We report the results of an expanded trial of 5-fluorouracil (5-FU) combined with high-dose folinic acid for treatment of patients with advanced colorectal or advanced gastric adenocarcinoma. In each treatment course, the patients received both 5-FU (340 to 400 mg/m2/d by intravenous (IV) infusion for a period of 15 minutes) and folinic acid (200 mg/m2/d by IV bolus) for 5 consecutive days, with a 21-day interval between courses. Eighty-six patients with colorectal carcinoma were evaluated. The combined complete and partial response rates were 39% for 54 patients who did not receive prior chemotherapy and 22% for 32 patients who had previously received chemotherapy. Four patients who were previously resistant to 5-FU attained objective responses. The median time to disease progression for the 28 responders was 10 months. The median survival time of responders was 19.5 months, and the probability of their being alive at 2 years was 40%. Of 27 patients with gastric adenocarcinoma, 13 (48%) responded to therapy. Their median time to disease progression was 5.5 months. The median survival time of responders was 11 months, and their probability of being alive at 15 months was 30%. Toxicity was within acceptable limits. Toxic effects included stomatitis, diarrhea, conjunctivitis, skin rash, and mild myeloid hypoplasia. In a separate study, plasma concentrations of L-folates greater than 10(-5) mol/L were achieved after a rapid single IV injection of 200 mg/m2 of folinic acid. Comparisons of our results with those reported in previous studies on 5-FU administered as a single agent suggest that, in advanced colorectal and gastric adenocarcinoma, folinic acid administered in high doses enhances the effectiveness of 5-FU administered concomitantly. Furthermore, some colorectal tumors that were previously resistant to 5-FU become sensitive to this drug. The survival of the patients who responded to therapy was markedly improved over that observed in reported series of untreated patients with advanced colorectal and gastric adenocarcinomas.

No abstract

Summary: Aliogeneic bone marrow grafts carried out after previous administration of antilymphocytic serum alone were attempted in 16 patients. Of these, six had acute myeloblastic leukaemia, four acute lymphoblastic leukaemia, and one a blast cell crisis in polycythaemia vera. Ten of these patients were in an overt phase of the disease and resistant to chemotherapy, while nine had complete agranulocytosis. In five of these patients erythrocyte and leucocyte antigenic markers demonstrated the establishment of the graft. One patient had thalassaemia major, and four others had aplasia of the bone marrow, in one case due to chloramphenicol poisoning and in another to virus hepatitis. The grafts were successful in the last two patients and transformed their clinical condition.No signs of early acute secondary disease were noted in any of the patients, either when the donor had been given antilymphocytic serum or when he was untreated. The grafts had no adoptive immunotherapeutic effect on the acute leukaemia. These observations have clearly shown that antilymphocytic serum has an immunosuppressive effect in man when it is used alone.

A patient suffering from acute lymphoblastic leukemia in the third progressive phase, refractory to the majority of available treatments, was given total-body irradiation of 800 r. dosage, after administration of methyl-nitro-imidazolyl-mercaptopurine (300 mg. daily for 4 days). One week after irradiation, he received an infusion of a mixture of equal parts of bone marrow from six donors (mother, sister, father and three brothers), a total of 5.8 x 1010 nucleated cells. Myeloid restoration began 2 weeks after the infusion and continued to progress rapidly. The reality of the graft was demonstrated by study of the erythrocytic antigens. Nearly all the erythrocytes found in the blood after 6 months belonged to the phenotype of one of the male donors. Studies of chromosomes and leukocyte sex chromatin suggested that a small proportion of leukocytes were being produced by the cells of one of the female donors. The patient was found to produce beta 2A, beta 2M and gamma globulins of the Inv type of the donors, suggesting that lymphoid cells may also have been successfully grafted. A skin graft from the male donor whose marrow graft had apparently been accepted was still perfectly intact 7 months after grafting, whereas the grafts from other donors were rejected, indicating a specific tolerance to tissues from this donor. Previous studies of compatibility between the recipient and the various donors by a histocompatibility test described by us, or by means of similarities in leukocyte antigens, indicated that the accepted donor had been antigenically more nearly compatible than the others. What appeared to be a secondary syndrome became manifest 1 week after marrow transfusion; it consisted of weight loss, digestive disorders (anorexia, nausea, vomiting, diarrhea), hepatic disturbances (hepatomegaly, increased serum concentrations of various enzymes), transient polyadenopathy (histologically composed of histiocytic proliferation and lymphocytic aplasia), desquamative erythrodermia, eosinophilia exceeding 50 per cent, and superinfection (including a probable miliary tuberculosis). The syndrome was controlled by careful symptomatic treatment; its intensity gradually abated. Reactivation of the secondary syndrome was accomplished by reinjection of leukocytes from the donor whose graft had been tolerated. This was controlled by Δ-1-cortisone and symptomatic treatment. The patient was still alive and in apparently complete hematologic remission from the leukemia 12 months after the treatment described above. Particular reasons for this success possibly include the absence of previous blood transfusions and the use of multiple marrow donors.