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We determined the concentration and effusion/serum ratio of mucin-like carcinoma-associated antigen (MCA) in comparison to carcinoembryonic antigen, carbohydrate antigen 19-9, cancer antigen 125, and cancer antigen 15-3 in 80 sera and 99 effusions from 64 patients with histologically confirmed malignancies (4 patients out of this group showed various effusions simultaneously, which were analyzed separately) and 31 patients with various nonneoplastic diseases. Tumor cells were detected by cytological examination in 41 effusions (60.3%) from patients with neoplastic diseases, while in another 27 cases this method failed to demonstrate the malignant origin of the effusion. Of the cytological "positive" malignant effusions 90% were also correctly identified by an elevated MCA concentration at a cutoff level of 10 U/ml, whereas only one effusion of benign origin (3%) showed a slightly elevated MCA concentration of 10.5 U/ml. In 33% of cytologically "negative" effusions of patients with neoplastic diseases, the MCA concentration was also elevated, with a maximum of 453 U/ml. Increased MCA levels in cytologically confirmed malignant effusions were not restricted to metastatic breast cancer. All 17 cytologically "positive" "non-breast cancer" effusions were correctly identified by their MCA concentrations. None of the other tumor markers reached this high sensitivity at the same level of specificity. The ratio of effusion/serum concentration of all tumor markers as well as the concentration of cancer antigen 125 in effusions was of little diagnostic value. Our results indicate that the MCA concentration in an effusion correlates very closely with its malignant origin and is superior to all the other antigens tested.(ABSTRACT TRUNCATED AT 250 WORDS)

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In four cases of severe neutropenia of unknown origin we found a strong inhibition of the growth of granulocyte-macrophage (GM) progenitor cells. The development of GM colonies in culture (GM-CFU-c) was more than 80% reduced in comparison to the control group. In particular, the interleukin 3-(IL-3) and granulocyte macrophage colony-stimulating factor-(GM-CSF) dependent growth was affected; a combination of growth factors (IL-3, GM-CSF, and G-CSF, the granulocyte colony-stimulating factor) resulted in a less reduced growth. The findings were primarily compatible with drug-induced bone marrow failure. Among the medications given to the patients, famotidine, an H2-receptor blocker, was discussed as an agent which possibly triggers off this process. After the withdrawal of famotidine, in three cases a continual increase of the growth of GM precursors was detected, reaching the normal level 7-17 days later. In one case, further investigations of the progenitor cells could not be carried out due to the death of the patient, but the rapid increase of neutrophils in the peripheral blood after withdrawal of famotidine pointed to the recovery of hematopoiesis. In vitro studies showed that famotidine, depending on the dose, inhibits the single growth factor-dependent colony growth (IL-3, GM-CSF, or G-CSF) of bone marrow progenitors from a concentration as low as 10 micrograms/ml. With the combination of all three growth factors only slight inhibitory effects were detectable (up to 150 micrograms/ml famotidine). These results indicate that famotidine, in common with other H2-receptor antagonists, can affect hematopoietic progenitor cells. However, the plasma concentration of famotidine normally used in ulcer therapy does not seem to influence the hematopoiesis. Apparently, the progenitor cells of only a few patients possess a higher sensitivity to the blockade of H2-receptors at this concentration of famotidine. This was demonstrated in one case (patient 3) 2 years after the patient had recovered from famotidine-induced neutropenia. The growth of peripheral myeloid, erythroid, and multilineage progenitor cells of this patient was remarkably reduced even at famotidine concentrations of 0.1-5.0 micron/ml whereas in the control group no inhibition was detected at these famotidine concentrations. Again, the IL-3-dependent colony formation was more affected than in the case of the combination of IL-3, GM-CSF, and G-CSF. After the removal of accessory cells the inhibitory effect of famotidine persisted, demonstrating that accessory cells do not play a major role in this process.

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In the dose finding study we were able to demonstrate that an increase of the epirubicin dose to 120 mg/m2 in combination with cyclophosphamide (600 mg/m2) is possible. The phase II trial had to check the efficacy and the toxicity of this combination with a therapy interval of 21 days. 34 patients with metastatic breast cancer previously not treated with chemotherapy for metastatic disease entered this phase II trial, which tested the efficacy and toxicity of the chemotherapy combination epirubicin 120 mg/m2 and cyclophosphamide 600 mg/m2 (HD-EC regimen) i.v. every three weeks. Excluded from the trial were patients at risk of anthracycline toxicity and those with bone or brain metastases. Results compare favourably with best data reported in the literature for chemotherapy of metastatic breast cancer: overall remission rates of 73% (35% CR, 38% PR), median TTP of 58 weeks for CR (range 32-168 weeks) and 52 weeks for the PR group (range 24-110 weeks); median survival time for CR 71+ weeks (range 52-196+), for PR 74+ weeks (range 40-134+ weeks). No therapy was given for remission maintenance after a stable remission was obtained. This results in a very favourable ratio of time with chemotherapy to maintenance time without chemotherapy, which is 10 weeks/62 weeks for CR and 12 weeks/49 weeks for PR. Evidence of tumor remission was found in 80% of the patients who already responded to chemotherapy after the first cycle. The early onset of tumor response as well as the short induction chemotherapy period necessary to obtain best response are considered major advantages of the HD-EC regimen.

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Pirarubicin is a more lipophilic derivative of doxorubicin, with a higher uptake rate of cells, lower cardiotoxicity and better antitumor efficacy in preclinical models. Thirty-four patients with metastatic breast cancer were treated in a multicenter phase II study with pirarubicin (THP) using a dosage of 75 mg/m2/every 3 weeks. The patients had a median age of 56 years (range 41-73) and a performance status of WHO grade 0-2. Patients pretreated with anthracyclines, or who were older than 75 years and without sufficient bone marrow reserve were excluded. The 32 evaluable patients received a median number of 4 cycles (range 2-8). The myelosuppression was dose-limiting and led to infections (grades 1 and 2) in 5 patients. Twenty-eight patients developed leukocytopenia grade 3 and 4 toxicity and 7 patients experienced thrombocytopenia grade 1 and 2. The drug was subjectively well tolerated and nausea, vomiting and alopecia were mild. One complete remission with a duration of 15.4 months (67 weeks) and 7 partial remissions with a median duration of 9.3 months (40 weeks) were achieved, which resulted in an overall response rate of 25%. Twenty-one patients were stable for 17 weeks (median) under the treatment with pirarubicin.

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Eighteen patients with advanced squamous cell carcinoma of the esophagus without prior chemotherapy were treated with carboplatin. Based on experimental data a split dose of carboplatin of 130 mg/m2 given on days 1, 3 and 5 was administered. In cases showing no WBC and platelet suppression, an escalated dose of 160 mg/m2 was proposed. Out of 18 evaluable patients no complete and partial responses were observed and there were only 5 patients with stable disease (27.8%) lasting 2-7 months. Therefore, carboplatin in the regimen used shows no meaningful antitumor activity in patients with advanced esophageal carcinoma. The escalated dose (mean 107-123% of the starting dose) was well tolerated and was followed by only minor gastrointestinal and hematological toxicity. Therefore, this regimen can be recommended for future trials.

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Excess red blood cells (RBC) in patients with polycythemia vera (PV) are usually removed by repeated phlebotomy. In order to improve the efficacy of this treatment, we used isovolemic large-volume erythrocytapheresis (EA) by a cell separator. A retrospective analysis of our experience with 69 PV patients (206 EA procedures) is reported. EA induced a rapid, well-tolerated, and long-lasting reduction of Hct, Hb, and RBC counts, as well as an immediate disappearance or reduction of clinical symptoms of PV, while tissue oxygen tension - as measured in 8 patients - increased. Hct was reduced by EA from 56.8% +/- 5.6% to 41.9% +/- 6.6%, Hb from 17.5 +/- 2.3 to 12.7 +/- 2.4 g%, RBC counts from 7.4 +/- 0.9 to 5.4 +/- 0.9 x 10(6)/mm3. The mean volume of the apherisate was 1410 +/- 418 ml, (mean Hct 79.7% +/- 9.3%), and the actual RBC volume removed 1113 +/- 367 ml. The isovolemic procedure was well tolerated and the acceptance by patients seemed to be better than with repeated phlebotomy. In 21 patients whose Hct values (Hct before and after EA 58% +/- 5.7% and 41.5% +/- 4.9%) were regularly followed after EA the mean period with Hct less than 50% after a single EA procedure was 6.1 +/- 4.1 months (median, 6); in 14 out of these 21 patients a Hct of less than 43% after EA was reached and their mean period with Hct less than 50% after EA was 7.6 +/- 4.0 months (median, 7.5). For three patients this period was 11, 13, and 15 months, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

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Serum factors may be responsible for reduced host-anti-tumor defence. Although there is still confusion about their origin, attempts have been made to immobilize serum components by Protein A columns as a therapeutic modality. In our study the in vitro adsorption of 90% of the IgG from cancer sera on "immobilized protein A" did not influence the inhibitory serum activity as measured in a mixed lymphocyte culture. Therefore, IgG or immune complexes do not seem to be the suppressive serum factor in patients with advanced colorectal carcinoma. There is evidence for leakage of small amounts of protein A from the columns which have immunostimulatory activity. Perhaps this may explain necrosis after a therapeutic immunoadsorption.

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The nature of the inhibitory activity of sera of patients with metastatic cancer on in vitro immunoassays remains unclear. Serum glycoprotein levels in cancer patients show a reasonable correlation with the clinical status, especially with progressive metastatic disease. Glycoproteins like acute phase reactants have been connected with immunosuppressive activity in cancer patients' sera. In this study, we examined the influence of glycoprotein fractions of normal and cancer sera, separated by Con A immunoadsorption, on the mixed lymphocyte culture as a reference system for suppressive activity. Glycoprotein rich fractions with the utmost recovery of the acute phase reactants inhibited the mixed lymphocyte culture in a dose-dependent manner. This effect was more pronounced in patients sera as compared to control sera. But there is evidence of additional blocking activity in the glycoprotein poor serum fraction, indicating blocking factors still to be identified.

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23 patients with advanced metastatic colorectal adenocarcinoma and measurable metastases were treated with chemotherapy until resistance to chemotherapy was evident. Chemotherapy was then not discontinued but administered for at least a further cycle combined with large-volume plasma exchange (PE). 15 of 23 patients responded again for 4-45 weeks, an average of 13. This effect was thought to be due to dilution or elimination of serum-blocking factors, which could be measured by mixed lymphocyte culture (MLC) assay. 16 of 20 patients showed a positive correlation between the clinical course and MLC activity, if the basic MLC reactivity was compared with the MLC levels at the start of each subsequent PE in each patient. It is postulated that in some tumors there is a resistance to chemotherapy mediated by plasma-blocking factors.

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44 patients with advanced squamous cell carcinoma of the head and neck were randomized and treated preoperatively either with arm "A": cis-DDP (3 mg/kg iv day 1) and BLM (15-20 mg iv continuously day 2-6) or arm "B": MTX (30 mg/m2 iv day 1 + 6) and VDS (3 mg/m2 iv day 2 + 7). Treatment with arm "A" was superior producing 73% complete and partial remissions (CR + PR) compared to 40% for arm "B" (p = 0,05). The number of patients with CR could be increased from 2 to 26 by surgery and/or radiotherapy. The median survival for patients with chemotherapeutically induced CR and PR was 16 months but this did not differ significantly from the median survival (13 months) of non responders (p = 0.25). For patients with CR and PR achieved by surgery and/or x-ray therapy the median survival point has not yet been reached, and this is significant compared to the non responders (p = 0.001). Five of 26 patients with CR died after 39 months of observation and 6 are living with recurrence. In addition to clinical trials, chemotherapy is indicated for patients with inoperable tumours. The value of chemotherapy can only be answered by randomized trials comparing chemotherapy combined with standard procedures against surgery and radiotherapy alone.

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79 patients were randomized and treated either with cis-DDP 33 mg/kg i.v. day 1 and BLM 15 mg/m2 i.v. continuously day 2-6 (arm A) or less aggressively with MTX 30 mg/m2 i.v. day 1 + 6 and VDS 3 mg/m2 day 2 + 7 (arm B). Patients with inadequate response were further treated with the alternative regimen ("cross over"). Regarding response rates therapy A was superior to B (p = 0.01) respectively p = 0.05 for the cross over patients. Not pretreated in comparison to pretreated patients demonstrated not significantly better results. Pretreated patients had statistically superior response rates with arm A than with arm B (p = 0.05). All other prognostic factors were without any influence on treatment results. CR induced by chemotherapy (2 X) in not pretreated patients could be increased by additional surgery and X-ray therapy (CR = 26X). Survival times demonstrated no difference between both regimes. Chemotherapy was of less influence on median survival times after 39 months than in comparison to post-chemotherapeutically performed surgery +/- radiotherapy in 44 not pretreated patients. Chemotherapy: CR + PR to MR + NC + PD 16 respectively 13 months with 38 respectively 48% survivors (p = 0.25). Surgery +/- radiotherapy: CR + PR median not reached yet, MR + NC + PD 13 months with 60 respectively 18% survivors (p = 0.001).

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The efficacy of chemotherapy with sequential methotrexate (MTX) and 5-fluorouracil (5-FU) in metastatic colorectal cancer was studied in a multicenter phase II trial using a seven-hour time interval. Forty-two patients were evaluable for response and 16 achieved objective tumor regression (greater than 50%). Median survival of all patients was 12.5 months. The result of this study indicates that MTX and 5-FU are synergistic in human colorectal cancer if given sequentially with a seven-hour time interval. This is supported by a review of the literature that reveals a significantly higher response rate in patients treated with a four-hour or more MTX/5-FU interval as compared to a one-hour interval.

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The arguments favouring the hypothesis that chemotherapeutic agents might act in cooperation with host defence mechanisms are reviewed briefly. In patients with far advanced solid tumours plasma factors blocking in vitro immune reactions have been identified and successfully removed by immune adsorption or plasma exchange. By plasmapheresis performed in patients with metastatic malignancies resistant to chemotherapy it was possible to induce tumour regressions. In 25/28 patients responding to the combined plasmapheresis/chemotherapy procedure a positive correlation was found to clinical results and patterns of plasma-blocking factor activities.

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Clinical significance of immune complex-like material in the serum was investigated in tumour patients undergoing plasma exchange with albumin-saline solution and subsequent chemotherapy. Immune complexes were detected by the Clq binding assay or the Raji cell radioimmunoassay in nine out of forty-five patients before this therapy. Levels of immune complexes were decreased to 10-30% of the initial value by plasma exchange depending on exchanged plasma volume. In contrast to other serum proteins like alpha 1-antitrypsin and alpha 2-macroglobulin, which showed protein specific increase during follow up after plasma exchange in all patients, recovery rates of immune complexes and IgG were highly individual but parallel in each patient. Clinical response to this protocol did not correlate with immune complex status, suggesting that removal of the measured immune complex like material had little clinical significance or was not longlasting enough to provide therapeutic benefit.

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Chemotherapy resistance in cancer patients may be due to serum blocking factors, which can be diminished or eliminated by large volume plasma exchange (PE). This procedure was performed with the IBM blood cell separator in 69 patients resistant to chemotherapy. Immediately after PE the chemotherapy was given but it was reinstituted, if clinical evaluation revealed partial remission, minor response or no change. 37 out of 69 patients (53.6%) responded again, 32 (46.4%) did not. Response duration ranged from 2 to 45 weeks. Best clinical results were obtained in patients with colorectal cancer, 15 out of 23 showed improvement between 4 to 45 weeks. Serum blocking activity was measured using a modified mixed lymphocyte culture assay (MLC). There was a 80% positive correlation between clinical course of patients and MLC levels, if basic activity before the first PE was compared to MLC inhibition before the following PE's.

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52 patients with epidermoid cancer of the head and neck region were either treated with cis-DDP and bleomycin (arm A) or with methotrexate and vindesine (arm B). In case of resistance patients were further treated with the alternative regimen (A leads to B or B leads to A). Treatment results are superior in arm A. Complete and partial remission were in A: 54%, in B: 31%, after crossover 46% and 0%, respectively. Status of pretreatment (operation and/or radiotherapy) is of minor importance for arm A than for the "soft" treatment of arm B. Preliminary analysis of survival and remission duration shows no significant difference in regard to A or B and status of pretreatment. However, those patients resistant to B and further treated with A have an increase of median survival from 3 to 9 months (p = 0.02). With primary chemotherapy inoperable tumors can be made operable with curative intention.

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