O. Ross McIntyre

Clinical studies of dichloromethotrexate (NSC 29630)

Dichloromethotrexate (DCM) is much superior to methotrexate (MTX) in inhibiting L1210 leukemia and C3H lymphosarcoma in mice. This greater effectiveness obtains for parenterally administered DCM and is much less apparent when DCM is given by mouth. The toxicity of DCM in animals is qualitatively similar to that produced by MTX. DCM is fifty to one hundred fold less toxic than MTX in rats and mice but only tenfold less toxic in dogs. It is concluded from clinical studies reported in this paper that: (1) The tolerated dose of DCM is fivefold that of MTX and the toxic manifestations are similar. (2) The tolerated doses of oral and iniramuscular DCM are equivalent. (3) Equitoxic, and presumably optimal, doses of oral DCM, oral MTX, and intramuscular DCM produce comparable antitumor effects in adults with lymphosarcoma and Hodgkins disease. There is complete tumor regression in 10 to 20 per cent and partial regression in another 20 to 30 per cent of patients. These tumor regressions are, in general, short‐lasting. (4) The dose response relationship is steep. A twofold difference in dose of DCM or MTX results in a significant difference in toxicity and antitumor effect. (5) There are at least four other more effective modalities of treatment for lymphoma which should be employed before conventional folic acid antagonist therapy is considered.

Biologic properties of E myeloma proteins

Abstract E myeloma protein PS (PS protein) from the serum of the second known patient (P.S.) with IgE myeloma was purified by DEAE-cellulose column chromatography and Sephadex ® G-200 gel filtration. The physicochemical properties of this protein were identical with those of E myeloma protein ND (ND protein) from the first patient with IgE myeloma; however, double immunodiffusion studies revealed distinct idiotypic antigenic determinants probably belonging to the Fd portion of the molecule in both E myeloma proteins. Patient P.S. failed to accept passive sensitization with reaginic antibodies (the Prausnitz-Kustner reaction) and reacted only to the intradermal injections of high concentrations of antilgE (the reversed Prausnitz-Kustner reaction). He was capable of reacting normally to the intradermal injection of histamine. It is postulated that the absence of passive sensitization with reaginic antibodies was due to saturation of IgE-fixing sites of target cells with E myeloma protein. The impaired reversed Prausnitz-Kustner reaction may be explained by failure of the injected anti-IgE to react with cell-fixed IgE because of the presence of an excessive amount of E myeloma protein in extracellular fluid. Histamine release from the patients leukocytes by treatment with anti-IgE was studied. Studies of IgE metabolism were also made, using 125 I-PS protein and 131 I-ND protein. The metabolic parameters of both proteins were identical, with a half-time of 5.1 days and fractional catabolic rate of 16 per cent in patient P.S., in contrast to 2.5 days and 89 per cent, respectively, in normal subjects.

Fetal Group C Trisomy After Cytosine Arabinoside and Thioguanine

Excerpt In contrast to the conclusion in the recent letter by Pawliger, McLean, and Noyes in the June 1971 ANNALS OFINTERNALMEDICINE(p. 1012), we cannot conclude that cytosine arabinoside is a rela...

Palpable spleens: ten-year follow-up.

Excerpt To the editor: In 1967 we reported that 63 of 2200 (2.9%) freshmen at Dartmouth College had a palpable spleen at the time of routine physical examination (1). Fifty-eight of the students we...

Spontaneous regression of malignant melanoma: Pathologic and immunologic study in a ten year survivor☆☆☆

Abstract A gradual decrease in lymphocyte blastogenesis to autologous tumor cells was observed in a patient with an eight year history of metastatic cutaneous malignant melanomas. The appearance of visceral metastases was associated with a complete loss of lymphocyte reactivity in the mixed leukocyte-tumor cell assay. Simultaneously the marked infiltration of lymphocytes and plasma cells disappeared from the tumor nodules. This change in host response to autologous tumor was not associated with a generalized deterioration of the patients immune responsiveness. These findings suggested the gradual emergence of a new cell line which was less antigenic than that of the original tumor. A serum factor that augmented lymphocytotoxicity disappeared after the emergence of visceral metastases.

Anti-keyhole limpet hemocyanin antibody in normal unsensitized individuals

Antibody to keyhole limpet hemocyanin (KLH) has been detected in normal unimmunized subjects by means of a sensitive micropassive hemagglutination technique. Prior sensitization was not detected by either skin testing or lymphocyte transformation. After immunization with KLH there was no correlation between the level of this antibody and subsequently acquired skin test reactivity and lymphocyte transformation.

Chromosomal aberrations and neoplasm—a family study

A family is described in which four out of five siblings have chromosomal aberrations both in the myeloid and lymphoid cells. One of these died in the blastic phase of chronic myelogenous leukemia, another had myelofibrosis and carcinoma of the breast, a third had squamous cell carcinoma of the lip, and the other two siblings are normal. The mother had carcinoma or the breast. Two of the siblings have had occupational exposure to organic solvents. The relationship of genetic pre‐disposition to malignancy, chromosomal instability, and environmental stresses is discussed.

Procoagulant Synthesis by Cultured Fibroblasts triggered by Cell Adhesion

SYNTHESIS of a potent procoagulant by cells in tissue culture has been demonstrated but its identity is obscure1. Activity is low at the beginning of culture of normal human fibroblasts and increases several hundred-fold after 12–24 h of incubation at 37° C. This increase is readily detected by the one-stage assay for factor VIII (antihaemophilic globulin) but can also be demonstrated by the two-stage factor VIII assay based on the thromboplastin generation test. Studies in progress to characterize this procoagulant have demonstrated a marked increase of factor XI as well as factor VIII activity and evolution of factor XI activity during contact activation with celite. Increase in activity detectable in the one-stage assay for factor IX and XII was much less. The procoagulant was incapable of clotting a fibrinogen solution and no change in assays for factor V and VII was observed during culture.

Comparison of oral melphalan, CCNU, and BCNU with and without vincristine and prednisone in the treatment of multiple myeloma. Cancer and leukemia group B experience

A total of 361 evaluable patients with previously untreated multiple myeloma were randomized to receive oral melphalan (0.15 mg/kg/day for seven days, followed by 0.05 mg/kg/day after recovery from the nadir of the leukocytes), BCNU (150 mg/m2 intravenously every six weeks) or CCNU (100 mg/m2 orally every six weeks). All patients received a tapering six‐week course of prednisone starting at 0.8 mg/kg for the first two weeks. At week 22, one‐half of the patients were randomized to receive vincristine (1 mg/m2) and prednisone (0.6 mg/kg for seven days) every two months in addition to previous therapy. The melphalan treated patients showed a significantly higher overall objective response frequency (59%), according to Myeloma Task Force criteria, when compared to those treated with BCNU (40%) or CCNU (42%). The survivals for all patients were not statistically different for the three treatment programs. However, the good‐risk patients treated with melphalan had significantly longer survival (P = 0.02) than the equivalent patients who received BCNU or CCNU. The addition of vincristine and prednisone at week 22 did not significantly increase the percentage of subsequent objective responses or prolong the subsequent survival of any treatment group. It is concluded that oral melphalan is superior to BCNU and CCNU in producing objective responses and in prolonging survival in good risk patients. Cancer 50:1669‐1675, 1982.

Reduced tissue factor (thromboplastin) activity in von Willebrand's disease

Abstract Identification of tissue factor in cultures of human skin fibroblasts permitted assessment of tissue factor activity in patients with bleeding disorders. Tissue factor activity was studied by means of a one-stage assay patterned after the prothrombin time and a two-stage test in which activation of factor X by tissue factor in the presence of factor VII was assessed. Tissue factor activity observed in cultured skin fibroblasts from five subjects with hemophilia A and B was not significantly different from that observed in pooled fibroblasts from normal controls. By contrast, tissue factor activity in cultured skin fibroblasts from four subjects with von Willebrands disease was significantly lower than that in the control. It is postulated that the observed tissue factor defect may be related to the pathogenesis of von Willebrands disease.