Pirarubicin (4'-o-tetrahydropyranil-adriamycin) for treatment of advanced breast cancer. A Clinical Phase II study.

In a phase II study, 77 patients with metastatic breast cancer were treated with pirarubicin, 70 mg/m2 iv every 3 weeks. Most of them had received prior hormonal (n = 39) and/or chemotherapeutic drug treatment for advanced disease, including anthracycline-containing regimens in 17. After a median of 5.5 treatment cycles (range 1-14), objective tumor response was seen in 22/71 (31%) evaluable patients (4CR, 18 PR). Stable disease occurred in 34 (48%) patients, whereas the tumor progressed in 15 (21%). Significant hematologic toxicity (WHO grade III-IV) requiring interval and/or dose adjustments was observed in 41 (58%) patients. Other treatment-related side effects were generally mild, and included alopecia in 52 (73%), nausea and/or emesis in 50 (70%), and stomatitis and diarrhea in 3 patients each. There was no treatment-related death, nor was there any evidence of cardiac toxicity thus far. In summary, the early results of this trial suggest that pirarubicin is an active and rather well tolerated drug in pretreated patients with advanced breast cancer.

Influence of local radiotherapy of breast cancer patients on the frequency of cytotoxic T lymphocyte precursor cells.

Alloantigen-specific cytotoxic T lymphocyte precursor (CTL-p) frequencies were analyzed in ten patients with histologically proven breast cancer receiving prophylactic RT. The frequency of CTL-p was assessed by limiting dilution (LD) analyses before, immediately after discontinuation of treatment and at various times following RT. The number of pbmnc, adherent cells and T cells was determined in parallel. Local RT led to a minor and transient reduction of CTL-p frequencies lasting approximately three months: on average a 25% decrease of CTL-p numbers was seen immediately after RT. Three months following treatment, a 20% reduction was still evident. Values subsequently returned to pretreatment levels. Moreover, these changes in the frequency of antigen-specific CTL were accompanied by a 25% to 39% decrease in the blood T cell counts lasting for more than 12 months. The reductions following local RT were less pronounced than those induced by immunosuppressive drugs in allograft recipients.

Steroid hormone receptors and prognosis in breast cancer.

The importance of steroid receptors for the prognosis of mammary carcinoma has been evaluated by investigating the course of disease in 163 patients for a median follow up time of 66 months after mastectomy. Multivariate analysis including estrogen receptor (ER), progesterone receptor (PgR), the presence of 8S and 4S ER together or 4S ER only, and the lymph node status revealed only the latter to have significant (p less than 0.001) predictive potency. Lymph node positive (N-pos) patients had a 3.3 (1.7-6.2) fold risk of death and 2.8 (1.7-4.7) fold risk of recurrence relative to node negative (N-neg) patients. When we compared overall survival (OAS) and disease-free survival (DFS) in the various receptor-positive groups with the groups that displayed neither ER nor PgR, significant differences in prognosis were only seen in N-neg patients. PgR did not turn out to be a better prognostic factor than ER, nor was the 8S ER a sign of increased OAS and DFS compared to total ER. However, the number of patients in this group was too small to allow a definite statement.

Enhanced serum levels of beta-2-microglobulin, neopterin, and interferon-gamma in patients treated with recombinant tumor necrosis factor-alpha.

The effect of different doses of recombinant human tumor necrosis factor-alpha (rTNF-alpha) on serum levels of neopterin, beta-2-microglobulin and interferon-gamma (IFN-gamma) was investigated in tumor patients. Twelve patients with advanced malignant disease were treated and received single doses of either 1, 10, or 100 micrograms/m2 rTNF-alpha on days 0 and 7. Neopterin, beta-2-microglobulin and IFN-gamma serum levels were measured from day -2 to day 12 of the study. Application of rTNF-alpha leads to a marked and dose-dependent increase of neopterin and beta-2-microglobulin levels; no rTNF-alpha-dependent changes were observed after 1 microgram/m2, and maximum increments were seen in patients receiving 100 micrograms/m2. Serum levels of both parameters peaked after 2 days and returned to baseline values within 1 week. IFN-gamma levels were also elevated after application of rTNF-alpha. We failed, however, to demonstrate a clear correlation between the serum levels of IFN-gamma, beta-2-microglobulin, and neopterin because of the wide range of pre- and posttreatment levels of IFN-gamma. We conclude that neopterin and beta-2-microglobulin represent useful markers for monitoring biological response to treatment with rTNF-alpha.

[Experience using bone marrow transplantation in the treatment of hematologic neoplasms and solid tumors]. / Erfahrungen mit der Knochenmarkstransplantation in der Behandlung hämatologischer Neoplasien und solider Tumoren.

Between October 1983 and October 1985, 12 allogeneic bone marrow transplantations from HLA-identical siblings were performed for treatment of malignant disease (11 haemopoietic malignancies) or severe aplastic anaemia (1 case). All patients showed prompt and complete engraftment of donor cells on average around day 17 after transplantation. 10 patients are alive and well 50-760 days after transplantation, without any signs of recurrence and partly without immunosuppressive therapy. Two patients died, one due to relapse of the leukaemia, and one as a result of CMV interstitial pneumonia. Graft versus host disease was seen in 6 of the 12 patients. Additional immunosuppressive therapy was necessary in 4 of them. The incidence of idiopathic interstitial pneumonia in our group of patients was low (two cases). Also tested was an experimental protocol for the treatment of chemotherapy-resistant metastatic solid tumours. After removal of all clinically detectable tumour tissue by maximal surgical therapy in 5 patients, residual systemic metastases were treated by means of total body irradiation and high-dose cyclophosphamide, followed by autologous bone marrow transplantation with curative intention. Relapse occurred in 4 patients between day 100 and 720 after BMT bone marrow transplantation. Only one patient remains without sign of relapse.

Influence of ethylene-2,2'-bis (dithio)bis(ethanol) on certain human in vitro and in vivo lymphocyte functions.

The influence of in vivo or in vitro exposure of human lymphocytes to ADA 202-718 (ethylene-2,2'-bis (dithio) bis (ethanol)) was tested. Evaluated were spontaneous, lectin, or alloantigen-induced proliferation as well as the release of IFN-alpha, gamma and of neopterin. The spontaneous cell mediated lysis (NK lysis) of K 562 tumor targets was also assessed. In vitro exposure to ADA 202-718 slightly enhanced lectin and alloantigen-induced human lymphocyte proliferation. IFN-gamma release was also slightly increased. These parameters were not clearly affected by in vivo treatment with ADA 202-718. In vitro and in vivo-treatment with this drug did not affect spontaneous lymphocyte blastogenesis. Statistically significant effects, however, were seen when NK activity was assessed. Preincubation of either effector or target cells with ADA 202-718 as well as in vivo treatment caused an increase of NK lysis. When these results obtained with human cells were compared with those previously seen in a murine system, immunostimulatory activity of ADA 202-718 was more pronounced in the murine system.

Treatment with low dose human recombinant interferon-alpha-2-ARG induces complete remission in patients with hairy cell leukemia.

Five cases with advanced hairy cell leukemia refractory to treatment with splenectomy and chemotherapy as well as one patient presenting with a stage-A response to splenectomy were treated with rhu-IFN-alpha 2-arg. 5 X 10(6) were administered intramuscularly every day. Both patients, with advanced disease resistant to conventional therapy and treated for six or more months with rhu-IFN-alpha 2-arg, achieved complete clinical remissions. Three further cases treated for less than half a year and also with advanced disease achieved partial remission states with marked reduction of circulating hairy cells and with recovery of normal hemopoiesis. Minimal residual disease in the remaining patient during a three-month period of treatment did not respond. Side effects of rhu-IFN-alpha 2 low dose therapy were minimal in 5 cases and comprised a severe leukopenia reversible after dose reduction in one patient.

[Initial clinical experiences with allotransplantation of the pancreas]. / Erste klinische Erfahrungen mit der Allotransplantation des Pankreas.

Since 1979 7 pancreas transplantations have been performed in 8 type I diabetics. 5 of these 7 recipients had already been dialysed; 2 were awaiting their first dialysis. Furthermore, diabetes had caused severe retinopathy in 5 patients. The pancreas was transplanted simultaneously with a kidney from the same donor in 5 recipients; in 3 cases the pancreas was grafted 16 to 230 days after successful renal transplantation. 1 pancreas graft was removed immediately after revascularisation because of ischaemic damage. While the pancreatic duct was occluded in the first 4 patients, enteric diversion of the pancreatic juice was applied in the next 3 recipients. The first two patients were treated with conventional immunosuppression, whilst all the others received cyclosporin A and low-dose steroids. Small amounts of insulin had to be given initially for a few days in 2 cases, only. 2 grafts were lost due to surgical complications and 3 for immunological reasons. 1 functioning graft had to be removed because the patient was not willing to continue immunosuppression after irreversible rejection of her renal transplant. There was no perioperative death. 2 pancreatic and 5 renal grafts are functioning well at the present time. Technical aspects and problems in the diagnosis of rejection are discussed.

Tamoxifen (Nolvadex) for premenopausal patients with advanced breast cancer.

Clinical results of tamoxifen ('Nolvadex'-ICI) monotherapy in 44 premenopausal women with advanced breast cancer have been reviewed. Objective tumor regression was achieved in 12 (27%) patients and a further 10 (22%) were classified as 'stabilized'. Median duration of response was 12.7 months at the time of analysis. Greatest benefits occurred in soft tissue dominant and receptor-positive tumors, but there was no correlation between tumor response and other clinical manifestations of estrogen deprivation (e.g. menstrual disturbance, hot flushes). The benefits of conventional doses of tamoxifen do not therefore appear to be influenced by menopausal status and compare favorably to achievements reported after surgical oophorectomy.