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At least 811 records · Page 45Linked to original sources
PubMed2005

Studies of the site and distribution of CD34+ cells in idiopathic myelofibrosis.

The frequency and distribution of CD34+ cells in the bone marrow (BM) of patients with idiopathic myelofibrosis (IM) were determined using an immunohistochemical technique. The percentage and absolute number of circulating CD34+ cells were enumerated. Patients with IM exhibited a continuum of number of BM CD34+ cells ranging from 1 to 85 per 5 mm(2). The frequency of BM CD34+ cells was inversely related to the number of circulating CD34+ cells. The BM biopsy specimens obtained from 4 patients with IM who underwent allogeneic stem cell transplantation were examined sequentially. Quantitative measurement revealed that the reticulin fiber volume was progressively reduced after allogeneic stem cell transplantation. All 4 patients had normocellular marrow with normal numbers of BM CD34+ cells after transplantation. These findings suggest that the BM fibrosis and abnormal hematopoietic stem cell distribution in patients with IM is a consequence of the progeny of a malignant hematopoietic stem cell clone.

Adult↗
PubMed2006

MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia.

BACKGROUND: The JAK2V617F allele has recently been identified in patients with polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis with myeloid metaplasia (MF). Subsequent analysis has shown that constitutive activation of the JAK-STAT signal transduction pathway is an important pathogenetic event in these patients, and that enzymatic inhibition of JAK2V617F may be of therapeutic benefit in this context. However, a significant proportion of patients with ET or MF are JAK2V617F-negative. We hypothesized that activation of the JAK-STAT pathway might also occur as a consequence of activating mutations in certain hematopoietic-specific cytokine receptors, including the erythropoietin receptor (EPOR), the thrombopoietin receptor (MPL), or the granulocyte-colony stimulating factor receptor (GCSFR). METHODS AND FINDINGS: DNA sequence analysis of the exons encoding the transmembrane and juxtamembrane domains of EPOR, MPL, and GCSFR, and comparison with germline DNA derived from buccal swabs, identified a somatic activating mutation in the transmembrane domain of MPL (W515L) in 9% (4/45) of JAKV617F-negative MF. Expression of MPLW515L in 32D, UT7, or Ba/F3 cells conferred cytokine-independent growth and thrombopoietin hypersensitivity, and resulted in constitutive phosphorylation of JAK2, STAT3, STAT5, AKT, and ERK. Furthermore, a small molecule JAK kinase inhibitor inhibited MPLW515L-mediated proliferation and JAK-STAT signaling in vitro. In a murine bone marrow transplant assay, expression of MPLW515L, but not wild-type MPL, resulted in a fully penetrant myeloproliferative disorder characterized by marked thrombocytosis (Plt count 1.9-4.0 x 10(12)/L), marked splenomegaly due to extramedullary hematopoiesis, and increased reticulin fibrosis. CONCLUSIONS: Activation of JAK-STAT signaling via MPLW515L is an important pathogenetic event in patients with JAK2V617F-negative MF. The bone marrow transplant model of MPLW515L-mediated myeloproliferative disorders (MPD) exhibits certain features of human MF, including extramedullary hematopoiesis, splenomegaly, and megakaryocytic proliferation. Further analysis of positive and negative regulators of the JAK-STAT pathway is warranted in JAK2V617F-negative MPD.

Amino Acid Substitution↗
PubMed2002

Negligible clinical effects of thalidomide in patients with myelofibrosis with myeloid metaplasia.

We conducted a nonrandomized prospective phase II study of thalidomide in anemic patients with myelofibrosis with myeloid metaplasia (MMM), with or without preceding polycythemia vera or essential thrombocythemia, with a primary aim to improve anemia. Thalidomide was given in escalating doses with a target dose of 800 mg daily, but the median dose of thalidomide that was actually tolerated was 400 mg daily. Fifteen patients were entered into the study and 14 were evaluable for response. Five of 14 (36%) patients discontinued thalidomide before 3 mo because of side effects, and none of these five patients had a response at the time when thalidomide was stopped. When evaluated after 3 mo of therapy, none of the remaining nine patients exhibited a discernible clinical response. Three patients showed progressive disease defined as > 50% increase in the need for red cell transfusions. Treatment was poorly tolerated, with all patients reporting side effects of thalidomide, the most prominent being fatigue documented in 80% of patients. Two patients died while on study, one from acute myelogenous leukemia and one from pneumonia. We conclude that thalidomide given in doses employed in the treatment of multiple myeloma gives no clinically relevant hematological effects in advanced MMM and is hampered by a very high incidence of side effects.

Adult↗
PubMed2005

Dynamics of bone marrow changes in patients with chronic idiopathic myelofibrosis following allogeneic stem cell transplantation.

Scant knowledge exists about the dynamics of fibro-osteosclerotic bone marrow (BM) lesions and regeneration of hematopoiesis following allogeneic peripheral stem cell transplantation (SCT) in chronic idiopathic myelofibrosis. Therefore, an immunohistochemical and morphometric study was performed on BM biopsies in 20 patients before and at standardized intervals (days 30 through 384) following SCT. In responding patients, a total regression of the pretransplant increased fibrosis was completed in the posttransplant period after about six months, while the extent of osteosclerosis did not change significantly during observation time. The quantity of CD61+ megakaryocytes including precursors was strikingly variable after SCT and, by using planimetric methods, atypical microforms exhibiting a dysplastic aspect could be demonstrated. These anomalies may be responsible for posttransplant thrombocytopenia. CD34+ progenitor cells were increased before transplantation, however, their number declined rapidly to normal values in responding patients. Nucleated erythroid precursors revealed a decreased amount before and after SCT accounting for anemia. Large clusters of this cell lineage indicated an initial hematopoietic reconstitution comparable with the expansion of the neutrophil granulopoiesis. Proliferative activity and apoptosis showed an increase until one year after SCT that implied a still regenerating hematopoiesis in keeping with an enhanced cell turnover.

Adolescent↗
PubMed2006

Experimental therapy in myelofibrosis with myeloid metaplasia.

Myelofibrosis with myeloid metaplasia (MMM) is a Philadelphia chromosome-negative myeloproliferative disorder that is characterised by constitutional symptoms, progressive anaemia and extramedullary haematopoiesis. There are no curative therapies available for patients with MMM apart from stem cell transplantation, which is associated with significant morbidity and mortality, and for which most patients are not suitable candidates. Traditional pharmacological therapy of MMM has focused on the palliation of symptoms associated with myeloproliferation and correction of cytopoenias. Recently, new findings regarding the molecular basis of MMM and the pathogenesis of the associated bone marrow stromal reaction have provided both basic and clinical researchers with invaluable tools to develop effective targeted therapies for patients with MMM. Several novel treatment strategies are being investigated including antiangiogenic agents, signal transduction inhibitors, inhibitors of fibrogenesis and small-molecule inhibitors of the JAK2(V617F )mutation. This article reviews the current status of experimental novel therapies for MMM.

Angiogenesis Inhibitors↗
PubMed2007

Coronary artery bypass grafting in idiopathic myelofibrosis: a case report.

The concomitant presence of myeloproliferative disorders and the need for coronary artery bypass surgery is a surgical dilemma. Thrombosis and hemorrhage can cause difficult problems and might require different approaches during and after surgery. We report a patient who had idiopathic myelofibrosis and underwent a successful coronary artery bypass surgery.

Aged↗
PubMed2004

Primary myelofibrosis terminated in basophilic leukemia and successful allogeneic bone marrow transplantation.

Transformation of primary myelofibrosis (PMF) to basophilic leukemia is very rare. We report the case of a 44-year-old man who had had PMF for 6 years. His hematopoiesis deteriorated with marked splenomegaly, requiring multiple red blood cell and platelet transfusions. Soon after splenectomy, progressive basophilia (32.3 x 10(9)/L) developed, infiltrating the skin as well as the bone marrow. The patient underwent allogeneic bone marrow transplantation with cells from an HLA-matched sibling. Despite the presence of hyperhistaminemia (99.1 ng/mL) after conditioning with cyclophosphamide, the pregrafting and post-grafting periods were uneventful. Prophylactic administration of both H1 and H2 receptor antagonists and sufficient hydration appeared to be important.

Adult↗
PubMed2006

Molecular profiling of CD34+ cells in idiopathic myelofibrosis identifies a set of disease-associated genes and reveals the clinical significance of Wilms' tumor gene 1 (WT1).

This study was aimed at the characterization of a gene expression signature of the pluripotent hematopoietic CD34(+) stem cell in idiopathic myelofibrosis (IM), which would eventually provide novel pathogenetic insights and/or diagnostic/prognostic information. Aberrantly regulated genes were revealed by transcriptome comparative microarray analysis of normal and IM CD34(+) cells; selected genes were also assayed in granulocytes. One-hundred seventy four differentially expressed genes were identified and in part validated by quantitative polymerase chain reaction. Altered gene expression was corroborated by the detection of abnormally high CD9 or CD164, and low CXCR4, membrane protein expression in IM CD34(+) cells. According to class prediction analysis, a set of eight genes (CD9, GAS2, DLK1, CDH1, WT1, NFE2, HMGA2, and CXCR4) properly recognized IM from normal CD34(+) cells. These genes were aberrantly regulated also in IM granulocytes that could be reliably differentiated from control polycythemia vera and essential thrombocythemia granulocytes in 100% and 81% of cases, respectively. Abnormal expression of HMGA2 and CXCR4 in IM granulocytes was dependent on the presence and the mutational status of JAK2(V617F) mutation. The expression levels of both CD9 and DLK1 were associated with the platelet count, whereas higher WT1 expression levels identified IM patients with more active disease, as revealed by elevated CD34(+) cell count and higher severity score. In conclusion, molecular profiling of IM CD34(+) cells uncovered a limited number of genes with altered expression that, beyond their putative role in disease pathogenesis, are associated with patients' clinical characteristics and may have potential prognostic application.

Algorithms↗
PubMed2006

Advances in the therapy of chronic idiopathic myelofibrosis.

The molecular basis of chronic idiopathic myelofibrosis (CIMF) has remained elusive, thus hampering the development of effective targeted therapies. However, significant progress regarding the molecular mechanisms involved in the pathogenes is of this disease has been made in recent years that will likely provide ample opportunity for the investigation of novel therapeutic approaches. At the fore front of these advances is the discovery that 35%-55% of patients with CIMF harbor mutations in the Janus kinase 2 tyrosine kinase gene. Until very recently, the management of patients with CIMF involved the use of supportive measures, including growth factors, transfusions, or interferon, and the administration of cyto-reductive agents, such as hydroxyurea and anagrelide. However, several trials have demonstrated the efficacy of antiangiogenic agents alone or in combination with corticosteroids. In addition, the use of reduced-intensity conditioning allogeneic stem cell transplantation has resulted in prolonged survival and lower transplant-related mortality.

Antineoplastic Agents↗
PubMed1993

Myelodysplastic syndrome associated with myelofibrosis, a report of 3 cases.

Three cases of primary myelodysplastic syndrome (MDS) associated with myelofibrosis were initially diagnosed as refractory anemia by the presence of bicytopenia or pancytopenia and having normo- or hypercellular marrow with dysplastic features. The bone marrow aspiration of these patients showed dry tap a few months after admission, or on admission. Their bone marrow biopsy specimens revealed various grades of increased formation of reticulin fibers. One patient entered into complete remission in response to metenolone, while the other two patients died of cerebral hemorrhage several months after admission. These results indicate that this disease should be classified as a distinct subgroup of MDS.

Aged↗
PubMed1995

CD34-positive blastoma in a patient with idiopathic myelofibrosis.

We report CD34-positive "blastoma" which developed in a patient with idiopathic myelofibrosis (IMF). A 48-year-old woman was diagnosed as having essential thrombocythemia, then the disease had transformed into IMF 41 months later. Finally, a subcutaneous tumor, composed of blastic cells positive for CD34 but negative for lineage-specific antigens, developed without any evidence of systemic leukemia transformation.

Antigens, CD34↗
PubMed2000

Tumor-like splenic extramedullary hematopoiesis in a patient with myelofibrosis.

A 61-year-old woman, who was diagnosed in 1982 as having polycythemia vera, was admitted to our hospital in July 1998 because of a splenic tumor in an enlarged spleen due to myelofibrosis. As it was difficult to identify the etiology of the splenic tumor, partial splenectomy was carried out. The resected tumor proved to be an extremely proliferative lesion as the result of extramedullary hematopoiesis. Since it is difficult to diagnose the etiology of splenic tumor, the collection and analysis of reports of relevant cases may well facilitate diagnosis.

Diagnosis, Differential↗
PubMed2004

Myelofibrosis with myeloid metaplasia: new developments in pathogenesis and treatment.

Myeloid metaplasia with myelofibrosis (MMM) is a chronic myeloproliferative disorder (CMPD) characterized by progressive anemia, massive splenomegaly, both hepatosplenic and non-hepatosplenic extramedullary hematopoiesis (EMH), a leukoerythroblastic blood smear, circulating progenitor cells, and marked bone marrow stromal reaction including collagen fibrosis, osteosclerosis and angiogenesis. The overall median survival is 5 years although it might range from 2 to 15 years depending on the presence or absence of clinically defined prognostic factors. Death is often due to leukemic transformation, portal hypertension or infection. In addition to shortened survival, quality of life is often affected by frequent red blood cell transfusions, profound constitutional symptoms, and cachexia. Drug therapy and autologous hematopoietic stem cell transplantation (HSCT) are of only palliative value and have not been shown to improve survival. The role of allogeneic HSCT, both myeloablative and non-myeloablative, is actively being investigated. Both splenectomy and radiation therapy have defined therapeutic roles to control EMH-associated symptoms. Analysis of the molecular biology of the disease is underway with the aid of animal models leading to the identification of novel therapeutic targets. Among the novel agents tested, thalidomide seems the most promising although newer agents are on the horizon.

Aged↗
PubMed1987

Lysozyme secreting tumor: a case of gastric cancer associated with myelofibrosis due to disseminated bone marrow metastasis.

One patient with gastric carcinoma and secondary myelofibrosis due to disseminated bone marrow metastasis had markedly elevated lysozyme (LZM) levels in serum and urine with the intense presence of LZM within tumor tissues. It is considered to be a case of gastric carcinoma with LZM secreting functional capacities. To date, there were many reported cases to verify the LZM positive cells by LZM staining in the tissue of gastric carcinoma and to demonstrate the elevated serum levels of LZM in malignant tumor bearing patients, whereas no papers to disclose the elevated levels of LZM in serum and urine originated from the productions and secretions of gastric carcinoma cells. So, this report might be the first reported case of LZM secreting tumor verified by LZM staining of carcinoma cells except for haematological malignancies such as acute monocytic leukemia or myelomonocytic leukemia.

Adenocarcinoma↗
PubMed1982

Prognostic factors in myelofibrosis.

The prognostic significance of spleen size, hemoglobin level (Hb), platelet count and hemopoietic cellularity of the bone marrow was assessed in 33 patients with myelofibrosis. Of these 4 parameters, only the Hb (P less than 0.01) and bone marrow cellularity (P less than 0.001) were found to be useful indicators of prognosis. Patients with Hb greater than 10 g/dl had a median survival greater than 110 mth while those with Hb less than 10 g/dl had a median survival of 22.5 mth; patients with hemopoietic hypercellularity in the bone marrow had a median survival greater than 110 mth while those with a normo- or hypocellularity had a median survival of 20.5 mth. There was significant correlation (P less than 0.01) between the marrow cellularity and the Hb level; 71% of patients with a normo- or hypocellular marrow had Hb less than 10 g/dl, while 79% of those with a hypercellular marrow had Hb greater than 10 g/dl.

Adult↗
PubMed1988

Effect of chemotherapy on tear drop poikilocytes and other peripheral blood findings in myelofibrosis.

A leukoerythroblastic blood picture and tear drop shaped red cells are two characteristic features of myelofibrosis (MF). Following our earlier observation of an increase in the hemoglobin level with chemotherapy, we have now reviewed the pre- and post-treatment peripheral blood smears from 14 patients with MF to assess the effect of treatment on the above mentioned peripheral blood features. Our results suggest that these features are reversible with effective chemotherapy.

Aged↗
PubMedDate not supplied

Palliative splenectomy in myelofibrosis with myeloid metaplasia.

Myelofibrosis with myeloid metaplasia (MMM) is a chronic myeloproliferative disorder in which the accumulation and growth of circulating myeloid progenitors in the spleen lead to pathologic enlargement of the organ with resulting mechanical discomfort, hypercatabolic symptoms, anemia, thrombocytopenia, and portal hypertension. Medical therapy and splenic irradiation may be of benefit in certain patients, yet many may still require splenectomy to palliate their symptoms. Although there is no clear survival advantage to splenectomy in MMM, the procedure can result in substantial palliation of symptoms. However, the surgical procedure is associated with an approximately 9% mortality rate, and the postsplenectomy occurrence of extreme thrombocytosis, hepatomegaly, and leukemic transformation is of major concern. The management of splenomegaly and the role of splenectomy in MMM are discussed in this review.

Disease Management↗
PubMed1993

Paroxysmal nocturnal hemoglobinuria with myelofibrosis: progression to acute myeloblastic leukemia.

A 58-year-old male was diagnosed as having paroxysmal nocturnal hemoglobinuria (PNH) with myelofibrosis in 1984. The administration of hydroxyurea and low dose splenic irradiation were initiated for abdominal distention due to splenomegaly in 1987. In May 1990 the patient developed smouldering acute myeloblastic leukemia (AML); and the blasts proliferated in response to G-CSF administered for refractory pneumonia. The patient died of pneumonia and pleural involvement of leukemia in September 1990. FACS analysis of the blasts using anti-decay accelerating factor (DAF) (CD55) and CD59 (membrane attack complex inhibition factor: MACIF) monoclonal antibodies demonstrated that 25.5% and/or 87.3% of the blasts were negative for DAF or CD59 respectively. There is the earlier evidence that about 90% leukemic myeloblasts from non-PNH AML patients are positive for DAF, and nearly 100% of non-PNH neutrophils have been shown to be positive for both DAF and CD59. Our data suggest that the leukemic blasts from this patient may have derived from the PNH clone.

Antigens, CD↗