Erythropoiesis in primary (idiopathic) osteomyelofibrosis: Quantification, PCNA‐reactivity, and prognostic impact

Thiele, Jüergen; Windecker, Roland; Kvasnicka, Hans Michael; Titius, Baerbel Ruth; Zankovich, Rudolph; Fischer, R.

doi:10.1002/ajh.2830460107

Cited by 15 publications

(11 citation statements)

References 44 publications

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“…Thus, corresponding alterations of the dynamics of hematopoiesis might be also expected in various stages of the disease process in IMF. In this context, our results add to previous data showing significantly higher global proliferative activity in IMF than in normal bone marrow [37]. On the other hand, the frequency of apoptosis in IMF is similar to normal values, thus resulting in an increased cellularity.…”

Section: Discussionsupporting

confidence: 88%

“…The conspicuous increase in bone marrow cellularity is caused by the expanding (clonally transformed) myeloid cell mass in these cases. According to former studies [37], the increase in PCNA labeling results from an unduly prolonged S-phase of the cell cycle, related to abnormalities of DNA synthesis caused by folate (hematinic) deficiency. On the other hand, the higher incidence of apoptosis, i.e., enforced cell death, results in an impairment of the neoplastic cell mass.…”

Section: Discussionmentioning

confidence: 97%

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Prognostic impact of apoptosis and proliferation in idiopathic (primary) myelofibrosis

Kvasnicka

Thiele

Regn

et al. 1999

Annals of Hematology

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A retrospective study of 120 patients with the clinically and histologically established diagnosis of idiopathic (primary) myelofibrosis (IMF) was performed to determine prognostic factors of predictive value, including parameters characterizing the dynamics of hematopoietic cell kinetics. In contrast to previous studies, our cohort comprised the full spectrum of the disease, from initial prefibrotic to advanced osteosclerotic stages. The in situ end-labeling (ISEL) technique was used to demonstrate apoptosis, in order to determine dynamic parameters of predictive value. Cell proliferation was evaluated by employing the monoclonal antibody PC10 directed against proliferating cell nuclear antigen (PCNA). Proliferative activity (PCNA index) and frequency of apoptosis showed significant differences between early and advanced fibrosclerotic stages of disease. Decrease in proliferation indicated a significantly shorter survival, whereas a higher frequency of apoptotic cells was associated with a better prognosis. It may be speculated that a normal or enhanced proliferation rate expressed by PCNA positivity (late G1- and S-phase of the cell cycle) that is accompanied by a higher incidence of apoptosis reflects the regenerative (turnover) capacity of hematopoiesis. This may apply especially to early hypercellular stages without relevant myelofibrosis. In consideration of a recently published multivariate risk model, a simplified synthesis score for stratification of a patient's prognosis was constructed. Age, degree of anemia, leukocytes, and platelet count were regarded as the most important parameters. A substantial improvement of prognostic efficiency was further achieved by including PCNA index and frequency of apoptosis. Our results are in keeping with the assumption that generalization, indicated by myeloid metaplasia, has a prodigious impact on prognosis in IMF. Furthermore, in this context dynamic features such as proliferative activity and frequency of apoptosis exert an additional predictive value.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 97%

Prognostic impact of apoptosis and proliferation in idiopathic (primary) myelofibrosis

Kvasnicka

Thiele

Regn

et al. 1999

Annals of Hematology

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“…The characteristic increase of clustering of enlarged megakaryocytes, increased erythropoiesis with increased granulopoiesis, and no stainable iron in erythrocytes and histiocytes are the diagnostic hallmarks of PV to distinguish it from the other MPDs and from congenital and SE. [137][138][139][140][141][142][143] In CMGM or prefibrotic IMF, granulopoiesis is always increased, whereas erythropoiesis is not. CMGM or prefibrotic IMF is dominated by atypical megakaryocytes due to increases of nuclear and cellular size.…”

Section: Bm Histopathology and Abnormal Megakaryocytopoiesis In CML Amentioning

confidence: 99%

The 2001 World Health Organization and Updated European Clinical and Pathological Criteria for the Diagnosis, Classification, and Staging of the Philadelphia Chromosome-Negative Chronic Myeloproliferative Disorders

Michiels

Raeve

Berneman

et al. 2006

Semin Thromb Hemost

138

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The clinical criteria according to the Polycythemia Vera Study Group (PVSG) do not distinguish between essential thrombocythemia (ET), thrombocythemia associated with early-stage polycythemia vera (PV) and prefibrotic chronic idiopathic myelofibrosis (CIMF). The criteria only classify the advanced stage of PV with increased red cell mass. The classification of myeloproliferative disorders (MPDs), proposed by the World Health Organization (WHO) in 2001, is a compromise of the clinical PVSG and WHO bone marrow criteria, and excludes early stages of ET and PV. The updated European clinical and pathological criteria combine the WHO bone marrow criteria with established and new clinical, laboratory, biological, and molecular MPD markers. This allows clinicians and pathologists to diagnose early-stage MPD and to differentiate ET, PV, and prefibrotic chronic idiopathic myelofibrosis (CIMF). Depending on laboratory tests and diagnostic criteria used, the population of the MPD patients defined as ET, PV, and CIMF are heterogeneous at the clinical, laboratory, and biological and pathological levels. The recent discovery of the JAK2 V617F mutation, which is the cause of a distinct trilinear MPD in its manifold clinical manifestations during long-term follow-up, increases the specificity of a positive JAK2 V617F polymerase chain reaction (PCR) test for the diagnosis of MPD (near 100%), but only half of the ET and CIMF patients according to the PVSG (sensitivity 50%) and the majority of PV patients (sensitivity 95%) are JAK2 V617F positive. A comparison of the laboratory features of JAK2 V617-positive and JAK2 wild-type ET patients clearly showed that JAK2 V617-positive ET is characterized by higher values for hemoglobin, hematocrit, and neutrophil counts; lower values for serum erythropoietin (EPO) levels, serum ferritin, and mean corpuscular volume; and by increased cellularity of the bone marrow in biopsy material. This indicates that JAK2 V617-positive ET patients, diagnosed according to the PVSG criteria, represent a "forme fruste of PV" consistent with early PV mimicking ET (JAK2 V617F trilinear MPD). In contrast, the JAK2 wild-type ET patients had significantly higher platelet counts and usually had a clinical picture of ET with normal serum EPO levels, PRV-1 expression, and leukocyte alkaline phosphatase score, and a typical WHO ET bone marrow picture. The clinical and pathological data on JAK2 V617F-positive MPD patients suggest that the JAK2 V617F mutation defines one disease entity with several sequential steps of ET, PV, and secondary myelofibrosis during long-term follow-up, and that the wild-type JAK2 MPDs may represent another distinct entity with a related but different molecular etiology. MPD-specific markers such as serum EPO, endogenous erythroid colony formation (EEC), and JAK2 V617F have high specificities, but the sensitivities are not high enough to detect the early stages of the MPDs, ET, PV, and prefibrotic CIMF. Bone marrow histopathology in addition to clinical, laboratory, biological, and molecular...

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“…7,8 Due to BM fibrosis, in MF patients as well as those with post ET/PV MF, an extramedullary hematopoietic process starts in the spleen or in multiple organs as an attempt to override BM failure, often leading to the development of splenomegaly or hepatosplenomegaly. Moreover, splenomegaly exacerbates cytopenias through the sequestration and destruction of hematopoietic elements.…”

Section: Introductionmentioning

confidence: 99%

Palliative splenic irradiation in primary and post PV/ET myelofibrosis: outcomes and toxicity of three radiation schedules

Federíco

Pagnucco²,

Russo

et al. 2009

Hematol Rep

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Splenectomy and splenic irradiation (SI) are the sole treatment modalities to control drug resistant splenomegaly in patients with myelofibrosis (MF). SI has been used in poor surgical candidates but optimal total dose and fractionation are unclear. We retrospectively reviewed 14 MF patients with symptomatic splenomegaly. Patients received a median of 10 fractions in two weeks. Fraction size ranged from 0.2–1.4 Gy, and total dose varied from 2–10.8 Gy per RT course. Overall results indicate that 81.8% of radiation courses achieved a significant spleen reduction. Splenic pain relief and gastrointestinal symptoms reduction were obtained in 94% and 91% of courses, respectively. Severe cytopenias occurred in 13% of radiation courses. Furthermore patients were divided in three groups according to the radiation dose they received: 6 patients in the low-dose group (LDG) received a normalized dose of 1.67 Gy; 4 patients in the intermediate-dose group (IDG) received a normalized dose 4.37 Gy; the remaining 4 patients in the high-dose group (HDG) received a normalized dose of 9.2 Gy. Subgroup analysis showed that if no differences in terms of treatment efficacy were seen among dose groups, hematologic toxicity rates distributed differently. Severe cytopenias occurred in 50% of courses in the HDG, and in the 14.3% and in 0% of the IDG and LDG, respectively. Spleen reduction and pain relief lasted for a median of 5.5 months in all groups. Due to the efficacy and tolerability of the low-dose irradiation 4 patients from the LDG and IDG were retreated and received on the whole 12 RT courses. Multiple retreatments did not show decremental trends in terms of rates of response to radiation nor in terms of duration of clinical response. Moreover, retreatment courses did not cause an increased rate of adverse effects and none of the retreated patients experienced severe hematologic toxicities. The average time of clinical benefit in retreated patients was much longer (21 months, range 44–10) than patients who were not retreated (5.75 months, range 3–6).

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Erythropoiesis in primary (idiopathic) osteomyelofibrosis: Quantification, PCNA‐reactivity, and prognostic impact

Cited by 15 publications

References 44 publications

Prognostic impact of apoptosis and proliferation in idiopathic (primary) myelofibrosis

Prognostic impact of apoptosis and proliferation in idiopathic (primary) myelofibrosis

The 2001 World Health Organization and Updated European Clinical and Pathological Criteria for the Diagnosis, Classification, and Staging of the Philadelphia Chromosome-Negative Chronic Myeloproliferative Disorders

Palliative splenic irradiation in primary and post PV/ET myelofibrosis: outcomes and toxicity of three radiation schedules

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