Biomedical subjects

H M Kvasnicka

Publications and source records attributed to H M Kvasnicka.

107 records · Page 6Linked to original sources

PubMed1995

The impact of interferon versus busulfan therapy on the reticulin stain-measured fibrosis in CML--a comparative morphometric study on sequential trephine biopsies.

To evaluate treatment-related changes of the reticulin stain-measured fibrosis in Ph(1+)-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.

Adolescent↗

PubMed1995

[3-dimensional reconstruction of serial sections in light microscopy].

Computer-based three-dimensional reconstruction of serially cut light microscopic sections is being increasingly used in medical and biological research. Compared with conventional two-dimensional evaluation of histological sections, complex histotopographical relationships and structural details are easy to assess and could be imposingly visualized on the graphics screen. Because of the rapid progress in modern computer hardware, uncomplicated and fast reconstruction systems are available on standard personal computers. Therefore, 3D reconstruction is applicable for a wide range of investigations that warrant 3D exploration. Own results are presented and the principles of 3D reconstruction, as well as the problems and difficulties in this new technique, are discussed. The complex ameboid morphology of megakaryocytes in bone marrow of primary (idiopathic) osteomyelofibrosis is examined with this new method in combination with selective immunohistochemical staining procedures. 3D reconstruction can visualize the complexity of cytoplasmic and nuclear formation impressively. Moreover, the models generated permit exact quantitative measurements of cell morphology. The technique presented is a powerful tool for anatomical-morphological investigations and can furthermore increase our comprehension of complex histomorphological objects.

Bone Marrow↗

PubMed1995

CD34+ human hemopoietic progenitor cells of the bone marrow differ from those of the peripheral blood: an immunocytochemical and morphometric study.

CD34+ progenitor cells were harvested from bone marrow and peripheral blood from 10 healthy donors by immunomagnetic isolation and enrichment procedures. The CD34+ cell population was investigated using a battery of enzyme reactions and monoclonal antibodies on cytospin preparations. Additionally, morphometric measurements were carried out and also liquid suspension culture studies were performed to ascertain vitality and stem cell character. More than 95% of the total yield of medullary CD34 progenitors expressed CD45 (LCA), CD43 (MT1) and beta-glucuronidase. Reactivity with CD33 (My9), CD15 (LeuM1), CD38 (Leu17), CD20 (L26) and Ret40f (glycophorin C) was assumed to be in keeping with a transition into more differentiated elements of the various hemopoietic lineages. Morphometric analysis revealed conspicuous heterogeneity of the CD34+ cell population considering size measurements. This finding was in line with the diversities of antigen expression, indicating the more committed nature of CD34+ stem cells derived from the bone marrow in comparison with those progenitors isolated from the peripheral blood. Moreover, proliferation marker staining by PCNA disclosed a positivity in a considerable number of progenitors in contrast to the findings in CD34+ cells that are found in the peripheral blood.

Antibodies, Monoclonal↗

PubMed1994

Erythropoiesis in primary (idiopathic) osteomyelofibrosis: quantification, PCNA-reactivity, and prognostic impact.

In 64 patients with primary (idiopathic) osteomyelofibrosis (OMF), a morphometric analysis has been performed on bone marrow trephine biopsies following sequential double-immunostaining with monoclonal antibodies against proliferating cell nuclear antigen (PCNA) and erythroid precursor cells (glycophorin C). The purpose of this study was to quantify erythropoiesis and its PCNA-staining capacity and, further, to determine the impact of these parameters for the development of anemia and for prognosis. In comparison with a control group (15 patients), a significant reduction in the number of erythro-normoblasts could be demonstrated, associated with an increase in PCNA-labelling. Moreover, significant correlations between the amount of nucleated erythroid marrow cells and degree of anemia (hemoglobin level, hematocrit, erythrocyte count) and survival could be calculated. Adverse relationships were assessed between number of erythroid cells, thrombocyte count, and spleen size, and also argyrophilic (reticulin/collagen) fiber density. These interactions were thought to reflect the biological behaviour of the disease process, i.e., the progression or extent of myeloid metaplasia. Our findings support ferrokinetic studies suggesting erythroid hypoplasia as one of the major causes of anemia in OMF. The remarkable high PCNA-labelling index of the macrocytic-megaloblastoid appearing erythropoiesis is probably caused by an overexpression of this marker protein. A comparative evaluation of Ki-67 antigen immunostaining in splenic tissue (myeloid metaplasia) and of the PCNA-labelling in pernicious anemia lend support to the assumption of an undue prolongation of the S-phase generated by secondary folate (hematinic) deficiency.

Aged↗

PubMed1994

Megakaryocytes and sinus walls in primary osteomyelofibrosis: transendothelial migration as revealed by three-dimensional reconstruction of serial sections following sequential double-immunostaining.

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.

Aged↗

PubMed1994

Proliferating cell nuclear antigen (PCNA) expression of megakaryocytopoiesis in normal human bone marrow and reactive lesions with special emphasis on HIV-myelopathy.

A morphometric analysis was performed on bone marrow trephine biopsies using sequential double-immunostaining, to evaluate endoreduplicative activity of megakaryocytopoiesis. A total of 104 marrow specimens were studied with employment of monoclonal antibodies PC10 (anti-proliferating cell nuclear antigen-PCNA) and Y2/51-CD61 (anti-platelet glycoprotein IIIa). In addition to the control group patients included non-specific inflammatory changes, HIV-myelopathy with normal or decreased platelet counts, idiopathic thrombocytopenic purpura (ITP), and finally reactive thrombocytosis (TH). To exclude an undue overexpression of PCNA, in a comparative pilot study we also applied MIB1 (Ki-67 antigen) on normal bone marrow specimens. In accordance with the various modalities of cell-cycle marker expression, no significantly different findings were disclosed. PCNA-labelling index was relatively low, ranging from 0.8 to 1.7% of the total megakaryocytopoiesis (promegakaryoblasts to mature platelet-shedding megakaryocytes). A significant relationship between megakaryocyte size and PCNA-expression was determinable. This implies that some of the cases with a prevalence of small megakaryocytes, like ITP, have the tendency to show a higher proportion of positively-stained cells. Moreover, this feature confirms a hypothesis postulating a decrease in the time for DNA-synthesis (S-phase) and a relative prolongation of the G1/G2-phases of the cell-cycle at higher ploidy levels (large-sized megakaryocytes). On the other hand, it may be speculated that some of the hyperpolyploid giant megakaryocytes may have reached their endstage of endoreduplication and enter into G0-phase. In comparison with the control group and the other entities under study, a significant reduction of PCNA-reactivity was recognizable in HIV-myelopathy accompanied by thrombocytopenia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1994

Evolution of fibro-osteosclerotic bone marrow lesions in primary (idiopathic) osteomyelofibrosis--a histomorphometric study on sequential trephine biopsies.

Evolution of fibro-osteosclerotic bone marrow lesions in the course of primary (idiopathic) osteomyelofibrosis (OMF) was studied in 36 patients (17 males, 19 females; median age 57 years) by morphometric evaluation of sequential trephine biopsies. The mean interval between first and terminal examination was 33 months (range 6 to 121 months). Two biopsies were performed in 31 and three and more in five patients. Morphometry consisted of a determination of argyrophilic (reticulin and collagen) fiber density, measured per area of hematopoiesis or marrow cellularity, and the calculation of the extent of trabecular bone tissue. In 13 of our 36 patients increase in reticulin and collagen deposits was only borderline to minimal during the observation period. On the other hand, in 23 of the 36 patients a slight to gross accumulation of reticulin and collagen fibers, partially associated with osteosclerotic changes was recognizable. No regression of fibrosis was encountered in our cohort of patients which included three cases with preceding low-dose busulfan therapy. Analysis of the different lengths of intervals between the first and the last biopsy and degree of fibrosis as well as osteosclerosis, suggested that alterations developed progressively, however, at an unpredictable and considerably varying rate. Thus our findings were not in keeping with several studies on smaller series of patients, which generally contested a progression of fibro-osteosclerotic lesions in OMF and additionally reported reversal of the pathology following chemotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Biopsy↗

PubMed1994

Three-dimensional reconstruction of histologic structures in human bone marrow from serial sections of trephine biopsies. Spatial appearance of sinusoidal vessels in primary (idiopathic) osteomyelofibrosis.

Computer-based three-dimensional (3D) reconstruction of histologic features permits the assessment of the spatial arrangement of complex structures and has the additional advantage of demonstrating aspects that may be obscured in conventional, two-dimensional evaluations. Until now the spatial appearance of histotopographic details in human bone marrow has not been investigated. In the present study we explored the use of 3D visualization techniques to determine the configuration of sinusoidal vessels and surrounding megakaryocytes in osteomyelofibrosis. Up to 34 serial sections were cut from each trephine biopsy block and stained sequentially by monoclonal antibodies against collagen type IV and megakaryocytes (CD61-Y2/51) to discriminate relevant structures selectively and with high contrast. Images were digitized, and contours were traced manually. A new fast and graphically interactive software package for the reconstruction of 3D objects employing a low-cost personal computer was developed. The system allows reconstructions from any serial image in solid model form using a fast triangulation algorithm. 3D reconstruction emphasizes the close spatial relationship between sinus walls and megakaryocytes in this disorder and exhibits enhanced vascularity with a complex 3D meshwork of branching and tortuous sinusoidal vessels. Furthermore, an increase in luminal distention and aberration from normal shape could be observed. Large and ameboid megakaryocytes were frequently found adjacent to the abluminal surface of the sinus. The method described permits more elaborate insight into the complex topographic relationship of these two morphologic features in human bone marrow and may stimulate applications to other interesting specimens that warrant 3D visualization.

Biopsy↗

PubMed1994

Megakaryopoiesis in chronic myeloproliferative disorders: immunohistochemical evaluation of endoreduplicative activity by PCNA-staining reaction.

A morphometric analysis has been performed on bone marrow trephine biopsies following sequential double-immunostaining with monoclonal antibodies PC10 (anti-proliferating cell nuclear antigen--PCNA) and Y2/51-CD61 (anti-platelet glycoprotein IIIa) to evaluate endoreduplicative activity of megakaryopoiesis. In addition to a control group, patients included different subtypes of chronic myeloproliferative disorders (CMPDs) like chronic myeloid leukaemia (CML), polycythaemia vera (P. vera), primary thrombocythaemia (PTH) and finally primary (idiopathic) osteomyelofibrosis (OMF). In comparison with the normal bone marrow and also with P. vera and PTH a significant increase in PCNA-labelling (late G1 and S phases) of megakaryocytes was recognizable in OMF, contrasting with a striking reduction of this marker in CML. Particularly in advanced stages of OMF, secondary folate deficiency leading to a megaloblastoid appearance of erythroid precursors is a frequent finding. In pernicious anaemia previous cytokinetic studies have demonstrated an arrest in the S phase (DNA synthesis) of the cell cycle due to vitamin B12/folate (haematinic) deficiency. A similar pathomechanism may also be effective in OMF. Consequently, a block in the S phase of the cell cycle is assumed which is in keeping with the increased numbers of PC10-positive megakaryocytes. Significant correlations were calculable between megakaryocyte sizes and PCNA-staining capacity in the normal bone marrow and CMPDs. According to morphometry small-sized (hypoploid) megakaryocytes showed a prevalence of PCNA labelling. This finding is confirmative with a hypothesis on the dynamics of endoreduplicative activity of megakaryocytes, i.e. the prolongation of G1/G2 phases in larger (polyploid) elements. On the other hand, some of the giant polyploid megakaryocytes may cease endoreduplication and enter into G0 phase, which could partially explain the predominance of PCNA-negative large-sized cells of this lineage.

Aged↗

PubMed1993

Overestimation of osteopenia using standard analysis software for peripheral quantitative computed tomography.

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.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1993

Velocity of ultrasound at the patella: influence of age, menopause and estrogen replacement therapy.

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.

Adult↗

PubMed1993

Histological features of prognostic significance in CML--an immunohistochemical and morphometric study (multivariate regression analysis) on trephine biopsies of the bone marrow.

To evaluate the prognostic significance of clinical as well as histological disease features at the time of diagnosis, an immunohistochemical and morphometric study was performed on bone marrow trephine biopsies in 130 patients with Ph(1+)-CML. For identification of all cell elements of the megakaryocytopoiesis we used the monoclonal antibody CD61 (Y2/51) and for the macrophages, the recently characterized antibody PG-M1. Density of argyrophilic fibers was determined per fat cell-free marrow area. Based on a multivariate analysis-derived risk model, the reproducibility of the prognostic score described by Sokal and co-workers was tested, particularly with regard to histological variables. Additionally, we calculated the disease-specific loss in life expectancy. Our prognostic model (Cox model) consisted of the variables: age, spleen size, peripheral erythro-normoblasts, pseudo-Gaucher cells, and fiber density. To assess the validity of this new CML score, a receiver-operating curve (ROC) of sensitivity and specificity was constructed. The improved prognostic efficiency of this newly developed risk model in predicting death within 3 years after diagnosis of CML was demonstrated in comparison with generally accepted staging systems. Immunohistochemistry revealed that not the total number of macrophages, but only the subfraction of pseudo-Gaucher cells exerted a significant impact on survival. Furthermore, it was feasible to calculate the number of atypical micromegakaryocytes and pro- and megakaryoblasts. This abnormal and immature cell population showed a significant correlation with fiber density and prognosis. Finally, the practical value of the Hannover classification was tested. This histological classification enabled a discrimination between two groups with different survival patterns, i.e., granulocyte and/or megakaryocyte-rich subtypes versus subtypes with increase in reticulin and collagen fibers.

Adolescent↗

PubMed1993

Erythropoiesis in CML--immunomorphometric quantification, PCNA-reactivity, and influence on survival.

An immunohistochemical and morphometric analysis was performed on trephine biopsy specimens in 60 patients with chronic myeloid leukemia (CML) to quantify erythropoiesis and its proliferation capacity and to assess the stainable marrow iron (hemosiderin). For this purpose, an elaborate double-immunostaining technique was applied. This included a monoclonal antibody (PC10) that is directed against proliferating cell nuclear antigen (PCNA), followed by an antibody against glycophorin C (Ret40f), to identify all nucleated erythroid precursor cells. Additionally, morphometric data were derived from immunostaining of megakaryocytes (CD61) and macrophages (PG-M1), including its hemosiderin-laden subpopulation. Finally the determination of argyrophilic (reticulin) fiber density was carried out. In comparison with a control group (15 patients) without any hematologic disorder, in CML patients morphometric evaluation showed a significant reduction in the number of erythroblasts and normoblasts. This feature was associated with a PCNA-labeling index within the normal range and a decreased stainable marrow iron (number of hemosiderin-storaging macrophages). Several parameters were established to exert a predictive value on survival. A worsening of prognosis was associated with a decrease in the number of erythroid precursors (< 460/mm2), a low hemoglobin level (< 10 g/dl), a high megakaryocyte count (> 50 cells/mm2), an increased density of reticulin fibers (> 30 i x 10(2)/mm2) and splenomegaly (> 15 cm below costal margin). Our findings are in keeping with results obtained from in vitro studies of cell proliferation in CML, which is not significantly altered in comparison with the normal bone marrow. Finally, the present data, although derived from a small group of patients, emphasize the impact of histologic variables to be included in one of the major clinical trials on prognosis in CML.

Bone Marrow↗

PubMed1992

[Reproducibility of bone density measurements of the distal radius using a high resolution special scanner for peripheral quantitative computed tomography (Single Energy PQCT)].

Reliable determination of bone loss in the skeletal system depends on the accuracy of bone mineral density (BMD) measurements. We investigated short-term and long-term accuracy in vitro and in vivo using a new, commercially available special-purpose computed tomography scanner (Single Energy Peripheral QCT: XCT 900, Stratec FRG) for BMD measurements. Using a phantom, the long-term accuracy (3 months) in vitro yielded a coefficient of variation (cv) of 0.18%. Repeated measurements in 37 patients showed excellent reproducibility, with a cv of 0.71%. The differentiation into groups of low, average and high trabecular bone density demonstrated values of 0.61%, 0.59% and 0.98%, respectively for cv. BMD determination with pQCT is a high-precision method. It seems to be suitable for detection of trabecular bone loss in the range of the annual decrease in bone mass, provided the forearm is positioned with maximum care.

Bone Density↗

PubMed1989

[The prognostic significance of the differential blood count in patients with chronic myeloid leukemia].

In 66 patients (37 male/29 female, median age 51 years) with CML in stable phase the initial smears of the peripheral blood were evaluated in regard to survival. Differential count was performed on 500 nucleated cells by two investigators working independently and blind. Scrutinized statistical analysis revealed not only the well-known predictive value of the number of myeloblasts, but also a significant prognostic impact for the percentages of polymorpho-nuclear granulocytes, eosinophils and basophils.

Blood Cell Count↗

PubMedDate not supplied

Hematopoietic turnover index in reactive and neoplastic bone marrow lesions: quantification by apoptosis and PCNA labeling.

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.

Acute Disease↗

PubMedDate not supplied

Comparative effects of interferon and hydroxyurea on bone marrow fibrosis in chronic myelogenous leukemia.

Therapy-related changes of the bone marrow fiber content remain a controversial issue in hematopathology. This conflict of opinion firstly depends on difficulties to determine the quantity of fibers exactly (semiquantitative grading, morphometry, reference to cellularity). Secondly, the appropriate selection of patients with specific monotherapies including hydroxyurea (HU) and interferon-alpha (IFN) seems to present some problems. Finally, assessment of myelofibrosis is further biased by the different endpoints of sequential examinations. The latter shortcoming can be improved upon by the calculation of the myelofibrosis progression/regression index which describes the ratio between difference of fiber density and observation time. Using strictly defined therapeutic regimens and intervals between sequential trephine biopsies a stimulating effect of IFN administration on bone marrow fibrosis in Ph1+-chronic myelogenous leukemia (CML) has been found. This result is comparable with the failure of this agent to improve myelofibrosis (and splenomegaly) in a considerable number of patients with allied subtypes of chronic myeloproliferative disorders. This is in contrast to the effect HU exerts which is a more fibrolytic or even stabilizing influence on bone marrow fibrosis. This phenomenon is readily demonstrable by the assessment of dynamic features (myelofibrosis progression index). In addition, patients showing a rapid progression of myelofibrosis during IFN and HU treatment of Ph1+-CML are generally associated with a poor risk outcome and a significant worsening of survival.

Humans↗