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At least 577 records · Page 32Linked to original sources
PubMed2003

Elevated thrombopoietin levels in patients with myelofibrosis may not be due to enhanced production of thrombopoietin by bone marrow.

Thrombopoietin (TPO) is recognized as the primary regulator of megakaryocyte and platelet production. Two alternative hypotheses for the mechanism of regulation have been proposed: (1) platelet and/or megakaryocyte mass regulate circulating TPO levels by binding to TPO through TPO receptors (c-MPL), with subsequent internalization and degradation of the protein; (2) TPO mRNA produced by bone marrow (BM) stromal cells or BM cells modulates blood TPO levels or platelet counts. In myeloproliferative disorders (MPD), including primary myelofibrosis (MF) and essential thrombocythemia (ET), elevated blood TPO levels occur despite increased platelet and megakaryocyte mass. Therefore, in these diseases, elevated blood TPO levels cannot be explained by the first mechanism. The present study, was designed to measure TPO mRNA production by BM mononuclear cells and BM stromal cells using a relative RT-PCR technique, to verify the second mechanism. We found no increase of TPO mRNA production in either BM cells or in BM stromal cells in patients with MF and ET. Furthermore, in those patients with MF who had elevated plasma TPO levels, TPO mRNA levels in bone marrow fibroblasts (BMFs) or BM cells were not elevated as compared with controls. Therefore, we concluded that in patients with MF, the elevated plasma TPO levels are not due to enhanced production of TPO mRNA either by BMF, or BM cells. The TPO receptor (c-MPL) abnormalities including reduced MPL protein levels or defective TPO induced signal transduction pathways are the likely mechanisms.

Anemia, Hypochromic↗
PubMed2003

Bone marrow immunohistochemical studies of angiogenic cytokines and their receptors in myelofibrosis with myeloid metaplasia.

Bone marrow specimens from 11 patients with myelofibrosis with myeloid metaplasia (MMM) and seven normal controls were studied immunohistochemically to determine expression of transforming growth factor beta (TGF-beta), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and corresponding receptors. Staining distribution and intensity for TGF-beta, PDGF, VEGF, TGF-beta type II receptor, a receptor for PDGF, and receptors for VEGF and bFGF were similar in patients and controls. Bone marrow from 10 MMM patients showed increased TGF-beta type I receptor (TGF-betaRI) expression in small vessel endothelial cells. Eight patient specimens had bFGF overexpression in megakaryocytes. Increased microvessel density and decreased concentration of bFGF-staining stromal cells accompanied these changes. Microvascular TGF-betaRI upregulation and bFGF overexpression by megakaryocytes may cause bone marrow microenvironmental changes in MMM patients.

Adult↗
PubMed1997

Idiopathic myelofibrosis (agnogenic myeloid metaplasia): clinicopathological analysis of 32 patients.

The prognostic value of clinicopathological parameters, recorded at diagnosis, in idiopathic myelofibrosis (IMF) was retrospectively analyzed in a consecutive series of 32 patients followed for a minimum of 5 and maximum of 134 months in the period 1983-1994. Of the 32 patients, 18 were males and 14 were females. The mean age was 59.8 years (S.D., 10.4; range, 44-78 years). At the time of closure of the study (May 1995), 10 patients were dead, 18 were alive, and four were lost to follow up. The mean survival was 41 months (range 2-130 months). Univariate analysis showed that the following features were associated with a significantly shorter survival: (1) anemia (hematocrit <30%), (2) platelet count < 100,000/mm3. Age, sex, size of spleen and liver, WBC count, increased reticulin and collagen fibrosis were not of prognostic significance. Clinicopathological correlation was found between the sinusal hemopoiesis and the number of WBC precursors in peripheral blood, and between WBC precursors and spleen size. Medullary fibrosis was found to be associated with striking predominance of large and very mature megakaryocytes. Erythroid hyperplasia in the bone marrow correlated negatively with WBC precursors and spleen and liver size, and positively with reticulocyte count.

Adult↗
PubMed1997

Secondary amyloidosis in the course of idiopathic myelofibrosis.

Secondary amyloidosis without a known cause, diagnosed antemortem in a patient with idiopathic myelofibrosis, is reported here. This is the first such case, to our knowledge. Amyloid deposits were seen in the bone marrow, renal glomeruli and jejunum. Reasons for investigating for amyloidosis were hypogammaglobulinemia, proteinuria and recurrent diarrhea.

Agammaglobulinemia↗
PubMed1999

Resident bone marrow macrophages in idiopathic (primary) myelofibrosis (IMF): a histochemical and morphometric study on sequential trephine biopsies.

A histochemical and morphometric study was performed on sequential bone marrow biopsies in 65 patients with idiopathic (primary) myelofibrosis (IMF) to quantify the resident-mature CD68+ macrophages and a peculiar, so-called activated subpopulation. Statistical analysis revealed no significant correlations between number of macrophages, density of argyrophilic fibers and degree of myeloid metaplasia. Our results are reflecting in vitro findings on cytokine release, macrophage activation and their complex functional associations with myelofibrotic matrix formation. Macrophage growth is assumed to be related to a number of putative pathomechanisms including abnormal (upregulated) cytokine expression (PDGF, TGF-beta, IL-1), enhancement and activation by CSF-1 (M-CSF) and possibly also phagocytic stimulation. The latter feature may be triggered by increased degradation of senescent megakaryocytes, frequently occurring as endstages of growth factors-releasing fibrogenetic megakaryopoiesis.

Antigens, CD↗
PubMed2002

Frequency of structural abnormalities of the long arm of chromosome 12 in myelofibrosis with myeloid metaplasia.

Among cytogenetic studies of 205 patients diagnosed as myelofibrosis with myeloid metaplasia, we found seven cases with structural abnormalities of the long arm of chromosome 12. The karyotype showed six balanced translocations, that is, t(4;12)(q33;q21), t(5;12)(p14;q21), t(1;12)(q22;q24), t(12;17)(q24;q11), t(7;12) (p11;q24), and t(1;12)(p12;q24), as well as other cytogenetic abnormalities such as del(12)(q21;q24) and inv(12) (p12q24). Some isolated cases involving the 12q21 region have also been described in the literature. Importance of rearrangement of chromosome 12 in 12q21 or 12q24 is underlined by the authors suggesting a proto-oncogene accountable mechanism of leukemogenesis.

Adult↗
PubMed1997

Coexistence of tetrasomy 8 and trisomy 8 in a case with myeloid metaplasia with myelofibrosis.

We present a case of myeloid metaplasia with myelofibrosis (MM/MF), with tetrasomy 8 as the sole cytogenetic abnormality detected by conventional cytogenetic studies. Tetrasomy 8 was also detected by in situ interphase studies and confirmed by chromosome painting in metaphase. To our knowledge, this is the first case of MM/MF with tetrasomy 8. Noteworthy is the association with neurofibromatosis.

Adult↗
PubMed1999

Translocation (2;3)(p21;q26) as the sole anomaly in a case of primary myelofibrosis.

Translocation t(2p;3q) is a rare but recurrent finding in myeloid disorders. We present the first case of primary myelofibrosis with t(2;3)(p21;q26) as the sole chromosomal anomaly. The comparison with the 11 other previously published myeloid-associated t(2p;3q) cases confirms that this nonrandom translocation involves a pluripotent stem cell and is associated with a poor prognosis.

Aged↗
PubMedDate not supplied

[Hodgkin's disease disclosed by myelofibrosis of primary appearance. Apropos of 2 cases].

Two male patients, aged 36 and 73 years respectively, gradually developed febrile pancytopenia with profound alteration of their general condition and major inflammatory repercussions. No superficial or deep lymph node enlargement was found initially. Patient n degree 2 had an enlarged spleen. In both cases histological examination of the bone marrow showed an extensive and apparently nonspecific myelofibrosis. The subsequent development of superficial lymphadenopathy provided a firm diagnosis of Hodgkin's disease with mixed cellularity. These two cases belong to the category of exceptional massive medullary forms of Hodgkin's disease described by Duhamel et al. in 1979.

Adult↗
PubMed1997

Idiopathic myelofibrosis: pathogenesis, natural history and management.

Idiopathic myelofibrosis is a chronic myeloproliferative disorder characterized by bone marrow fibrosis, extramedullary haematopoiesis and a leucoerythroblastic blood picture. The marrow fibrosis results from an increased deposition of various interstitial and basement membrane glycoproteins, including collagen types I, III, IV, V and VI, fibronectin, vitronectin, laminin and tenascin. In addition, a marked neovascularization is present, even in the early proliferative phase of the disease. In contrast to the clonal haematopoiesis, the increased bone marrow stromal tissue is thought to be a reactive phenomenon, resulting from the inappropriate release of megakaryocyte/platelet-derived growth factors, including PDGF, TGF-beta, EGF, bFGF and calmodulin. Recent cytogenetic studies have highlighted three defects, namely del(13q), del(20q) and partial trisomy 1q, that account for nearly 70% of all abnormalities at diagnosis, and suggests that in many patients gene loss and/or inactivation may be an important pathogenetic mechanism. The median survival is approximately 4 years, although individual survival varies greatly. Prognostic schema enable the identification of patients with a limited life expectancy, for whom bone marrow transplantation should be considered. However, for the majority of patients therapy is supportive and consists of blood transfusions, androgens to sustain erythropoiesis, cytoreductive agents to prevent thrombocythaemia and, in carefully selected cases, splenectomy. The role for a number of experimental therapies, such as vitamin D3 analogues, alpha and gamma interferons and erythropoietin has yet to be defined.

Humans↗
PubMed2003

Spontaneous STAT5 activation induces growth factor independence in idiopathic myelofibrosis: possible relationship with FKBP51 overexpression.

Spontaneous growth of megakaryocyte progenitors is one of the biologic hallmarks of idiopathic myelofibrosis (IMF). The molecular mechanisms underlying this hypersensitivity to cytokines are poorly understood. Using a differential display approach, we previously observed FK506 binding protein 51 (FKBP51) overexpression in pathologic megakaryocytes from IMF. Using an FKBP51-overexpressing cell line, we found sustained STAT5 activation associated with JAK2 phosphorylation. We subsequently tested whether this transcription factor was activated in patient samples. We detected a STAT5 nuclear translocation and activation in spontaneously grown megakaryocytes and in circulating CD34(+) cells from the majority of patients studied. The biologic role of this JAK/STAT pathway activation was demonstrated by inhibiting both the anti-apoptotic phenotype mediated by FKBP51 overexpression in UT7 cells and the spontaneous megakaryocytic growth by addition in culture of the JAK2 inhibitor AG490 or overexpression of a STAT5b dominant negative or SOCS-1. These results demonstrate that a constitutive STAT5 activation in IMF is indispensable for spontaneous growth of megakaryocytes. They also suggest that FKBP51 overexpression could be involved in STAT5 activation in IMF cells and in subsequent abnormal growth.

Blotting, Western↗
PubMed2000

Gelatinous bone marrow transformation in a case of idiopathic myelofibrosis: a morphological paradox.

A 74-year-old woman with severe, but asymptomatic weight loss was found to have splenomegaly, thrombocytosis, and neutrocytosis. A trephine biopsy showed a hypercellular bone marrow with a proliferation of abnormal megakaryocytes, mild reticulin fibrosis, and osteosclerosis, i.e., features of an early stage of idiopathic myelofibrosis. In contrast to this predominant pattern, the marrow also contained a distinct hypocellular focus of gelatinous transformation (GMT) in which hematopoietic and fat cells were replaced by gelatinous substances that were characterized as hyaluronic acid mucopolysaccharides histochemically. GMT is a rare disorder of unknown pathogenesis, and is an unspecific indicator of severe illness which most often occurs in patients with a background of weight loss. This is the first reported case of gelatinous changes in an otherwise fibrotic bone marrow, a constellation which a priori seemed to be incompatible.

Adipose Tissue↗
PubMed1988

Follow-up studies with sequential bone marrow biopsies in chronic myeloid leukaemia and so-called primary (idiopathic) osteo-myelofibrosis. Evolution of histopathological lesions and clinical course in 40 patients.

A clinicopathological follow-up study was performed on 17 patients with chronic myeloid leukaemia (CML) and 23 cases with so-called primary (idiopathic) osteo-/myelofibrosis (OMF) concentrating on a comparison between clinical data and multiple sequential biopsies of the bone marrow. Histological classification of bone marrow lesions was done according to the subtypes proposed by Georgii et al. At clinical diagnosis initial trephine biopsies in CML showed in only 6/17 cases a pronounced granulocytic proliferation or CGL. In 9/23 patients with OMF a so-called hyperplastic or early hypercellular stage was encountered with a mixed megakaryocytic-granulocytic pattern without or with minimal reticulin fibres (CMGM/EMS). The histopathology of this early stage OMF as well as the later evolving advanced fibrosclerotic lesions (AMS/OMS) were by morphological aspects alone not distinguishable from cases with CML showing prominent fibrosclerotic alterations. At presentation 5/17 patients with CML displayed already some degree of reticulin fibre formation (EMS). Following serial trephine biopsies in CML with an increased megakaryocyte proliferation (CMGM), a remarkable tendency for myelofibrosis was present. The dynamics of this fibrosclerotic transformation seem to be variable in CML and OMF likewise. However, they are related to abnormal megakaryopoiesis as well as to duration respectively progress of disease, paralleled by corresponding haematological parameters. This longitudinal case control study emphasizes that histopathology of the bone marrow taken at clinical diagnosis may reflect different stages of chronic myeloproliferative diseases and therefore should be always accompanied by relevant clinical and cytogenetic findings to enable a correct diagnosis.

Adult↗
PubMed2001

Prognostic factors and current practice in treatment of myelofibrosis with myeloid metaplasia: an update anno 2000.

Median survival of patients with myelofibrosis with myeloid metaplasia (MMM) ranges from 3.5 to 5 years, but there is a wide variability. The degree of anemia (Hb < 10 g/dL) is the most important prognostic factor, followed by constitutional symptoms and abnormal karyotype. In recent years, different prognostic scoring systems for MMM have been proposed. In some of them three prognostic groups (low, intermediate, and high risk) are recognized, while others recognize a high and a low-risk group only. Median survival of the low-risk group ranges from seven to nine years, while the minority of high-risk patients survive for a median of less than two years. Younger patients with MMM survive longer (median survival above ten years). Among the latter patients, based on Hb value, constitutional symptoms, and blood blast-cell percentage, two prognostic groups can also be identified, with median survival of less than three years and almost 15 years, respectively. Conventional treatment of MMM is mostly palliative and based on cytolytic treatment (usually hydroxyurea), androgen therapy and splenectomy in selected patients. Allogeneic hemopoietic transplant is a therapeutic possibility with the potential for cure in younger patients with bad prognostic features. The role in MMM of newer treatment strategies such as autologous transplantation or the administration of anti-angiogenic drugs such as thalidomide is currently being evaluated.

Aged↗
PubMed2001

Epidemiology of the myeloproliferative disorders: essential thrombocythaemia, polycythaemia vera and idiopathic myelofibrosis.

As to the epidemiology of myeloproliferative disorders (MPD) very little solid information is available in the literature. The present work attempted to study the incidence of MPD in the city of Göteborg, Sweden during a period of ten years. Therefore, retrospectively we assessed the number of subjects afflicted with polycythaemia vera (PV), essential thrombocythaemia (ET) and idiopathic myelofibrosis (IM) over the study period of 1983-1992. The yearly calculated incidence for PV was 2.8 per 100,000 population. For ET and IM the corresponding figures were 1.5 and 0.4, respectively. The results for PV demonstrated the highest incidence rate reported in literature so far. As to ET and IM our results largely agree with what has been reported previously in the literature.

Adult↗
PubMed1998

Idiopathic myelofibrosis: a clinical review.

Idiopathic myelofibrosis (MF) is a chronic myeloproliferative disorder (MPD) in which a clonal haemopoietic stem cell proliferation is accompanied by reactive fibrosis. Despite this clear understanding of pathogenesis, the majority of patients with MF are still poorly treated in comparison to those with other types of MPD. This article reviews the clinical and laboratory features in light of our current knowledge on the pathogenesis and pathopathology of MF; discusses the various prognostic factors to enable stratification of patients to the 'long-lived' group (median survival around 10 years) or the 'short-lived' group (median survival around 2 years); highlights the need to treat patients more effectively with specific therapy directed against the underlying neoplastic clonal stem cell proliferation; argues for long-term, if intermittent, maintenance therapy to improve the quality of life and hopefully, also their life-span; and, provides a summary of the various treatment options currently available for patients with MF.

Humans↗
PubMed1991

Acute non-lymphocytic leukaemia and myelofibrosis following sequential hemibody irradiation for prostatic carcinoma.

Sequential hemibody radiotherapy (SHBI) is currently being evaluated in clinical trials as adjuvant treatment in cancer patients who are potential long-term survivors. The potential late adverse effects of this therapeutic modality on the bone marrow may place patients at risk for the complications of aplasia, leukaemia, and myeloproliferative syndromes. We describe a case of acute non-lymphocytic leukaemia and myelofibrosis following SHBI for prostate carcinoma. The possible role of radiation in the induction of these abnormalities is discussed.

Adenocarcinoma↗
PubMed1998

Pathogenesis and management of idiopathic myelofibrosis.

Idiopathic myelofibrosis is the least common and carries the worst prognosis of the chronic myeloproliferative disorders. The primary disease process is a clonal haematopoietic stem cell disorder which results in a chronic myeloproliferation and an atypical megakaryocyte hyperplasia. In contrast, the characteristic stromal proliferation is a reactive phenomenon, resulting from the inappropriate release of megakaryocyte/platelet-derived growth factors, including PDGF, TGF-beta bFGF and calmodulin. The median survival is approximately 4 years, although individual survival varies greatly. A variety of prognostic schema have been developed which enable the identification of high-risk patients, for whom bone marrow transplantation should be considered. Management for the majority of patients, however, is directed towards the alleviation of symptoms and improvement in quality of life. This review summarizes the recent advances in our understanding of the disease's pathogenesis and discusses the limited therapeutic options available to clinicians.

Anemia↗