[Clinico-pathologic conference: hemiplegia and coma in acute lymphatic leukemia].
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Adolescent↗
Biomedical subjects
A Gratwohl
Publications and source records attributed to A Gratwohl.
[12 years' experience in bone marrow transplantation in leukemic patients in Switzerland].
Between 1974 and December 1985 180 bone marrow transplants were performed in Switzerland for patients with leukemia. They were performed in 4 centers (Basle 133, Zurich 28, Geneva 17, Berne 2). The overall probability of survival at 10 years for all patients is 20%. Results are better for younger patients, for patients transplanted in recent years and for patients transplanted either in the first complete remission of acute leukemia or in the chronic phase of chronic myeloid leukemia.
Adolescent↗
[Antibiotic-resistant Corynebacteria--a new problem of infection in immunosuppressed patients].
Corynebacterium species can normally be found on the skin and mucous membranes but rarely cause infections. They are sensitive to most antibiotics. Two patients with severe aplastic anemia undergoing antilymphocyte globulin therapy developed septicemia with a highly antibiotic-resistant corynebacterium (JK-group) only sensitive to vancomycin. Both patients had prolonged severe neutropenia, defects of the mucocutaneous barrier and intensive antibiotic treatment for gram negative infections. In both cases surveillance cultures already revealed the causative microorganism before fever started. One patient was even colonized with corynebacterium for several months before. If this strain is detected in the blood when new fever develops during prolonged neutropenia and broad-spectrum antibiotic therapy, it indicates serious infection in these highly compromised patients. Both cases illustrate that regular microbial surveillance can help to reveal colonization of high risk patients with multiple antibiotic-resistant corynebacterium strains and thus allow early initiation of treatment with vancomycin, which is the only effective antibiotic.
Anti-Bacterial Agents↗
The release of interleukin-2 (IL-2) and colony stimulating activity (CSA) in aplastic anemia patients: opposite behaviour with improvement of bone marrow function.
Peripheral blood cells from patients with aplastic anemia were tested for their ability to release interleukin-2 (IL-2) and colony stimulating activity (CSA) before treatment. IL-2 release--as measured in the mouse thymocyte assay--was abnormally high in 18/34, and abnormally low in 10/34 patients. "Low" release was due to simultaneous release of thymocyte inhibitors. In 18 patients who achieved self-sustaining hemopoiesis after high dose immunosuppressive therapy, excess IL-2 release decreased to low levels (p less than 0.001), and the release of inhibitors disappeared. In contrast, the release of CSA by patient cells--which did not correlate with peripheral blood monocyte counts--either remained high or increased to excessively high values in 24/24 patients tested before and after successful immunosuppressive treatment. Patients with stable hemopoietic grafts after bone marrow transplantation for aplastic anemia, did not release excess CSA. It is concluded that IL-2 and CSA play opposite roles in aplastic anemia. High IL-2 release seems associated with disease activity, whereas high CSA-release appears to reflect a repair mechanism.
Adolescent↗
Immunoadsorption for removal of anti-A and anti-B blood group antibodies in ABO-incompatible bone marrow transplantation.
About 10-15 percent of all patients undergoing allogeneic bone marrow transplantation have a major ABO-incompatibility with their donors. The risk of acute hemolytic reactions due to the infusion of an incompatible donor marrow into the recipient can basically be prevented by recipient antibody depletion or by donor marrow red cell depletion. Nine patients were treated by immunoadsorption using a cartridge with chemically synthesized human blood group A and B antigen as immunoadsorbent for antibody depletion. Within a four-hour-procedure about 2-4 times the patient plasma volume could be processed, thus lowering the anti-A and -B hemagglutinins by 2 to 3 tubes. There was a tendency of better IgG removal when titers initially were high, showing a high antibody clearing capacity. There was no significant correlation between starting titer or amount of plasma volume processed and titer reduction. No decrease in titers were observed in one case. We propose repeated immunoadsorption procedures over 2-3 consecutive days before BMT. The procedure is largely safe and without serious side effects. A major advantage is the avoidance of nonautologous human blood products compared to the conventional plasma exchange. All 8 patients surviving long enough had prompt and stable engraftment of all three cell lines post BMT. No late serological complications occurred when patients were regularly monitored and in vivo adsorption was used when titers increased.
ABO Blood-Group System↗
Influence of graft-versus-host disease prophylaxis on early T-lymphocyte regeneration following allogeneic bone marrow transplantation.
An early decrease in the ratio between T4+ and T8+ T lymphocytes has been shown to correlate with the development of grade II-IV GVHD in allogeneic bone marrow transplant (BMT) recipients receiving methotrexate (MTX) as prophylaxis for acute graft-versus-host disease (GVHD). This study compares the onset of T-cell regeneration in patients receiving cyclosporin A (CyA) with those receiving MTX. Firstly, lymphoid recovery occurred at a significantly faster rate in the patients on CyA. Secondly, in those patients, the repopulation of T4+ and T8+ T cells started simultaneously, whereas in patients on MTX the repopulation of the T8+ subset lagged about a week behind that of the T4+ subset. Thirdly, the decrease in the T4/T8 ratios as a function of the lymphocyte counts occurred at a significantly slower rate in the patients on CyA than in those on MTX. Thus, the differences in the onset of T-cell regeneration in BMT recipients on CyA as compared with those on MTX abolished the correlation of the T4/T8 ratio changes with grades II-IV GVHD as described in patients receiving MTX.
Adolescent↗
Acquired aplastic anaemia: a PNH-like disease?
Bone marrow from 20 patients with aplastic anaemia at different stages of disease and from three patients with paroxysmal nocturnal haemoglobinuria (PNH) was incubated in isosmolar sucrose with 5% autologous serum prior to culture in methylcellulose. If fresh serum was used, colony formation by granulocyte-macrophage colony forming cells (GM-CFC) and immature erythroid precursors (BFU-E) was reduced to approximately 50% in all patients tested, at any stage of disease, including complete autologous bone marrow recovery. Heat inactivation and complement inactivation with EDTA completely abrogated this inhibitory serum effect. Selective inactivation of the classical, antibody dependent complement pathway with Mg2+ EGTA reduced the inhibitory effect by 50%. Complement sensitivity of haemopoietic precursors is a known feature of PNH. Since the majority of our patients did not have PNH as judged by a negative sucrose-test on mature erythrocytes, we conclude that, in aplastic anaemia, haemopoietic cells express a PNH-like defect at a primitive level.
Anemia, Aplastic↗
Increased frequency of DR2 in patients with aplastic anaemia and increased DR sharing in their parents.
68 patients with aplastic anaemia, their parents and healthy siblings were typed for HLA-A, B and DR antigens. Among the patients there is an overrepresentation of DR2. The parents of affected children show an increased compatibility at the DR locus. This situation could favour the expression of recessive gene(s) involved in haematopoiesis and located in the HLA locus.
Alleles↗
Efficacy and clinical cross-resistance of a new combination therapy (AMSA/VP16) in previously treated patients with acute nonlymphocytic leukemia.
We investigated the tolerance, efficacy, and clinical cross-resistance of a new combination chemotherapy in 38 patients with previously treated acute myeloblastic leukemia (AML). It consisted of 120 mg2/d 4'(9-acridinylamino) methanesulfon-m-Anisidide (m-AMSA) in a one-hour infusion and 80 mg/m2/d etoposide (VP-16) in a 24-hour infusion, both administered for 5 days. The first 27 patients also received vinblastine, 6 mg/m2 on day 8, but this therapy was discontinued because of intestinal complications. Thirteen of 23 patients (56%) at first or subsequent relapse and five of 15 patients (33%) who were primarily resistant to an anthracycline/cytarabine combination achieved a complete response (CR) (hemoglobin level not taken into account) with a median CR duration of 5 months and 2 months, respectively. The response rate was as high as 63% for patients at first or second relapse whether the remission was maintained or not. The median times to recovery of normal bone marrow cellularity, of blood granulocyte counts greater than 500/microL, and of platelets greater than 20,000/microL were 34, 27, and 22 days, respectively. Marked but reversible gastrointestinal toxicity was observed in 24% of the patients, and two patients died of infection during induction. The one-hour AMSA/continuous VP-16 combination is effective for patients with relapsing AML and shows no cross-resistance in a proportion of patients refractory to the standard anthracycline-cytarabine combination.
Adolescent↗
Cyclosporine toxicity in rabbits.
Rabbits treated with an immunosuppressive dose of cyclosporine for a prolonged period of time developed a clinically distinct toxic syndrome characterized by wasting, loss of weight, reduced food and water consumption and reduced movement. Ultimately 74 of 153 animals died within 60 days of treatment with a distended stomach and intestines full of dry undigested food. The syndrome was dose dependent but seemed unrelated to the route of administration. It occurred in two strains and two different colonies. No infectious agent was implicated. Histological examination and a variety of laboratory tests did not elucidate the syndrome. It could not be prevented by drugs that increased bowel movement or gastric emptying and was more pronounced in animals given additional indomethacin. Reduction of cyclosporine dose reduced toxicity but at the expense of reduced immunosuppression. We were unable to define a therapeutic non-toxic range by serial determination of cyclosporine blood concentrations. This highlights the difficulty in obtaining a therapeutic dosage level in rabbits on long-term cyclosporine immunosuppression.
Animals↗
Biological and immunological characterization of ATG and ALG.
Antithymocyte globulin (ATG) and antilymphocyte globulin (ALG) are effective therapies in aplastic anemia; their mechanism of action is undefined. We assayed multiple properties of ATG and ALG to address the biological and immunological bases for differences between ATG and ALG and lot variation. In addition, we studied a lot reported to be inactive in an American clinical trial; however in retrospect, this lot appeared to be active in patients treated in Europe. Immunoprecipitation of thymocyte and lymphocyte membrane proteins with ATG and ALG showed between 14 and 18 major bands on SDS-PAGE, but the patterns for ATG and ALG were not identical. The ability of ATG and ALG to block binding of labeled monoclonal antibodies was assessed using flow cytometry and a radioimmunoassay. In general, there was more lot variation among ALGs than ATGs; however, all ALG lots were more potent blockers of binding of anti-HLA-DR and anti-Leu 1 antibodies than was ATG. Both ALG and ATG effectively blocked binding of anti-Leu 2a, anti-Leu 3a, anti-Leu 4, anti-Leu 5b, and anti-IL 2 receptor abs; neither blocked binding of anti-Leu 7. All preparations were capable of inducing T-cell blastogenesis, although there was considerable lot variation. All lots lysed 60% to 75% T cells in a rabbit complement-mediated cytotoxicity assay, with most having a plateau of activity at 5 to 10 ug/mL. Two lots of ALG, including the lot reported to be clinically inactive, showed less toxicity at suboptimal concentrations and did not plateau even at 80 ug/mL. In total, these results indicate important differences between ATG and ALG in general, more lot variation among ALGs than ATGs and only differences in cytotoxicity between an "inactive" lot of ALG and most, but not all, other active ATG and ALG preparations.
Anemia, Aplastic↗
Treatment of severe aplastic anemia.
A total of 100 patients with severe aplastic anemia were treated and evaluated in a prospective study at our hospital between January 1976 and October 1983: 28 patients had an HLA-identical sibling donor and were treated with bone marrow transplantation, and 72 patients without an HLA-identical sibling donor were given antilymphocyte globulin followed by oral low-dose androgen therapy. At 1 1/2-9 years after treatment, 13 patients (46%) survive in the transplant group and 45 patients (75%) survive in the second group. All except one in the second group have self-sustaining hematopoiesis without need for transfusions. There is one major difference between the two therapies. Marrow transplantation restores bone marrow function completely and no late hematologic complications have been seen in this group. The majority of patients treated with antilymphocyte globulin in contrast have residual abnormalities of hematopoiesis: macrocytosis, mild granulocytopenia, and mild thrombopenia. Relapse (11 of 72 patients) and clonal hematologic disorders, such as paroxysmal nocturnal hemoglobinuria (four patients) and leukemia (one patient) can occur years after complete bone marrow reconstitution with antilymphocyte globulin. These late disorders are of concern. Despite this, we conclude that antilymphocyte globulin treatment is an effective therapy with low early mortality and morbidity and a high chance for a long, sustained remission. Results are better or at least equivalent to bone marrow transplantation and patients with donors should be given the option of transplant or antilymphocyte globulin.
Adolescent↗
Bone marrow transplantation with ciclosporin.
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Animals↗
Effect of splenectomy before bone-marrow transplantation on survival in chronic granulocytic leukaemia.
Splenectomy is commonly carried out before bone-marrow transplantation in chronic granulocytic leukaemia to reduce tumour burden and prevent relapse and blastic transformation. In a retrospective analysis of 210 European patients transplanted between 1980 and 1984, 105 splenectomised and 105 not, neither splenectomy nor splenic irradiation was found to alter survival and relapse. Debulking in this disease is of no value, and routine splenectomy before transplantation should be abandoned.
Adolescent↗
Importance of highly sensitive serological tests for cytomegalovirus in bone marrow transplant patients.
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Adult↗
B/T cell ratio of rabbit peripheral blood lymphocytes. Influence of separation technique on results.
Spontaneous in vitro T cell rosette formation at room temperature leading to enrichment of B cells has been reported. We tested 10 individual New Zealand White rabbits sequentially, separating the lymphocytes either at room temperature or at 37 degrees C. T cells are lost constantly at room temperature but to a lesser extent at 37 degrees C. The determination of the yield of lymphocytes after Ficoll separation gives the best control for the accuracy of the results. If lymphocytes are separated at 37 degrees C and if the yield of lymphocytes is greater than 45%, the variation in T cells is small and their number is constant between 62 and 74%. These data show that the reported wide range of T cells in rabbit peripheral blood is due to methodological errors and not inherent in the rabbit.
Animals↗
[Invasive pulmonary aspergillosis--a diagnostic and therapeutic problem in patients with severe aplastic anemia].
Three young patients with severe aplastic anemia undergoing intensive immunosuppressive therapy developed fever and pulmonary infiltrates during longlasting severe granulocytopenia, despite multiple broad spectrum antibiotic combinations and granulocyte transfusions. Invasive pulmonary aspergillosis was diagnosed only by thoracotomy. In conjunction with high dose amphotericin-B therapy complete resolution of aspergillosis was achieved in two cases, paralleled by slow recovery of bone marrow function, whereas in the third case only a partial remission was possible together with transient amelioration of granulopoiesis. We suggest early aggressive surgical methods to establish the diagnosis of aspergillosis in these severely menaced patients, so that antifungal therapy with high dose amphotericin-B can be initiated at an early stage.
Adolescent↗
Stimulatory serum factors in aplastic anaemia. II. Prognostic significance for patients treated with high dose immunosuppression.
Serum from patients with aplastic anaemia contains two distinct stimulatory activities on haemopoiesis in culture. The first is a highly unstable enhancing activity, which mainly stimulates colony formation from BFU-E and macrophage precursors, and only acts when added directly to target bone marrow cultures. It is destroyed by Sephadex G-150 chromatography, and thus differs from colony stimulating activity (CSA) and burst promoting activity (BPA). Its mode of action is unknown. It was elevated in 70/97 patients with severe aplastic anaemia (SAA). 71 of these 97 patients were treated with high dose immunosuppression. 55/71 who achieved self-sustaining haemopoiesis had higher serum stimulating activity on BFU-E than 16/71 who never achieved remission (P = 0.0004). It was predictive of response as an all or none phenomenon, independent of the time required for recovery. It was, however, unsatisfactory as a single prognostic test. Bone marrow reconstitution also occurred in 4/71 patients whose serum inhibited BFU-E in direct culture. The second stimulator acts via enhancement of CSA- and BPA-release by accessory cells and is therefore termed 'releaser' activity. It was elevated in 27 of 51 aplastic anaemia patients and did not correlate with direct stimulatory activity. High 'releaser' activity was not predictive of response in 42 patients treated with high dose immunosuppression. However, the ability of patient cells to respond to autologous 'releaser' activity was a positive risk factor. Patients whose cells released an excess of CSA in the presence of autologous serum had a significantly higher chance of autologous recovery within 3 months than patients who produced little or no CSA in the presence of normal or excess releaser activity (P less than 0.0001). A scoring system which includes these two good risk factors is proposed for estimation of a patient's probability to recover autologous bone marrow reconstitution.
Anemia, Aplastic↗