Ifosfamide, methotrexate, and 5-fluorouracil in advanced pretreated breast cancer.

Thirty-five patients with a median age of 55 years (range, 28 to 68 years) and a median Karnofsky status of 80% (range, 40% to 100%) were treated with ifosfamide (1.5 g/m2 plus mesna), methotrexate (40 mg/m2), and 5-fluorouracil (600 mg/m2) intravenously (IV) days 1 and 8 at intervals of 4 weeks. Thirty-four patients had received previous chemotherapy, including anthracyclines in 28 patients. All patients were evaluable for response. A partial remission was achieved in six patients (17%), stable disease in 13 patients (37%), and 16 patients (46%) were unresponsive. Median time to progression was 7 months (range, 4 to 13 months) for partial responders, and 4 months for patients with stable disease. Median survival was 9 months for all patients, 13 months for partial responders, 16 months for no change, and 3 months for progressive disease. Toxicity was tolerable, with myelotoxicity being a dose-limiting factor, mainly in heavily pretreated patients. No treatment-related death occurred. In conclusion, this combination is effective and well tolerated. Ifosfamide is suggested for further evaluation in advanced breast cancer.

Epirubicin and ifosfamide in metastatic breast cancer.

In a randomized, phase II trial, we evaluated the effectiveness of continued chemotherapy with epirubicin/ ifosfamide versus unmaintained treatment interruption in advanced metastatic breast cancer. Three hundred fifty-seven patients were enrolled and 331 were evaluable for response. Complete response was achieved in 25 patients (8%) and partial response in 121 patients (37%). Pretreatment status correlated significantly with response (complete and partial response). While 54% of unpretreated patients responded, only 42% of the patients responded who had been pretreated with adjuvant chemotherapy and 33% who had been pretreated in the metastatic stage of disease; 69 patients (21%) had disease progression. Of 11 patients pretreated in both the adjuvant and metastatic setting, only two responded. Toxicity of treatment was mild, with leukopenia being the treatment-limiting factor. Thrombocyte levels were not altered significantly by treatment. Thus, there seems to be room for dose escalation using granulocyte colony-stimulating factor. There was no considerable cardiotoxicity, central nervous system toxicity, or cystitis observed. The low rate of cardiotoxicity appeared to be related to dose fractionation of epirubicin. After randomization of patients to treatment interruption versus continuation of chemotherapy, a longer relapse-free survival was observed for patients who continued chemotherapy (mean relapse-free survival, 2+ months); however, this did not translate into prolonged survival. The cumulative scores of toxicity and quality of life parameters showed increasing superiority for treatment interruption. Therefore, a strategy of treatment until maximum response and subsequent treatment interruption seems to be superior to treatment continuation.

Solubilization of hexokinase activity by an effect of thiopental on the mitochondrial membrane.

In thiopental anesthesia of rats cerebral mitochondrial hexokinase activity was solubilized. This solubilization was also observed when the period necessary for the removal of the rat brain was shortened to 15 s by brain blowing. The influence of the drug on the binding of hexokinase activity to mitochondria of brain, liver and neuroblastoma cells was studied in vitro. Solubilization of hexokinase activity was achieved in all systems at therapeutically relevant thiopental concentrations. On the other hand, chlorpromazine as a highly lipophilic drug only solubilized hexokinase activity at concentrations being already lytic to the membrane. Thus, it is concluded that thiopental solubilize hexokinase activity by affecting the mitochondrial membrane, and that this effect is not only dependent on the lipophilic character of a drug.

Fibronectin and factor VIII-related antigen in liver cirrhosis and acute liver failure.

The liver is involved in the turnover of fibronectin in two different ways: hepatic synthesis contributes substantially to the plasma fibronectin pool, while Kupffer-cells, performing an important role of the reticuloendothelial system, remove fibronectin opsonized material from the circulation. In 45 patients with histologically confirmed liver cirrhosis and six patients with acute liver failure due to intoxication we determined fibronectin concentration in plasma by electroimmunoassay and additionally measured factor VIII-related antigen, which is a large glycoprotein not synthesized in the liver. Fibronectin levels in plasma were decreased in liver cirrhosis. This decrease was correlated with the extent of porto-caval collateral circulation. Very low levels were found in patients with acute liver failure. Factor VIII-related antigen levels were greatly increased as a function of the hepatic insufficiency. Between both parameters there was a significant inverse correlation. It is concluded that the simultaneous determination of both proteins provides reliable information about the remaining liver function.

Fibronectin and factor VIII-related antigen in acute leukaemia.

The glycoprotein fibronectin is, as well as by various other cells, also produced in leucocytes and is said to play an important role in malignant transformation of cells. Therefore, the behaviour of plasma fibronectin and of factor VIII R:AG was investigated in acute leukaemia in order to prove their significance as prognostic and therapeutic markers (method: electroimmunoassay). In patients with acute myeloid leukaemia (n = 29) and acute lymphoblastic leukaemia (n = 11) no significant changes in fibronectin concentration could be evaluated. Fibronectin levels declined significantly only during therapy with asparaginase in patients with acute lymphoblastic leukaemia, probably as a result of disturbed synthesis in the liver. Using crossed immunoelectrophoresis against fibronectin antiserum, one normal and one slower migrating antigen (FN:C) could be observed in nearly all plasma samples in patients with acute leukaemia. By means of in vitro tests with highly purified substances and intermediate gel electrophoresis it could be shown that FN:C represents fibronectin which has bound fibrinogen, probably crosslinked by activated factor XIII. Factor VIII R:AG was found to be greatly raised in patients with acute leukaemia--up to 1400% of the normal level. Increased levels correlated well with a worsening of the disease. The protein seems to be suitable for estimating the activity and prognosis of acute leukaemia.

Invasive bronchopulmonary aspergillosis leading to rapidly progressive respiratory failure in a patient with severe aplastic anemia.

A 22-year-old man with severe aplastic anemia was treated with antilymphocyte globulin, prednisone, and oxymetholone. Fourteen days after initiation of treatment he developed a fulminant mediastinal and subcutaneous emphysema leading to respiratory failure refractory to mechanical ventilation. Fiberoptic bronchoscopy showed nodular lesions typical of aspergillus. Cultures of bronchial mucus revealed Aspergillus fumigatus as the responsible pathogen.

[Tumor lysis syndrome in a young patient with Burkitt-type lymphoblastic lymphoma]. / Tumorlysesyndrom eines jugendlichen Patienten mit lymphoblastischem lymphom vom Burkitt-Typ.

A tumor lysis syndrome with hyperkalaemia, hyperphosphataemia, hyperuricaemia and hypocalcaemia developed 48 hours after start of combined cytostatic treatment in a 16-year-old boy with Burkitt's lymphoma. Despite prophylactic administration of allopurinol and urinary alkalization, postrenal precipitation of urates and calcium phosphate caused acute renal failure. Ureteric splinting and percutaneous fistulization of the contralateral renal pelvis became necessary. Elevated renal retention values became normal after these measures and infusions with balanced alkalized electrolyte solutions, and the hypocalcaemia was counteracted.

[Therapy of primary resistant or recurrent small cell bronchial carcinoma with vindesine and ifosfamide]. / Therapie des primär resistenten oder rezidivierenden kleinzelligen Bronchialkarzinoms mit Vindesin und Ifosfamid.

A combination of vindesine (3 mg/m2, day 1) and ifosfamide (60 mg/kg, days 1-5 + Mesna) was administered every three weeks to 11 patients with primary resistant and 23 with recurrent small-cell bronchial carcinoma. All patients had been pre-treated with chemotherapy, 16 in addition with radiotherapy. At the onset of the vindesine-ifosfamide treatment the cancer was in a localized regional stage in ten patients, while in 24 it was in a more widely spread stage. In 29 patients whose treatment results could be evaluated the remission rate was 38%, with two complete and nine partial remissions. In a further eight patients the cancer was arrested. The patients with complete remission (for 46 and 53 weeks, respectively), those with partial remission (median of 39 weeks) and those with stationary disease (median of 31 weeks) survived significantly longer than those with progressing disease (13 weeks). There was no correlation between treatment result and pre-treatment. On recurrence after complete remission or in the localized regional stage the remission rate was 70% and 60%, respectively, and the survival time was extended in 90% of cases. In addition to nausea, alopecia and myelosuppression, side-effects included vomiting, reversible CNS symptoms, polyneuropathy and urotoxicity. On the basis of acceptable toxicity, combined vindesine and ifosfamide constitute an effective treatment of otherwise treatment-refractory cases of small-cell bronchial carcinoma.

[Progressive multifocal leukoencephalopathy. Late complication in chronic lymphatic leukemia]. / Progressive multifokale Leukoenzephalopathie. Spätkomplikation bei chronischer lymphatischer Leukämie.

In a 44 year old patient with chronic lymphatic leukemia and secondary antibody deficiency syndrome, a disorder of articulation and a left hemiparesis developed during a thrombocytopenic phase. Computer tomography of the cranium, CSF diagnostics and the electroencephalogram did not provide any indication for the cause of the rapidly progressive cerebral symptoms. In the NMR tomogram, a diffusedly increasing intensity in the T2-weighted tomograms were shown around the central region in the right brain. The patient died of a Pseudomonas septicemia. At autopsy, a typical finding of progressive multifocal leukoencephalopathy was found in the areas altered in the NMR tomography. Papova-like virions could be demonstrated in glial cells by electron microscopy.

Sodium transport and phosphorus metabolism in sodium-loaded yeast: simultaneous observation with sodium-23 and phosphorus-31 NMR spectroscopy in vivo.

Simultaneous 23Na and 31P NMR spectra were obtained from a number of yeast suspensions. Prior to NMR spectroscopy, the yeast cells were Na-loaded: this replaced some of the intracellular K+ with Na+. These cells were also somewhat P-deficient in that they had no polyphosphate species visible in the 31P NMR spectrum. In the NMR experiments, the Na-loaded cells were suspended in media which contained inorganic phosphate, very low Na+, and a shift reagent for the Na+ NMR signal. The media differed as to whether dioxygen, glucose, or K+ was present individually or in combinations and as to whether the medium was buffered or not. The NMR spectra revealed that the cells always lost Na+ and gained phosphorus. However, the nature of the Na+ efflux time course and the P metabolism differed depending on the medium. The Na+ efflux usually proceeded linearly until the amount of Na+ extruded roughly equalled the amount of NH4+ and orthophosphate initially present in the medium (external phosphate was added as NH4H2PO4). Thus, we presume this first phase reflects a Na+ for NH4+ exchange. The Na+ efflux then entered a transition phase, either slowing, ceasing, or transiently reversing, before resuming at about the same value as that of the first phase. We presume that this last phase involves the simultaneous extrusion of intracellular anions as reported in the literature. The phosphorus metabolism was much more varied. In the absence of exogenous glucose, the P taken up accumulated first as intracellular inorganic phosphate; otherwise, it accumulated first in the "sugar phosphate" pool. In most cases, at least some of the P left the sugar phosphate pool and entered the polyphosphate reservoir in the vacuole. However, this never happened until the phase probably representing Na+ for NH4+ exchange was completed, and the P in the polyphosphate pool never remained there permanently but always eventually reverted back to the sugar phosphate pool. These changes are interpreted in terms of hierarchical energy demands on the cells under the different conditions. In particular, the energy for the Na+ for NH4+ exchange takes precedence over that required to produce and store polyphosphate. This conclusion is supported by the fact that when the cells are "forced" to exchange K+, as well as NH4+, for Na+ (by the addition of 5 times as much K+ to the NH4+-containing medium), polyphosphates are never significantly formed, and the initial linear Na+ efflux phase persists possibly 6 times as long.(ABSTRACT TRUNCATED AT 400 WORDS)

Ifosfamide, methotrexate and 5-fluorouracil for pretreated advanced breast cancer.

A total of 51 fully evaluable patients with advanced and intensively pretreated breast cancer were treated with a combination chemotherapy of ifosfamide plus mesna, methotrexate and 5-fluorouracil. All patients had received at least one series of combined chemotherapy, 30 patients had received more than one combination and 41 patients had had anthracyclines before. Metastatic lesions in more than one site were found in 42 patients, and 24 patients had metastatic liver lesions. Partial remission was achieved in 10 patients (20%) and no change in 16 patients (31%). Survival was almost identical in both groups of responding patients and significantly shorter in treatment failures. Response was favorable in patients without pretreatment with anthracyclines. Two patients who received this protocol directly after progression with cyclophosphamide, methotrexate and 5-fluorouracil (CMF protocol) responded with a partial remission. Median time to progression was 7 months for partial responders and 4.5 months for patients achieving a no-change status. Median survival was 8 months for all patients. Toxicity was tolerable. Leukocytopenia and thrombocytopenia were treatment-limiting parameters. Overall, this protocol is well tolerable and effective in breast cancer patients with advanced disease and in intensively pretreated patients.