Prognostic factors and follow-up parameters in patients with paroxysmal nocturnal hemoglobinuria (PNH): experience of the Austrian PNH network.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disease characterized by a deregulated complement system, chronic Coombs-negative, intravascular hemolysis, and a variable clinical course with substantial risk to develop thromboembolic events. We analyzed diagnostic and prognostic parameters as well as clinical endpoints in 59 adult patients suffering from PNH in 5 hematology centers in Austria (observation period: 1978-2015). Median follow-up time was 5.6 years. The median clone size at diagnosis amounted to 55% and was higher in patients with classical PNH (81%) compared to patients with PNH associated with aplastic anemia (AA) or myelodysplastic syndromes (MDS) (50%). The clone size also correlated with lactate dehydrogenase (LDH) levels. In one patient, anemia improved spontaneously and disappeared with complete normalization of LDH after 16 years. Seventeen patients received therapy with eculizumab. The rate of thromboembolic events was higher in the pre-eculizumab era compared with eculizumab-treated patients but did not correlate with the presence of age-related clonal hematopoiesis or any other clinical or laboratory parameters. Peripheral blood colony-forming progenitor cell counts were lower in PNH patients compared with healthy controls. Only two patients with classical PNH developed MDS. Overall, 7/59 patients died after 0.5-32 years. Causes of death were acute pulmonary hypertension, Budd-Chiari syndrome, and septicemia. Overall survival (OS) was mainly influenced by age and was similar to OS measured in an age-matched healthy Austrian control cohort. Together, compared with previous times, the clinical course and OS in PNH are favorable, which may be due to better diagnosis, early recognition, and eculizumab therapy.

Proposed diagnostic criteria and classification of basophilic leukemias and related disorders.

Basophils form a distinct cell lineage within the hematopoietic cell family. In various myeloid neoplasms, including chronic myeloid leukemia, basophilia is frequently seen. Acute and chronic basophilic leukemias, albeit rare, have also been described. However, no generally accepted criteria and classification of basophilic leukemias have been presented to date. To address this unmet need, a series of Working Conferences and other meetings were organized between March 2015 and March 2016. The current article provides a summary of consensus statements from these meetings, together with proposed criteria to delineate acute basophilic leukemia (ABL) from chronic basophilic leukemia (CBL) and primary forms of the disease where no preceding myeloid malignancy is detected, from the more common 'secondary' variants. Moreover, the term hyperbasophilia (HB) is proposed for cases with a persistent peripheral basophil count ⩾1000 per µl of blood. This condition, HB, is highly indicative of the presence of an underlying myeloid neoplasm. Therefore, HB is an important checkpoint in the diagnostic algorithm and requires a detailed hematologic investigation. In these patients, an underlying myeloid malignancy is often found and is then labeled with the appendix -baso, whereas primary cases of ABL or CBL are very rare. The criteria and classification proposed in this article should facilitate the diagnosis and management of patients with unexplained basophilia and basophil neoplasms in routine practice, and in clinical studies.

Revisiting guidelines for integration of flow cytometry results in the WHO classification of myelodysplastic syndromes-proposal from the International/European LeukemiaNet Working Group for Flow Cytometry in MDS.

Definite progress has been made in the exploration of myelodysplastic syndromes (MDS) by flow cytometry (FCM) since the publication of the World Health Organization 2008 classification of myeloid neoplasms. An international working party initiated within the European LeukemiaNet and extended to include members from Australia, Canada, Japan, Taiwan and the United States has, through several workshops, developed and subsequently published consensus recommendations. The latter deal with preanalytical precautions, and propose small and large panels, which allow evaluating immunophenotypic anomalies and calculating myelodysplasia scores. The current paper provides guidelines that strongly recommend the integration of FCM data with other diagnostic tools in the diagnostic work-up of MDS.

Molecular pathways of early CD105-positive erythroid cells as compared with CD34-positive common precursor cells by flow cytometric cell-sorting and gene expression profiling.

Special attention has recently been drawn to the molecular network of different genes that are responsible for the development of erythroid cells. The aim of the present study was to establish in detail the immunophenotype of early erythroid cells and to compare the gene expression profile of freshly isolated early erythroid precursors with that of the CD34-positive (CD34(+)) compartment. Multiparameter flow cytometric analyses of human bone marrow mononuclear cell fractions (n=20) defined three distinct early erythroid stages. The gene expression profile of sorted early erythroid cells was analyzed by Affymetrix array technology. For 4524 genes, a differential regulation was found in CD105-positive erythroid cells as compared with the CD34(+) progenitor compartment (2362 upregulated genes). A highly significant difference was observed in the expression level of genes involved in transcription, heme synthesis, iron and mitochondrial metabolism and transforming growth factor-ß signaling. A comparison with recently published data showed over 1000 genes that as yet have not been reported to be upregulated in the early erythroid lineage. The gene expression level within distinct pathways could be illustrated directly by applying the Ingenuity software program. The results of gene expression analyses can be seen at the Gene Expression Omnibus repository.

Standardization of flow cytometry in myelodysplastic syndromes: a report from an international consortium and the European LeukemiaNet Working Group.

Flow cytometry (FC) is increasingly recognized as an important tool in the diagnosis and prognosis of myelodysplastic syndromes (MDS). However, validation of current assays and agreement upon the techniques are prerequisites for its widespread acceptance and application in clinical practice. Therefore, a working group was initiated (Amsterdam, 2008) to discuss and propose standards for FC in MDS. In 2009 and 2010, representatives from 23, mainly European, institutes participated in the second and third European LeukemiaNet (ELN) MDS workshops. In the present report, minimal requirements to analyze dysplasia are refined. The proposed core markers should enable a categorization of FC results in cytopenic patients as 'normal', 'suggestive of', or 'diagnostic of' MDS. An FC report should include a description of validated FC abnormalities such as aberrant marker expression on myeloid progenitors and, furthermore, dysgranulopoiesis and/or dysmonocytopoiesis, if at least two abnormalities are evidenced. The working group is dedicated to initiate further studies to establish robust diagnostic and prognostic FC panels in MDS. An ultimate goal is to refine and improve diagnosis and prognostic scoring systems. Finally, the working group stresses that FC should be part of an integrated diagnosis rather than a separate technique.

Immunophenotyping of acute leukemia and lymphoproliferative disorders: a consensus proposal of the European LeukemiaNet Work Package 10.

The European LeukemiaNet (ELN), workpackage 10 (WP10) was designed to deal with diagnosis matters using morphology and immunophenotyping. This group aimed at establishing a consensus on the required reagents for proper immunophenotyping of acute leukemia and lymphoproliferative disorders. Animated discussions within WP10, together with the application of the Delphi method of proposals circulation, quickly led to post-consensual immunophenotyping panels for disorders on the ELN website. In this report, we established a comprehensive description of these panels, both mandatory and complementary, for both types of clinical conditions. The reason for using each marker, sustained by relevant literature information, is provided in detail. With the constant development of immunophenotyping techniques in flow cytometry and related software, this work aims at providing useful guidelines to perform the most pertinent exploration at diagnosis and for follow-up, with the best cost benefit in diseases, the treatment of which has a strong impact on health systems.

Iron overload in myelodysplastic syndromes (MDS) - diagnosis, management, and response criteria: a proposal of the Austrian MDS platform.

Transfusion-related morbidity is an emerging challenge in chronically transfused patients with low-risk myelodysplastic syndromes (MDS). In these patients, transfusion-induced iron overload may represent a leading medical problem. However, although iron-chelating drugs are available, little is known about optimal diagnostic tools, predisposing factors, and the optimal management of these patients. In the current article, we provide recommendations for the diagnosis, prevention and treatment of iron overload in MDS and propose treatment response criteria. Consensus criteria and resulting recommendations were discussed and formulated by members of the MDS platform of the Austrian Society of Haematology and Oncology in a series of meetings and conferences in 2006 and 2007. These recommendations should facilitate and assist in recognition of iron overload, selection of patients, timing of treatment, drug selection and the measurement of treatment responses.

Impact of the factor II: G20210A variant on the risk of venous thromboembolism in relatives from families with the factor V: R506Q mutation.

OBJECTIVES: Factor V: R506Q mutation and the prothrombin G20210A variant (factor II: G20210A variant) are associated with an increased risk of venous thromboembolism (VTE). In cohorts of unrelated patients a cosegregation of both mutations has been shown to be associated with an increased risk of developing VTE. The aim of this study was to investigate the impact of the coinheritance of both mutations on the risk of VTE in relatives of symptomatic carriers of the factor V: R506Q mutation and the factor II: G20210A variant. PATIENTS AND METHODS: Four families with 48 family members were investigated for the presence of the factor V: R506Q mutation and the factor II: G20210A mutation, and their clinical history was evaluated. RESULTS: VTE was more frequent in family members with a combined defect (3/10; 30%) compared to those with a single mutation (1/16; 6%) or without a defect (1/12; 8%). The probability for VTE for 40-yr-old individuals with both mutations, a single mutation and no mutation was 56%, 12% and 20%, respectively. CONCLUSIONS: These data suggest that the G to A transition at position 20210 of the prothrombin gene leads to an increase in the risk of VTE in carriers of the factor V: R506Q mutation. The determination of the factor II: G20210A variant in index patients carrying a factor V: R506Q mutation and, if present, in family members may help to identify individuals who are at high risk for VTE.

Superiority of high-dose over intermediate-dose cytosine arabinoside in the treatment of patients with high-risk acute myeloid leukemia: results of an age-adjusted prospective randomized comparison.

Although cytosine arabinoside (AraC) represents the most effective single agent in the treatment of adults with acute myeloid leukemia (AML) when given at doses exceeding 200 to 500 mg per application, its optimal dosage is still a matter of controversial discussion. While pharmacokinetic investigations suggest that the AraC-activating enzyme deoxycytidine kinase is saturated at drug concentrations achieved by short-term infusion of 0.5 to 1.0 g/m2 AraC and that higher doses are therefore not more effective, recent evidence indicates that additional mechanisms of AraC cytotoxicity may exist which could be enhanced by further dose escalation. In order to test this thesis in the clinical setting, a prospective randomized comparison of high-dose (HD-AraC) vs intermediate-dose (ID-AraC) AraC was carried out in patients with refractory or relapsed AML on the basis of the sequential high-dose AraC and mitoxantrone regimen (S-HAM). AraC was given as a 3-h infusion q 12 h on days 1, 2, 8 and 9. Patients younger than 60 years were randomized to AraC doses of 3.0 g/m2 vs 1.0 g/m2 while older patients received either 1.0 g/m2 or 0.5 g/m2 per single dose. Mitoxantrone was given to all patients on days 3, 4, 10 and 11 at a daily dose of 10 mg/m2. Randomization was stratified for primary refractoriness against induction therapy and length of first remission in relapsed patients. From 186 evaluable patients, 88 (47%) and 10 cases (5%) achieved a complete (CR) or partial (PR) remission, 39 patients (21%) had persisting leukemia (non-response (NR)), and 49 cases (26%) died within 6 weeks after the start of therapy (early death (ED)). In patients younger than 60 years the higher dose level resulted in a significant reduction of NR (12% vs 31%; ordinal chi2 test: P = 0.01) but also a higher rate of ED (32% vs 17%) thus leading to a marginally higher CR rate only (52% vs 45%). Within the subgroup of patients with refractory AML the tendency towards a higher CR rate after HD-AraC was more pronounced (46% vs 26%; P = 0.045). In patients older than 60 years, corresponding though less evident differences were observed with a higher rate of NR in the lower dose group (26% vs 16%) and ED occurring more frequently after higher doses (36% vs 26%). These data indicate that HD-AraC reveals a significantly higher antileukemic efficacy than ID-AraC as expressed by a significant reduction of failure from NR. This advantage, however, does not fully translate into an increase in remission rate due to a higher incidence of ED after HD-AraC predominantly from uncontrolled infections. In order to take full advantage of the higher antileukemic activity of HD-AraC an improvement of supportive care and infection control is warranted.

Chemotherapy in patients with acquired immunodeficiency virus syndrome associated with non-Hodgkin's lymphoma.

We retrospectively analyzed our chemotherapy results in patients with the Acquired Immunodeficiency Virus syndrome (AIDS) and lymphoma over a 10 year period. Thirty out of 492 (6%) Human Immunodeficiency Virus (HIV) positive patients developed a non-Hodgkin's lymphoma. Thirteen patients with high-grade histology were treated with chemotherapy, 6 patients received CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) and 7 patients received CEOP/IMVP-Dexa (cyclophosphamide, epirubicin, vincristine, prednisolone, ifosfamide, methotrexate, VP-16, and dexamethasone). The overall response rate was 77%, with no difference between the CHOP and CEOP/IMVP-Dexa regimens. There was no difference between the two treatment groups with respect to median overall survival (9 months for CHOP and 11.4 months for CEOP/IMVP-Dexa) or median lymphoma free survival (10.7 months for CHOP and not reached for CEOP/IMVP-Dexa). All patients treated with CEOP/IMVP-Dexa had WHO grade 3 or 4 infections, while only 2 of 6 patients treated with CHOP had WHO grade infections, and no grade 4 infection occurred (P < 0.01). Intensive regimens such as CEOP/IMVP-Dexa seem to be too toxic for patients with HIV-associated non-Hodgkin's lymphoma.

First-line treatment of Waldenström's disease with cladribine. Arbeitsgemeinschaft Medikamentöse Tumortherapie.

PURPOSE: To assess the activity and side effects of cladribine (2-CdA) treatment in patients with advanced Waldenström's disease. PATIENTS AND METHODS: Ten symptomatic patients without prior therapy were included in a prospective multicenter trial. 2-CdA was administered daily at 0.12 mg/kg body weight in a 2-h i.v. infusion over 5 consecutive days: this was repeated every 28 days for four cycles. Patients achieving a remission received interferon alfa-2c (1F) 15 micrograms s.c. three times a week for 1 year. RESULTS: All 10 patients responded to 2-CdA (100%; 95% confidence interval, 68-100%), with one complete (CR) and eight partial responders (PR): one patient had only one 2-CdA cycle and showed a minor improvement (MR). Patients tolerated the treatment well. Despite considerable immunosuppression, an infection occurred in only two patients. After a median observation period of 57 weeks, three patients had shown progression, including one who died of lymphoma. CONCLUSION: 2-CdA induction and IF maintenance is a well-tolerated therapy for symptomatic untreated patients with advanced Waldenström's disease and offers excellent palliation.

Autoimmune reactions in patients with silicone breast implants.

Silicone breast implants have been surgical routine for over 30 years. An association between silicone augmentation and immune related diseases has been reported in approximately 100 cases. In a retrospective single center study we investigated 36 non-selected women with silicone breast implants and 36 sex- and age-matched controls. Autoimmune reactions were evaluated by measuring antinuclear antibodies (ANA), rheumatoid factor (RF) and thyroid gland antibodies (TMS), along with angiotensin-converting enzyme (ACE), C-reactive protein (CRP) and other immunological and laboratory parameters. In the controls only 3 (8%) women had an elevated ANA titer and 1 demonstrated thyroid autoantibodies (microsomal), giving a total of 4 (11%) women with detectable autoantibodies. By contrast, 12 (33%) of the 36 women with silicone augmentation had raised ANA titers (> or = 1 : 80), a significantly higher percentage than in the control group (p < 0.02). Of the 12 women, 1 showed antismooth muscle antibodies (ASMA; titer 1 : 40) and 2 of the patients displayed antineutrophilic cytoplasm antibodies (ANCA; 1 : 320 and 1 : 40, respectively), one of the latter also being positive for rheumatoid factor. 2 further women demonstrated thyroid autoantibodies (microsomal), giving a total of 14 (39%) women in whom significant autoantibodies were detectable. Clinical symptoms (musculoskeletal) were present in 1 patient. Most of the observed autoantibodies were organ-unspecific, with a predominance of elevated ANA titers of the heterogeneous type and not related to a distinct clinical entity. However, none of the investigated women with silicone breast implants showed clinical symptoms or signs of connective tissue disease according to ARA criteria.

Factors influencing the timing of peripheral blood stem cell collection (PBSC).

High-dose conditioning regimens followed by autologous peripheral blood stem cell rescue are frequently used for the treatment of solid tumors and hematological malignancies. In 24 patients up to four peripheral stem cell collections (PBSC) were performed after priming with various chemotherapies and G-CSF (300 micrograms s.c. per day). In 16 patients (group A) more than 2 x 10(6) CD 34 positive cells per kg bodyweight could be collected; fewer were harvested in the remaining eight patients (group B). The amount of collected CD 34 positive cells correlated with the median number of these cells in the peripheral blood at the start of PBSC. The two groups differed both in recovery time after priming-induced cytopenia (4 vs 6 days from nadir) and in the number of WBC (21 x 10(6) mL-1 vs 6.1 x 10(6) mL-1) and platelets (133 x 10(6) mL-1 vs 58 x 10(6) mL-1) reached at first day of PBSC. No difference between the two groups was seen according to age, duration of disease or disease status. However, the intensity of prior treatment was significantly greater in group B than in group A. These observations indicate that the toxicity of previous chemotherapy is the most important factor for the mobilization of sufficient CD 34 positive cells into the peripheral blood.

Mast cell-lineage versus basophil lineage involvement in myeloproliferative and myelodysplastic syndromes: diagnostic role of cell-immunophenotyping.

Mast cells and blood basophils are distinct hemopoietic cells. They can be distinguished from each other and from all other lymphohemopoietic cells using antibodies against surface receptors or stored cytoplasmic molecules. In patients with myelodysplastic syndromes (MDS) or myeloproliferative syndromes (MPS), an elevation of metachromatically granulated cells (MCS) is frequently seen. These cells can be classified as basophils or mast cells using monoclonal antibodies (mAbs) against leukocyte antigens, including mast cell tryptase, c-kit (= mast cell growth factor [MGF] receptor), interleukin-3 receptor alpha chain (IL-3R alpha = CD123), and CD11b (C3biR). In a stable phase of MDS or MPS, the circulating MCS usually are basophils (histamine+, tryptase-, c-kit-, IL-3R alpha +, CD11b+). In an accelerated or terminal phase of disease, however, mast cell lineage involvement and circulating mast cell precursors (histamine+, tryptase+, c-kit+, IL-3R alpha-, CD11b-) are found in a subset of patients. The use of mAbs against mast cell antigens and granulocyte antigens is diagnostic in these patients.

Immunophenotypic analysis of HL-60 cells during basophilic differentiation.

Differentiation along specific myeloid lineages may be accompanied by characteristic cell surface marker changes. We have examined leukemic HL-60 cell changes under conditions which induce basophilic differentiation. An increased surface expression of CD35, CD11b, and decreased expression of CD15 was found by flow cytometry during the 5-day induction period. Further investigation revealed two cell populations after 5 days in vitro: (i) a CD35-positive population (61% of cells present) containing a significant number of CD15-negative cells, and (ii) a CD15-positive/CD35-negative population. The CD35-positive subset appears to account for the majority of the basophilic cells induced under these conditions, as measured by histamine content and metachromatic staining. In addition, this subset contains a small number of early monocytic cells (CD14 and CD23 positive). The expression of CD11b is variably found on the CD15-positive/ CD35-negative subset of induced cells. These results suggest that CD35 and CD15 surface immunophenotyping can be used to map steps involved in myeloid development. A role for CD35 and CD15 in early basophil differentiation is proposed.

Metabolic responses after laparoscopic or open hernia repair.

BACKGROUND: The purpose of a prospective randomized study was to compare the surgical trauma in patients undergoing laparoscopic or open hernia repair. METHODS: Postoperative pain, analgesic consumption, and metabolic response to surgery were assessed in 30 patients undergoing laparoscopic (group 1; n = 15) or open (group II; n = 15; Shouldice repair) unilateral inguinal hernia repair. Both groups were comparable with respect to age, sex, and type and size of inguinal hernia. RESULTS: Postoperative visual analogue scales (VAS) for pain were reduced on mobilization for patients of group I with a significant difference (P = 0.02) on the operative day, whereas pain scores at rest and analgesic requirements were similar for both groups. No differences between groups I and II were found in postoperative levels of interleukin-1, interleukin-6, tumor necrosis factor alpha, C-reactive protein, fibrinogen, transferrin, alpha-1-antitrypsin, and white blood cells. Postoperative polymorphonuclear (PMN) elastase concentrations remained within normal range in group II but showed a significant increase in patients operated laparoscopically for postoperative days 1 and 2. CONCLUSIONS: No major surgical trauma was found after herniorraphy compared to open hernia repair.

Potentiation of granulocyte colony-stimulating factor-induced mobilization of circulating progenitor cells by seven-day pretreatment with interleukin-3.

Granulocyte colony-stimulating factor (G-CSF) as a single agent is increasingly used for the mobilization of peripheral blood progenitor cells (PBPCs) for stem cell transplantation. In patients with perturbed hematopoiesis the mobilizing capacity of G-CSF alone may be inadequate. We have shown in rhesus monkeys that interleukin-3 (IL-3) pretreatment markedly potentiated the increase in PBPC numbers by subsequent administration of granulocyte/macrophage-CSF (GM-CSF). Here we studied the effect of IL-3 pretreatment on G-CSF-induced mobilization of PBPCs in 6 patients with Hodgkin's disease (n = 5) or non-Hodgkin's lymphoma (n = 1) who had low progenitor cell numbers because of previous chemotherapy. Patients were treated in cycle 1 with G-CSF at a dose of 5 microgram/kg/d for 5 days and, after a treatment-free interval, received cycle 2 consisting of 5 microgram/kg/d of IL-3 for 7 days followed by G-CSF again at a dose of 5 microgram/kg/d for 5 days. G-CSF alone increased the mean number of circulating colony-forming units-GM (CFU-GM) by 21-fold, the number of burst-forming units-erythroid (BFU-E) by 9-fold, and the number of CFU-mix by 24-fold over pretreatment values. Treatment with 5 microgram/kg/d of IL-3 for 7 days did not mobilize by itself but significantly potentiated G-CSF-induced mobilization of all progenitor cell types leading to a 56-, 15-, and 46-fold increase over baseline of CFU-GM, BFU-E, and CFU-mix numbers, respectively. In 2 patients in whom leukapheresis was performed after G-CSF alone the target number of 2 x 10(6)/kg CD34+ cells was not reached. However, leukapheresis after the IL-3/G-CSF combination obtained > or =2 x 10(6)/kg CD34+ cells in 3 of 6 patients, including both patients who had inadequate collection after G-CSF alone. In one patient adequate function of mobilized progenitors could be shown by the demonstration of rapid trilineage engraftment after infusion of progenitors after myeloablative chemotherapy. Seven-day pretreatment with IL-3 may be a useful mean to augment mobilization of circulating progenitors by G-CSF. The combination of IL-3 and G-CSF seems to allow the procurement of sufficient numbers of PBPCs in some patients who cannot be mobilized adequately by G-CSF alone.

Effect of interleukin-3 pretreatment on granulocyte/macrophage colony-stimulating factor induced mobilization of circulating haemopoietic progenitor cells.

Recombinant human colony stimulating factors (CSFs) as single agents are increasingly used for mobilizing peripheral blood progenitor cells (PBPCs) for stem cell transplantation. We have shown in rhesus monkeys that interleukin-3 (IL-3) pretreatment markedly potentiated the increase in PBPC numbers of subsequent administration of granulocyte/macrophage-CSF (GM-CSF). Here we studied the effect of IL-3 pretreatment on GM-CSF-induced mobilization of PB progenitors in patients who were potential candidates for autologous stem cell transplantation (n = 16). Patients were treated with GM-CSF at a dose of 5 micrograms/kg/d for 5 d and after a treatment free interval received another cycle of GM-CSF immediately following pretreatment with IL-3 at different doses and duration: 2.5 micrograms/kg/d (n = 4), 5 micrograms/kg/d (n = 3) and 10 micrograms/kg/d (n = 3) for 3 d, 5 micrograms/kg/d for 7 d (n = 4) and 5 micrograms/kg/d for 14 d (n = 2), respectively. Only 7 d pretreatment with IL-3 showed consistent effects. Although IL-3 did not mobilize by itself, pretreatment with 5 micrograms/kg/d of IL-3 for 7 d significantly potentiated GM-CSF-induced mobilization of PB CFU-GM numbers, leading to a mean increase in PB CFU-GM numbers over baseline by 18.5 +/- 5.2 (SEM) fold by IL-3/GM-CSF as compared to a 4.7 +/- 1.7-fold increase by GM-CSF alone. A significant enhancement by the 7 d IL-3 pretreatment was also observed for erythroid (BFU-E) and multipotential progenitor cells (CFU-mix) which were 3.3 +/- 1.3- and 3.4 +/- 0.9-fold, respectively, mobilized by GM-CSF alone, as compared to 8.5 +/- 2.3- and 19.2 +/- 3.4-fold, respectively, by the IL-3/GM-CSF combination. Our results suggest that 7 d pretreatment with IL-3 may be a useful mean to augment mobilization of circulating progenitors by more lineage-restricted CSFs. These findings may be important for the design of mobilization strategies that use growth factors without preceding chemotherapy.

[Autologous stem cell harvesting after high dosage chemo- and/or growth factor therapy]. / Autologe Stammzellgewinnung nach hochdosierter Chemo- und/oder Wachstumsfaktortherapie.

5 patients with metastatic tumors and 4 patients with hematological malignancies were treated either with G- or GM-CSF alone (5 micrograms/kg s.c.) or in combination with cyclophosphamide (7 g/m2) or epirubicin (120 mg/m2) to reduce either tumor mass or to maintain remission and to prime for peripheral stem cell collection.

Comparison of the effects of aprotinin and tranexamic acid on blood loss and related variables after cardiopulmonary bypass.

Aprotinin reduces blood loss after cardiopulmonary bypass, but may sensitize recipients and is expensive. Tranexamic acid, a synthetic antifibrinolytic, has less disadvantages, but opinions differ regarding its efficacy. We studied three groups of patients undergoing cardiopulmonary bypass for coronary disease: recipients of aprotinin (total dose 4.2 x 10(6) kallikrein inhibiting units, n = 14), recipients of tranexamic acid (total dose 20 mg/kg body weight, n = 15), and nonmedicated controls (n = 14) during 24 hours after cardiopulmonary bypass. Compared with controls, aprotinin reduced blood loss, the number of patients requiring transfusions, and the mean number of transfused red cell units (all with p < 0.05), whereas the recipients of tranexamic acid did not differ either from aprotinin recipients or from controls. Aprotinin and tranexamic acid both mitigated the early postoperative reduction of adenosine diphosphate-induced platelet aggregation seen in the controls (p < 0.05). Postoperative increases of plasma concentrations of the prothrombin activation fragment F1 + 2 and the thrombin-antithrombin III complex showed an activation of intravascular coagulation, without any intergroup differences. The balance between concentrations of tissue plasminogen activator and the type 1 plasminogen activator inhibitor disclosed an activation of fibrinolysis, without differences between the groups. The concentrations of D-dimer, a breakdown product of cross-linked fibrin, remained at baseline in the recipients of aprotinin and tranexamic acid but tripled in the controls (p < 0.05). By contrast, the plasma antiplasmin activity was equally depressed in the tranexamic acid and the control groups but decreased less in the recipients of aprotinin (p < 0.05). This discrepancy may reflect the different modes of action of the two agents, which may make aprotinin more efficacious than tranexamic acid in the "nonfibrinolytic" act of protecting platelet function against attack by plasmin during cardiopulmonary bypass.