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Biomedical subjects

T M Fliedner

Publications and source records attributed to T M Fliedner.

At least 73 records · Page 4Linked to original sources
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↗
PubMed1987

Variation of treatment conditions alters the outcome of fetal liver transplantation in dogs.

Fetal liver transplants (FLT) were carried out in 25 beagles under various conditions. Graft recipients were prepared with fractionated total body x-irradiation (TBI) of 3 X 6 Gy or 2 X 6 Gy and rescued with cryopreserved fetal liver cells (FLC) from 51- to 52-day-old or 43- to 46-day-old, DLA-identical siblings or DLA-haploidentical, homozygous half-siblings. In all groups, FLC grafts contained comparable numbers of granulocyte-macrophage progenitor cells. Initial engraftment was achieved in all dogs. However, low TBI dose and DLA haplotype disparity between donor and recipient were associated with graft failure in 1/3 and 2/9 recipients, respectively, within 10-16 days of treatment. Lectin-responsive host type lymphocytes circulated for more than 5 weeks, whereas bone marrow metaphases were always of donor sex. Reduced TBI dose and young donor age were associated with delayed granulocyte recovery. Moreover, circulating platelets and total lymphocytes as well as T and B-cell numbers and rose more slowly in recipients of immature FLC grafts than in the other groups. Delayed cutaneous hypersensitivity reactions were normal one year after FLT, whereas the IgM component of the hemagglutinin response to sheep red blood cells was depressed. In mixed leukocyte culture, chimeric lymphocytes were tolerant to host antigens. Nonetheless, clinical and histological signs compatible with low-grade graft-versus-host disease were recorded in 10 or 25 animals. Thus FLT in dogs could be carried out, even across DLA barriers, without severe graft-versus-host disease. However, a low pretransplant TBI dose, incomplete DLA match and young age of the fetal donor were associated with graft rejection and protracted restoration of hemopoiesis and immune functions.

Animals↗
PubMed1987

What kind of morphologically recognizable haemopoietic cells do we inject when doing foetal liver infusion in man?

There is no agreement, how to define the age of the embryo/foetus. From the 15th (fertilization) week onwards the whole foetal liver contains some 10(9) free haemopoietic cells. Before, and up to the 30th-34th weeks, the liver is the main site of haemopoiesis. The differential of embryonic smears (up to wk 9) differs from that of foetal ones. The first invasion of circulating primitive erythroblasts seeding in the liver (early 5th wk) is accompanied by the appearance of a lot of sinusoidal macrophages. Definitive erythropoiesis expands during the 6th-7th wks. Granulocytic representation peaks at 15-16 wks. Megakaryocytes are small and have few nuclei/nuclear lobes. Five to 8, or even more per cent of single haemopoietic cells were lymphoid-like cells in the 5th-6th wk liver smear. These cells precede the development of any lymphoid structure in the foetus. Ordinary lymphocytes amount to less than 2% between 10 and 18 wks, and reached 3% at wk 24. Percentage of dyserythropoietic nuclei in smears has been used to decide whether the injected cells could be regarded as 'physiological' cells. Ten out of 11 apparently healthy foetuses, delivered by hysterectomy/hysterotomy for maternal interest, aged 10 1/2 to 20 1/2 weeks, had mean 4.5% liver dyserythropoiesis. Extremely high dyserythropoiesis was associated with multilineage, instead of overwhelmingly erythroid haemopoiesis.

Cell Differentiation↗
PubMed1987

Development and histogenesis of the thymus in dog. A light and electron microscopical study.

The development of the thymus was studied with histological, transmission electron microscopic (TEM) and histochemical methods in 100 dog fetuses (beagle), between day 19 of gestation and day 21 after birth. Thymus development could be divided in three stages: 1/Formation of epithelial palisades; 2/Initiation of lymphopoiesis; 3/Differentiation of the medulla and Hassall's bodies (HB). The epithelial anlagen were seen at day 23 of gestation showing the characteristic palisade structure of the endodermally derived epithelium. Ten days later the beginning of lymphoiesis and the reticularization of the epithelial cells could be seen. The first HB could be found at day 38 when cortical-medullary differentiation is recognized. The histochemical observation demonstrated a rich content of PAS positive coarse granules in the cytoplasm of reticulo-epithelial (RE) cells. On the other hand, the HB showed a diffuse PAS positive reaction. The ultrastructural investigations demonstrated the presence of desmosomes connecting RE cells to one another. Desmosomes were not found between RE and lymphocytes. The growth of the developing thymus into the mesenchymal matrix resulted in the lobulation of the organ by connective tissue cells and fibers. The first mast cells were seen at day 35 of gestation, most abundantly in the interlobular connective tissue (ICT) although a few were present in the cortex and somewhat more in the medulla, near the HB. At the end of development small groups of neutrophil cell precursors appeared in the ICT and the cortex. Cysts were not present up to day 21 after birth.

Animals↗