[Rare differential diagnosis of free intra-abdominal air. Pneumatosis cystoides intestinalis].
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Adult↗
Biomedical subjects
U W Schaefer
Publications and source records attributed to U W Schaefer.
Prolonged administration of interferon-alpha in patients with chronic-phase Philadelphia chromosome-positive chronic myelogenous leukemia before allogeneic bone marrow transplantation may adversely affect transplant outcome.
To assess the influence of pretransplant cytoreductive therapy with special reference to interferon-alpha (IFN-alpha) treatment on major endpoints of allogeneic bone marrow transplantation (BMT), we studied 133 consecutive patients with Philadelphia chromosome (Ph1)-positive chronic myelogenous leukemia (CML) in first chronic phase who received marrow grafts from HLA-identical family (n = 103) or alternative donors (n = 30) at a referral-based transplant center. Fifty of these patients (38%) were previously exposed to IFN-alpha for a median duration of 14 months (range, 1 to 61 months), whereas 83 patients (62%) exclusively received hydroxyurea and/or busulfan therapy between 1 and 129 months (median, 15 months) pretransplant. Using the categorized treatment duration with each pretransplant cytoreductive agent as a measure for individual patient exposure to each agent, prolonged ( > 12 months) IFN-alpha administration was identified as the sole significant pretransplant therapy-related predictor of transplant outcome by proportional hazards regression analysis. The adjusted risk ratio (RR) of transplant-related mortality (TRM) was 2.5-fold higher (95% confidence limits [95% CL], 1.4 to 4.5; P < .004) compared with other pretransplant therapy and this was mainly attributable to a 3.1-fold higher RR (95% CL, 1.4 to 6.4; P < .005) of fatal posttransplant infections after prolonged IFN-alpha treatment pretransplant. Marrow graft failure developed exclusively among 7 of 30 patients (23%) with donors other than HLA-identical family members and was further restricted to patients who had been previously exposed to IFN-alpha. The probability of graft failure was 49% +/- 28% in 17 patients pretreated with IFN-alpha compared with 0% for the other 13 patients with mismatched family or unrelated donors (P < .008). In addition, a significant delay in neutrophil and platelet count reconstitution was observed among patients with donors other than HLA-identical family members after pretransplant IFN-alpha exposure. No influence of pretransplant cytoreductive therapy on either acute and chronic graft-versus-host disease or leukemic relapse was detected in this study. As a consequence of its adverse effect on TRM, prolonged pretransplant IFN-alpha treatment was independently associated with a 2.5-fold lower likelihood (95% CL, 1.4 to 4.5; P < .003) of 5-year overall survival and with a 2.3-fold lower likelihood (95% CL, 1.3 to 4.2; P < .004) of 5-year disease-free survival postransplant after adjustment for other significant prognostic factors in multivariate analysis.(ABSTRACT TRUNCATED AT 400 WORDS)
Adolescent↗
Association of increased bronchoalveolar lavage fluid albumin and serum beta 2-microglobulin with pulmonary complications after allogeneic bone marrow transplantation.
The aim of this prospective study was to identify markers in bronchoalveolar lavage fluid (BAL fluid) and serum predictive for the development of pulmonary complications in the early phase (< 50 days) post-BMT. Concentrations of BAL fluid albumin (alb) and serum beta 2-microglobulin (S-beta 2m,) were determined 10 days before BMT (BAL-B, baseline) and on day 1 post-BMT (BAL-1) in 20 patients who subsequently developed pulmonary complications (group 1) and in 66 patients who remained free of complications for a minimum of 12 months (group 2). Median BAL fluid alb concentrations were significantly (P < 0.05) higher in group 1 patients as compared to group 2 patients at BAL-B (40 vs 28 mg/l) and at BAL-1 (30 vs 15 mg/l). S-beta 2m at BAL-1 was also significantly elevated in group 1 patients (median 1.3 mg/l) compared to group 2 patients (median 1.15 mg/l). Using cut-off values for BAL fluid alb (> 23 mg/l) and S-beta 2m (> 0.8 mg/l) we identified 12 patients out of 19 who developed subsequent pulmonary complications from 12 out of 62 patients without such complications, 1 day post-BMT.
Adolescent↗
Detection of minimal residual disease and persistence of host-type hematopoiesis: a study in 28 patients after sex-mismatched, non-T cell-depleted allogeneic bone marrow transplantation for Philadelphia-chromosome positive chronic myelogenous leukemia.
We investigated the persistence of host-type hematopoiesis as defined by mixed chimerism (MC) in 28 male patients with chronic myelogenous leukemia (CML) who underwent opposite sex, non-T cell-depleted bone marrow transplantation (BMT) by amplification of Y-chromosome specific sequences, and correlated these results with the detection of minimal residual disease (MRD) by BCR/ABL mRNA amplification. Patients were studied at two time periods (> 3 months and > 24 months post-BMT). All but two patients were conditioned with total body irradiation (TBI) and cyclophosphamide (CY). One patient received busulfan (Bu), thiothepa (Thio) and CY, another patient CY and Bu. Detection of MRD occurred exclusively among patients with a MC (significance P < 0.04). Six of 18 patients with MC had detectable MRD, four of these consecutively developed cytogenetic and hematological relapse. Of 28 patients studied more than 3 months post-transplant, 18 (64%) had mixed chimerism and 10 (36%) had exclusively donor-derived blood cells. Nineteen patients were followed for their chimeric status between 24 months and 136 months post-BMT. Four patients converted from MC to complete chimerism and 10 patients (53%) remained mixed chimeric. The high incidence of MC in patients who underwent BMT without T cell depletion was measured by using a PCR assay with a sensitivity of 0.001%. As previously described by other investigators patients with complete chimerism developed more acute GVHD grade I-II (seven of 10 patients (70%) than patients with MC (nine of 18 patients (50%), not significant). This study also suggests that chimeric status might depend upon the regimen to prevent GVHD. One of four patients who received weekly methotrexate as GVHD prophylaxis developed MC, whereas in 11 of 18 patients receiving short course methotrexate and cyclosporine MC was detectable. All of six patients, prophylactically treated with a murine monoclonal antibody directed to the human alpha/beta T cell receptor in combination with cyclosporine, were mixed chimeras.
Adult↗
Twenty years of bone marrow transplantation in Essen - 1995 update.
Allogeneic BMT provides potential life-saving therapy for a variety of inherited and acquired diseases of the hemopoietic and the immune systems, including malignancies. At the University of Essen more than 800 transplants have been performed during the past 20 years. CML was the most frequent indication for BMT in Essen. Patients transplanted in first chronic phase had a high probability of disease-free survival, whereas patients transplanted with more advanced disease had long-term remission only in a minority of cases. With AML, optimal timing for transplantation remains undetermined. Patients at high risk of chemotherapy failure and relapse may have a better overall chance of long-term disease-free survival and cure if transplanted in first remission. BMT for patients with ALL are generally reserved for patients failing chemotherapy or in first remission with prognostic factors predicting a high risk of failure with chemotherapy alone. Compared with conventional bone marrow harvest, the advantages of mononuclear-blood-cell apheresis will probably change the standard procedure for bone marrow harvest in the future. Since 1995, an increasing number of blood stem cell transplants have been successfully performed in allogeneic transplants at the University of Essen.
Academic Medical Centers↗
Recurrent acute inflammatory demyelinating polyradiculitis after allogeneic bone marrow transplantation.
We report a patient who developed recurrent acute inflammatory demyelinating polyradiculitis (AIDP) receiving immunosuppressive treatment with cyclosporin and prednisone for secondary chronic graft versus host disease (GVHD) following allogeneic bone marrow transplantation (BMT) from an unrelated donor for chronic myelogenous leukemia (CML). After the second relapse of AIDP, cyclosporin was discontinued and a rapid, sustained improvement of his neurological deficits occurred. The role of cyclosporin and systemic CMV infection in the pathogenesis of AIDP in this patient are discussed.
Acute Disease↗
Presence of re-appearance of BCR-ABL-positive cells years after allogeneic bone marrow transplantation for chronic-phase chronic myelogenous leukemia in patients in hematological remission.
Allogeneic bone marrow transplantation (BMT) is considered to be the only curative therapy for chronic myelogenous leukemia (CML). The cytogenetic marker of CML, the Philadelphia (Ph) chromosome, or the molecular alterations caused by the BCR-ABL gene fusion can be used to monitor the success of treatment. A sensitive two-step reverse-transcription polymerase chain reaction (RT-PCR) was done to score BCR-ABL-mRNA-positive leukemic cells in frozen bone marrow samples of 15 CML patients retrospectively. These patients, 4 females, 11 males, had undergone BMT during the first chronic phase after a preparative regimen consisting of total body irradiation (TBI) and cyclophosphamide; median age at BMT was 38 years (range 20-49 years). At the time of this study, 8 patients were in cytogenetic and/or clinical remission. Seven patients relapsed after BMT; all presented with Ph-chromosome-positive metaphases and BCR-ABL-positive cells at the time of relapse. In only 1 patient in hematologic remission was no positive PCR analysis obtained in the two samples tested. However, 5 patients have remained or became Ph-chromosome and/or PCR-positive after BMT without clinical symptoms of disease. In samples from another patient, transient presence of leukemic cells was observed only early after BMT. Clinically, these patients were relapse free at days 3,055, 2,581, 2,252, 1,846, 1,839, 1,747, and 1,173 after BMT, respectively. Based on these data, the presence of single BCR-ABL-positive cells > 1 year after BMT has no prognostic significance.
Adult↗
Transfer of insulin-dependent diabetes between HLA-identical siblings by bone marrow transplantation.
Insulin-dependent diabetes was observed in a woman, aged 29, 4 years after transplantation of bone marrow from her HLA-identical brother with insulin-dependent diabetes. Both had classic symptoms and insulin dependency from onset. At diagnosis of diabetes the recipient was positive for high-titre islet cell antibodies (ICA) whereas she had been ICA negative before transplantation. Chromosomal analyses verified that all circulating leucocytes were of male donor type. These findings suggest transfer of insulin-dependent diabetes by bone marrow cells and confirm the immune nature of the disease.
Adult↗
Lung effects after total body irradiation of mice and bone marrow transplant patients: comparison of experimental and preliminary clinical data.
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Adult↗
Rapid detection of engraftment using T cell receptor gene polymorphism after allogeneic bone marrow transplantation in an alloimmunized child with severe aplastic anemia.
A severely alloimmunized boy with aplastic anemia received an HLA-identical BMT from his brother. Despite intensive immunosuppression and large marrow dose, peripheral signs of engraftment occurred only late under G-CSF treatment. With leukocyte counts of < 0.5 x 10(9)/l, chimerism could be proven not only by oligonucleotide fingerprinting but also within 48 h by analysis of polymorphism in the TCR gene family. This rapid and sensitive method to detect engraftment before it became quantitatively evident was important for the clinical management of the patient, obviating the need to search for an alternative marrow donor.
Anemia, Aplastic↗
Constant intravenous pentoxifylline infusions in allogeneic marrow transplant recipients: results of a dose escalation study.
An uncontrolled open prospective dose escalation study of daily constant-rate 24-h i.v. pentoxifylline (PTX) infusions was performed in 24 consecutive adult patients with hematologic malignancies undergoing allogeneic BMT. The objective of this study was to determine the maximum tolerable dose and to evaluate steady-state plasma concentrations of PTX and its major active 5-hydroxylated metabolite (MI) with this application route. On each of three dose levels of PTX (10, 15 and 20 mg/kg/day), eight patients were enrolled in this study. The prominent dose-dependent and dose-limiting adverse effect attributable to PTX infusions was moderate to severe nausea and vomiting which occurred on the 15 mg/kg and 20 mg/kg dose levels. In addition, one patient on each of the higher doses developed central nervous system toxicity which manifested as acute obtundation and myoclonias. Monitoring of steady-state plasma concentrations revealed that metabolite MI contributed 70-80% to both active compounds with a dose-dependent increase of parent drug and metabolite MI concentrations. In patients pretreated by high-dose busulfan and cyclophosphamide (CY), steady-state plasma concentrations of metabolite MI were significantly increased on all dose levels over those of patients who received total body irradiation and CY as a preparative regimen. Furthermore, impairment of excretory liver function led to significant accumulation of parent drug and metabolite MI. In conclusion, constant i.v. PTX infusions in allogeneic marrow transplant recipients are limited by dose-dependent nausea and vomiting with an estimated maximum tolerable dose in the range of 10 mg/kg/day.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Interferon alpha and gamma alter the binding of progenitor cells to fibronectin of patients with CML.
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Fibronectins↗
Evidence that sustained growth suppression of intestinal anaerobic bacteria reduces the risk of acute graft-versus-host disease after sibling marrow transplantation.
The influence of intestinal bacterial decontamination on the occurrence of grades II to IV acute graft-versus-host disease (GVHD) was retrospectively analyzed in 194 predominantly adult patients treated by genotypically identical sibling marrow transplantation under conditions of strict protective isolation and intestinal antimicrobial decontamination. Forty-five patients (23%) developed acute GVHD and univariate analysis identified four features that significantly increased the risk for this reaction: chronic myeloid leukemia as the underlying disease, as compared with all other disease categories (P < .0001); female marrow donors for male recipients, as compared with other gender combinations (P < .005); ineffective, as compared with sustained growth suppression of intestinal anaerobic bacteria (P < .006); and methotrexate as the sole immunoprophylactic compound, as compared with cyclosporine containing regimens (P < .05). Using the duration of anaerobic growth suppression as a time-dependent explanatory variable, proportional hazards regression analysis confirmed these features as independent predictors for acute GVHD with relative risk estimates of 1.9 (95% confidence interval [CI], 1.3 to 2.7) for the immunoprophylactic regimen (P < .0004), of 1.8 (95% CI, 1.3 to 2.5) for the underlying disease (P < .0005), of 1.7 (95% CI, 1.2 to 2.5) for anaerobic decontamination (P < .002), and of 1.3 (95% CI, 1.1 to 1.6) for the donor/recipient gender combination (P < .008), respectively. Best subset selection modeling also identified the quality of anaerobic decontamination as the third most important predictor for acute GVHD, when all four significant features were included. Estimates of acute GVHD stratified by the quality of anaerobic bacterial growth suppression showed a strong influence of anaerobic decontamination in patients burdened by at least one of the other unfavorable factors (P < .009). In conclusion, this study provides strong evidence that sustained growth suppression of intestinal anaerobic bacteria after clinical sibling marrow transplantation can independently modulate the occurrence of grades II to IV acute GVHD, which is in concordance with previous results from animal transplantation models. Antimicrobial chemotherapy specifically targeted to the intestinal anaerobic bacterial microflora may be complementarily useful in preventing acute GVHD and should be investigated in a prospective trial.
Adolescent↗
Activity testing of alveolar macrophages and changes in surfactant phospholipids after irradiation in bronchoalveolar lavage: experimental and clinical data.
This study presents results of bronchoalveolar lavage (BAL) after irradiation to the lungs in mice as well as clinical data. The number of BAL cells, mainly macrophages, lymphocytes, and granulocytes, changed in a time-dependent manner. The phagocytic activity of the macrophages measured as the phagocytosis of microbeads and measured as the esterase activity also showed a strong time-dependent increase during the acute phase up to 21 days after irradiation. The contents of surfactant phospholipids (SF) and sphingomyelin (SPH; as a parameter for cell death) were quantified by HPLC. Both were significantly changed between day 2 and 21 after irradiation. Three BALs of a patient with idiopathic interstitial pneumonitis, who had received an allogenic bone marrow graft after total body irradiation with 10 Gy, showed similar effects in the cellular and surfactant parameters. These data indicate that there are positive interactions between the number of different BAL cells, macrophage activity, and SF and SPH content in the preclinical model of the mouse as well as in the clinical situation after lung irradiation.
Animals↗
[Bone marrow transplantation. Overview and personal results].
Main indications for allogeneic bone marrow transplantation are severe aplastic anemia, severe combined immunodeficiency, acute leukemia and chronic myeloid leukemia. In standard risk situations survival rates are 50 to 80%. The probability of disease-free survival after bone marrow transplantation is depending on the stage of disease. If possible bone marrow transplantation should be performed early, not in advanced disease when conventional measures failed. Main problems are therapy-related organ toxicity, rejection, graft-versus-host disease and a long lasting risk of infection. Usually histocompatible relatives of the patients are selected as marrow donors. Bone marrow transplantation using unrelated donors is under investigation. Autologous transplantations with cryopreserved marrow are performed in acute leukemia, malignant lymphomas and some solid tumors, but prospective studies comparing transplantation and conventional therapeutic procedures are still missing.
Adolescent↗
Combined effect of very early intensification and prolonged post-remission chemotherapy in patients with AML.
The study combines the effects of prolonged postremission chemotherapy with that of very early intensification. 900 adult patients at all ages with newly diagnosed AML uniformly received TAD for induction and consolidation followed by monthly myelosuppressive maintenance for 3 years. In patients of 60+ years with persistent bone marrow blasts a second TAD course was given. In all patients of less than 60 years a second induction course started on day 21 even in aplasia with no blasts. Second induction was randomly either TAD or HAM. In the younger age group 69% attained CR and similar in the two arms the CR rate after 5 years is 35%. Including the 50% patients attaining CR in the higher age group the CR rate after 5 years is 32%. In 40 patients receiving allogeneic BMT and 21 patients receiving autologous BMT in first CR relapse free survival is similar to that from chemotherapy alone in a matched pair analysis. We conclude that age adapted very early intensification followed by prolonged postremission chemotherapy represents a therapeutic progress.
Adolescent↗
Longterm effects of prolonged maintenance and of very early intensification chemotherapy in AML: data from AMLCG.
In order to further improve the cure rate in AML we investigated the effect of more chemotherapy--in terms of its intensity and its duration--in 2 studies. In our 1981 study patients received TAD 1-2 courses for induction, 1 course for consolidation and randomly no further treatment or monthly myelosuppressive maintenance for 3 years. Evaluating 213 responders remission duration was clearly longer in the maintenance group with 24% CCR after 5 and 10 years. In our 1985 study the same successful strategy was further intensified by a second induction course given regardless of response to the first course to all patients up to 60 years of age while older patients received standard induction as before. This age-adapted concept resulted in a further increase of 5 years CCR in the 461 responders to as much as 34% not achieved for unselected patients in other multicenter trials. 20 patients receiving auto-BMT in first CR show the same relapse free survival as their counterparts receiving chemotherapy according to the 1985 protocol in a matched-pair analysis. We conclude that both very early intensification and prolonged maintenance contribute to a higher cure rate that is not further improved even by a maximum intensity short-term treatment. The limits of chemotherapy in AML may be overcome by modulating its myelotoxicity and antileukemic potency using GM-CSF as shown in 2 studies of our group.
Acute Disease↗
[Maintenance of remission in acute myeloid leukemia by allogeneic or autologous bone marrow transplantation].
Over a 10-year period 120 patients (58 women, 62 men; median age 33 [14-53] years) with acute myeloid leukaemia were treated by allogenic (n = 90) or autologous bone marrow transplantation to maintain remission. After a median observation time of 41 (11-126) months 64 patients (53%) remain alive without recurrence of leukaemia. Ten years after allogenic transplantation performed during the first complete remission the probability of disease-free survival is 50 +/- 8%, as compared with 50 +/- 9% at 4.5 years after autologous transplantation. Significant factors influencing disease-free survival after allogenic transplantation during the first complete remission were the time interval up to the onset of remission and the length of the remission before transplantation. The chance of disease-free survival after allogenic transplantation in the second complete remission does not so far differ from the results achieved by transplantation in the first complete remission. The risk of recurrence after autologous transplantation in the first complete remission (47 +/- 10%) is significantly higher than that following allogenic transplantation (18 +/- 10%, P less than 0.0001). Acute graft versus host reactions occurred in 16% and chronic reactions in 36% of patients after allogenic transplantation. The mortality was 38% after allogenic transplantation and 7% after autologous transplantation.
Acute Disease↗