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At least 703 records · Page 39Linked to original sources
PubMed1992

Establishment of a novel granulocytic sarcoma cell line which can adhere to dermal fibroblasts from a patient with granulocytic sarcoma in dermal tissues and myelofibrosis.

A novel human myeloid cell line, designated HSM-1, has been established from the pleural effusion of a patient with granulocytic sarcoma (GS) who had been followed as having primary myelofibrosis for 10 years. When he was diagnosed as having granulocytic sarcoma in dermal tissues, no evidence of malignant transformation into leukaemia was found in both the peripheral blood and bone marrow. The established cell line was positive for myeloperoxidase, Sudan black B, Naphthol AS-D chloroacetate esterase. Surface marker analysis revealed that HSM-1 expressed CD4, CD13, CD11a, CD11b, Leu8, CD49b, CD49d, CD49e, CD29 and HLA-DR. To clarify why the unusual myeloid tumours developed in non-haematopoietic tissues, we examined the capability of HSM-1 to bind to skin fibroblast layers. The HSM-1 cells were found to bind to both bone marrow stromal layers and skin fibroblast layers. Among the other myeloid cell lines tested, none was found to bind to skin fibroblast layers. These findings suggest that the GS cell line may be derived from a haematopoietic precursor cell which can bind to skin fibroblasts and is localized in non-haematopoietic tissues resulting in the formation of extramedullary myeloid metaplasia. HSM-1 is a useful tool for analysing the characteristics of granulocytic sarcoma and homing receptors for haematopoietic stem cells.

Antigens, Surface↗
PubMed1993

Serum erythropoietin in patients with myelofibrosis with myeloid metaplasia.

Serum erythropoietin levels (s-Epo) were measured by radioimmunoassay in 61 consecutive anaemic patients (Hb < 12 g/dl) with myelofibrosis with myeloid metaplasia (MMM). S-Epo was inversely correlated with Hb (r = -0.48, P < 0.0001). When observed s-Epo values were compared with predicted levels based on the relationship between s-Epo and Hb in control subjects, all but eight patients (87%) had s-Epo levels appropriate for the degree of anaemia. The observed/predicted (O/P) s-Epo ratio was significantly lower in patients with signs of active disease, and a significant inverse correlation was found between the O/P ratio and erythrokinetic measurement of the extent of erythropoiesis (r = 0.31; P = 0.02). Circulating Epo levels were appropriate for the variations in Hb during the postsplenectomy period in three patients. In conclusion, this study does not support the idea that therapy with erythropoietin should be extensively used in anaemic patients with MMM, but rather that it should be considered only in selected cases.

Adult↗
PubMed1994

Plasma soluble interleukin-2 receptor in patients with primary myelofibrosis.

Using en enzyme-linked immunosorbent assay (ELISA) test, the level of soluble Tac peptide, one chain of the human interleukin-2 receptor, was measured in the plasma of 26 patients with primary myelofibrosis (MF), seven patients with polycythaemia vera and 11 normal controls. The plasma soluble interleukin-2 receptor (sIL-2R) was found to be significantly elevated in patients with primary MF compared to polycythaemia vera or controls (P < 0.001), while the plasma sIL-2R of patients with polycythaemia vera also was found to be significantly elevated compared to controls (P < 0.01). The significantly elevated value of sIL-2R seen in primary MF may be secondary to T cell activation resulting from autoimmune phenomena, and myeloblast activation with release of sIL-2R may also be a contributing factor. In primary MF, plasma sIL-2R levels were also found to be correlated to survival, circulating blast cell counts, and thrombocytopenia, but not to white blood cell counts, LDH levels, degree of marrow fibrosis, or degree of splenomegaly. Patients with primary MF with higher titre of plasma sIL-2R had a shorter survival. Further studies involving more patients and longer follow-up may substantiate that plasma sIL-2R is an important prognostic indicator in primary MF.

Biomarkers↗
PubMed1994

Raised urinary calmodulin levels in idiopathic myelofibrosis: possible implications for the aetiology of fibrosis.

Platelet growth factors (e.g. PDGF and TGF-beta) are thought to be pathogenetically important in the stromal reaction characteristic of idiopathic myelofibrosis (IM). We have investigated a possible pathogenetic role for a further platelet mitogen, calmodulin. Platelets are rich in calmodulin, of which 30-40% is releasable with a time course that differs from alpha-granule proteins. In IM urinary calmodulin concentrations were 3-fold those of the normals controls. We suggest that an abnormal release of calmodulin may occur from platelets/megakaryocytes in patients with IM, and that calmodulin should be considered, along with other growth factors, in the pathogenesis of marrow fibrosis.

Aged↗
PubMed1994

Karyotypic and ras gene mutational analysis in idiopathic myelofibrosis.

Karyotypic analysis was performed in a total of 69 patients with well-characterized idiopathic myelofibrosis. Karyotypic abnormalities were detected in 46% of cases examined during the chronic phase (29/63); with three abnormalities, del(13q), del(20q) and partial trisomy 1q, accounting for 75% of all abnormalities at diagnosis. The absence of del(5q), trisomy 8 and 21, as well as the rarity of monosomy 7, contrasts with pooled published data and may reflect our exclusion of closely related disorders, in particular MDS with fibrosis. Chromosomal aberrations increased to approximately 90% (8/9) in patients analysed during acute transformation. Mutational activation of codons 12, 13 and 61 of N-, Ha- and Ki-ras genes were assessed by polymerase chain reaction and hybridization with synthetic non-radioactive digoxigenin-labelled probes. Three mutations were detected in samples of peripheral blood DNA taken from 50 patients during the chronic phase of their disease: one N12 Asp (GGT-->GAT) and two N12 Ser (GGT-->AGT) mutations. The results from this study indicate that karyotypic abnormalities are present in at least 29% of cases at diagnosis and that del(13q), del(20q) and partial trisomy 1q are the most frequent findings. Ras mutations were relatively infrequent (6%) and appeared restricted to the N-ras gene. Karyotypic analysis at diagnosis was found to be of prognostic significance.

Adult↗
PubMed2004

Spleen neoangiogenesis in patients with myelofibrosis with myeloid metaplasia.

Neoangiogenesis is an integral component of bone marrow myeloproliferation in patients with myelofibrosis with myeloid metaplasia (MMM). As extramedullary haematopoiesis is a constitutive feature of MMM, we studied spleen neoangiogenesis by a computerized image analysis in MMM patients. Compared with five normal subjects, spleen CD34-staining capillary vascular density (CVD) was 2.1-3.03 times higher than the upper range of normal in six of the 15 (40%) MMM patients. CD8-staining sinusoidal vascular density (SVD) was constantly normal or lesser than normal and was inversely correlated with CVD (R = -0.53; P = 0.04). In MMM patients who did not receive cytoreductive or radiation therapy in the month before splenectomy (n = 9), the CVD was a significant determinant of spleen size (R = 0.88; P = 0.04). In MMM patients, the number of spleen CD34+ haematopoietic stem cells was increased from 1.2 to 98 times the upper limit of normal, and predicted the expansion of CVD (R = 0.57; P = 0.03). A population of cells expressing the CD34+/CD133+/VEGFR-2+ angiopoietic phenotype was present in the blood and spleen of five of seven patients. These results document that neoangiogenesis is an integral component of spleen re-localization of haematopoietic stem cells and suggest a cellular mechanism for spleen neoangiogenesis.

Adult↗
PubMed2004

Erythropoietin treatment of the anaemia of myelofibrosis with myeloid metaplasia: results in 20 patients and review of the literature.

Recombinant human erythropoietin (rHuEPO) is an effective treatment for the anaemia that occurs secondary to various conditions, but its role in myelofibrosis with myeloid metaplasia (MMM) is not well established. rHuEPO, at an initial dose of 10 000 U thrice a week, was given to 20 patients with MMM and anaemia. Complete response (CR) was defined as transfusion cessation with normal haemoglobin (Hb) levels and partial response (PR) as a transfusion decrease > or =50% and Hb > 10 g/dl maintained for at least 8 weeks. Nine patients (45%) showed a favourable response to treatment, including four CR and five PR, four of whom have maintained their response at a median follow-up of 12.5 months (range: 4-21 months) from the start of treatment. The pretreatment factors associated with a favourable response were lack of transfusion requirement (P = 0.002) and higher Hb at start treatment of (P = 0.01). An analysis of the present series (n = 20) and 31 patients from the literature identified 28 (55%) favourable responses to rHuEPO, including 16 CR and 12 PR. In the multivariate analysis, serum erythropoietin level <125 U/l was found to be associated with a favourable response to rHuEPO, whereas lack of transfusional support had borderline significance.

Aged↗
PubMed2005

Peripheral blood CD34 count in myelofibrosis with myeloid metaplasia: a prospective evaluation of prognostic value in 94 patients.

In a prospective study, peripheral blood (PB) CD34 count, bone marrow histology and other clinical parameters were concurrently evaluated in 94 patients with myelofibrosis with myeloid metaplasia (MMM) and the study cohort followed for a minimum of 3 years. Median PB CD34 count was 0.0547 x 10(9)/l (range 0-5.345 x 10(9)/l) with 86% of the patients displaying above normal levels (>0.005 x 10(9)/l). In a multivariate analysis, only leucocyte count and PB blast percentage correlated with PB CD34 count in an independent and consistent fashion. After a median follow up of 41 months from PB CD34 analysis, 43 patients (46%) have died with a projected 5-year survival of 50%. In a univariate analysis, PB CD34 count above 0.1 x 10(9)/l correlated significantly with shortened survival, leukaemic transformation and clinical progression. However, such statistical significance was lost during multivariate analysis, which identified only anaemia and leucocytosis as independent risk factors for shortened survival. Furthermore, sequential analysis of PB CD34 count was performed in 53 patients and 43% of those who progressed clinically did not display a concomitant rise in their PB CD34 count. The current prospective study does not support an independent prognostic value for PB CD34 count in MMM.

Adult↗
PubMed2005

Pilot study of reduced-intensity conditioning followed by allogeneic stem cell transplantation from related and unrelated donors in patients with myelofibrosis.

A prospective pilot study was performed to evaluate the effect of reduced-intensity conditioning with busulphan (10 mg/kg), fludarabine (180 mg/qm) and anti-thymocyte globulin followed by allogeneic stem cell transplantation from related (n = 8) and unrelated donors (n = 13) in 21 patients with myelofibrosis. The median age of the patients was 53 years (range, 32-63). No primary graft failure occurred. The median time until leucocyte (>1.0 x 10(9)/l) and platelet (>20 x 10(9)/l) engraftment was 16 (range, 11-26) and 23 d (range, 9-139) respectively. Complete donor chimaerism on day 100 was seen in 20 patients (95%). Acute graft-versus-host disease (GvHD) grades II-IV and III/IV occurred in 48% and 19% of cases and 55% of the patients had chronic GvHD. Treatment-related mortality was 0% at day 100 and 16% [95% confidence interval (CI): 0-32%] at 1 year. Haematological response was seen in 100% and complete histopathological remission was observed in 75% of the patients and 25% of the patients showed partial histopathological remission with a continuing decline in the grade of fibrosis. After a median follow-up of 22 months (range, 4-59), the 3-year estimated overall and disease-free survival was 84% (95% CI: 67-100%).

Adult↗
PubMed2005

Gains on 9p are common genomic aberrations in idiopathic myelofibrosis: a comparative genomic hybridization study.

Ideopathic myelofibrosis (IMF) is a chronic myeloproliferative disorder resulting in bone marrow fibrosis as a consequence of growth factor release from clonal haematopoiesis. Conventional cytogenetic analysis identifies abnormalities in approximately a third of cases at diagnosis, although rarely uncovers unique, primary genetic events. We have used comparative genomic hybridization (CGH) to study 25 IMF cases and have compared the results with conventional cytogenetics. Metaphase cells were available for analysis in 13 cases, of which seven showed an abnormal karyotype. CGH chromosomal profiles showed imbalances in 21 of 25 cases. The most frequent aberrations were gains of 9p (12 cases), 2q (seven cases), 3p (seven cases), chromosome 4 (seven cases), 12q (seven cases), 13q (eight cases). The main losses were at 17q and occurred in six cases. The results for CGH and cytogenetics were matched for one case only. Investigation of IMF by CGH suggests that genomic aberrations are much more common than has been previously indicated by conventional cytogenetic analysis and occur in the majority of cases. Gains of 9p were the most frequent finding, occurring in 50% of patients and suggests that genes on 9p may play a crucial role in the pathogenesis of IMF.

Aged↗
PubMed2005

Efficacy and tolerability of danazol as a treatment for the anaemia of myelofibrosis with myeloid metaplasia: long-term results in 30 patients.

Androgens are considered the treatment of choice for the anaemia of myelofibrosis with myeloid metaplasia (MMM). Good results have been reported in a few patients treated with danazol, a synthetic attenuated androgen. The long-term efficacy and tolerability of danazol as treatment for the anaemia of MMM was evaluated in 30 patients, who received 600 mg/d, with progressive tapering to the minimum effective dose in the responders after 6 months. Complete response (CR) was defined as transfusion cessation with normal Hb and partial response (PR) as an Hb increase >/=1.5 g/dl with transfusion-independent Hb values >10 g/dl maintained for at least 8 weeks. Median follow-up was 20.5 months (range: 3.5-58 months). Response was achieved in 11 patients (37%), including eight CRs and three PRs. Median time to response was 5 months (range: 1-9 months). Four patients stopped responding at 6-24 months, two responders discontinued treatment because of toxicity, and five maintained response at 3.5-42 months. Pretreatment variables associated with response were lack of transfusion requirement (P= 0.001) and higher Hb at treatment start (P= 0.02). Toxicity was usually moderate, leading to treatment withdrawal in only two cases. Danazol is effective and well tolerated in a substantial proportion of MMM patients with anaemia.

Adult↗
PubMed2005

Osteosclerosis in advanced chronic idiopathic myelofibrosis is associated with endothelial overexpression of osteoprotegerin.

Advanced chronic idiopathic myelofibrosis (IMF) with osteosclerosis and increase and thickening of bone trabeculae is typically contrasted by the absence or sparse presence of osteoclasts. Because osteoclast formation can be inhibited by osteoprotegerin (OPG) we investigated OPG expression in IMF with severe fibrosis and osteosclerosis, which expressed significantly higher (up to 71-fold) OPG mRNA levels when compared with prefibrotic cellular IMF and control cases. The receptor activator of nuclear factor kappaB ligand (RANKL), a positive regulator of osteoclast differentiation and putative antagonist of OPG was overexpressed by up to 34-fold exclusively in advanced IMF. Case-specific calculation of the RANKL/OPG ratio in advanced IMF showed a wide range without significant differences when compared with the prefibrotic IMF and non-neoplastic haematopoiesis. Immunohistochemical detection of OPG protein revealed strong labelling of endothelial cells within proliferating vessels in fibrotic IMF and heterogeneously labelled megakaryocytes, and fibroblasts. Osteosclerosis and impaired osteoclast function in IMF appears to be associated with upregulated endothelial OPG expression but concomitant reduction of the antagonist RANKL could not be demonstrated. We conclude that osteosclerosis in IMF is associated with increased endothelial OPG expression without concomitant RANKL downregulation.

Adult↗
PubMed2005

Der(6)t(1;6)(q21-23;p21.3): a specific cytogenetic abnormality in myelofibrosis with myeloid metaplasia.

Chromosome anomalies are detected in approximately half of patients with myelofibrosis with myeloid metaplasia (MMM) although none of the most prevalent lesions are specific to the disease. In a prospective cytogenetic study of 81 patients with MMM, we encountered three with an unbalanced translocation between chromosomes 1 and 6 with specific breakpoints; der(6)t(1;6)(q21-23;p21.3). A subsequent Mayo Clinic cytogenetic database search identified 12 patients with this chromosome anomaly among 17 791 consecutive patients. A similar database search from Royal Hallamshire Hospital in Sheffield, UK revealed two additional patients among 8000 cases. The clinical phenotype and survival for each of these 14 patients was typical of MMM. These findings suggested that der(6)t(1;6)(q21-23;p21.3) is a highly specific cytogenetic anomaly that may harbour gene(s) specifically associated with MMM. In a preliminary fluorescence in situ hybridization study, the breakpoints on chromosome 6 in two additional cases were found to be telomeric to the gene for 51 kDa FK506-binding protein (FKBP51).

Adult↗
PubMed2005

The JAK2(V617F) tyrosine kinase mutation in myelofibrosis with myeloid metaplasia: lineage specificity and clinical correlates.

An association between an activating JAK2 mutation (JAK2(V617F)) and BCR/ABL-negative myeloproliferative disorders was recently reported in multiple simultaneous publications. In the current study, mutation analysis for JAK2(V617F) was performed in peripheral blood mononuclear cells (PBMC) from 157 patients with myelofibrosis with myeloid metaplasia (MMM) including 117 with agnogenic (AMM), 22 with postpolycythaemic (PPMM), and 18 with post-thrombocythaemic (PTMM) myeloid metaplasia. The detection rate for JAK2(V617F) was significantly higher in PPMM (91%; homozygous in 18%) compared with either AMM (45.3%; homozygous in 2.6%) or PTMM (38.9%; homozygous in 11.1%). Concomitant analysis in granulocytes (n=57) and CD34(+) cells (n=25) disclosed a higher incidence of homozygous JAK2(V617F) mutation but the overall mutation rate was similar to that obtained from PBMC. JAK2(V617F) was not detected in DNA derived from T cells (n=19). In AMM, the presence of JAK2(V617F) was associated with an older age at diagnosis and a history of thrombosis or pruritus. Multivariate analysis identified only age and the Dupriez prognostic score as independent prognostic factors; JAK2(V617F) had no prognostic significance. In conclusion, JAK2(V617F) is a myeloid lineage-specific event, its incidence in MMM is significantly higher with an antecedent history of polycythaemia vera (PV), and its presence in AMM does not affect prognosis but is associated with PV-characteristic clinical features.

Adolescent↗
PubMed2006

Darbepoetin-alpha for the anaemia of myelofibrosis with myeloid metaplasia.

Darbepoetin-alpha, a novel hyperglycosylated erythropoiesis-stimulating protein, was administered to 20 patients with myelofibrosis with myeloid metaplasia and anaemia. The initial weekly dose, 150 mug, was increased to 300 mug when no response was observed after 4-8 weeks. Eight patients (40%) responded to treatment, including six complete and two partial responses, and five maintained their response at a median follow-up of 12 months (range 4-22). Univariate analysis indicated that older age was the only factor associated with a favourable response to treatment (P = 0.006). None of the patients with appropriate serum erythropoietin levels responded. Treatment was usually well tolerated.

Adult↗
PubMed2006

Different outcome of allogeneic transplantation in myelofibrosis using conventional or reduced-intensity conditioning regimens.

Allogeneic haematopoietic stem cell transplantation remains the only curative treatment of myelofibrosis with myeloid metaplasia (MMM). Previous reports have indicated significant treatment-related mortality (TRM) for patients transplanted after myeloablative conditioning but superior survival has been reported after reduced-intensity conditioning (RIC). We report the results of a survey of all allogeneic transplantations for MMM performed in Sweden at six transplant units between 1982 and 2004. Twenty-seven patients were transplanted; 17 with a myeloablative conditioning regimen and 10 with RIC. The median age was 50 years (5-63 years) at transplantation. After a median follow up of 55 months, 20 patients are alive. TRM was 10% in the RIC group and 30% in the myeloablative group. There was no difference in survival for high or low-risk patients according to Cervantes score or between sibling and unrelated donor transplantations.

Adult↗
PubMed2006

Concurrent MPL515 and JAK2V617F mutations in myelofibrosis: chronology of clonal emergence and changes in mutant allele burden over time.

MPLW515L/K and JAK2V617F can co-exist in myelofibrosis with myeloid metaplasia (MMM). The chronology of clonal emergence was studied in three such cases using serially stored bone marrow. At diagnosis, a major MPL515 mutant clone was accompanied by a minor JAK2V617F clone in all three instances. At 25 time points over a period of 4-8 years, allele burden fluctuated but remained high for MPLW515L/K and low for JAK2V617F. We conclude that MPLW515L/K and JAK2V617F are both early events in MMM and allele burden, rather than the mere presence of these mutations, might be relevant to phenotypic variation in myeloproliferative disorders.

Alleles↗
PubMed2005

Myelofibrosis in a patient with pachydermoperiostosis.

Pachydermoperiostosis (idiopathic or primary hypertrophic osteoarthropathy) is a rare condition of unknown origin involving the skin and the skeleton, with an autosomal dominant transmission. We report a case of anaemia in a patient with pachydermoperiostosis indicating myelofibrosis, and review the literature and the pathogenetic mechanisms.

Acitretin↗