytarabine in previously untreated patients with acute myeloid leukemia.

A total of 44 adults aged 18-78 years were allocated to an open randomized study whose aim was to compare the efficacy and toxicity of mitoxantrone with those of daunorubicin in previously untreated patients presenting with acute myeloid leukemia. In one arm, induction treatment consisted of mitoxantrone plus cytarabine given on a 3- plus 7-day schedule. Post-induction treatment consisted of two courses of mitoxantrone plus cytarabine given on a 2- plus 5-day schedule. In the control arm, mitoxantrone was replaced by daunorubicin. In all, 14 of 21 eligible and evaluable patients in the mitoxantrone arm achieved a complete remission (CR). In the control arm, 14 of 20 subjects attained a CR. The median survival was 365 days for patients randomized to mitoxantrone-cytarabine and 401 days for those given daunorubicin-cytarabine. The efficacy and toxicity of mitoxantrone were similar to those of daunorubicin.