D.J.Th. Wagener

Activity of cisplatin in adenocarcinoma of the pancreas

The activity of cisplatin in metastatic adenocarcinoma of the pancreas was assessed in 33 patients. Cisplatin was administered in a dose of 100 mg/m2, every 4 weeks. There were 2 complete responses and 5 partial responses (a response rate of 21%). The median duration of response was 5 months (range, 2+ to 15 months). Cisplatin is a modestly active drug in advanced pancreatic cancer.

Monocyte purification with counterflow centrifugation monitored by continuous flow cytometry

Continuous monitoring of cell light scatter during counterflow centrifugation of a mononuclear cell suspension allows counting and size recognition of the cell types elutriated. With this method an optimal separation point between monocytes and lymphocytes, determined for each individual donor, may be established. With a constant flow of 15 ml/min this separation point is found at centrifugal velocities ranging from 2348 to 2444 rpm (n = 10). From 50 ml venous blood, 84.1% +/- 4.1% (15.7 +/- 8.6 x 10(6)) of all elutriated monocytes, with a purity of 92.4% +/- 1.4%, is collected in a volume of 50 +/- 1 ml. In the same run, 92% +/- 4.3% of the lymphocytes is gathered in one fraction with a purity of 98.9% +/- 0.7%. After counterflow centrifugation, 91.6 +/- 10.5% of the cells loaded is recovered; viability exceeds 98%.

Phase II trial of 5-fluorouracil, adriamycin and cisplatin (FAP) in advanced gastric cancer.

SummaryTwenty patients (15 male, 5 female) with nonresectable gastric adenocarcinoma were treated with FAP (5-fluorouracil 300 mg/m2 IV on days 1–5, adriamycin 50 mg/m2 IV on day 1, cisplatin 20 mg/m2 IV on day 1–5). Each course was repeated every 21 days. Eighteen patients were evaluable for response. The median age was 51 years, the range extending from 34 to 68. None had undergone chemotherapy. The median Karnofsky performance score was 80%. Nine (50%) partial responses (PR) and eight (44%) cases of stable disease (SD) were observed. One patients showed progression of the disease and died after 6 months. The median duration of response was 6+ months for PR and 6 months for SD. The median survival was 12 months. FAP toxicity was moderate, with the median WBC nadir 3.2×109/l (range 0.7–4.2). One patient in PR died of septicemia. Nausea and vomiting were not dose-limiting. Neuropathy was mild in four and moderate in two patients. This FAP combination appears to be as effective with respect to response rate and duration as reported for 5-fluorouracil, adriamycin and mitomycin C (FAM).

Phase II trial of 5-fluorouracil, adriamycin and cisplatin (FAP) followed by radiation and 5-fluorouracil in locally advanced pancreatic cancer

SummaryA total of 19 patients (7 men, 12 women) with locally advanced pancreatic adenocarcinoma were treated with six cycles of FAP (5-fluorouracil, 300 mg/m2 i. v. on days 1–5; Adriamycin, 50 mg/m2 i. v. on day 1; cisplatin, 20 mg/m2 i. v. on days 1–5). Each course was repeated every 28 days. After six cycles, the treatment was followed by irradiation amounting to 4,000 cGy (split course) in combination with 5-FU (500 mg/m2) on days 1–3 of the two irradiation periods. The median age of our patients was 55 years (range, 40–64 years). The median WHO performance status was 1, with a range of 0–2. Three (16%) complete (CR) and six (31%) partial responses (PR) were observed, as were six cases of stable disease (SD) and four of progressive disease (PD). The median duration of response was 11 months, with a range of 4–24 months, and the median survival was 14 months (range, 5–27 + months). FAP toxicity was tolerated fairly poorly. The dose-limiting toxic effect was myelosuppression, with a mean WBC nadir of WHO grade 1.6 (range, 0–3) and a mean platelet count of WHO grade 1.1 (range, 0–4). Nausea and vomiting were not dose-limiting. Complete alopecia was seen in 14/19 patients. Neuropathy was mild (WHO grade 1) in seven and moderate (grade 2) in four. Irradiation in combination with 5-FU was generally well tolerated. Due to several reasons, only ten patients could be treated with all six cycles of FAP. We conclude that in future combined modality studies, irradiation should be given after three cycles of chemotherapy, and that combined modality treatment for locally advanced pancreatic cancer is feasible and warrants further testing.

The immunoglobulins in Hodgkin's disease☆

Abstract Serum immunoglobulin levels IgG, IgA and IgM have been investigated in 51 untreated patients with Hodgkins disease and 102 control persons. In the patients with Hodgkins disease the mean IgG and IgA level was significantly raised (P: 0·0001 for both). The mean IgM level in males was normal and was significantly increased (P: 0·0012 ) in females. The increase in IgA level was the most pronounced among the three immunoglobulins.

Increased antibody-dependent cytotoxicity mediated by purified monocytes in Hodgkin's disease

Monocyte antibody-dependent cytotoxicity was studied in 19 patients with Hodgkins disease and 14 normal controls. This function was investigated after isolation of the monocytes by means of a modified elutriation technique. Direct sizing and counting of the cells present in the effluent enabled individual adjustment during each separation procedure. The absolute monocyte count in the peripheral blood of patients with Hodgkins disease was higher (P less than 0.002) than in normal controls. Nearly 90% pure monocyte suspensions, representing 82% of all elutriated monocytes, were obtained. The elutriation characteristics of the monocytes in both groups were essentially the same, irrespective of marked interindividual differences. Kill of antibody-coated chicken red blood cells was measured by DNA flow cytometry. In comparison to normal controls, a significantly increased (P less than 0.0004), stage-independent, monocyte antibody-dependent cytotoxicity was found in patients with Hodgkins disease. The percentage of kill in symptomatic patients tended to be higher than in the asymptomatic group; no correlation was found with the absolute number of circulating monocytes.

Non-selective lymphocyte isolation from human blood by nylon wool filtration and density centrifugation

A new method was employed to isolate lymphocytes from human peripheral blood. Continuous flow filtration through a nylon wool filter, at a flow rate of 1.4 ml/min, produced a lymphocyte yield of 90.5% and a purity of 96% without any shift in the B-T cell ratio. Ficoll-Isopaque with a specific gravity of 1.085 g/ml instead of 1.077 g/ml could be used to remove the erythrocytes. An overall recovery, including defibrination, filtration, Ficoll-Isopaque centrifugation and washing step, of 74.5% was achieved.

Lymphocyte density distribution profile and spontaneous transformation related to the stage of Hodgkin's disease.

. Density distribution profiles of peripheral lymphocytes were made in 41 untreated patients with Hodgkins disease and in 14 normal controls. The fraction of lymphocytes with a low specific gravity in patients was significantly increased in comparison to normal controls (P= 0.0007). These low density lymphocytes in Hodgkins disease patients showed an elevated spontaneous 3H‐thymidine incorporation compared to normal controls (P < 0.0001). In 78% of the patients the spontaneous DNA synthesis of the low density lymphocytes was above the normal range. A positive correlation (P= 0.002) was found between the spontaneous 3H‐thymidine uptake and the stage of the disease.

Effect of carbogen breathing on the pharmacodynamics of 5-fluorouracil in a murine colon carcinoma

To determine whether carbogen breathing has an effect on 5-fluorouracil (5-FU) uptake, retention and metabolism in C38 murine colon tumours grown in C57Bl/6 mice, we used in vivo 19F nuclear magnetic resonance (NMR) spectroscopy. Eleven tumour-bearing mice were treated with 150 mg/kg of 5-FU given intraperitoneally (i.p.). Five mice received carbogen gas (95% O(2) and 5% CO(2)) for 9.5 min, starting 1 min before 5-FU administration. We found increased levels of 5-FU and its anabolites and catabolites by sequential ¿19F NMR spectroscopy in the group treated with 5-FU in combination with carbogen compared with the group treated with 5-FU alone. The maximum of normalised values of 5-FU and its metabolites, reached after carbogen breathing, was almost 2-fold higher than after treatment with 5-FU alone. Despite these increased concentrations no significant effect of carbogen on growth inhibition of the tumour by 5-FU was observed, which may be related to the size as well as the well vascularised and perfused conditions of the tumours studied.

Growth characteristics of head and neck squamous cell carcinoma in nude mice

Growth behaviour of human squamous cell carcinoma from the head and neck region was studied in nude mice. Tumour growth was observed in 10 out of 13 tumours transplanted with a primary take rate of 77 and 100% for serial passaging. The take rate percentage related to the number of tumour inocula used, varied from 10 to 90% in the first passage and from 70 to 100% in the subsequent passages. No significant difference could be established in the growth character, except from the first to the second passage. Histological studies demonstrated preservation of the original histopathological features, micro- and macroinvasion of two tumour lines into the fibrous capsule and cyst formation. Comparison of growth curves with histological features demonstrated that growth curves are not a reliable measure for the number of vital tumour cells present.