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Biomedical subjects

B Speck

Publications and source records attributed to B Speck.

At least 37 records · Page 2Linked to original sources
PubMed1996

Peripheral blood pressure cells transplants across a major histocompatibility barrier in rabbits: positive effects of a higher number of precursor cells?

Peripheral blood precursor cells (PBPCs) are used with increasing frequency for hematopoietic transplants and have more or less replaced autologous bone marrow transplants. First clinical and experimental reports document the feasibility of PBPCs as a source for allogeneic transplants. Few data exist on the optimal procedure and the ideal number of cells for the transplant. We have previously shown in rabbits that PBPCs can be used for transplants even across a major histocompatibility barrier. We used this model to test whether the number of transplanted precursor cells would influence graft outcome. Adult outbred Red Burgundy rabbits were used as donors, New Zealand White rabbits of the opposite sex as recipients. One individual donor was taken for one individual recipient. Conditioning consisted of single-dose total body irradiation of 10 Gy followed by a short course of cyclosporine to enhance engraftment. Donor animals were treated with recombinant human granulocyte-colony-stimulating factor, 10 micrograms/kg subcutaneously daily from day -2 until day +9. PBPCs were obtained from the artery of the donor animal by repetitive centrifugation of 2 x 40 ml heparinized blood on each day of donation, i.e. days 0, +2, +3, +6, +8, and +10 and infused without further manipulation. Eight animals underwent transplantation. Seven took the grafts, six died of graft-versus-host disease and pneumonia between days 12 and 55 (median survival of all animals: 34 days). One animal was still alive after 120 days. Transplanted nucleated cells varied from 7.3 to 15.4 x 10(8)/ kg (median 9.2 x 10(8)/kg) and CFU-GM from 12.3 to 176.8 x 10(4)/kg (median 42 x 10(4)/kg). Survival tended to increase with more CFU-GM) r = 0.716, p = 0.0704). These data confirm that allogeneic PBPCs can engraft across a major histocompatibility barrier and suggest that a higher number of CFU-GM might be advantageous.

Animals↗
PubMed1996

Fatal vascular leak syndrome with extensive hemorrhage, peripheral neuropathy and reactive erythrophagocytosis: an unusual complication of recombinant IL-3 therapy.

A 39-year-old patient with severe aplastic anemia (AA), resistant to therapy, received recombinant human IL-3 (rhIL-3) on a phase I/II trial. During treatment she developed disseminated skin lesions, suggestive of vasculitis, and severe progressive peripheral neuropathy culminating in complete paralysis. She died 25 days after beginning treatment from profuse bleeding. On autopsy, evidence of vascular leaks with widespread bleeding and extensive hemorrhagic involvement of peripheral nerves was found. An additional feature was massive reactive erythrophagocytosis in lymph nodes, spleen and bone marrow. The coincidence between rhIL-3 administration and the dramatic events suggest a causal relation. As a possible pathogenic mechanism, an rhIL-3 induced excessive stimulation of macrophages and production of secondary cytokines such as tumor necrosis factor (TNF) is suggested. TNF is considered as a major factor in the development of both a vascular leak and reactive erythrophagocytosis. This case report can be regarded as an example of the possible unusual pathologic phenomena we may expect to see in the near future with increasing use of growth factors.

Adult↗
PubMed1996

Treatment of Aplastic Anemia.

There is general agreement that in children and adolescents with an HLA-identical or syngeneic sibling, bone-marrow transplantation (BMT) should be performed without delay. More controversial are young-to-middle-aged adults with an HLA-identical sibling. Because of comparable survival rates, some centers advocate BMT; others advocate immunosuppression as primary treatment. BMT cures severe aplastic anemia (SAA), but has a higher early mortality. Immunosuppression usually induces hemopoietic improvement and has hardly any early mortality. However, there are late problems. After immunosuppression, there may be relapse and clonal hematopoietic disease. After BMT, there may be late graft failure, severe or even fatal chronic graft-versus-host-disease (GVHD). Both procedures are followed by a slight increase in second malignancies. Retrospective studies show no significant differences in long-term survival between the two treatment modalities. In patients over the age of 40, immunosuppression is favored by most centers because in this age group there is a very high transplant-related mortality with BMT. Androgens and hematopoietic growth factors have hardly any role in therapy of SAA. Splenectomy helps some patients with severe thrombocytopenia and problems with supportive care, but does not improve the overall prognosis. BMT with unrelated donors has usually been performed in late stages of the disease with disappointing results.

Journal Article↗
PubMed1996

Allogeneic peripheral blood precursor cell transplants in rabbits.

This report summarizes a series of experiments undertaken to evaluate the role of mobilized peripheral blood precursor cells (PBPC) for transplantation across a major histocompatibility barrier. Adult outbred red Burgundy rabbits were used as donors, New Zealand white rabbits of the opposite sex as recipients. Conditioning consisted of single dose total body irradiation (TBI) of 10 Gy supported by a short course of cyclosporine to enhance engraftment. Human recombinant G-CSF at a dose of 10 micrograms/kg was used for mobilization of precursor cells. Three methods of PBPC transplants were tested initially in 5 animals each. PBPC were collected and infused at once on day 0; collected initially, cryopreserved for one month, infused on day 0 and followed by 3 additional fresh donations or collected and infused on 6 occasions between days 0 and + 11. 13 animals engrafted, 2 became complete, longterm chimeras. Survival was best in the group given repetitive infusions (39 days median, 12 days to > 180 days, range). 10 additional animals were transplanted as in the last group and the number of transplanted nucleated cells (10.5 x 10(8)/kg median, 7.3 - 15.7 x 10(8)/kg range) and colony forming units CFU-GM (42 x 10(4)/kg median, 12.3 - 176.8 x 10(4)/kg range), were compared with outcome. Median survival of the 10 animals was 29 days (12 - 55 days range; 1 autologous reconstitution). Survival did not correlate with total nucleated cells per kg (r = 0.10; p = 0.79), but there was a trend to prolong survival with higher numbers of CFU-GM per kg (r = 0.47; p = 0.19). These data show that allogeneic PBPCT can engraft across a major histocompatibility barrier, that the high number of CFU-GM per kg might be advantageous, but also that additional methods are warranted to reduce acute GvHD.

Animals↗
PubMed1996

HLA-identical sibling bone marrow transplants vs chemotherapy for acute myelogenous leukemia in first remission.

There is controversy whether adults with acute myelogenous leukemia (AML) in first remission are best treated with chemotherapy or an HLA-identical sibling bone marrow transplant. We studied 1097 adults, 16-50 years old, with AML in first remission. Results of transplants from HLA-identical siblings reported to the International Bone Marrow Transplant Registry (IBMTR; n = 901) were compared with results of chemotherapy in comparable persons treated by the German AML Cooperative Group (GAMLCG; n = 196). Preliminary analyses identified subject- and disease-related variables differing between the cohorts and associated with treatment outcome within each cohort. We adjusted for these variables and differences in time-to-treatment in subsequent comparisons of treatment-related mortality, relapse, survival and leukemia-free survival (LFS). Five-year probability of treatment-related mortality was greater for transplants than chemotherapy (43% (95% confidence interval, 37-49%) vs 7% (3-11%); P< 0.0001). Five-year relapse probability was less for transplants than chemotherapy (24% (20-28%) vs 63% (55-71%); P< 0.0001). Five-year probability of survival was similar with transplants and chemotherapy (48% (43-53%) vs 42% (33-51%); P = 0.24). Five-year LFS probability was higher for transplants than chemotherapy (46% (42-50%) vs 35% (28-41%); P= 0.01). These data indicate that bone marrow transplants from HLA-identical siblings result in comparable survival but greater LFS than chemotherapy in adults with AML in first remission.

Adolescent↗
PubMed1995

Bone marrow transplantation for Fanconi anemia.

Fanconi anemia is a genetic disorder associated with diverse congenital abnormalities, progressive bone marrow failure, and increased risk of leukemia and other cancers. Affected persons often die before 30 years of age. Bone marrow transplantation is an effective treatment, but there are few data regarding factors associated with transplant outcome. We analyzed outcomes of HLA-identical sibling (N = 151) or alternative related or unrelated donor (N = 48) bone marrow transplants for Fanconi anemia performed between 1978 and 1994 and reported to the International Bone Marrow Transplant Registry. Fanconi anemia was documented by cytogenetic studies in all cases. Patient, disease, and treatment factors associated with survival were determined using Cox proportional hazards regression. Two-year probabilities (95% confidence interval) of survival were 66% (58% to 73%) after HLA-identical siblings transplants and 29% (18% to 43%) after alternative donor transplants. Younger patient age (P .0001), higher pretransplant platelet counts (P = .04), use of antithymocyte globulin (P = .005), and use of low-dose (15 to 25 mg/kg) cyclophosphamide plus limited field irradiation (P = .009) for pretransplant conditioning and cyclosporine for graft-versus-host disease prophylaxis (P = .002) were associated with increased survival. Bone marrow transplants are effective therapy for Fanconi anemia. The adverse impact of increasing age and lower pretransplant platelet count on transplant outcome favors earlier intervention, especially when there is an HLA-identical sibling donor.

Adolescent↗
PubMed1995

[Bone marrow transplantation].

Bone marrow transplantation (BMT) has evolved from an experimental undertaking to an established therapeutic strategy for hematological neoplasias, severe aplastic anemia, congenital immunological and metabolic disorders and some solid tumors. This report summarizes the main indications for autologous and allogenic transplants, the prerequisites and potential techniques, early and late complications as well as preventive and therapeutic strategies. The results of 397 BMT, 357 allogeneic and 40 autologous transplants, performed in Basel between 1973 and 1995, illustrate the present potential and main prognostic factors: stage of disease, age and histocompatibility. 50% of the patients treated with an allogeneic BMT from an HLA-identical sibling early in the disease are alive 15 years post BMT, 80% free of disease and reintegrated into work and family. New strategies are testing the use of unrelated HLA-compatible volunteer donors and the potential of mobilized peripheral blood precursor cells instead of bone marrow for allogeneic and autologous transplants.

Bone Marrow Transplantation↗
PubMed1995

[Hydroxyurea, erythrocyte volumes and hemoglobin F].

Hydroxyurea is used in the treatment of sickle cell anemia and beta-thalassemia major to increase the content of hemoglobin F (HbF) and presumably ameliorate clinical symptoms. Under therapy with hydroxyurea an increase of the mean corpuscular volume (MCV) of the erythrocytes can be observed. To evaluate a possible estimation of the content of HbF using the increase of MCV under treatment with hydroxyurea, we measured MCV and HbF during therapy with hydroxyurea. The median MCV before therapy was 87.8 fl (range 74.3-95.7) and under hydroxyurea 104.1 fl (81.0-139.5), and the median HbF 1.8% (0.1-5.4). Although both MCV and HbF increased under treatment with hydroxyurea, a linear correlation between these two parameters was not detectable. Therefore, MCV cannot replace the measurement of HbF.

Erythrocyte Indices↗
PubMed1995

[Activation of endothelium-dependent hemostatic factors following bone marrow transplantation].

Changes in hemostatic factors after bone marrow transplantation (BMT), with or without thrombotic complications, have already been described. The endothelium seems to be actively involved in such processes. Over a period of 2 years we evaluated various hemostatic factors, associated or not with endothelial stimulation, in 44 patients with BMT (40 leukemias and 4 aplastic anemias). Factor VIII activity (VIII:C), von Willebrand factor antigen (vWF:Ag), tissue plasminogen activator antigen (tPA), plasminogen activator inhibitor activity (PAI-1), antithrombin III, protein C and protein S were assayed before and 1, 3, 6, 12, 18, and 24 months after BMT. Factor VIII:C, vWF and tPA were found to be significantly increased 1-6 months after BMT, returning to normal later. Patients with acute graft versus host disease, fever or cyclosporin treatment had significantly higher VIII:C, vWF and tPA. The increase in these factors implies lasting stimulation of their release and/or synthesis from endothelial cells that is enhanced by some complications of BMT. The degree and character of these changes could favor activation of thrombotic processes.

Adolescent↗
PubMed1995

Recombinant human interleukin-3 in refractory severe aplastic anaemia: a phase I/II trial.

In a prospective open-labelled phase I/II trial we tested efficacy and tolerability of recombinant human interleukin-3 (rhIL-3) alone in patients with refractory severe aplastic anaemia (SAA). 15 patients with idiopathic (12 patients) or secondary (one post-hepatitic, one drug induced, one dyskeratosis congenita) SAA, refractory or relapsing after one to three courses of antilymphocyte globulin were included. 14 patients were transfusion dependent (RBC 14, platelet 12). RhIL-3 was planned for three patients each at five escalating dose levels of 1, 2, 4, 8 and 16 micrograms/kg, given daily as 24 h continuous infusion for 21 d. RhIL-3 was prematurely withdrawn at days 10 and 11 for adverse events in two patients. 9/15 patients showed an increase in WBC; 2/6 at the 1-2 micrograms/kg and 7/9 at the 4-16 micrograms/kg level, but no sustained effects were seen. No patient showed a response in platelet counts. Additionally, platelet and RBC transfusion requirements were unchanged pre and post study. All patients experienced one or more adverse event, mainly fever (15 patients), bleeding (nine patients), and headache (six patients). Occurrence of adverse events was dose related and the maximum tolerated dose was reached with 8 micrograms/kg. Five patients suffered serious adverse events. RhIL-3 as single growth factor and used alone is of minimal benefit in severe aplastic anaemia.

Adolescent↗
PubMed1995

Persistent growth impairment of bone marrow stroma after antilymphocyte globulin treatment for severe aplastic anaemia and its association with relapse.

Bone marrow from 65 patients with aplastic anaemia (AA) was tested for stroma growth in short term cultures (2 weeks) and for colony formation by haemopoietic precursor cells during the course of their disease. In 18 untreated patients, mean stroma growth was 30% of normal and colony formation was virtually absent. After treatment with immunosuppression (IS), as estimated from 90 examinations in 54 patients, stroma growth was approximately 50% and colony growth approximately 10% of normal. Growth impairment of stroma and haemopoietic precursors persisted for 10 and more years after IS. Results of 2-week stroma cultures were compared with results of long term bone marrow cultures in 10 AA patients and 4 controls. At 2 weeks, growth of aplastic marrow was delayed compared to normal, but this difference became less evident with prolonged incubation time. In vitro growth abnormalities were compared with the clinical evolution after IS. The development of late haematological complications (paroxysmal nocturnal haemoglobinuria (PNH)) and myelodysplastic syndrome (MDS), did not correlate with the degree of stroma growth impairment. However, relapse of aplasia was associated with poor stroma growth: 8/29 patients with stroma confluence of < or = 30% during haematological remission versus 1/25 with stroma confluence of > 30% relapsed. We conclude that (i) the haematopoietic microenvironment is frequently coinvolved in the disease process of AA, (ii) a defect is detected in short term rather than in long term stroma cultures and, (iii) relapse is more frequent in patients with poor stroma growth.

Adolescent↗
PubMed1995

Transplantation of G-CSF mobilized allogeneic peripheral blood stem cells in rabbits.

Mobilized peripheral blood precursor cells (PBPC) are used with increasing frequency to restore autologous hematopoiesis following high-dose radio-chemotherapy. The success of this method has aroused interest in the use of mobilized PBPC for allogeneic transplants. This approach would eliminate the need for marrow aspiration and general anesthesia. In this project we tested the feasibility of allogeneic histoincompatible PBPC transplants in rabbits. Adult outbred Red Burgundy rabbits were used as donors, histoincompatible New Zealand White rabbits of the opposite sex as recipients. One individual donor was used for one individual recipient. Conditioning consisted of 10 Gy total body irradiation (TBI). Donor animals were pre-treated with recombinant human granulocyte colony-stimulating factor (rh G-CSF) given s.c. at 10 micrograms/kg daily. Three schedules of PBPC collection and reinfusion were tested in 3 groups of animals, each consisting of 5 donor recipient pairs: (A) PBPC were collected either on days -2, -1 and 0, and infused at once after TBI on day 0; (B) collected and infused on days 0, +2, +4, +7, +9, and +11; (C) collected on 3 consecutive days, cryopreserved for 1 month and infused on day 0 followed by 3 fresh donations on days +4, +8 and +11. The median amount of blood processed from donor animals was 470 ml (312-602) containing about 10 x 10(8) (5-71 x 10(8)) nucleated cells. Recipient animals received a median of 2.7 x 10(8) cells/kg equivalent to 9.6 x 10(4) colony-forming units granulocyte-macrophages (CFU-GM)/kg (data derived from Group C of the animals).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

[Pneumocystis carinii pneumonia during therapy with 2-chlorodeoxyadenosine (2-CDA)].

We report the case of a 70-year-old patient with B-cell chronic lymphocytic leukemia. During therapy with the new purine analog 2-chloro-deoxyadenosine (2-CDA) the patient developed Pneumocystis carinii pneumonia (PCP). Although the mechanism of action of 2-CDA suggests the incidence of opportunistic infections and therefore pneumocystis pneumonia, this is the first case of PCP among 140 patients of the Swiss study of 2-CDA. The mechanism of action of 2-CDA is described and the occurrence of PCP among patients without acquired immunodeficiency syndrome is discussed.

Aged↗
PubMed1994

[Isolation ward: initial experiences after 4 years].

UNLABELLED: Since October 1988 there has been an isolation ward at Basle Cantonal Hospital. Its purpose is to treat patients with high dose chemotherapy and bone marrow transplantation under protective isolation and by standardized criteria. The isolation ward has two sub-units, viz. the reverse isolation for neutropenic patients (8 single room units) and the LAF unit (5 laminar airflow units) for allogeneic bone marrow transplantation (BMT). Up to July 1992, 287 patients (152 males and 133 females) required 527 hospitalizations. The median age was 41 (5-82) years in the reverse isolation unit and 28 (4-61) years in the LAF unit. Bed occupation was 90% and 82% throughout the period. 71% of patients were from the Basle area and the rest from elsewhere in Switzerland or from other countries. DIAGNOSIS: acute leukemias (112); myelodysplastic or myeloproliferative syndromes (52); severe aplastic anemia or agranulocytosis (46); lymphoproliferative syndromes (50); solid tumors (28). Indications for hospitalisation: BMT (107); complications after BMT (infections, GvHD) (63); chemotherapy on protocols of SAKK (105); other chemotherapies (64); antilymphocyte globulin or growth factor treatment (27); splenectomies (18); neutropenic fever (62); patient work-up (59); terminal care (20). Patients in reverse isolation were hospitalized for a median 17 (1-142) days; in the LAF unit for 52 (1-121) days.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Late clonal complications in severe aplastic anemia.

One hundred and seventy patients with severe aplastic anemia (SAA) were treated in Basel, from 1976 to 1992. Forty one underwent bone marrow transplantation (BMT) and 129 antilymphocyte globulin (ALG) therapy. As of January 1, 1993, 99 of the 170 patients are alive (58% +/- 7%) and the probability to be alive at 15 years is 54% +/- 4%. Until now, 29 patients have developed a clonal complication. All occurred within the ALG group. Nine patients developed a myelodysplastic syndrome (MDS), 16 patients paroxysmal nocturnal hemoglobinuria (PNH) and 4 patients both, PNH and MDS. The cumulative risk of developing a clonal complication after ALG-therapy is 42% +/- 13% at 15 years; for MDS this risk is 26% +/- 8% and for PNH 25% +/- 5%. The development of a clonal disease directly affects long term prognosis. The survival of the patients with stable disease is 81% +/- 10% and 36% +/- 13% for those with clonal evolution (p = 0.001). The most important risk factor is the type of treatment. In contrast to patients treated with ALG, none of the patients treated with BMT developed MDS or PNH (p < 0.001). No other clinical parameter, such as age, sex, etiology of SAA, severity of the disease and splenectomy correlate with an increased risk of developing this complication. In contrast, morphological parameters at the time of diagnosis, during bone marrow regeneration and at remission are indications in this respect.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗