PubMed Health⌕ Search

Biomedical subjects

T M Fliedner

Publications and source records attributed to T M Fliedner.

At least 19 recordsLinked to original sources
PubMed1992

Haematological effects of rhGM-CSF in dogs exposed to total-body irradiation with a dose of 2.4 Gy.

It was the specific aim of this study to test the stimulatory effects of recombinant human GM-CSF (rhGM-CSF) on haemopoietic regeneration in dogs which had received total-body irradiation (TBI) with a dose of 2.4 Gy. In normal dogs rhGM-CSF given subcutaneously at 10 microgram/kg per day or 30 microgram/kg per day for 21 days caused strong but transient increases in the peripheral blood neutrophils. The monocyte counts also showed a transient rise during treatment in a dose-dependent fashion, whereas the lymphocyte counts increased only at the higher dose of rhGM-CSF and the platelet counts were transiently depressed during the course of the treatment. In the irradiated animals treatment with rhGM-CSF decreased the severity and shortened the duration of neutropenia but had no significant influence on monocyte or lymphocyte recovery. The granulocyte values showed a characteristic pattern of fluctuations with the first peak occurring at the same time (day 10 to day 13) when the abortive rise was observed in the untreated dogs. In contrast the GM-CFC in the peripheral blood remained depressed during the whole treatment course, similar to the untreated irradiated controls. These results indicate that treatment with GM-CSF can be an effective biological monotherapy for radiation-induced bone marrow failure, but that for higher radiation doses the number of GM-CSF responsive target cells will become a critical determinant of therapeutic efficacy.

Animals↗
PubMed1992

Cancer after bone marrow transplantation. IBMTR and EBMT/EULEP Study Group on Late Effects.

Cancer may be serious late effect of marrow transplantation. Radiation, chemotherapy, immunosuppression and the original disease for which transplantation was performed may predispose to the development of cancer. 116 of 9732 patients reported to the IBMTR (International Bone Marrow Transplant Registry) have developed a new malignancy. Late effects were evaluated by the EBMT-EULEP (European Bone Marrow Transplant-European Late Effect Project) Late Effect Study Group in 147 patients surviving 6 years and 79 patients surviving more than 10 years. New malignancies developed in 11 of these patients. Lymphomas and leukemia comprised 73 cases reported to the IBMTR and one case reported to the EBMT-EULEP study. Tumors of the skin, oropharynx, vulva vagina and cervix prevailed in 41 patients with solid tumors. The distribution of malignancies is similar to that observed in organ transplant patients not given radiation or chemotherapy and suggests immunosuppression as a major contributory factor. In dogs the incidence of malignancies was studied after either chemotherapy or total body radiation in various regimens and marrow transplantation. Both chemotherapy and radiation shortened tumor-free survival in comparison to untreated dogs. Higher doses, larger fractions and shorter treatment schedules enhanced earlier tumor development. Soft tissue sarcomas and thyroid carcinoma were most frequent in treated, mammary carcinoma in untreated dogs. In treated dogs deaths from cancer were observed starting at the age of 5 years as compared to untreated dogs at the age of 9 years. The data from animal experiments indicate that the incidence of solid tumors in marrow transplant patients may still rise in the coming decades.

Animals↗
PubMed1991

Autologous blood stem cell (ABSCT) versus purged bone marrow transplantation (pABMT) in standard risk AML: influence of source and cell composition of the autograft on hemopoietic reconstitution and disease-free survival.

Complete and sustained hemopoietic function following myeloablative therapy can be successfully achieved by autologous transfusion of blood derived hemopoietic stem cells. It was the purpose of this study to compare autologous blood stem cell transplantation (ABSCT) in 20 patients with autologous transplantation of a mafosfamide purged marrow (pABMT) in 23 patients; all were transplanted in first complete remission (CR) of acute myelogenous leukemia (AML) using the same pretransplant regimen (14.4 Gy total body irradiation and 200 mg/kg cyclophosphamide). The autografts, mostly differing in source of hemopoietic stem cells, cell composition and CFU-GM number, were evaluated for their ability to reconstitute hemopoiesis and induce long-term disease-free survival (DFS). Prior to harvest, hemopoietic stem cells were mobilized by inducing transient myelosuppression (ara-C 100 mg/m2 every 12 h s.c. days 1-5 and daunorubicin 45 mg/m2, days 3 and 4) followed by an overshooting of peripheral stem cell concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Early indicators of response to accidental radiation exposure and the relevance for clinical management strategies.

In the development of clinical strategies to manage radiation accident casualties, the medical doctor in charge should be encouraged to use a "decision tree" to establish by a "sequential diagnosis procedure". This should be done within the first few days after exposure to determine whether or not a spontaneous recovery of hemopoietic function can be expected. With the assistance of a computer simulation model it appears possible to relate certain granulocyte response patterns to the extend and quality of damage caused in the hematopoietic stem cell pool. The determination of this damage is of great importance because it quantifies the strain inflicted upon the hemopoietic system by radiation exposure. It must be remembered that some stem cells are intact or are able to repair the damage completely. These stem cells serve as the ultimate source of hemopoietic recovery. The other stem cells that are left with the restricted hematopoietic potential are the source for the so called abortive recovery. On this basis it must be recognized that the day-to-day detailed analysis of documentation of blood cell changes for the first 5-10 days after exposure is of critical importance in order to be able to answer the question whether a spontaneous hemopoietic recovery can be expected or not. If the stem cell pool is sufficiently damaged (less than 6-8 in 10,000 stem cells) then one can expect a particular constellation of blood cells around day 5-7 characterized by severe granulocytopenia, severe lymphopenia and beginning thrombocytopenia. This blood cell response pattern is indicative of an irreversible stem cell damage. In this case, a transplantation of stem cells may well be life saving if done using the criteria developed for the treatment of severe aplastic anemia by bone marrow transplantation including an appropriate conditioning regimen for immune suppression.

Accidents↗
PubMed1990

Autologous blood stem-cell transplantation in patients with advanced Hodgkin's disease and prior radiation to the pelvic site.

Patients with relapsed Hodgkin's disease who respond to salvage therapy are successfully treated with cyclophosphamide, carmustine (BCNU), and etoposide (VP-16) (CBV) followed by autologus bone marrow transplantation (ABMT). Because of heavy pretreatment including radiation to the pelvic site, marrow harvest was not feasible in those patients. We therefore used blood-derived hemopoietic precursor cells as an alternative stem-cell source to rescue them after superdose chemotherapy. Hemopoietic precursor cells were mobilized into the peripheral blood either by chemotherapeutic induction of transient myelosuppression followed by an overshooting of blood stem-cell concentration, or by continuous intravenous (IV) granulocyte-macrophage colony-stimulating factor (GM-CSF) administration. The median time to reach 1,000 WBC per microliter, 500 polymorphonuclear cells (PMN) per microliter, or 20,000 platelets per microliter was 10, 20.5, and 38 days, respectively, for 50% of all patients. The platelet counts of two patients never dropped below 20,000/microL following autologous blood stem-cell transplantation (ABSCT), whereas two other patients had to be supported with platelets for 75 and 86 days posttransplant until a stable peripheral platelet count of 20,000/microL was attained. Among the 11 assessable patients, seven are in unmaintained complete remission (CR) at a median follow-up of 318 days. This is a first report on a series of ABSCTs in patients with advanced Hodgkin's disease proving that, despite prior damage to the marrow site, the circulating stem-cell pool is still a sufficient source of hemopoietic precursor cells for stem-cell rescue.

Adult↗
PubMed1990

[The stem cell system of hematopoiesis: physiological and pathophysiological concepts].

It is the purpose of this review to describe the physiological as well as the pathophysiological principles of the hematopoietic stem cell system. The concept of hemopoietic stem cells has a long history which is now understood on the basis of its embryogenesis and after collecting extensive experimental and clinical experience using stem-cell transplantations as a means to restore hematopoietic function of the bone marrow after appropriate conditioning. The hemopoietic stem cells cannot be distinguished by light microscopy from "lymphocytes" considered to be a heterogeneous group of mononuclear cells. These stem cells can respond to specific regulatory factors with specific differentiation and proliferation, and are very radiosensitive and resistant to cryopreservation. The system responds to perturbations in a manner characteristic for feed back regulation and is bound in its physiology to an intact stromal matrix.

Animals↗
PubMed1990

Prediction of clinical outcome of radiation accident victims.

On the basis of the analysis of more than 350 individuals that were exposed to ionizing radiation in the course of more than 25 radiation accidents reported world wide since 1945, a biomathematical computer model was developed that simulates the pattern of granulocyte changes seen. It allows one to calculate the number of stem cells remaining intact to initiate recovery. It is shown that the major question to be asked is whether a spontaneous stem cell recovery can be expected or not. This question can be readily answered within 3-5 days after radiation exposure on the basis of the constellation of hematopoietic findings and devised stem cell pool size calculations.

Accidents↗
PubMed1989

Disease-free survival after autologous bone marrow transplantation in patients with acute myelogenous leukemia.

Autologous bone marrow transplantation (ABMT) makes it possible to escalate the dose of cytotoxic treatment to a lethal range. Disease-free survival (DFS) following myeloablative therapy and ABMT has been shown to be superior to conventional treatment in high risk patients with acute myelogenous leukemia (AML). It was the purpose of the present study to compare hematopoietic reconstitution, actuarial DFS, and relapse rate of patients transplanted in first complete remission (CR) of AML with those in second or subsequent CR, and to evaluate transplant related mortality. Fifty-two patients with AML, 22 in first CR (low risk) and 30 in second or subsequent CR (high risk), underwent total body irradiation (12.1 to 16.7 Gy) and cyclophosphamide (CY) treatment (200 mg/kg) followed by ABMT. The autograft was incubated with the active CY derivative Mafosfamide (ASTA Werke, Bielefeld, Federal Republic of Germany) to reduce the number of possibly contaminating clonogenic tumor cells. All patients showed three lineage engraftments with platelet recovery observed as being the slowest. The transplant related death rate was low at 5.8%. There was no significant difference in the kinetics of polymorphonuclear (PMN) cell or platelet reconstitution between the low and high risk patient subgroups. The estimated probability of DFS (relapse) after ABMT in first CR was 61% (36%) compared with 34% (65%) in second or subsequent CR, the longest follow-up being 55 months and 57 months, respectively (median follow-up 31 months and 19 months, respectively). ABMT offers a stable long-term DFS when performed in first CR with no relapses occurring in over a year after transplantation. Six later relapses, however, were seen after ABMT in second or subsequent CR, although DFS was not statistically different from that of first remission patients (P = .72).

Adult↗
PubMed1989

[Dose, radiation effect and initial symptoms following unexpected whole body irradiation: an analysis of 19 accidents].

The radiation induced effects on the haemopoietic system and the human body after acute unexpected whole body irradiation are manifold. Therefore it is meaningful to incorporate the scientific foundations of radiation effects in the available knowledge about the consequences of radiation exposure. From this aspect the present paper evaluates 19 acute radiation accidents which were published between 1945 and 1986 in the scientific literature involving about 597 individuals. Even in the case of an uncomplicated radiation effect the physician must not rely on the estimated physical dose because it does not or does not necessarily correlate with the different course of events taken by the individual categories of the acute radiation syndrome. In fact, the dose is of minor importance to the physician because as a rule it can only be determined too late due to the complex parameters. The classification, therapy and prognosis of the accident victims is largely governed by the pathophysiology which results from the random probability of the cell killing mechanisms by radiation, inhomogeneous dose distribution and the scattered distribution of the haemopoietic system in the human body. The fact that in the case of accidentally induced total body irradiation there is only inhomogeneous distribution of radiation dose is a life-saving factor in most cases. Furthermore, it is pointed out that by means of simple diagnostic methods, e.g. the initial symptoms, the first classification of accident victims is also largely possible without referring to the dose.

Accidents↗
PubMed1989

[Reversible and irreversible damage to hematopoiesis following unexpected whole body irradiation: markers in peripheral blood].

During the past decade worldwide experience concerning radiation accidents demonstrated that the medical diagnosis and therapy of radiation victims has to be reconsidered. This paper describes and analyzes the clinical relevance of one of the most simple diagnostic methods, namely daily monitoring of the characteristic blood cell changes. On the basis of these methods the physician is in the position to decide at an early stage-independently of the physical dose-whether reversible or irreversible damage of the hemopoiesis is present. This is of great importance because the expected clinical development and, thus, the therapy and prognosis are different. The different behaviour of the blood cells depends on their life span, cell kinetics, radiation sensitivity and pathophysiology. Reversible damage (category I-IV) can be recognized at the latest on the 5th-6th day after radiation exposure and, according to the degree, may require supportive therapy. Irreversible damage which can probably be repaired by stem cell transfusion (category V) can also be determined on the 5th to the 6th day after radiation exposure. Irreversible damage without any chance of survival (category VI) can already be diagnosed 24 hours after the radiation event. Reversible and irreversible damage to hemopoiesis with the typical blood cell changes is presented with reference to some patients exposed to ionizing radiation in the Marshall Islands 1954, in Oak Ridge 1958, in Chernobyl 1986, in Los Alamos II 1946 just as III 1958, and in Wood River Junction 1964.

Accidents↗
PubMed1989

Hematological effects in dogs after irradiation of the lower part of the body with a single myeloablative dose.

The lower body of dogs, containing approximately 30% of the total bone marrow, was exposed to 300 kV X-rays with a single myeloablative dose of 11.7 Gy, whereas the upper body was shielded by a lead box. The results of the present study are discussed in connection with recently published results obtained after irradiation of the upper body (UBI), containing approximately 70% of the total bone marrow mass. The main findings are as follows: (1) the nadir in the blood concentration of thrombocytes, lymphocytes, and granulocytes strongly depends on the volume of irradiated bone marrow; (2) apart from some quantitative differences, the time-related pattern of changes in the concentration of granulocyte/macrophage progenitor cells (GM-CFC) in irradiated and shielded bone marrow sites is very similar after irradiation of the lower part of the body (LBI) and UBI, i.e. is apparently independent of the relative amount of damaged bone marrow at volumes applied in the present models; (3) the concentration of GM-CFC in the blood after LBI shows a transient increase during the first phase of most rapid bone marrow GM-CFC regeneration, i.e. between day 7 and day 23; the magnitude of this transient increase obviously depends on the fraction of irradiated bone marrow.

Animals↗
PubMed1989

Hematological effects in dogs after sequential irradiation of the upper and lower part of the body with single myeloablative doses.

The compensating mechanisms determining the tolerance of the hemopoietic system to sequential hemibody irradiation (HBI) with large single doses, the regeneration of the irradiated bone marrow and the long-term effects of such treatment were studied in dogs. The main emphasis was laid on the determination of the granulocyte/macrophage progenitor cells (GM-CFC) in the bone marrow and blood. The general pattern of events in the GM-CFC compartment after each exposure was similar. Irradiation with a dose of 11.7 Gy of the upper body (UBI), that involved the abrogation of approximately 70% of the total active marrow, was followed by an immediate increase in the proliferation and differentiation of GM-CFC in the protected bone marrow. Repopulation of the GM-CFC in the irradiated sites most probably due to seeding of hemopoietic cells from the protected marrow already became evident at day 7 after UBI. At day 56 after UBI, when the irradiation of the lower body (LBI) was performed, the GM-CFC had recovered to between 30 and 40% of their pre-treatment values. Despite this incomplete regeneration, the GM-CFC compartment responded to LBI in a similar way as the GM-CFC had in the protected (normal) marrow after UBI, i.e. by an increased proliferation for at least 21 days. Already at day 7, the bone marrow of the iliac crest that had been exposed to LBI showed a considerable number of GM-CFC. Within no more than 370 days all the bone marrow sites irradiated during either the first or the second treatment had regained their normal GM-CFC values.

Animals↗
PubMed1988

Blood cell changes after radiation exposure as an indicator for hemopoietic stem cell function.

This paper describes the criteria to be used in the management of persons accidentally exposed to ionizing radiation for predicting whether the stem cell pool damage was reversible or irreversible. This question is of importance. If the damage was reversible, the clinical management may be restricted to symptomatic therapeutic measures (antibiotics, platelet transfusions). If the indicators show that the stem cell damage is irreversible (from a clinical viewpoint) then stem cell transplantation must be considered and performed. A granulocyte computer simulation model is discussed that may be useful in the analysis and evaluation of blood cell regeneration patterns after radiation and transfusion of stem cells from different sources.

Animals↗
PubMed1988

Repopulating potential of hematopoietic precursor cells.

Experiments were performed in 1800 cGy whole-body x-irradiated dogs. Mononuclear cells were collected from bone marrow, peripheral blood, and fetal liver. They were cryopreserved in -196 degrees C liquid nitrogen until used for transplantation. The thawed transfusates were adjusted to contain 1.5-1.6 x 10(5) CFU-GM per kg body weight. The blood granulocyte recovery was rapid after transfusion of blood-derived stem cells as compared to the use of bone-marrow-derived stem cells. In both instances, however, normal values were not reached for several weeks. In contrast, the use of fetal-liver-derived stem cells resulted in a very rapid initial granulocyte increase with a return of values to normal (or even overshoot) within 3 weeks after transplantation. A biomathematical granulocyte renewal simulation system is described that permits calculation of the absolute number of pluripotent stem cells in the transfusate. The data after fetal liver stem cell transplantation can be fitted only if an initial stem cell replication rate of 0.95 is assumed (in contrast to 0.65 using bone marrow or blood-derived stem cells).

Animals↗