No abstract

Substantial amounts of both dopamine and norepinephrine in addition to serotonin were found in a mesenteric metastasis of an ileal carcinoid tumor. Correspondingly, the norepinephrine-synthesizing enzymes were present in the tumor tissue and tyrosine hydroxylase was found in amounts substantially higher than the levels normally present in adrenal medullary cells. These findings confirm that the carcinoid tumors belong to the APUDomas and indicate that catecholamines might play an important role in the pathogenesis of the carcinoid syndrome.

The macrophage activator muramyl tripeptide-phosphatidyl ethanolamine (MTP-PE) was infused in liposomal form in 14 metastatic cancer patients (4 mg i.v. during 30 min twice weekly for 12 weeks). Clinical, pharmacokinetic and immunological parameters were studied before and 0.5, 2, 4, 24 and 72h after start of drug infusion in week 1, 4, 8 and 12. No tumor regressions were seen. Tumors progressed in 11 patients, in 4 of them within 2 months; 3 patients had stable disease. The intensity and frequency of side effects (fever and nausea) diminished from week 1 to 12. The rate of disappearance of total and free MTP-PE from blood was rapid and mean serum concentration-time curves remained unchanged throughout 12 study weeks. MTP-PE caused a marked increase of serum TNFa, IL-1 receptor antagonist (IL-1ra) and IL-6 in week 1, but not thereafter. In contrast, MTP-PE caused a persistent, 2-fold increase in serum neopterin and young forms of granulocytes (bands) during week 1 to 12. Before therapy, monocyte tumor cytotoxicity and in-vitro monocyte derived TNFa, IL-1 beta and IL-6 production were low in 9 patients (group L, < 15%) and high in 5 patients (group H, > 40%). Monocyte cytotoxicity and in-vitro cytokine production was transiently enhanced in week 1 in group L, it declined under therapy in group H. In conclusion, MTP-PE induced marked initial immunomodulation; the extent of the ex vivo monocyte cytokine and tumor cytotoxic response was dependent on pre-therapy cell activity. A decrease of the cytokine and IL-1ra response during prolonged therapy contrasted with a persistent increase of neopterin and juvenile blood granulocytes. The long lasting biologic effects may be relevant to direct future clinical studies with liposomal MTP-PE in an adjuvant setting.

Immunologic parameters were examined preoperatively in 104 patients with breast cancer, staged according to the TNM classification and in 95 age‐matched healthy women. The immunologic evaluation in the peripheral blood included lymphocyte and monocyte counts, determination of E‐rosette‐forming T‐lymphocytes (SER+) and B‐lymphocytes (MER+), T‐lymphocyte subsets defined with monoclonal antibodies (Leu‐1, Leu‐2a, Leu‐3a) and with lectin fractionation (soybean agglutinin), lymphocyte transformation test with phytohemagglutinin (PHA) and concanavalin A (ConA), and colony formation of T‐lymphocytes in agar (T‐lymphocyte colony‐forming cells, [TL‐CFC]). Two age groups (Group A: 30–50 years; Group B: 51–70 years) and the different tumor stages (Stage I‐IV) were analyzed. Patients and controls did not differ in the absolute numbers of lymphocytes, T‐ and B‐cells. In patients of Group B, the absolute number of monocytes was increased slightly in Stage II and III and significantly in Stage IV (P < 0.05). Similarly, the lymphocyte response to PHA was significantly reduced in Stage IV Group B only (P < 0.05). ConA‐induced lymphocyte proliferation and TL‐CFC capacity were not different in patients and controls. In the small number of patients and age‐matched controls in whom T‐lymphocyte subsets were determined, the absolute numbers of T‐cells with helper or suppressor phenotype as defined with Leu‐3a, Leu‐2a, or lectin fractionation with soybean agglutinin were similar. This study demonstrates that in patients with early breast cancer (Stage I‐III), immunocompetence as defined by either functional in vitro studies or surface marker analysis is not significantly altered at the time of diagnosis. In contrast, patients with advanced disease (Stage IV) show a significant increase in the absolute number of monocytes and a depressed PHA responsiveness of mononuclear cells.

Conjugates of the chemotactic peptide fMet-Leu-Phe (fMLP) to IgG retain chemotactic and antigen recognition function in vitro and enhance intra-tumour macrophage numbers in a guinea pig model. We report a study approved by the ethics committee on the acute toxicity of fMLP conjugates in ten consenting cancer patients with metastasizing melanoma and colon cancer. They were given increasing single doses (1-2500 micrograms) IgG-fMLP made with the anti-melanoma monoclonal antibody (mAb) 9.2.27. Clinical examinations and blood cell counts, urinalysis, electrolytes, and liver and kidney function tests before and after the infusion and weekly thereafter revealed no relevant toxicities. One patient had a herpes zooster exacerbation on day 1, which was judged to be coincidental. Peak post-infusion conjugate serum concentrations fell to unmeasurable levels within a few days. In no case was a human humoral anti-(mouse Ig) immune response detected.