D. J. Theo Wagener

Sequential non-cross-resistant chemotherapy regimens (MOPP and CAVmP) in Hodgkin's disease stage IIIB and IV

Fifty consecutive patients with advanced Hodgkins disease were treated in a multicentre study with 6 cycles of an alternating scheme of MOPP and CAVmP followed by irradiation to a dose of 20 Gy. The objective was to increase complete remission (CR) and cure rates by alternating two effective noncross‐resistant regimens with subsequent consolidation of the remission by irradiating bulky nodes. A total of 47 patients completed the treatment and are evaluable. In the first 13 patients the irradiation fields amounted to a total or subtotal nodal irradiation with inclusion of the spleen. In case of organ involvement the affected organ was also included in the irradiation field. The irradiation protocol was later changed to an irradiation of the initially involved sites because of severe leucopenia and thrombopenia. After completion of the chemotherapy 32 (68%) patients (for Stage IIIB and IV patients: 63% and 71%, respectively) achieved a CR, after ending the radiotherapy the percentage of CR increased to 87% (for stage IIIB and IV patients: 90% and 86%, respectively). Five of the patients relapsed in an irradiated and nonirradiated area, three patients in a nonirradiated field. The actuarial 3‐year survival rate for the entire group was 86% and for patients in CR 94%. The relapse‐free survival was 73%. It is concluded that this alternating chemotherapy scheme followed by irradiation is at least equally effective as MOPP treatment in achieving a CR, and is probably superior in terms of survival.

The influence of splenectomy on the in vitro lymphocyte response to phytohemagglutinin and pokeweed mitogen in Hodgkin's disease

Using tissue culture techniques, the 14C‐thymidine incorporation of peripheral lymphocytes in 17 Hodgkins patients was tested before and after splenectomy under stimulation with phytohemagglutinin and pokeweed. Incorporation under phytohemagglutinin stimulation about 10 days after splenectomy was not affected in Hodgkins patients with pathologic Stages I and II, but was significantly (p < 0.005) increased in those with Stages III and IV. The total PHA stimulation potency, i.e. the product of the lymphocyte count and PHA stimulation, increased slightly in both groups. Incorporation under pokeweed stimulation after splenectomy did not significantly differ from that before the operation in the two groups. Although the number of cases studied is rather small, it is concluded that splenectomy causes no demonstrable untoward effect on the cellular immunologic potency. The immunologic state is more likely to be favorably influenced than unfavorably.

Hypothyroidism and goiter in a patient during treatment with interleukin-2

The development of transient hypothyroidism and goiter in a patient with a metastasized malignant melanoma during treatment with recombinant interleukin‐2 (rIL‐2) and dacarbazine is reported. Signs of autoimmune thyroiditis became apparent 2 weeks after the start of treatment and disappeared after treatment stopped. It is likely that rIL‐2 was responsible by interfering with preexisting autoimmune thyroid disease. The possible mechanisms are discussed here. Patients with positive antithyroid microsomal antibody titers are prime candidates for rIL‐2‐induced thyroiditis.

Phase II trial of cisplatin for adenocarcinoma of unknown primary site

Abstract The activity of cisplatin against advanced metastatic adenocarcinoma of unknown primary site (ACUP) was evaluated in 21 patients. Cisplatin (100 mg/m 2 ) was given as a 4-h continuous infusion every 3 weeks, with appropriate fluids and diuretics. The overall response rate was 19% with 1 complete remission for 12 months and 3 partial remissions lasting from 4 to 7 months. 7 patients achieved stable disease and in 9 patients the disease was progressive. The median duration of response was 6.5 months. The median survival 7.5 months. The median survival of the total patient group was 5 months (range 1–18 months). Toxicity comprised mainly nausea and vomiting, mild creatinine elevation and leukocytopenia. Slight ototoxicity was observed in 6 patients.

The influence of splenectomy on cellular immunologic parameters in Hodgkin's disease.

Cellular immunity was evaluated in 15 untreated patients with Hodgkins disease before and about 10 days after splenectomy. Skin test‐reactivity was not affected by the operation. The number of lymphocytes was moderately increased in patients with pathologic stage I and II disease. The relative proportion of E‐binding lymphocytes in the peripheral blood diminished significantly (p =.001) in patients with splenic weights of 240 g and more, whereas the PHA‐stimulated thymidine incorporation increased significantly (p =.015) and the proportion of EAC‐binding lymphocytes increased significantly (p =.023). The PHA‐stimulation of peripheral lymphocytes in patients with pathologic stage I and II disease was at the same level before and after operation, but increased significantly (<0.02) in the more disseminated forms. The stimulation of the lymphocytes in vitro by a cocktail of antigens, and by allogeneic cells (MLC) remained unchanged. Although the number of cases studied is rather small, it is concluded that about 10 days after, splenectomy has no demonstrable untoward effect on the cellular immunologic potency.

Pharmacokinetics of the antitumor antibiotic n-pentyl-sparsomycin in beagle dogs

SummaryN-pentyl-sparsomycin (PSm) is a lipophilic analogue of sparsomycin (Sm), which is a well known inhibitor of protein synthesis. This compound was selected for preclinical pharmacokinetic studies because of its high in vitro and in vivo antitumor activity. In this study in which the drug was evaluated in beagle dogs under anaesthesia, the drug concentrations in plasma, urine and bile samples were determined using high performance liquid chromatography (HPLC). Plasma protein binding was approximately 54%. The mean t1/2 β was 0.2 hours (12 minutes) and t1/2 τ was 0.75 ± 0.1 hours (45 ± 6 minutes). During continuous infusions up to 5.25 hours, the steady state was reached in 3 out of 6 experiments, suggesting that in some cases the real t1/2 τ was longer than measured. PSm was actively reabsorbed from the renal tubuli. This process was saturable at the higher doses. Tubular reabsorption played only a minor role in pharmacokinetics as most of the drug (67%) was eliminated by the non-renal clearance. The non-renal clearance was saturable at higher doses of PSm and was the reason for non-linearity of pharmacokinetics.

Total serum haemolytic complement activity, erythrocyte sedimentation rate and plasma fibrinogen as indicators of the stage in Hodgkin's disease

Abstract. Total serum haemolytic complement activity, plasma fibrinogen, erythrocyte sedimentation rate and other biological values in forty‐three patients with Hodgkins disease were correlated with results of staging.

In vivo antitumor activity of sparsomycin and its analogues in eight murine tumor models.

SummarySparsomycin (Sm) is a known inhibitor of ribosomal protein synthesis with an attractive anticancer potential. Recently, several analogues of Sm which are more active than the parent drug were selected for further study on the basis of in vitro investigations. Six analogues as well as the parent drug were tested for their antitumor activity in eight in vivo murine tumor models: P388 and L1210 leukemias, RC renal cell carcinoma, B16 melanoma, C38 colon carcinoma, LL Lewis lung carcinoma, C22LR osteosarcoma and M5076 sarcoma. Sm itself appeared to have only borderline activity on L1210 leukemia. The analogues that were most active in vitro showed also the highest in vivo activity. The most sensitive tumors were RC, L1210 and P388. Minimal activity was found on B16 and no activity on C22LR, M5076, C38 and LL. The most active compounds are deshydroxy-Sm, ethyl-deshydroxy-Sm and n-pentyl-Sm. There was a considerable loss of activity when L1210 leukemia was implanted sc while the drugs were administered iv. Only one drug, ethyl-deshydroxy-Sm appeared to be active in this assay. No single most effective compound could be found in this study. The overall activity of Sm and its analogues is moderate. The three analogues which show high activity in three ascitic tumors will be further investigated using human tumor xenograft models.

High spontaneous thymidine incorporation into a non-T lymphocyte population in Hodgkin's disease unmasked after cell fractionation.

In order to study the nature of the spontaneously stimulated cells in Hodgkins disease, lymphocytes from 10 patients with Hodgkins disease and 10 healthy control subjects were separated into low‐ and high‐density fractions. Both fractions were subdivided into T and non‐T cell populations by means of rosette sedimentation. In Hodgkins disease patients, non‐T cells with a high density showed a significantly increased spontaneous thymidine incorporation (mean, 5677 cpm; range, 405–26490 cpm) compared to corresponding cells from control subjects (mean, 484 cpm; range, 235–850 cpm), and to unseparated high‐density lymphocytes in Hodgkins disease patients. Evidence is presented that in Hodgkins disease, the high‐density lymphocyte fraction comprises non‐T cells with an apparent potency for DNA synthesis which is, however, inhibited by T cells present in the same high‐density fraction.

In vivo potentiation of cis-diamminedichloroplatinum (II) antitumor activity by pretreatment with sparsomycin

The influence of protein synthesis inhibition by sparsomycin (Sm) on in vivo cisplatin activity has been studied on BALBc X DBA2: F1 mice bearing L1210 leukemia i.p. Sm alone at the dose range from 0.5 to 3.0 mg/kg did not significantly improve animal survival. Sm potentiated cisplatin activity only when given 3 or 6 h prior to cisplatin (P less than 0.001). Sm 0.5-1.5 mg/kg 3 h prior to cisplatin resulted in a significant prolongation of animal survival (P less than 0.001) and 66% cures in each group versus 0% due to cisplatin alone. Sm pretreatment decreased weight loss due to cisplatin suggesting that it probably is able to decrease cisplatin toxicity.