ALBERT

Beschreibung: Dogs given 1200 r of total body irradiation were cross-circulated with dogs having normal marrow function. Irradiated controls died in from 4 to 11 days with marrow aplasia. Dogs cross-circulated daily for 6 to 9 days showed histologic evidence of bone marrow repopulation after 1 week. Male dogs cross-circulated with female partners showed typical female drumsticks on mature granulocytes after repopulation had occurred. Cytogenetic studies of an irradiated male dog cross-circulated with a female partner showed all mitotable cells from the bone marrow and peripheral blood to be of female donor type. Allogeneic bone marrow engraftment was associated with an early and severe secondary syndrome which resulted in the death of the animals in the second week. When methotrexate was given, survival was increased to 3 weeks. It was concluded that (1) cross circulation provided leukocytes and platelets adequate for support during the period of radiation-induced marrow aplasia, (2) allogeneic marrow engraftment was produced consistently by cells transferred in the peripheral blood of the normal cross circulation partner, (3) the grafts were associated with an early and severe form of secondary disease, and (4) methotrexate given during the early period of engraftment reduced the severity of the secondary disease.

Beschreibung: The effect of recombinant human granulocyte-macrophage colony- stimulating factor (rhGM-CSF) was evaluated in 37 patients with marrow graft failure after allogeneic (n = 15), autologous (n = 21), or syngeneic (n = 1) bone marrow transplantation. rhGM-CSF was administered by 2-hour infusion at doses between 60 and 1,000 micrograms/m2/d for 14 or 21 days. At doses of less than 500 micrograms/m2, rhGM-CSF was well-tolerated and did not exacerbate graft- versus-host disease in allogeneic transplant recipients. No patient with myelogenous leukemia relapsed while receiving rhGM-CSF. Twenty-one patients reached an absolute neutrophil count (ANC) greater than or equal to 0.5 x 10(9)/L within 2 weeks of starting therapy while 16 did not. None of seven patients who received chemically purged autologous marrow grafts responded to rhGM-CSF. The survival rates of GM-CSF- treated patients were significantly better than those of a historical control group.

Beschreibung: Frommeyer, Epstein and Taylor: Refractoriness in hemophilia to coagulation-promoting agents: Whole blood and plasma derivatives. Blood 5: 401-420 (May), 1950. The authors wish to note that the following changes should have appeared in the article: Page 402, first line: "Lawrence and Johnson, 1941,8 reported" (instead of "Lawrence and Johnston, in 1946,8 reported"). Page 402, second sentence of same paragraph: "In this instance the patient had received whole blood and plasma in therapeutic management prior to the appearance of resistance to therapy." (instead of ". . . had received chemically prepared plasma fractions in the form of Fraction I of Cohn in addition to whole blood and plasma in therapeutic management prior to . . . "). Page 420, reference 8. To this reference should be added: "(Presented before the American Clinical and Climatological Society, October 1941.)".

Beschreibung: Six patients with advanced chronic lymphocytic leukemia were treated with extracorporeal irradiation and followed for one to three years. There was a marked reduction in the circulating white cells in all patients, but in four cases the white cell counts returned to high levels in 3-7 months. Two patients are in good partial remission 37 and 22 months after the initial course of ECI. Clinical and hematological events in these cases are detailed. It was concluded that ECI is effective in lowering leukocyte levels without systemic toxicity and is beneficial in some cases of chronic lymphocytic leukemia.

Beschreibung: Twenty-two patients with classic hemophilia were studied from the point of view of refractoriness to the usual coagulation-promoting effect of whole blood, and of chemically prepared plasma fractions. Of these, 5 patients showed clinical and laboratory evidence of refractoriness to therapy. All had previously received by intravenous injection for therapeutic purposes during bleeding episodes large amounts of plasma fractions in addition to whole blood and plasma. Subsequently, each refractory patient exhibited a poor clinical response to therapy during hemorrhagic episodes. Thus, despite the administration of whole blood, plasma, or plasma derivatives in amounts which were usually effective, bleeding continued unabated and the blood coagulation time was not significantly reduced. An anticoagulant distinct from antithrombin, antithromboplastin, antiprothrombin and heparin was demonstrated in the plasma of each patient. Each had adequate amounts of fibrinogen and prothrombin in the circulating plasma. However, antibodies were demonstrated in the plasma of each patient by means of precipitin reactions with antigens possessing antihemophilic activity, including various plasma derivatives and Fraction I of Cohn. No such antibodies were demonstrable in a normal individual, in 2 anemic patients who had received many transfusions of whole blood, or in a patient with afibrinogenemia who had received large amounts of antihemophilic globulin because of its fibrinogen content. Prompt reduction in plasma anticoagulant activity, in precipitin titer, and coagulation time were effected only by the administration of large quantities of fresh whole blood. A secondary rise of antibodies always followed such a procedure within several days. When therapy was withheld, the anticoagulant effect and precipitin titer decreased in one patient over a period of six months and in another, had essentially disappeared by the end of a year. From these studies the following conclusions may be drawn: 1. A refractory state in hemophilia may develop following the therapeutic use of whole blood, plasma or chemically prepared plasma fractions. 2. This state is characterized by defective clinical and laboratory responses to therapy with whole blood, plasma or plasma fractions. An anticoagulant is demonstrable in the plasma as well as precipitins to various plasma derivatives possessing antihemophilic activity. 3. The formation of antibodies is apparently an immunologic response to a substance closely associated with antihemophilic activity in normal blood and in plasma derivatives previously employed in therapy. 4. The refractory state can be promptly and temporarily abolished and good clinical and laboratory responses can be effected by transfusions of very large amounts of fresh whole blood. 5. Because of their demonstrated ability to act as antigens in certain hemophilic patients, whole blood, plasma and chemically prepared plasma fractions should be withheld unless their employment as an emergency therapeutic measure is necessary.

Beschreibung: The syndecans comprise a family of integral membrane proteoglycans that regulate cell behaviors by binding to extracellular matrix and binding growth factors. In mouse blood cells, syndecan expression is restricted to cells of the B-cell lineage where it is expressed by pre-B cells and plasma cells, but is absent from circulating B cells. In the present study, we examined the expression, structure, and function of syndecan on human myeloma cell lines and myeloma patient bone marrow cells. On myeloma cells, syndecan is a small (modal relative molecular mass [M(r)] = 120 Kd) heparan sulfate proteoglycan localized at the cell surface. Syndecan was detected by immunodot blotting on 7 of 10 human myeloma cell lines and by reverse transcriptase polymerase chain reaction on 10 of 14 patient samples. Cell binding assays show that myeloma cells expressing syndecan bind to type I collagen via heparan sulfate chains, while those cell lines not expressing syndecan do not bind to collagen. Furthermore, the cell lines expressing syndecan were negative for CD19 and CD45 staining, indicating that syndecan expression is restricted to tumors having a well-differentiated phenotype. We conclude that syndecan acts as a matrix receptor on human myeloma cells but is not expressed by all tumors, suggesting that syndecan may participate in regulating myeloma cell adhesion to the bone marrow stromal matrix.

Beschreibung: Anti-B-blocked ricin (anti-B4-bR) combines the specificity of the anti- B4 (CD19) monoclonal antibody with the protein toxin “blocked ricin.” In blocked ricin, affinity ligands are attached to the ricin B-chain to attenuate its lectin binding capacity. In a phase I trial, Anti-B4-bR was administered by 7-day continuous infusion to 12 patients in complete remission after autologous bone marrow transplantation (ABMT) for relapsed B-cell non-Hodgkin's lymphoma (NHL). Patients were treated at 20, 40, and 50 micrograms/kg/d for 7 days. Potentially therapeutic serum levels could be sustained for 3 to 4 days. The maximum tolerated dose was 40 micrograms/kg/d for 7 days (total 280 micrograms/kg). The dose-limiting toxicities were reversible grade IV thrombocytopenia and elevation of hepatic transaminases. Mild capillary leak syndrome was manifested by hypoalbuminemia, peripheral edema (4 patients), and dyspnea (1 patient). Anti-immunotoxin antibodies developed in 7 patients. Eleven patients remain in complete remission between 13 and 26 months post-ABMT (median 17 months). These results show that Anti-B4- bR can be administered with tolerable, reversible toxicities to patients with B-cell NHL in complete remission following ABMT.

Beschreibung: Forty-seven patients with hematologic neoplasia received recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) by daily 2-hour infusion following allogeneic bone marrow transplantation from HLA-identical sibling donors in a phase I-II dose-escalation trial. Dose levels ranged from 30 to 500 micrograms/m2/d. At doses at or below 250 micrograms/m2/d, toxicity felt to be caused by rhGM-CSF was negligible. However, three of five patients treated with 500 micrograms/m2/d had unacceptable side effects caused by rhGM-CSF. Two different graft-versus-host disease (GVHD) prophylactic regimens were administered. Twenty-seven evaluable patients were administered regimens that did not contain methotrexate (MTX) (Group I) and reached an absolute neutrophil count of 1,000/microL by a median of day 14. In contrast, 18 patients who received GVHD prophylactic regimens containing MTX (Group II) reached an absolute neutrophil count of 1,000/microL on a median of day 20. Patients in Group I had fewer febrile days and, of those discharged, had shorter initial hospitalizations than patients in Group II. The overall incidence of severe acute GVHD (grade 2 or greater) in the rhGM-CSF-treated patients was 28% and was similar to that in historical “good risk” patients who did not receive rhGM-CSF. These preliminary data suggest rhGM-CSF is unlikely to exacerbate GVHD in HLA-identical sibling donor transplants and indicate the need for randomized trials of rhGM-CSF in allogeneic marrow transplant patients.

Beschreibung: The percentages of mononuclear cells synthesizing DNA and RNA in serial studies of blood from 13 patients with infectious mononucleosis were determined. Early in the disease a high percentage of atypical lymphocytes were in DNA synthesis but this percentage decreased rapidly as the disease progressed. Late in the disease many atypical lymphocytes were still present but few, if any, were synthesizing DNA. Similar results were found for RNA synthesis. Presumably active proliferation of atypical cells in the tissues is restricted to an early period of the disease, whereas release of such atypical cells may continue for a considerable period.