Joseph E. Sokal

Lymphocyte response to phytohemagglutinin in Hodgkin's disease*

The in vitro response of lymphocytes to phytohemagglutinin (PHA) was correlated with various clinical features in seventy-eight patients with Hodgkins disease. PHA response was normal among patients in remission, except in a few instances in which depression could be attributed to antecedent radiation or chemotherapy. PHA response varied greatly among patients with active Hodgkins disease and appeared to be affected by a variety of factors related to the disease and to treatment. Radiation therapy induces a profound but temporary depression of lymphocyte response to PHA. Chemotherapy for Hodgkins disease also depresses lymphocyte responsiveness to this agent, but less markedly and less consistently than radiation. We conclude that measurement of lymphocyte response to PHA does not provide a dependable assessment of a patients immunologic competence or clinical status and that further investigation is needed to define the clinical significance of this laboratory test of lymphocyte behavior.

Antagonism between the effects of insulin and glucagon on the isolated liver.

Antagonism was demonstrated between the effects of insulin and glucagon, added simultaneously to the perfusing blood, on phosphorylase activity, glucose output and urea production of the isolated rat liver. However, the degree of antagonism varied greatly, according to the action under study, and there appeared to be a clear-cut hierarchy in the effects of each hormone. For glucagon, this was (stimulation of): (1) phosphorylase activity, (2) glycogenolysis and glucose release, (3) urea production. For insulin, it was (inhibition of): (1) urea production, (2) glycogenolysis, (3) phosphorylase activation. Thus, high concentrations of insulin completely failed to inhibit the phosphorylase activation induced by 1.4 mμg./ml. of glucagon, while modest concentrations of insulin totally suppressed the stimulation of urea production induced by sustained glucagon concentrations at least ten times greater, and well above the biologic range. Our findings argue against a single common primary site of action of these two hormones.

A Simplified Technique for in Vitro Studies of Lymphocyte Reactivity

Summary In vitro studies of lymphocyte reactivity to mitogens, soluble antigens and homologous cells were performed by diluting whole blood with culture medium and using 24-hr labeling with 3H-thymidine. Sensitivity, reproducibility and correlations with delayed skin test responses of the blood donors were superior to those obtained with conventional techniques using lymphocyte concentrates. At appropriate reactive cell densities, supplementation of the culture medium with agents such as fetal calf serum has not been necessary. This simplified technique offers considerable savings in effort, cost and volumes of blood required.

Splenectomy for hematologic depression in lymphocytic lymphoma and leukemia

Fifty patients with lymphocytic lymphoma and chronic lymphocytic leukemia underwent splenectomy for various combinations of anemia, thrombocytopenia, and leukopenia. All of these patients had advanced lymphoproliferative disease, and most had infiltration of bone marrow by neoplastic cells. Good response in all hematologic parameters was obtained in 27 of 48 evaluable patients. An additional 13 patients responded in one or two parameters; there were only 8 complete failures. The over‐all surgical mortality was 8%. The median duration of response was 4 months, and the mean, 7 months. Increased tolerance to further antitumor therapy and a decreased transfusion requirement were seen among responding patients. Those patients with anemia who had evidence of shortened erythrocyte survival and splenic sequestration of 51Cr‐labelled erythrocytes uniformly responded with rises in hemoglobin. However, half of the patients with negative splenic sequestration also showed improvement of anemia. Preoperative diagnostic studies failed to predict favorable responses of patients with thrombocytopenia or leukopenia. The classical criteria for the diagnosis of hypersplenism are not applicable in many cases of neoplastic lymphoproliferative disease; splenectomy could have been considered “contraindicated” in most of the patients in this series. We conclude that splenectomy is worth undertaking in patients with lymphoproliferative disease complicated by hematologic depression regardless of marrow findings or the results of other diagnostic studies.

Cardiac involvement in lymphosarcoma and reticulum cell sarcoma

Abstract Cardiac involvement was found at autopsy in 15 per cent of 170 patients who died of lymphosarcoma and in 27 per cent of 41 patients who died of reticulum cell sarcoma. The heart and epicardium were involved more frequently than the pericardium, which suggests that cardiac lesions arise from hematogenous dissemination rather than by direct extension from mediastinal tumor masses. Pericardial effusion appeared to be associated with myocardial and epicardial infiltration rather than with pericardial involvement; the presence of bloody pericardial fluid suggested infiltration of the epicardium. Except for pericardial friction rub and clinically demonstrable pericardial effusion, there were no clinical or electrocardiographic manifestations which represented reliable signs of cardiac involvement.

IMMUNOTHERAPY OF CHRONIC MYELOCYTIC LEUKEMIA: EFFECTS OF DIFFERENT VACCINATION SCHEDULES*

In a clinical trial of immunotherapy in chronic myelocytic leukemia, 62 patients received repeated intradermal injections of BCG‐cultured cell mixtures, while 16 were vaccinated with BCG alone. The lymphoblastoid cell lines used for vaccination were established from blood of patients with advanced myeloid leukemia and were reactive with “specific” primate antisera against myeloid leukemic cells. Both sensitization to target cell antigens and substantial general increases in delayed hypersensitivity responses were recorded among immunized patients. Major immunologic complications (hypersensitivity and “autoimmune” phenomena) were observed in 10 patients. These complications were attributable to the BCG content of vaccines, and their incidence correlated with intensity of immunologic stimulation.

Spontaneous remission of leukemic lymphoproliferative disease

Spontaneous remission was observed in 4 of approximately 400 patients with chronic lymphocytic leukemia or malignant lymphoma with leukemic manifestations. Findings prior to spontaneous remission in these patients included generalized lymphadenopathy and splenomegaly. In one patient, the remission followed an acute (presumably viral) infection. Relapse of disease after spontaneous remission, characterized by lymphadenopathy and tissue infiltration only, without lymphocytosis or bone marrow involvement, was seen in one patient with chronic lymphocytic leukemia and one with leukemic lymphosarcoma. Seven well‐documented cases of spontaneous remission in leukemic lymphoproliferative disease were found in a survey of the literature. The patterns of normalization of the peripheral blood count seen in the pooled cases included both rapid declines of lymphocyte counts, consistent with active destruction of leukemic cells, and very slow decreases which suggested that the mechanism of remission was cessation of production of leukemic cells, with their subsequent disappearance at a rate consistent with their known long life span. Only one death from lymphoproliferative disease is recorded among these pooled cases.

In Vitro Lymphocyte Response to Autologous Cultured Lymphoid Cells

Summary Circulating lymphocytes from five normal individuals and from five patients with neoplastic disease were unequivocally stimulated by irradiated cultured lymphoid cells of lines established from the same donors. This reaction suggests that there is an antigenic disparity between these two types of cells. It is possible that the surface antigens of lymphoid cells may change during multiplication in an in vitro environment.

Chemotherapy of the terminal phase of chronic myelocytic leukemia with combinations of colchicine derivatives and purine analogs

Abstract Forty-six patients in the terminal phase of chronic myelocytic leukemia were treated with combinations of desacetylmethylcolchicine or trimethylcolchicinic acid and 6-mercaptopurine or 6-thioguanine. The drugs were taken by mouth, in dosages intended to avoid severe granulocytopenia. The combinations were generally well tolerated and platelet and granulocyte counts were usually above life-threatening levels, permitting 57% of the patients to be treated principally as out-patients. Complete hematologic and clinical response was achieved in six patients (13%) and partial response was obtained in 18 (39%). There were no karyotypic remissions. Median survival for the 24 responders was 8 months, while that for the 22 patients who had no response or only minor improvement was 4 months. Survival was as good among patients with partial remission as among those with complete response.

Immunologic deficiency in Hodgkin's disease.

Hodgkins disease is characterized by a selective immunologic defect, progressive loss of cellular immune responses, while antibody production is maintained at normal or near-normal levels. Table 1 summarizes several studies of antibody production in typical populations of patients with Hodgkins disease. In most of these studies, the patients had normal antibody responses. In the remainder, about half the patients had defective responses, but half were entirely normal. The study of Aisenberg and Leskowitz (3) is particularly significant, since all 19 of the patients tested for antibody formation had previously been shown to be incapable of developing skin sensitization to dinitrochlorobenzene. However, two-thirds of them had entirely normal antibody responses to both types of pneumococcal polysaccharide. The cellular immune defect of Hodgkins disease is demonstrable quite early in the course of the disease; some loss of delayed hypersensitivity responses ,can be demonstrated even in newly diagnosed, asymptomatic patients with Stage I