We examined the role of a prostaglandin-producing suppressor cell in the hyporesponsiveness to phytohemagglutinin seen in Hodgkin's disease. Addition of indomethacin to phytohemagglutinin cultures of lymphocytes from six patients with Hodgkin's disease resulted in an increase of 182 +/- 60 per cent in 3H-thymidine incorporation versus a 44 +/- 18% increase in 29 controls (mean +/- S.D., P less than 0.001). Without indomethacin the mean response of the lymphocytes in Hodgkin's disease was 48% of that of control. With indomethacin it was 94% of the control value. Phytohemagglutinin cultures of Hodgkin-disease lymphocytes produced approximately fourfold more prostaglandin E2 after 48 hours than did normal lymphocytes (P less than 0.02). Removal of glass-adherent cells markedly decreased the enhancement seen with indomethacin; it reduced prostaglandin E2 production by more than 80% and eliminated the differences in response to phytohemagglutinin between Hodgkin-disease and normal lymphocytes. Thus, a glass-adherent, prostaglandin-producing suppressor cell is responsible for the hyporesponsiveness to phytohemagglutinin seen with Hodgkin-disease lymphocytes.

A case report and review of the literature of paraplegia following intrathecal chemotherapy with methotrexate and cytosine arabinoside is presented. Autopsy identified damage to the spinal nerve roots within the subarachnoid space, which accounted for the neurologic deficit. The only substances common to both chemotherapeutic agents were their preservatives, methylhydroxybenzoate and benzyl alcohol, which were used, in the diluent. Prolonged exposure to these preservatives is known to cause severe neurotoxicity. Though the specific agent responsible for paraplegia following intrathecal chemotherapy is unknown, there is evidence to suggest that the preservatives rather than the therapeutic agents themselves are responsible.

Bone marrow colony-stimulating factors (CSF) ameliorate hematologic toxicity of standard chemotherapy regimens and may allow relatively safe use of intensive and more efficacious doses of anticancer drugs. Twenty-four patients with cancers for which no standard regimens were likely to be effective received repeated courses of a combination of cisplatin (150 mg/m2), etoposide (1,500 mg/m2), and cyclophosphamide (5,000 mg/m2) at doses for which bone marrow transplantation is usually used. A total of 10 patients received escalating doses of recombinant human granulocyte CSF (rhG-CSF); 11 patients receiving identical chemotherapy and supportive therapy without rhG-CSF served as controls for the first cycle of therapy. Five of these patients and 3 additional patients also served as their own controls, receiving rhG-CSF for all cycles after the first. No patient received bone marrow transplantation. rhG-CSF shortened the median duration of severe granulocytopenia (less than or equal to 100/mm3) in a dose-related fashion (P less than .03; Kruskal-Wallis test). Patients not receiving rhG-CSF had a median of 8.5 days of granulocytopenia. Those receiving 40 micrograms/kg of rhG-CSF for approximately 20 days from the third day after chemotherapy had a median of 7.0 days (P less than .23) and those receiving 60 micrograms/kg had a median of 5.5 days (P less than .007) of granulocytopenia. An rhG-CSF dose of 20 micrograms/kg had no effect. Recovery to a granulocyte count of at least 500/mm3 took a median of 12 days in the control group and 8 days (P less than .03) in patients receiving rhG-CSF at a dose of 60 mg/kg. The duration of antibiotic therapy (a median, 9.0 days v 5.0 days) was shortened with the two higher and effective doses of rhG-CSF compared with control patients. The duration of hospitalization (median of 20 days v 19 days) was not shortened. These findings that rhG-CSF decreases the risk of granulocytopenia associated with this particular dose-intensive chemotherapy regimen therapy administered without bone marrow transplantation.

The term soft tissue sarcoma refers to a large variety of malignant tumors arising in extraskeletal connective tissues that connect, support, and surround discrete anatomic structures. All visceral organs also contain a connective stroma that can undergo malignant transformation. Because of the histological similarities of this group of tumors and their relative rarity, treatment prescriptions for patients that have disseminated disease are most often uniform. In this study, we asked the question whether adding a third drug (cyclophosphamide or actinomycin D) to Adriamycin (Adr [Adria Laboratories, Columbus, OH])-(3,3-dimethyl-1-triazeno)- imidazole-4-carboxamide (DTIC) would improve the response rate and/or survival. A unique feature of this cooperative group clinical trial was the mandatory pathology review of the histological material. All patients of the Southwest Oncology Group between June 1, 1976, and November 17, 1979, who had a biopsy-confirmed diagnosis of a soft tissue sarcoma with convincing clinical or biopsy-documented evidence of metastatic disease were eligible for the study. Patients were randomized to receive (1) Adr, 60 mg/m2 intravenously, day 1, and DTIC, 250 mg/m2 every 3 weeks (104 patients); (2) Adr and DTIC as in (1) and cyclophosphamide, 500 mg/m2, day 1 (112 patients); or (3) Adr and DTIC as in (1) and actinomycin D, 1.2 mg/m2, day 1, (119 patients). There was no statistically significant difference in response rates (33%, 34%, and 24%) (P = .25). Median durations of response were 31 weeks in the Adr-DTIC arm, 26 weeks in the cyclophosphamide-DTIC-Adr arm, and 23 weeks in the Adr-DTIC-Actinomycin D arm (P = .78). Median durations of survival were 37, 42, and 50 weeks, respectively. Again, no statistically significant differences were observed (P = .59). Toxicities from each of these treatment arms were formidable and were equivalent. Prognostic factor analysis showed a prognosis based on bone marrow reserve, sex, and pathology subtype favorable to patients.

Previous studies showed that downregulation of pyrimidine salvage underlies resistance against 5-azacytidine (AZA), indicating an important role for de novo pyrimidine synthesis in AZA resistance. Because de novo pyrimidine synthesis is inhibited by the immunomodulator teriflunomide and its pro-drug leflunomide, we examined the effect of combined treatment with AZA and teriflunomide on AZA resistance to develop a novel strategy to cancel and prevent AZA resistance. Teriflunomide markedly inhibited the growth of AZA-resistant human leukemia cell lines (R-U937 and R-HL-60) in comparison with their AZA-sensitive counterparts (U937 and HL-60). In the presence of a non-toxic concentration of teriflunomide (1 μM), AZA induced apoptosis in AZA-resistant cells and leukemia cells from AZA-resistant patients. AZA acted as a DNA methyltransferase 3A inhibitor in AZA-resistant cells in the presence of 1 μM teriflunomide. Although AZA-sensitive cells acquired AZA resistance after continuous treatment with AZA for 42 days, the growth of AZA-sensitive cells continuously treated with the combination of AZA and teriflunomide was significantly inhibited in the presence of AZA, demonstrating that the combined treatment prevented AZA resistance. These results suggest that combined treatment with AZA and teriflunomide can be a novel strategy to overcome AZA resistance.