Paraproteinemia and reticulum cell sarcoma in an inbred mouse strain.

Mice of the inbred SJL/J strain have a high incidence of a proliferative disease affecting several cell types, including reticulum cells and plasma cells, which is frequently accompanied by gamma(1) and gamma(2) paraproteinemia. In only some instances can seriallytransplantable lines of neoplastic cells be obtained; these are reticulum cell sarcomas. Mice with transplanted reticulum cell e arcomas do not have paraproteinemia and may develop profound hypogammaglobulinemia. The disease may be viewed as an abnormal proliferation of reticulum cells which differentiate into plasma cells with consequent paraproteinemia; the subsequent emergence of transplantable reticulum cell sarcoma appears as an end stage in which this capacity to differentiate is lost.

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.

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.

Lack of response in nine patients with breast cancer treated with fibroblast interferon.

Nine patients with metastatic breast cancer were treated with a minimum of 6 X 10(6) U/day of beta-interferon (IFN-beta) for at least 6 weeks. In patients whose disease did not progress during this period treatment was continued to a maximum of 13 weeks, while in other patients doses were escalated. With daily treatments over 3 weeks the maximum tolerated dose was found to be around 60 X 10(6) U/day. Fever occurred regularly. The dose-limiting toxicities were granulocytopenia and increasing liver enzymes. No objective remissions were observed. One patient showed stable disease after her cancer en cuirasse had rapidly progressed under chemotherapy. One patient each with nasopharyngeal carcinoma and fibrous sarcoma were also treated without success. IFN-beta at this moderately toxic dose given over a period of 6-13 weeks is of no clinical value in the treatment of metastatic breast cancer in women.

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.

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.

[Chemotherapy of malignant bone tumors]. / Chemotherapie maligner Knochentumoren

In several primary malignant tumors significant improvement of formely bad prognosis has been achieved by the introduction of new cytostatic compounds and the study of new cytostatic combination regimens. Adjuvant chemotherapy in osteosarcoma and Ewing's sarcoma led to remarkable increase in survival rates. Leaning on natural history and on remission rates reached by cytostatic treatment in metastasizing stages of disease, proposals for adjuvant chemotherapy are made and chemotherapy regimen appliable on out-patient basis is described.

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.

[Chemotherapy of the ovarian carcinoma (author's transl)]. / Die Chemotherapie des Ovarialkarzinoms.

Ovarian carcinomas are highly sensitive to chemotherapy. The alkylating agents were most extensively investigated. With these drugs remissions can be obtained in about 50% of the patients. Some early results seem to show a higher response rate and a longer duration of remission after combination chemotherapy. In ovarian carcinoma it has to be the aim of the chemotherapy to obtain a complete remission. The indications for chemotherapy are not yet well defined. Treatment is definitely indicated in stage IV (FIGO) or in recurrent disease after radiotherapy. This treatment has to be given as a long-term therapy over a long period of time. In stage III and II b disease a combined treatment plan has to be developed by the radio- and chemotherapist. At the present time no data are available which prove or disprove the value of an adjuvant chemotherapy in the early stages of ovarian carcinoma. Remembering the somewhat promising results of adjuvant chemotherapy in breast cancer, it is conceivable that prophylactic chemotherapy will prove to be indicated in early stages of ovarian carcinoma.

[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.

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.

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.

[Chemotherapy of metastasizing breast cancers. Indications and results]. / Die chemotherapie des metastasierenden Mammakarzinoms. Indikation und Ergebnisse

Combined treatment with three or five chemotherapeutic drugs was given to 115 women with metastasizing breast cancer. These were unselected cases. Three drugs (cyclophosphamide, methotrexate and prednisone) were given to 49 patients, with remissions occurring in 28, arrest in a further five. Five drugs (additional to the three mentioned ones: vincristine and 5-fluorouracil) were given to 66, with remission in 45 and arrest of the disease in another eight. There was no certain difference between the response to the two forms of treatment. Mean survival time for both forms was 13 months in the remission group and six months in the failure group.