An autopsy case of myelodysplastic syndrome (MDS): diagnostic problems between MDS and the other haematopoietic disorders including acute myelofibrosis

We report an autopsy case of myelodysplastic syndrome (MDS) in a 35-year-old male, who presented with pancytopenia and bleedings. Bone marrow specimens disclosed myelofibrosis and hypercellular marrow with more than 60% atypical erythroblasts in the bone marrow cells. Type I or type II blasts were less than 10% of the peripheral blood and bone marrow cells during the clinical course. At autopsy, infiltration by myeloid and erythroid cells and megakaryocytes was noted in the liver, spleen and lymph nodes. According to the FAB classification, this case might be classified into refractory anemia with excess of blasts (RAEB) or RAEB in transformation. However, the remarkable neoplastic proliferation of three haematopoietic cell lines also indicates acute myeloproliferative disorder such as acute myelofibrosis or acute panmyelosis.     

Thrombopoietin administered during induction chemotherapy to patients with acute myeloid leukemia induces transient morphologic changes that may resemble chronic myeloproliferative disorders

Thrombopoietin (TPO), a potent stimulator of megakaryocyte and platelet production, has been used in clinical trials to reduce thrombocytopenia after chemotherapy in patients with acute myeloid leukemia (AML). We report that TPO therapy is associated with peripheral blood and bone marrow findings that can mimic myeloproliferative disorders. Peripheral blood and bone marrow samples of 13 patients with AML who received TPO were examined. A subset of bone marrow samples exhibited hypercellularity, megakaryocytic hyperplasia, and reticulin fibrosis after TPO administration. Cases demonstrated as many as 58.4 megakaryocytes per high-powerfield (MHPF) compared with 3.7 MHPF in the control group. Megakaryocytic atypia, increased mitoses, emperipolesis, intrasinusoidal megakaryocytes, and thickened trabeculae also were seen. Peripheral blood findings included leukoerythroblastosis, leukocytosis, thrombocytosis, and circulating megakaryocyte nuclei. Changes resolved within 3 months after discontinuation of TPO. This rapid resolution of the morphologic abnormalities induced by TPO distinguishes these findings from those seen in true chronic myeloproliferative disorders.     

Haematological changes in HIV infection

HIV infection is associated with a wide range of hematological abnormalities. The peripheral blood findings and the morphological abnormalities in the bone marrow can simulate myelodysplastic syndrome, myeloproliferative disorders, and T cell lymphoma. We studied the peripheral blood smear and bone marrow findings of 42 patients with HIV infection over a 3-year period with the aim of recognising the morphological findings sufficiently characteristic of HV infection. The salient peripheral blood smear findilngs were anemia, bicytopenia and pancytopenia. The bone marrow revealed trilineage dysplasia, plasma cells and eosinophils, increased megakaryocytes, increased iron and reticulin fibrosis. In two cases the bone marrow revealed granulomata.     

The small molecule inhibitor g6 significantly reduces bone marrow fibrosis and the mutant burden in a mouse model of jak2-mediated myelofibrosis

Philadelphia chromosome-negative myeloproliferative neoplasms, including polycythemia vera, essential thrombocytosis, and myelofibrosis, are disorders characterized by abnormal hematopoiesis. Among these myeloproliferative neoplasms, myelofibrosis has the most unfavorable prognosis. Furthermore, currently available therapies for myelofibrosis have little to no efficacy in the bone marrow and hence, are palliative. We recently developed a Janus kinase 2 (Jak2) small molecule inhibitor called G6 and found that it exhibits marked efficacy in a xenograft model of Jak2-V617F-mediated hyperplasia and a transgenic mouse model of Jak2-V617F-mediated polycythemia vera/essential thrombocytosis. However, its efficacy in Jak2-mediated myelofibrosis has not previously been examined. Here, we hypothesized that G6 would be efficacious in Jak2-V617F-mediated myelofibrosis. To test this, mice expressing the human Jak2-V617F cDNA under the control of the vav promoter were administered G6 or vehicle control solution, and efficacy was determined by measuring parameters within the peripheral blood, liver, spleen, and bone marrow. We found that G6 significantly reduced extramedullary hematopoiesis in the liver and splenomegaly. In the bone marrow, G6 significantly reduced pathogenic Jak/STAT signaling by 53%, megakaryocytic hyperplasia by 70%, and the Jak2 mutant burden by 68%. Furthermore, G6 significantly improved the myeloid to erythroid ratio and significantly reversed the myelofibrosis. Collectively, these results indicate that G6 is efficacious in Jak2-V617F-mediated myelofibrosis, and given its bone marrow efficacy, it may alter the natural history of this disease.     

Histological diagnosis of Ph-negative myeloproliferative neoplasia. An overview

A histological picture in pretreatment bone marrow trephine biopsy is an essential part of Ph-negative myeloproliferative neoplasm diagnosis according to WHO classification. Polycythaemia vera is histologically defined as a hypercellular trilinear myeloproliferation. Hypercellular haematopoiesis with granulocytic and megakaryocytic proliferation is typical for primary myelofibrosis. In essential thrombocythaemia the haematopoiesis is normocellular with proliferation of megakaryocytes only. The most important differential diagnostic features are morphology and distribution of megakaryocytes, and presence of fibrosis. In primary myelofibrosis there are typically ,dysplastic" megakaryocytes forming tight (dense) clusters, and variable extent of fibrosis, while mature megakaryocytes forming loose clusters and no fibrosis are found in essential thrombocythaemia. In reactive thrombocytosis and erythrocytosis the number of normally appearing megakaryocytes is not increased and they are not forming clusters. Prodromal (latent) phases of myeloproliferative neoplasms often unrecognized by recent WHO classification criteria are discussed as well as a differential diagnosis of myeloproliferative disorders associated with thrombocytosis.     

Early and late hemopoietic precursor cells in patients with chronic myeloproliferative diseases

We evaluated the content of early and late cobblestone area-forming cells, immediate progeny of hemopoietic stem cells, and committed precursor cells in the bone marrow and peripheral blood of patients with chronic myeloproliferative diseases and healthy donors. In patients with essential thrombocythemia, the number of late cobblestone area-forming cells in the peripheral blood decreased, while other parameters did not differ from those in healthy donors. In patients with idiopathic myelofibrosis, we found a decreased number of late and early cobblestone area-forming cells in the bone marrow and late cobblestone area-forming cells in the peripheral blood, while the count of early cobblestone area-forming cells in the peripheral blood increased. In patients with chronic myeloid leukemia, the number of early cobblestone area-forming cells in the bone marrow decreased, but the count of late and early cobblestone area-forming cells in the peripheral blood increased. The number of endogenous committed precursor cells in the peripheral blood increased in all groups of patients with chronic myeloproliferative diseases and, particularly, in patients with idiopathic myelofibrosis and chronic myeloid leukemia. Functional characteristics of immediate descendants of hemopoietic stem cells probably reflect the level of damage and attest to the existence of various mechanisms underlying the defect of the hemopoietic stem cell during chronic myeloproliferative diseases. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 144, No. 8, pp. 146–150, August, 2007     

Histopathology in the diagnosis and classification of acute myeloid leukemia, myelodysplastic syndromes, and myelodysplastic/myeloproliferative diseases.

In spite of the impressive advances in the area of molecular pathology, bone marrow morphology remains the diagnosis cornerstone to identify the various subtypes of myeloid neoplasms. Morphological examination of the bone marrow requires both bone marrow aspirate and bone marrow trephine biopsy. Immunohistochemistry of bone marrow biopsy with markers reactive in paraffin-embedded tissues represents a powerful diagnostic tool; its results can be easily correlated with those obtained by other techniques such as flow cytometry and genetic analysis, and above all, the clinical findings. The role of the bone marrow biopsy will be particularly stressed in this review article. Particular emphasis is being given to the correct identification of cases of myeloid neoplasms associated with myelofibrosis and for which the bone marrow biopsy represents the only available diagnostic mean. Moreover, the often low cellular yield of the bone marrow aspirate in these cases may also be insufficient to obtain adequate cytogenetic information. Such cases include two subtypes of acute myeloid leukemia which typically cause diagnostic difficulties: acute megakaryoblastic leukemia and acute panmyelosis with myelofibrosis (acute myelosclerosis). Acute myeloid leukemia with multilineage dysplasia, therapy-related myelodysplastic syndrome/therapy-related acute myeloid leukemia and de novo myelodysplastic syndromes (MDS) will also be discussed. The value of bone marrow biopsy in this group of disorders is generally well established. In MDS, in particular, bone marrow biopsy may help in confirming a suspected diagnosis by excluding reactive conditions in which dyshematopoietic changes may also be observed. It can increase the diagnostic accuracy and helps in refining the IPPS risk evaluation system. Among the alterations detected by bone marrow biopsy, a prognostically important finding is the presence of aggregates or clusters of immature myeloid precursor cells (myeloblasts and promyelocytes). These can also be identified by immunohistochemistry with CD34, an antigen expressed in progenitor and early precursor marrow cells, which can be used to demonstrate pathological accumulations of blasts in aggressive subtypes of myeloid neoplasms. Immunohistologic analysis is especially helpful in cases of MDS with fibrosis and cases with hypocellular marrows (hypoplastic MDS). In both of these variants, the presence of reticulin fibrosis or fatty changes in the bone marrow can make accurate disease characterization very difficult or impossible using bone marrow aspirates. Finally, the important group of the myelodysplastic/myeloproliferative disorders can only be accurately categorized by a careful multiparametric approach in which the bone marrow biopsy exerts a pivotal role.     

Elevated TNF-alpha and LDH without parathormone disturbance is associated with diffuse osteolytic lesions in leukemic transformation of myelofibrosis

Myelofibrosis is a clonal myeloproliferative disorder characterized by splenomegaly, abnormal deposition of collagen in the bone marrow, extramedullary hematopoiesis, dacriocytosis, and leukoerythroblastic blood smear. Development and maintenance of fibrosis are mediated by a complex network of several cytokines, including tumor necrosis factor-alpha (TNF-alpha). Osteosclerosis is the most frequently observed bone change in myelofibrosis. Based on this, we present an atypical case of leukemic transformation in myelofibrosis associated with diffuse osteolytic lesions and extremely elevated TNF-alpha and lactate dehydrogenase (LDH). Parathormone was not disturbed.     

Mast cell burden and reticulin fibrosis in the myeloproliferative neoplasms: A computer-assisted image analysis study

The mast cell has been associated with fibrosis in many different tissues, organs, and different disease processes including hematopoietic malignancies. Mast cells are often increased in the bone marrow of patients with primary bone marrow disorders, and patients with systemic mastocytosis often have a second concomitant neoplastic disease of the bone marrow. The goals of the current study were to determine the role the mast cell has in the pathogenesis of myeloproliferative neoplasms (MPN) and to correlate the mast cell burden with the degree of reticulin fibrosis.We used computer-assisted image analysis of bone marrow core biopsies stained for mast cell tryptase from patients with myeloproliferative neoplasms [31 cases: 12 chronic myelogenous leukemia (CML), 6 primary myelofibrosis (PMF), 4 essential thrombocythemia (ET), 4 polycythemia vera (PV), and 5 chronic myeloproliferative disorder, unclassifiable (CMPD-U)].Although the number of cases of some subtypes of MPN was small, the results suggested that PMF and ET each had significantly more mast cells than both CML and control cases (P<0.01 and 0.05, respectively, Mann–Whitney test). CMPD-U and PV showed no significant differences from the control cases, but the CML cases had significantly fewer mast cells than our control cases (P=0.02, Mann–Whitney test). In addition, the quantity of mast cells seen in the bone marrows of MPN patients correlated with reticulin fibrosis (P=0.04, Mann–Whitney test).Our studies highlight the different mast cell quantities in different myeloproliferative neoplasms and suggest a direct role for the mast cell in intramedullary fibrosis. Further studies are warranted to confirm our observation and to study the mechanisms by which mast cells contribute to fibrosis in the MPN setting.     

Immunocytochemical detection of megakaryocytes by endothelial markers: a comparative study.

By endothelial markers such as FVIII, UEA-I, CD31 and QBEND/10, the Authors have investigated the immunohistochemical pattern of bone marrow megakaryocytes in myelodysplastic (8 cases) and myeloproliferative (35 cases) disorders as well as in control biopsies (8 cases). An evident cytoplasmic positivity with FVIII and UEA-I was encountered in all normal and pathological specimens, whereas the immunolocalization of CD31 was limited to megakaryocytes present in normal bone marrow biopsies or in cases of myelofibrosis. No immunostaining with QBEND/10 was observed in any case, although the most selective staining of endothelial cells of bone marrow vessels was noted with this antibody. The usefulness to utilize endothelial markers in order to identify atypical and immature forms of megakaryocytes as well as micromegakaryocytes, especially in myelofibrosis by the aid of CD31, was also discussed.     

Complete regression of bone marrow fibrosis following allogeneic peripheral blood stem cell transplantation in a patient with idiopathic myelofibrosis

The authors present a case of a 47-year-old man with idiopathic myelofibrosis. The diagnosis of myelofibrosis was made in 1981. Because of progression of the disease and failure of hematopoiesis in 2002, allogeneic peripheral blood stem cell transplantation was performed; the donor was an HLA identical relative. Six months after transplantation, trephin biopsies were made and a complete regression of bone marrow fibrosis was documented. It is the first case of this treatment for idiopathic myelofibrosis in the University Hospital in Hradec Králové.     

Bone biopsy in haematological disorders

Bone marrow biopsies are now widely used in the investigation and follow-up of many diseases. Semi-thin sections of 8216 undecalcified biopsies of patients with haematological disorders were studied. Observations were made on the cytopenias and the myelodysplastic syndromes, the acute leukaemias the myeloproliferative disorders, Hodgkin's disease and the malignant lymphomas including multiple myeloma, hairy cell leukaemia and angioimmunoblastic lymphadenopathy. Bone marrow biopsies are essential for the differential diagnosis of most cytopenias and for the early recognition of fibrosis which most frequently occurred as a consequence of megakaryocytic proliferation in the myeloproliferative disorders. Different patterns of bone marrow involvement were found in the lymphoproliferative disorders and both their type and extent constituted factors of prognostic significance. A survey of the literature is given and the conclusion is drawn that bone marrow biopsies provide indispensible information for the diagnostic evaluation and the follow-up of patients with haematological disorders.     

The role of beta-catenin in chronic myeloproliferative disorders

The goal of the current study is to evaluate the role of beta-catenin in chronic myeloproliferative disorders. Expression of beta-catenin was analyzed by immunohistochemistry in formalin-fixed decalcified bone marrow biopsy specimens from 52 chronic myeloproliferative disorder cases and 6 nonchronic myeloproliferative disorder bone marrows as controls. The frequency of moderate to strong beta-catenin staining of megakaryocytes was significantly higher in polycythemia vera cases and in essential thrombocythemia cases than in chronic myelogenous leukemia cases (polycythemia vera versus chronic myelogenous leukemia, P = .002345, Fisher exact; and essential thrombocythemia versus chronic myelogenous leukemia, P = .002288), chronic idiopathic myelofibrosis cases (polycythemia vera versus chronic idiopathic myelofibrosis, P = .006707 and essential thrombocythemia versus chronic idiopathic myelofibrosis, P = .006932) or control cases (polycythemia vera versus control, P = .010489 and essential thrombocythemia versus control, P = .0113120). The erythroid and myeloid lineages showed absent to weak beta-catenin staining in most cases. In conclusion, these results indicate that the Wnt/beta-catenin signaling pathway may have a role in megakaryocytopoiesis in polycythemia vera and essential thrombocythemia. In addition, beta-catenin may be a useful marker for differentiating polycythemia vera and essential thrombocythemia from other types of chronic myeloproliferative disorders.     

Bone marrow stroma in idiopathic myelofibrosis and other haematological diseases. An immunohistochemical study

Bone marrow stroma was investigated immunohistochemically in 31 patients with haematological diseases, mainly idiopathic myelofibrosis (n = 8) and related chronic myeloproliferative disorders (n = 14). The bone marrow from patients with idiopathic myelofibrosis and some CML patients showed marked staining reactions with antibodies against type III procollagen (pN collagen), type IV collagen, fragment P1 of laminin and factor VIII. Patients with osteomyelosclerosis had particularly increased collagen content, including both newly deposited type III collagen (pN collagen) and mature collagen fibres. As in normal bone marrow, argyrophilic fibres and type III collagen displayed a close co-distribution, which was also demonstrated for type IV collagen and laminin. While normal bone marrow sinusoids had discontinuous basement membranes, fibrosing bone marrow was characterized by endothelial cell proliferation and capillarization, with the development of continuous sheets of basement membrane material beneath endothelial cells.     

Analysis of loss of heterozygosity and X chromosome inactivation in spleens with myeloproliferative disorders and acute myeloid leukemia.

Neoplastic myeloid proliferations are seen in the spleens of some patients with acute and chronic myeloproliferative disorders. Both acute myeloid leukemia (AML) and chronic myeloproliferative disorders have a variety of underlying cytogenetic defects that can be evaluated by loss of heterozygosity (LOH) studies. LOH studies have advantages over conventional cytogenetics by allowing the use of archival tissues. We evaluated the spleens in AML and chronic myeloproliferative disorders with neoplastic myeloid proliferations for the presence of LOH at several chromosome loci, and X-chromosome inactivation. A total of 17 spleens were evaluated (chronic myelogenous leukemia = 6; chronic idiopathic myelofibrosis = 6; essential thrombocythemia = 1; AML arising from previous chronic myeloproliferative disorders = 4). We examined LOH loci 7q (D7S2554), 8q (D8S263), 9p (D9S157, D9S161), 13q (D13S319), common sites of genetic abnormality in chronic myeloproliferative disorders, and TP53. In six cases, spleen LOH findings were compared to those of concurrent or preceding bone marrow biopsies. Five spleens of female patients were evaluated for the presence of clonality using X-chromosome inactivation. Of the 16 cases analyzed, 14 (88%) had at least one abnormal LOH locus, with 6/16 with two abnormal loci. The abnormalities were distributed as follows: D9S161-7/15 (47%), TP53-6/16 (38%), D7S2554-5/16 (31%), D9S157-5/15 (33%), D8S263-3/14 (21%), and D13S319-2/14 (14%). Of the six bone marrows, 4/6 showed concordance in bone marrow and spleen specimens, with additional LOH abnormalities being identified in the spleen specimens of all four cases. X-chromosome inactivation studies were showed nonrandom (clonal) patterns in two cases. Our results show that allelic losses were common in the neoplastic extramedullary hematopoiesis found in spleens of chronic myeloproliferative disorders and AML. Comparison of spleen and bone marrow specimens by LOH demonstrated additional abnormalities in the spleen compared to the marrow.     

Prognostische Faktoren und Überlebenszeiten bei chronischen myeloproliferativen Erkrankungen (CMPE)

The broad spectrum of clinical and hematological as well as histomorphological findings at diagnosis of chronic myeloproliferative disorders (CMPDs) is significantly associated with prognosis. However, in this context the impact of bone marrow histology is still being controversially discussed. This feature applies to CML in particular. Therefore, risk classification is mainly based on clinical data. In order to evaluate the predictive value of bone marrow morphology we performed a retrospective study on a total of 1023 patients with CMPDs. Relative survival rates and a disease-specific loss of life expectancy were calculated to adjust the age- and gender-specific mortality in older patients. Patients with chronic myeloid leukemia (CML) showed an average life expectancy of 5 years, with significantly longer survival times under interferon treatment. In contrast, the ET group did not disclose any relevant reduction in life expectancy. Initial bone marrow fibrosis and a reduction in erythropoiesis were the most important prognostic features in CML. Furthermore, Pseudo-Gaucher cells indicated a favorable outcome in the cohort of patients receiving chemotherapy. On the other hand, peripheral myelo- and erythroblasts were correlated with a worsening in survival. Regarding IMF, a simplified multivariate risk score was constructed, including age, hemoglobin level, platelet and leukocyte counts, and a leuko-erythroblastic blood picture as most important variables. The three risk groups derived showed significantly different survival patterns, but in this calculation bone marrow histology exerted no major influence on survival. On the other hand, initial (prefibrotic) stages of IMF revealed a better prognosis. In conclusion, our results underline the importance of bone marrow morphology in CMPDs, since significant correlations with patients' outcome were calculated. Particularly in CML, myelofibrosis and reduction of erythropoiesis were associated with survival and, thus, must be regarded as important predictive and independent parameters.     

Myeloproliferative neoplasms

The myeloproliferative neoplasms (MPN) are a group of clonal myeloid proliferations characterised by varying combinations of increased circulating red cells, granulocytes and platelets caused by excess proliferation of haemopoietic precursors in bone marrow with retained cellular maturation. These disorders typically pursue an indolent course requiring management of the consequences of the increased circulating elements (predominantly effects of thrombosis of haemorrhage in different body organs). Patients have complex symptoms, including fatigue, which are not yet fully explained. The MPN carry varying risks of progression to an acute phase characterised by increasing bone marrow and circulating blasts cells, and/or to fibrosis characterised by falling peripheral cell counts and increasing splenomegaly. Megakaryocyte morphology in BMT samples provides essential clues for diagnosis and subtyping in MPN; high quality and consistent reticulin staining for accurate assessment is also key.     

Philadelphia Chromosome–Negative Myeloproliferative Disorders: Biology and Treatment

The Philadelphia chromosome (Ph)-negative myeloproliferative disorders (MPDs) include essential thrombocythemia (ET), idiopathic myelofibrosis (IMF), and polycythemia vera (PV). All of these disorders are clonal hematologic malignancies originating at the level of the pluripotent hematopoietic stem cell. Recently, activating mutations of the intracellular cytokine-signaling molecule JAK2 have been identified in > 90% of patients with PV and in 50% of those with IMF and ET. In addition, a mutation of the thrombopoietin receptor, MPLW515L, has been documented in some patients with IMF. Both mutations activate JAK-STAT signaling pathways and likely play a role in disease progression. Both ET and PV are associated with prolonged clinical courses associated with frequent thrombotic and hemorrhagic events, and progression to myelofibrosis and acute leukemia. IMF has a much poorer prognosis and is associated with cytopenias, splenomegaly, extramedullary hematopoiesis, and bone marrow fibrosis. Stratification of risk for the development of complications from Ph-negative MPDs has guided the identification of appropriate therapies for this population. Intermediate/high-risk IMF or myelofibrosis after ET or PV is associated with a sufficiently poor prognosis to justify the use of allogeneic stem cell transplantation, which is capable of curing such patients. Reduced-intensity conditioning in preparation for allogeneic stem cell transplantation has permitted older patients with IMF to undergo transplantation with increasing success.     

Autopsy case of primary myelofibrosis in which myeloid sarcoma was the initial manifestation of tumor progression

Myeloid sarcoma (MyS) is defined as an extramedullary tumor-forming neoplasm consisting of immature myeloid cells with/without maturation. We experienced a case involving a 68-year-old Japanese male patient who had been followed-up for four years with a diagnosis of chronic idiopathic myelofibrosis/primary myelofibrosis (PMF) and noticed a painful mass in his left axilla. A wedge biopsy characterized the lesion as MyS that displayed megakaryoblastic/megakaryocytic differentiation. As his complete blood count included a few myeloid blasts (1% of WBC) and a bone marrow biopsy detected fibrosis without evidence of acute myelogenous leukemia (AML), a diagnosis of extramedullary blastic transformation of PMF was made, which was confirmed later by V617F mutation in Janus kinase-2 in both initial bone marrow biopsy and axillary tumor biopsy specimens. The patient died of pneumonia eight months after developing the axillary tumor. At autopsy, multiple MyS masses were detected in his soft tissue, but his bone marrow only contained fibrosis. Although MyS rarely develops before the leukemic transformation of PMF, no evidence of AML could be found in the patient's bone marrow at any point during the course of his disease. Thus, it is possible that the blasts in his peripheral blood were derived from the remaining MyS. Furthermore, the present case indicates that extramedullary blastic transformation, which is occasionally seen in CML, can also occur in PMF. Therefore, it is important to recognize that there is a wide variation in the pathogeneses of MyS and PMF.     

Multiple active X chromosomes in myelofibrosis with myeloid metaplasia

A woman with myelofibrosis and myeloid metaplasia had a karyotype of 47,X,del(X)(q22), +del(X)(q22) in unstimulated peripheral blood and bone marrow aspirate cultures. The normal X chromosome was late replicating, and the two deleted X chromosomes always replicated early and synchronously. The karyotype from phytohemagglutin-stimulated peripheral blood cultures was uniformly 46,XX. Structurally abnormal X chromosomes are exceedingly rare in myeloproliferative disease. The abnormal karyotype very likely reflects monoclonal proliferation of an abnormal myeloid cell line. The X chromosome inactivation process, which acts upon embryonic somatic cells of all mammals, apparently does not react to postembryonic nondisjunction of the active X chromosome.