New strategies for prophylactic platelet transfusion in patients with hematologic diseases.

There is an increasing demand for platelet transfusions due to intensive chemotherapy and blood stem cell or bone marrow transplantation for the treatment of hematologic and oncologic diseases. There has been a long-lasting debate over whether the traditional threshold for prophylactic platelet transfusion of 20,000/microl is really necessary to prevent hemorrhagic complications. During the last 10 years several studies with more than 1,000 patients together have proven the safety of a platelet transfusion trigger of 10,000/microl or even lower when patients are clinically stable without active bleeding. This experience has been mostly gathered in patients with acute leukemia. But this stringent platelet transfusion policy can be used also after blood stem cell and bone marrow transplantation. In stable patients with aplastic anemia and myelodysplasia, prophylactic transfusions should be replaced in most patients by a therapeutic transfusion strategy. Such restrictive platelet transfusion strategies decrease the risk of infectious disease transmission, immunization, and febrile transfusion reactions. Besides reduced hospital visits and a shorter hospital stay for the patients, the costs for platelet transfusions are lowered by 20%-30% compared with traditional transfusion strategies. The decision to administer platelet transfusions should incorporate individual clinical characteristics of the patients and not simply be a reflexive reaction to the platelet count. Further clinical studies are needed to answer the still open question of whether patients with acute leukemia should also be transfused therapeutically rather than prophylactically when they are in stable condition without signs of active bleeding.

Use of and attitudes held towards unconventional medicine by patients in a department of internal medicine/oncology and haematology.

A sizeable percentage of patients receiving conventional medical treatment also use unconventional medicine (UM). Surveys indicate that the prevalence of and motivation for the pursuit of the different approaches of UM is subject to individual, geographical, cultural and disease-related factors. We were interested in the concurrent use of and attitudes towards UM in patients who underwent conventional medical treatment in our oncologically orientated department of internal medicine in a regionally dominant teaching hospital. A representative sample (n = 131) of all inpatients and outpatients receiving treatment in the department or in its oncological/haematological outpatient clinic were asked to participate in a cross-sectional interview study on the use of unconventional therapies. In all, 128 patients (97.7%) agreed to participate in the study, and 65% of these patients were suffering from malignancies. Use of unconventional treatment was reported by 24% of all patients for their current medical problem, and 16% of the remaining patients had been thinking of adjunctive use. The use of UM was significantly higher among oncological patients (32%), and among oncological outpatients in particular (50%), than among patients with acute or chronic non-malignant diseases. Female patients predominated among the users of UM (71%). UM mainly took the form of various pharmacological and dietary approaches. Patients availing themselves of UM most frequently identified physicians (41%) as the source of treatment recommendation. Only 18% of the users of UM relied on these methods as a chance of cure. Use of UM was not generally motivated by dissatisfaction with conventional medical care. Only half the users informed their hospital physician of their adjunctive use of UM. Nearly 2 out of 3 of the users contended that UM had contributed to a mild or distinct improvement in their physical or psychological wellbeing. The use of UM in modern health care systems represents a widespread and intricate phenomenon, which cannot be understood by focusing exclusively on the objective assessment of clinical efficacy. Use of UM may be related more to a disease's unfavourable attribution than to its medically expected outcome. Coherence with individual illness paradigms and perceived efficacy are apparently important factors in patients' use of UM. These subjective aspects need to be recognised in caring patient-doctor communication.

Sequential cycles of high-dose chemotherapy with dose escalation of carboplatin with or without paclitaxel supported by G-CSF mobilized peripheral blood progenitor cells: a phase I/II study in advanced ovarian cancer.

To assess high-dose carboplatin chemotherapy with or without paclitaxel with filgrastim mobilized peripheral blood progenitor cell (PBPC) support in a phase I/II study, a total of 21 patients with mostly chemonaive disease received four cycles of high-dose chemotherapy. Cycle 1 (cyclophosphamide, 6 g/m2) was followed by two cycles of carboplatin (1600 mg/m2 or 1800 mg/m2). Cycle 4 consisted of carboplatin (1600 mg/m2), etoposide (1600 mg/m2), and melphalan (140 mg/m2). Further chemotherapy intensification was achieved by adding paclitaxel (175 mg/m2) to all cycles with a fixed carboplatin dose (1600 mg/m2). Ototoxicity was dose-limiting for escalation of sequential cycles of carboplatin. Grade 2 and grade 3 ototoxicity, hearing loss not requiring a hearing aid, or hearing loss correctable with a hearing aid, was observed with carboplatin at 1800 mg/m2. The maximum tolerated dose (MTD) of sequential carboplatin, therefore, was identified in this study as 1600 mg/m2. After cycles 1, 2, 3 and 4 the median duration of leukopenia (<1.0x10(9)/l) was 7, 4, 4 and 6 days. Severe grade 3 and 4 infections were seen in only 7% of cycles. Of the 21 patients evaluable for disease response, 57% had complete remissions and 43% experienced partial remissions resulting in an overall response rate of 100%. The median progression-free survival is 25 (15-36) months, the median overall survival 36.5 (15-38) months. Most patients were suboptimally debulked or had bulky residual disease at the start of chemotherapy. Sequential high-dose chemotherapy to a maximum dose of 1600 mg/m2 carboplatin is effective and feasible. A randomized, prospective trial comparing sequential high-dose chemotherapy with optimal standard chemotherapy is now warranted.

The use of CD34+-selected PBPC after high-dose chemotherapy in breast cancer patients is associated with prolonged recovery time and increased infectious complications.

High-dose chemotherapy with autologous stem cell rescue can result in autotransplantation of tumor cells. A possible approach to reduce tumor cell contamination is the positive selection of CD34+ PBPC, but this might be associated with a prolonged recovery time as well as an increased risk of infectious complications because of the loss of committed progenitor cells. To investigate this aspect, we compared two sequentially treated cohorts of high-risk breast cancer patients. Both groups received the same high-dose chemotherapy regimen followed by autologous peripheral stem cell transplantation. Group I received CD34+-selected blood progenitor cells, and group II received nonselected blood progenitor cells. We compared these two identically treated groups with regard to recovery time, need for blood products, infectious complications, need for antibiotic treatment, and length of the transplantation-related hospital stay. We found a prolonged recovery time for neutrophils up to 0.5 x 10(9)/L (14 days in the selected group/10 days in the nonselected group) and platelets up to 30 x 10(9)/L (29/12 days), associated with an increased requirement for RBC transfusions (5/3 U) and platelet transfusions (10/2 U). The rate of severe infectious complications (2/0), the need for nonprophylactic antibiotic treatment (15/10), and the length of the hospital stay (25/21 days) in group I were also increased. We conclude that positive selection of PBPC should not be used routinely until randomized studies show a clear long-term benefit of using CD34+-selected stem cell products in breast cancer patients.

Complete spontaneous remission in a patient with metastatic non-small-cell lung cancer. Case report, review of the literature, and discussion of possible biological pathways involved.

Spontaneous remission of cancer (SR) is defined as a complete or partial, temporary or permanent disappearance of all or at least some relevant parameters of a soundly diagnosed malignant disease without any medical treatment or with treatment that is considered inadequate to produce the resulting regression. We report the case of a 61-year-old man who presented with extensive metatastic disease five months after pneumonectomy for poorly differentiated large cell and polymorphic lung cancer. A vast metastatic tumour mass of the abdominal wall was confirmed histolologically and there was clinical and radiographic evidence of liver and lung metastases. Eight months later, the patient was operated on for a hernia, which had developed in the inguinal biopsy scar and the surgeon confirmed complete clinical SR of the abdominal wall metastases. Again five months later there was no longer any radiologic evidence of liver and lung metastases. Complete remission has persisted more than five years. Histology of the primary and of the abdominal metastases were reviewed by several independent pathologists. SR is an extremly rare event in lung cancer. This is the first documented case of clinically evident visceral metastases of a bronchiogenic adenocarcinoma developing after complete resection of the primary and then showing complete SR. The epidemiology of SR is reviewed and possible mechanisms involved in SR are discussed.

Comparison of three tropisetron-containing antiemetic regimens in the prophylaxis of acute and delayed chemotherapy-induced emesis and nausea.

There is still controversy as to what constitutes the optimal therapy for acute and delayed chemotherapy-induced emesis and nausea. We conducted a three-armed randomized multi-centre study in 193 chemotherapy-naive patients receiving highly emetogenic chemotherapy inducing both acute and delayed symptoms (cisplatin > or = 50 mg/m2, carboplatin > or = 300 mg/m2, cyclophosphamide > or = 750 mg/m2, ifosfamide > or = 1.5 g/m2 on day 1). Group A: 1 x 5 mg tropisetron i.v. on day 1 + 2, then 10 mg p.o. (oral dose now recommended: 5 mg); group B: tropisetron as for A+dexamethasone, 20 mg i.v., on days 1 + 2, then 4 mg i.v./p.o.; group C: tropisetron as for A+metoclopramide, 20 mg i.v. +2 x 10 mg p.o. on day 1, then 3 x 10 mg p.o. Treatment was continued for at least 2 days after the end of chemotherapy. Tropisetron+dexamethasone was significantly superior to tropisetron alone both for acute (P = 0.0064) and delayed (P = 0.0053) emesis. Complete control of acute and delayed emesis (nausea) was achieved in 80% (75%) and 53% (46%) in group A, 97% (90%) and 80% (58%) in group B, and 86% (80%) and 49% (45%) in group C. Patients completely asymptomatic during the whole cycle accounted for 26% of those in group A, 49% in group B and 28% in group C. The most frequent adverse events were constipation (16.6%), headache (7.3%) and tiredness (7.3%). Once-daily tropisetron+dexamethasone over several days is well tolerated and is a simple means of achieving further significant improvement in the efficacy of tropisetron against acute and delayed symptoms.

Effects of recombinant human thrombopoietin alone and in combination with erythropoietin and early-acting cytokines on human mobilized purified CD34+ progenitor cells cultured in serum-depleted medium.

The effects of recombinant thrombopoietin (TPO) alone and in combination with erythropoietin (EPO) and early-acting cytokines such as interleukin 3 (IL-3), stem cell factor (SCF) and GM-CSF on highly purified mobilized human CD34+ progenitor cells were studied in a serum-depleted culture system. Eight leukapheresis samples were cultured for seven days and analyzed; aliquots were replated and re-evaluated on day 12. Three-color flow cytometry was used together with morphologic analysis to determine proliferation and megakaryocytic or erythroid maturation. TPO alone was sufficient for cell survival and proliferation in serum-depleted medium. In the absence of other growth factors, almost all CD34+ cells differentiated along the megakaryocytic pathway within 12 days. Concomitantly, the progenitor cells gradually acquired the morphologic features of mature megakaryocytes. After exposure to TPO for one week, 50% of the cells still expressed CD34; by day 12 the remaining CD34+ cells (11%) were all coexpressing CD41. TPO alone did not support proliferation of glycophorin-A-positive cells. The addition of TPO to early-acting cytokines (EPO, GM-CSF, SCF and/or IL-3) not only increased the overall megakaryocyte expansion, but also generated a different maturation pattern of the CD41+ megakaryocyte progenitors. It further doubled the number of erythroid cells and c-kit+ cells in the second week of culture. Interestingly, the overall number of CD34+ cells was increased about fivefold when TPO was added to the early-acting cytokines, with a marked expansion of the CD34+/CD41+ and CD34+/CD117+ subpopulations. TPO can augment the pool of committed progenitors, thereby increasing the number of its own target cells and the number of EPO-responsive cells. These properties make TPO an interesting cytokine for the ex vivo expansion of human progenitor cells.

LW/SO cell line: a tool for studying the phenotypical characterization and commitment of hematopoietic stem cells.

We report our observations with the cell line LW/SO, which was recently derived from the bone marrow of a patient with acute myeloid leukemia. Based on the morphological and histochemical examination, the leukemic cells were classified primarily as FAB type M4. However, 2 years later, in relapse, the cells changed their morphology and were hence specified as FAB type M2 (slightly positive for acid phosphatase and Sudan black). The cells established have now been in culture for approximately 11 months and display nearly 100% CD4/5/7/15/25/71/120a,b at varying densities. Some of them spontaneously and reversibly become either CD34 + /38- or CD34 - /38+, yet the majority of the cells remain negative for both. All attempts to separate the cells with a distinct phenotype by limiting dilution or sorting through a flow cytometer failed repeatedly. The subsets, enriched up to 98% (regardless of their primary immunophenotype CD34 - / 38-, CD34 + /38-, or CD34 - /38+), soon displayed a phenotypical constellation similar to that before sorting. The ratio of CD34- to CD34+ seems to be influenced by the cell density: The greater the cell-to-cell contact, the lower the percentage of CD34-expressing cells. Some of the cells apparently differentiate into T-cell phenotype and acquire CD3 and T-cell receptor (TCR) alpha/beta molecules. While the quantity of CD34-expressing cells significantly increased in the presence of dexamethasone (10(-7) M), and some of them additionally acquired CD33 antigen, the percentage of CD3-positive cells was enhanced by adding 1% DMSO in medium. In contrast, cytokines such as IL-1, IL-2, IL-3, IL-4, IL-6, G-CSF, GM-CSF, or SCF (c-kit ligand) altered neither the proliferation capacity nor the phenotypical constellation of LW/SO cells (each tested alone). Although normal karyotype was obtained from the bone marrow cells, the LW/SO cells revealed a homogeneous chromosomal composition of 45, X, -X, der(9) inv(9) (p12q13) del(9) (p22?). These data suggested that LW/SO cells might be the leukemic counterpart of putative pre-CD34-positive progenitors. In order to substantiate this assumption, we analyzed the expression of other so-called T-cell markers on CD34+ cells from peripheral blood stem cell aphereses of five patients who later underwent high-dose chemotherapy and subsequent stem cell retransfusion. These data clearly revealed that a considerable amount of CD34+ hematopoietic progenitors co-express CD2/4/(5)/(7)/25 at an early stage of differentiation, and support the notion that CD34-negative LW/SO cells with the surface markers CD4/5/7/25 are probably phenotypical representatives of pluripotent stem cell. Hence, not all CD34-negative populations with so-called T-cell surface markers should be considered T-cells; some may constitute the ancestor of CD34 antigen-expressing progenitors.

Regulation of the density of the stem cell factor receptor (c-kit) by tumor necrosis factor alpha on a human myeloid cell line.

The GM/SO cell line bears a high level of stem cell factor receptors (SCF-R) i.e. c-kit protein, and therefore constitutes a potential model for studying the regulation of this crucial receptor on myeloid cells. In this study we evaluated the effect of tumor necrosis factor alpha (TNF-alpha) on the expression of SCF-R by flow cytometry. In contrast to 1 hour of preincubation, the experiments carried out after 24 hours preincubation revealed that TNF-alpha, if added alone, reduced the density of SCF-R on GM/SO cells in a dose-dependent manner. However, if combined with GM-CSF, which per se downregulates the SCF-R on these cells as well, TNF-alpha antagonized the effect of GM-CSF and slightly increased the density of SCF-R. Yet the cells incubated for 24 hours in medium without cytokines invariably expressed a higher level of SCF-R than the cells incubated in the presence of TNF-alpha and GM-CSF, either alone or in combination. In contrast to these cytokines, stem cell factor (SCF), which was also tested simultaneously in all experiments, downregulated its own natural receptor on these cells also after a preincubation of 1 hour. Furthermore, prolonged exposure of GM/SO cells to TNF-alpha for 5-7 days yielded a monocyte-macrophage-like morphology of some cells as these cells displayed an apparent glass and plastic adherence. In contrast, no such morphological changes could be observed in the presence of GM-CSF or SCF.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) reduces the density of stem cell factor receptors (c-kit oncogene product) on a GM-CSF-dependent human myeloid cell line.

By employing a monoclonal antibody against the stem cell factor receptor (SCF-R), c-kit oncogene product, we analysed in flow cytometric technique the density of SCF-R on GM/SO cells which were incubated under various culture conditions. These experiments revealed that there is an inverse correlation between the SCF-R density on the cells and the doses of granulocyte-macrophage colony-stimulating factor (GM-CSF) in culture medium; the lower the dose, the higher the density of SCF-R on the cells. More detailed analyses showed that, in contrast to SCF which rapidly downregulates its own receptor, GM-CSF does not alter the measurable level of SCF-R in an exposition period of 60 minutes, which suggests that the internalization or shedding of the receptor is not the mechanism of action. Since the most striking difference regarding density of SCF-R between GM-CSF-treated and untreated cells was observed on day 2, the modulation of c-kit oncogene protein by GM-CSF likely occur prior to expression of protein onto the cell surface. In order to exclude the possibility that altered cell viability due to insufficient GM-CSF content in culture medium might be responsible for the increased SCF-R densities on GM-CSF-dependent cells, we subsequently generated a GM-CSF-independent subclone which still responded to GM-CSF as well as the dependent did. The experiments carried out with this subclone confirmed the results presented above. Thus our data suggest that GM-CSF is directly involved in the regulation of SCF receptor density on GM/SO cells.

Long-term correction of neutropenia in Felty's syndrome with granulocyte colony-stimulating factor.

Neutropenia in Felty's Syndrome predisposes patients to recurrent bacterial infections. We have treated a patient for more than one year with G-CSF and ascertained that this growth factor can safely correct neutropenia over a long period of time. G-CSF may constitute a new agent for the treatment and prophylaxis of infection in Felty's syndrome.

Low-dose oral natural human interferon-alpha in 29 patients with HIV-1 infection: a double-blind, randomized, placebo-controlled trial.

OBJECTIVE: To evaluate clinical efficacy and toxicity of low-dose oral natural human interferon-alpha (nHuIFN alpha) on CD4+ lymphocyte counts and clinical symptoms in patients with HIV-1 infection. DESIGN: Double-blind, randomized, placebo-controlled trial with crossover. SETTING: Private practice specializing in the treatment of patients with AIDS. PATIENTS, PARTICIPANTS: Only patients with HIV-1 infection and CD4+ lymphocyte counts between 200 and 500 x 10(6)/l were included for study. Thirty out of thirty-one patients at study entry completed treatment with placebo, and 29 completed nHuIFN alpha treatment. Mean patient age was 36 years (range, 25-58 years). The 30 patients included 26 men, of whom 22 were homosexual, and four women; five were drug users and none were currently on zidovudine therapy, although three had been previously. INTERVENTIONS: Patients were randomly assigned to cohorts of 10 to receive either 200 IU nHuIFN alpha once daily orally absorbed or placebo with crossover after 6 weeks. MAIN OUTCOME MEASURES: Every 2 weeks, a detailed history, physical examination, and laboratory tests, including CD4+ and CD8+ lymphocyte counts, were conducted. RESULTS: There was only a slight, transient increase in mean CD4+ lymphocyte counts after 4 weeks of treatment with nHuIFN alpha, compared with a slight decline when placebo was administered. This effect reached statistical significance in a subgroup of patients only and was not sustained after 6 weeks. There were no significant changes in weight and clinical symptoms. All patients remained HIV-1-antibody-positive. Treatment-related adverse reactions were not observed. CONCLUSIONS: Our double-blind, randomized, placebo-controlled clinical trial did not confirm a previous report of efficiency of oral nHuIFN alpha. Although non-toxic, our data do not justify the widespread use of low-dose oral nHuIFN alpha in HIV-infected patients outside controlled clinical trials.

Prevention of chemotherapy-induced nausea and emesis in patients responding poorly to previous antiemetic therapy. Comparing tropisetron with optimised standard antiemetic therapy.

In a multicentre trial, 78 patients with a variety of malignancies, who had experienced insufficient control of emesis (greater than or equal to 3 episodes within 24 hours) while receiving standard antiemetics during previous chemotherapy, were randomly assigned to receive tropisetron 5mg once daily for 5 days or conventional antiemetic drugs. No attempt was made to standardise the conventional antiemetic treatment, which was given according to the usual practice of the participating institutions. Emesis was evaluated by counting emetic episodes and nausea by asking the patients to record on a diary chart the duration and severity of the nausea. Emesis was much better controlled with tropisetron than with standard drugs, complete control during the first 24 hours being achieved in 42% and 8% of patients, respectively, (p less than 0.001). Nausea was of significantly shorter duration (6.9 vs 10.3 hours; p less than 0.01) and was less severe (p less than 0.005) in the tropisetron group. The patients' overall assessment of treatment outcome was markedly better for tropisetron than for the standard antiemetic therapy. The superior efficacy of tropisetron was especially marked during the first 24 hours. For delayed nausea, no significant difference between treatments was seen. No serious adverse effects were observed.

Does dexamethasone enhance control of acute cisplatin induced emesis by ondansetron?

OBJECTIVE: To determine the contribution of dexamethasone to the efficacy of the 5-hydroxytryptamine antagonist ondansetron in control of cisplatin induced nausea and vomiting. DESIGN: Randomised double blind crossover study. SETTING: Two cancer centres in teaching hospitals, one in the United Kingdom and the other in Germany. SUBJECTS: 100 patients (53 men and 47 women) new to cisplatin chemotherapy, 84 of whom completed two consecutive courses of chemotherapy. INTERVENTIONS: Patients were given intravenous dexamethasone (20 mg) or physiological saline with intravenous ondansetron 8 mg before cisplatin, then ondansetron 1 mg/h for 24 hours. Oral ondansetron 8 mg was taken three times daily on days 2-6. MAIN OUTCOME MEASURES: Incidence of complete or major control of emesis (0-2 episodes in the 24 hours after chemotherapy). RESULTS: Complete or major control was obtained in 49 out of 71 (69%) of patients after receiving ondansetron plus dexamethasone compared with 40 out of 71 (56%) when they were given ondansetron alone (p = 0.012). This effect was most pronounced in the first 12 hours after chemotherapy. Patients receiving the combination also had significantly less nausea. Of the 53 patients who expressed a preference, 38 (72%) preferred the combination treatment (p = 0.002) to ondansetron alone. The effect of ondansetron on delayed emesis was less pronounced. CONCLUSIONS: Dexamethasone makes a significant contribution to the efficacy of ondansetron in the control of acute platinum induced emesis.

[New cytostatic drugs. Status: 1986]. / Neue Zytostatika. Stand: 1986.

In oncology phase-II studies are planned for testing antitumor activity in a series of malignant tumors. Most important is the development of drugs from entirely new classes of chemicals, fermentation products etc. Clinical research with analogues of known cytotoxic drugs aims at broader spectra of activity and at decreased toxicity in an attempt to avoid, for example, the cardiac toxicity of the anthracyclines or the renal and gastrointestinal toxicities of cis-platinum.