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  • 1
    Electronic Resource
    Electronic Resource
    Bone marrow changes in chronic myelogenous leukaemia after long-term treatment with the tyrosine kinase inhibitor STI571: an immunohistochemical study on 75 patients (2005)
    Oxford, UK : Blackwell Science Ltd
    Histopathology 46 (2005), S. 0 
    Details
    ISSN: 1365-2559
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Aims:  To carry out an immunohistochemical study on bone marrow (BM) biopsy specimens in 75 patients with chronic myelogenous leukaemia (CML) on long-term STI571 therapy.Methods and results:  Sequential BM specimens taken at intervals of 21 ± 6 months were investigated by enzyme- and immunohistochemistry including proliferating cell nuclear antigen and apoptosis. Evaluation was performed either by semiquantitative scoring or by morphometry (CD61+ megakaryopoiesis). In 41 patients with chronic phase CML, treatment resulted in a significant decrease in cellularity and neutrophil granulopoiesis contrasting with an accumulation of erythroid precursor cells. Morphometry showed a reduction of abnormal micromegakaryocytes consistent with normalization. Regression of myelofibrosis was identified in eight of 15 patients, whereas progression occurred in 17 patients; mostly in those with acceleration and blastic crisis. The increased post-treatment incidence of reactive lymphoid nodules was remarkable. Myeloblasts, CD34+ progenitors and immature myelomonocytic cells initially decreased, but recurred in 14 patients who later developed a relapse. STI571 exerted an inhibitory effect on cell proliferation associated with enhanced apoptosis in responding patients.Conclusion:  Long-term treatment with STI571 exerts pronounced changes on BM histopathology that not only involve haematopoiesis and stromal constituents, but also proliferation and apoptosis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1365-2559.2005.02119.x
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  • 2
    Electronic Resource
    Electronic Resource
    Bone marrow histopathology following cytoreductive therapy in chronic idiopathic myelofibrosis (2003)
    Oxford, UK : Blackwell Science Ltd
    Histopathology 43 (2003), S. 0 
    Details
    ISSN: 1365-2559
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Aims:  To analyse systematically therapy-induced lesions of haematopoiesis in chronic idiopathic myelofibrosis (IMF).Methods and results:  A total of 759 sequential bone marrow (BM) biopsies (median interval 32 months) were performed in 261 patients with IMF. Besides a control group (symptomatic treatment), monotherapies included busulfan, hydroxyurea and interferon. In all therapy groups hypoplasia of varying degree was a frequent finding and often accompanied by a patchy distribution of haematopoiesis. Most conspicuous was gelatinous oedema showing a tendency to develop discrete reticulin fibrosis (scleroedema). Minimal to moderate maturation defects of megakaryopoiesis and erythroid precursors occurred, but overt myelodysplastic features were most prominent following hydroxyurea and busulfan therapy. Acceleration and blastic crisis were characterized by the appearance of immature and CD34+ progenitor cells. Concerning the dynamics of fibrosis, no differences were observed between controls and the various therapy groups. In 143 patients (55%) without or with little reticulin at onset, an increase in myelofibrosis was detectable that progressed to overt collagen fibrosis.Conclusions:  Therapy-related bone marrow lesions in IMF comprise a strikingly variable spectrum that may include aplasia with scleroedema and a patchy distribution of myelodysplastic haematopoiesis associated with progressive myelofibrosis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1365-2559.2003.01732.x
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  • 3
    Electronic Resource
    Electronic Resource
    Changing patterns of histological subgroups during therapy of Ph1+ chronic myelogenous leukaemia (2000)
    Oxford, UK : Blackwell Science Ltd
    Histopathology 37 (2000), S. 0 
    Details
    ISSN: 1365-2559
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: AimsBone marrow histopathology reveals a striking heterogeneity at diagnosis of Philadelphia chromosome positive (Ph1+) chronic myelogenous leukaemia (CML). Based on semiquantitative evaluations of the number of megakaryocytes and the content of fibres, various histological subtypes have been postulated. However, little information exists on whether these groups represent stable categories of the different classification systems and whether therapeutic regimes exert any influence on the putative shift of histological patterns.Methods and resultsA retrospective clinicopathological study was performed on 396 bone marrow biopsies derived from 173 patients. There were at least two representative trephines taken at diagnosis and at median intervals of 16 months. Processing of the specimens involved immunostaining with CD61 (megakaryopoiesis) and Ret40f (erythropoiesis) and Gomori's silver impregnation technique. Based on morphometric analysis and in accordance with the general appearance of bone marrow histology three different histological subtypes were distinguished. These consisted of a granulocytic (51 patients), a predominantly megakaryocytic (73 patients) and a myelofibrotic pattern (49 patients). Follow-up biopsies revealed that a significant transition of histological groups occurred and that, independently of treatment modalities, the myelofibrotic category was associated with an unfavourable prognosis. Of the 124 patients without myelofibrosis at onset, 42% later transformed into the myelofibrotic subtype. However, these patients showed no prevalence of either a pre-existing granulocytic or megakaryocytic growth. Myelofibrotic changes were significantly associated with interferon (IFN) and busulfan (BU) therapy. On the other hand, a transition of a myelofibrotic into a nonfibrotic subtype was detectable in 17 of the 49 patients under study and related to hydroxyurea (HU) treatment.ConclusionsHistological classification systems of bone marrow features in CML do not represent stable patterns, but may be significantly altered by therapy, in particular IFN and HU.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1365-2559.2000.00993.x
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  • 4
    Electronic Resource
    Electronic Resource
    Macrophages and their subpopulations following allogeneic bone marrow transplantation for chronic myeloid leukaemia (2000)
    Springer
    Virchows Archiv 437 (2000), S. 160-166 
    Details
    ISSN: 1432-2307
    Keywords: Key words Macrophages ; Pseudo-Gaucher cells ; Chronic myeloid leukaemia ; Bone marrow transplantation ; Bone marrow biopsies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  A morphometric and immunohistochemical study was performed on 354 bone marrow trephine biopsies derived from 126 patients with chronic myeloid leukaemia (CML) before and after allogeneic bone marrow transplantation (BMT). The purpose of this investigation was to evaluate the macrophage population, including several subsets and their dynamics in the posttransplant period. In addition to the total CD68+ resident (mature) macrophages the so-called activated fraction identified by its capacity to express α-d-galactosyl residues, the pseudo-Gaucher cells (PGCs) and the iron-laden histiocytic reticular cells were also considered. Following immuno- and lectin-histochemical staining morphometric analysis was carried out on sequential postgraft bone marrow specimens at standardized intervals. Compared to the normal bone marrow and calculated per haematopoiesis (cellularity) an overall decrease of about 40–50% in the quantity of CD68+ macrophages and the BSA-I+ subpopulation was detectable in the early posttransplant period (9–45 days after BMT). Noteworthy was the temporal recurrence of PGCs in the engrafted bone marrow, which was not associated with a clonally transformed cell population or leukaemic relapse. Reappearance of postgraft PGCs was most prominent in the first 2 months after BMT. This conspicuous feature was presumed to be functionally associated with a pronounced degradation of cell debris following pretransplant myelo-ablative therapy (scavenger macrophages). Evidence for an activation of the BSA-I+ macrophage subset was derived from the identical carbohydrate-binding capacity shown by the PGCs. In the regenerating haematopoiesis shortly after BMT a significant correlation between the number of BSA-I+ macrophages and erythroid precursor cells was determinable. This result implicates a close functional relationship between postgraft reconstitution of erythropoietic islets and centrally localized activated macrophages. In conclusion, findings emerging from this study included the reappearance of PCGs in the engrafted bone marrow independently of a leukaemic relapse and the significant association of the activated BSA-I+ macrophage subset with the recovery of erythropoiesis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004280000224
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  • 5
    Electronic Resource
    Electronic Resource
    Overestimation of osteopenia using standard analysis software for peripheral quantitative computed tomography (1993)
    Springer
    Journal of molecular medicine 71 (1993), S. 600-603 
    Details
    ISSN: 1432-1440
    Keywords: Peripheral quantitative computed tomography ; Trabecular bone density ; Reference values
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary It is well established that measurement of bone mineral density (BMD) can estimate the risk of future fractures. To assess individual fracture risk BMD measurements are compared with a reference range provided by the manufacturer of the respective BMD technology. However, the power of trabecular bone measured by peripheral quantitative computed tomography (pQCT) to predict future fractures has not been shown up to now. We conducted measurements of trabecular bone density (TBD) at the distal radius (pQCT XCT 900, Stratec, Germany) in a sample of 506 healthy white women aged 40–60 years (mean 48) and compared the results with the manufacturer's normal range. We found a remarkable difference in TBD values between our healthy study population and the manufacturer's reference data in all age groups (e.g., age 50–54 years, 143.1 ± 43.2 mg/cm3 versus 181.1 ± 39.0 mg/cm3). Compared to the ± 2 SD limits of the manufacturer's reference range our study population showed mean TBD values that were about 1 SD below the mean of the reference range. About 50% of our healthy cohort were below the −1 SD limit of the reference range. Almost ten times as many normal subjects as expected (22.1%) were found below the −2 SD limit and therefore classified as individuals with increased fracture risk. This overestimation of fracture risk leads to discomfort of the patient, unnecessary therapeutic intervention, and significant costs to the public. This difference is probably due to the fact that the manufacturer's reference values were generated with the older device (SCT 900) using a 125I source, and that these were later used in devices with an X-ray source. Correction of the manufacturer's software is now underway; all devices with X-ray source distributed in Germany by the company must receive a new software with a generally agreed reference data-set. Our study indicates that a reliable reference database must become a prerequisite for the approvement of BMD technology prior to the use in patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00184482
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  • 6
    Electronic Resource
    Electronic Resource
    Velocity of ultrasound at the patella: Influence of age, menopause and estrogen replacement therapy (1993)
    Springer
    Osteoporosis international 3 (1993), S. 308-313 
    Details
    ISSN: 1433-2965
    Keywords: Estrogen replacement therapy ; Menopause ; Osteoporosis ; Velocity of ultrasound
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Determination of apparent velocity of ultrasound (AVU) in bone has been proposed as a valuable tool for discriminating between normal and osteoporotic women. We have studied the influence of age, menopause and estrogen replacement therapy (ERT) on AVU at the patella in a large sample of pre- and postmenopausal women. Three hundred and eighteen woman aged 40–60 year participated in the study (112 women were premenopausal, 21 were perimenopausal and 185 were postmenopausal of whom 110 had received ERT for a minimum of 1 year). AVU was determined as the mean of four measurements at each patella using a Signet instrument (Osteo-Technology, Framingham, MA). An age-dependent decline in AVU was observed only after menopause (r=−0.33,p=0.0055); in premenopausal women there was a slight but not significant decrease in AVU with age (r=−0.12,p〉0.05). AVU was significantly lower in postmenopausal women compared with premenopausal women (1882±84 m/s vs 1961±73 m/s,p〈0.05). ERT prevented the menopause-related fall in AVU. There was a significant positive correlation between the duration of ERT and AVU measurements. Our findings demonstrate a pronounced influence of estrogens on AVU at the patella, supporting the concept of a protective role of ERT in bone stability. AVU measurements therefore merit further investigation as an inexpensive method for predicting fracture risk that does not expose the subject to radiation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01637316
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  • 7
    Electronic Resource
    Electronic Resource
    Megakaryocytes and sinus walls in primary osteomyelofibrosis: transendothelial migration as revealed by three-dimensional reconstruction of serial sections following sequential double-immunostaining (1994)
    Springer
    Virchows Archiv 424 (1994), S. 383-387 
    Details
    ISSN: 1432-2307
    Keywords: Megakaryocytes ; Sinus wall ; Transmural migration ; 3D-reconstruction ; Double-immunostaining
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Using sequential double-immunostaining and a newly-developed three-dimensional (3D-) reconstruction technique on serially cut sections from bone marrow trephines, we studied the transmural passage of megakaryocytes through the sinus wall. Biopsies derived from patients with primary (idiopathic) osteomyelofibrosis were exposed to monoclonal antibody against type IV collagen to delineate the sinus walls and also the frequently thickened basement membrane. Staining with the primary antibody was followed by Y2/51 (CD61) to identify all elements of megakaryopoiesis. In most instances serial sectioning and 3D-reconstruction revealed an amoeboid shape of megakaryocytes and a tandem-like arrangement in close spatial contact with the abluminal surface of the sinus wall. Preceded by formation of cytoplasmic processes, straight penetration of entire megakaryocytes through gaps in the sinus walls into the lumen was seen. Where collagen deposits apparently presented a barrier, a mole-like tunnelling through the basement membrane material (type IV collagen) was recognizable. Our findings are in keeping with the assumption that megakaryocyte locomotion is an essential requirement for normal thrombocytogenesis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00190560
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  • 8
    Electronic Resource
    Electronic Resource
    The impact of interferon versus busulfan therapy on the reticulin stain-measured fibrosis in CML – a comparative morphometric study on sequential trephine biopsies (1995)
    Springer
    Annals of hematology 70 (1995), S. 121-128 
    Details
    ISSN: 1432-0584
    Keywords: Key words CML ; Myelofibrosis ; Dynamics ; Megakaryocytes ; Morphometry ; Interferon ; Busulfan ; Sequential bone marrow biopsies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  To evaluate treatment-related changes of the reticulin stain-measured fibrosis in Ph1+-CML, a clinicopathological study was performed on sequential trephine biopsies of the bone marrow following either interferon (IFN) or busulfan (BU) monotherapy. Using the monoclonal antibody CD61 for the identification of megakaryopoiesis and Gomori's silver impregnation method, number of megakaryocytes and density of argyrophilic (reticulin and collagen) fibers were determined by morphometry. We studied specimens from 26 patients with IFN-alpha 2b (including nine patients with additional IFN gamma) therapy and from 23 patients who had received BU. In both groups, repeated bone marrow biopsies (total 125) revealed a significant increase in the fiber content, as well as in the number of megakaryocytes during treatment. To assess the dynamics of myelofibrosis more precisely, computation of differences in the degree of fiber density between the first and last examination was carried out. Regarding the considerable variations in the biopsy intervals, a so-called myelofibrosis progression index (MPI) was calculated. Following this rationale, we were able to demonstrate that, in comparison to the BU-group, speed of progression of bone marrow fibrosis was significantly increased in CML patients treated with IFN. Preliminary statistical analysis indicated a relationship between myelofibrosis on admission, which was always associated with increased growth of megakaryocytes, and the MPI with survival. Even when these parameters were regarded, prognosis was significantly more favorable in the IFN-treated patients. The failure of IFN and BU to inhibit the evolution of myelofibrosis may be related to several conversely acting pathomechanisms. Among others, the inability of both therapeutic agents to reduce the number of megakaryocytes more effectively should be taken into consideration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01682031
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  • 9
    Electronic Resource
    Electronic Resource
    Hematopoietic turnover index in reactive and neoplastic bone marrow lesions: quantification by apoptosis and PCNA labeling (1997)
    Springer
    Annals of hematology 75 (1997), S. 33-39 
    Details
    ISSN: 1432-0584
    Keywords: Key words Apoptosis ; PCNA-labeling ; Idiopathic thrombocytopenia ; Polyglobuly ; Reactive thrombocytosis ; Primary thrombocythemia ; Polycythemia vera ; AML ; Hematopoietic turnover index ; Bone marrow
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  In order to determine the dynamics of hematopoietic cell turnover, proliferative activity and incidence of apoptosis (programmed cell death) were evaluated in bone marrow trephine biopsies. Selection of patients (20 in each group) included in addition to a control group, idiopathic thrombocytopenia (ITP), reactive thrombocytosis (TH), secondary polycythemia-smokers' polyglobuly (PG), primary (essential-hemorrhagic) thrombocythemia (PTH), polycythemia vera (PV), and finally acute myeloid leukemia (AML). Apoptosis was demonstrated by the in situ end-labeling technique (ISEL) and proliferative activity by applying the monoclonal antibody PC10 raised against proliferating cell nuclear antigen (PCNA). To assess dynamic features of hematopoiesis, an index was calculated consisting of the ratio between PCNA-positive nuclei and the apoptotic cell fraction. This factor was termed the hematopoietic turnover index (HTI). Morphometric analysis revealed that the HTI was significantly increased in AML and PV. According to cell culture studies both disorders are characterized by either a prevalent proliferation of the myeloid or erythroid cell mass. On the other hand, PG, PTH, and TH showed no relevant enhancement of this index in comparison to the control specimen. In vitro experiment results are in keeping with the finding that PG and PTH are not associated with a significant expansion of the erythroid lineage (CFU-E). Similar to ITP and TH, in PTH megakaryocyte proliferation (CFU-MEG) is the predominant feature of cell turnover. Differences between PTH and TH are in line with the reduced in vitro formation of CFU-MEG in the latter disorder. In conclusion, our in situ study on turnover rates of the bone marrow in various neoplastic and reactive lesions extends previous experimental data on hematopoietic cell kinetics.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002770050309
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  • 10
    Electronic Resource
    Electronic Resource
    Histochemistry and morphometry on bone marrow biopsies in chronic myeloproliferative disorders – aids to diagnosis and classification (1999)
    Springer
    Annals of hematology 78 (1999), S. 495-506 
    Details
    ISSN: 1432-0584
    Keywords: Key words Chronic myeloproliferative disorders ; Erythroid precursors ; Neutrophil granulopoiesis ; Megakaryocytes ; Macrophages ; Myelofibrosis ; Enzyme-immunohistochemistry ; Morphometry ; Bone marrow biopsy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The aim of this review is to evaluate morphological characteristics of the different subtypes of chronic myeloproliferative disorders (MPDs) derived by applying immunohistochemical and morphometric techniques to bone marrow biopsies and to combine these results with relevant clinical parameters. In comparison to control specimens, a significant decrease in erythroid precursors is determinable in chronic myeloid leukemia (CML), while this cell lineage is most prominent in polycythemia vera (PV) and moderately to markedly reduced in idiopathic myelofibrosis (IMF). On the other hand, neutrophilic granulopoiesis shows a predominance in CML and a relevant increase in PV, but no conspicuous changes are detectable in essential thrombocythemia (ET). CML is characterized by a prevalent growth of dwarflike micromegakaryocytes, occurring in particular in the so-called megakaryocyte-rich subtypes (about 30%). This finding differs significantly from the pleomorphous aspect, i.e., clusters of small to giant-sized megakaryocytes in PV and the grossly abnormal (dysplastic) appearance of this cell lineage in patients with IMF. Similar cytological abnormalities of megakaryopoiesis consistent with maturation defects are never encountered in ET. The incidence of mature (resident) macrophages (phagocytic reticular cells) is significantly enhanced in IMF in comparison to the other MPDs and controls. Moreover, there is a striking difference in the density of reticulin-collagen fibers, ranging from normal (ET) to extreme values (IMF). In IMF more than 80% of the patients present with some degree of myelofibrosis-osteosclerosis at diagnosis, while the rest show an initial prefibrotic, hypercellular stage. This feature deserves special attention since, when accompanied by thrombocythemia, it may simulate ET. Sequential bone marrow biopsies in patients with IMF disclose that evolution of myelofibrosis is progressive, but occurs at a variable and unpredictable speed. A synoptical approach regarding clinical diagnosis and histological subtyping of MPDs is explicitly recommended and demonstrated by sets of diagnostic criteria. This rationale requires equal consideration of laboratory data and morphology by clinicians to include well-defined subtypes of MPDs into prospective management studies. Furthermore, it may even warrant follow-up studies and repeated bone marrow examinations in initially unclassifiable cases.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002770050546
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