• Diagnostic and prognostic value of bone marrow angiogenesis and megakaryocyte c-Mpl expression in essential thrombocythemia.

• Essential thrombocythemia with ringed sideroblasts: a heterogeneous spectrum of diseases, but not a distinct entity.

• Chronic neutrophilic leukemia evolving from polycythemia vera with multiple chromosome rearrangements: a case report.

• [Dynamic contrast-enhanced MRI for evaluating bone marrow microcirculation in malignant hematological diseases before and after

• Tyrosine kinase fusion genes in chronic myeloproliferative diseases.

• Therapeutic options for essential thrombocythemia and polycythemia vera.

• Other secondary sequelae of treatments for myeloproliferative disorders.

• Cost-effectiveness considerations in the treatment of essential thrombocythemia.

• Remission of transformed myelodysplastic syndrome with fibrosis after danazol therapy.

• FTL3 internal tandem duplication mutations are rare in agnogenic myeloid metaplasia.

• Current opinion in essential thrombocythemia: pathogenesis, diagnosis, and management.

• Variation of PDGF, TGFbeta, and bFGF levels in essential thrombocythemia patients treated with anagrelide.

• Successful treatment of anemia in idiopathic myelofibrosis with recombinant human erythropoietin.

1
UI - 12010817
AU - Mesa RA; Hanson CA; Li CY; Yoon SY; Rajkumar SV; Schroeder G; Tefferi A
TI - Diagnostic and prognostic value of bone marrow angiogenesis and megakaryocyte c-Mpl expression in essential thrombocythemia.
SO - Blood 2002 Jun 1;99(11):4131-7
AD - Division of Hematology and Internal Medicine, the Division of Hematopathology, and the Cancer Center Statistics Unit, Mayo Clinic, Rochester, MN 55905, USA. mesa.ruben@mayo.edu
The lack of diagnostic certainty in some patients makes it difficult to distinguish between primary and secondary forms of thrombocytosis. To augment current diagnostic studies for thrombocytosis, we retrospectively evaluated clinical records and bone marrow trephine specimens of 183 patients with thrombocytosis-164 with essential thrombocythemia (ET), 19 with reactive thrombocytosis (RT)-for bone marrow angiogenesis, bone marrow megakaryocyte c-Mpl staining, and morphologic evidence of megakaryocyte proliferation. Angiogenesis was increased in patients with ET compared with healthy controls (P <.0001) and patients with RT (P =.006). In addition, an increase in angiogenesis was associated with certain disease features such as splenomegaly (P =.004) and reticulin fibrosis (P =.005). Decreased megakaryocyte c-Mpl staining was observed in a heterogeneous pattern in ET compared with healthy controls (P <.0001) and RT (P <.0001). Histologic stratifying criteria incorporating increased angiogenesis, decreased megakaryocyte c-Mpl expression, and marked megakaryocyte proliferation in the bone marrow was highly sensitive (97%) and specific (95%) for distinguishing ET from RT (P <.0001). However, with the current duration of follow-up available on the patients, none of the histologic features evaluated have yet demonstrated prognostic value for subsequent clinical course, vascular events, or survival.

2
UI - 11940483
AU - Schmitt-Graeff A; Thiele J; Zuk I; Kvasnicka HM
TI - Essential thrombocythemia with ringed sideroblasts: a heterogeneous spectrum of diseases, but not a distinct entity.
SO - Haematologica 2002 Apr;87(4):392-9
AD - Institutes of Pathology, Universities of Freiburg, Germany.
BACKGROUND AND OBJECTIVES: According to the recently published WHO-classification essential thrombocythemia with ringed sideroblasts (ET/RS) remains an ambiguous category which may be considered as myelodysplastic/myeloproliferative disease, unclassifiable. Because until now only case reports or very small series of patients have been described, a more systematically performed study is warranted. DESIGN AND METHODS: A retrospective evaluation was carried out on 38 patients with the diagnosis of ET/RS and more than 15 % ringed sideroblasts on smears. Simultaneously performed bone marrow biopsies, follow-up examinations and survival data were also available. RESULTS: Based on cytological features and particular bone marrow findings including immunohistochemistry three patterns could be determined. These were associated with different clinical features and in particular prognosis. Group I included six patients whose diagnosis was consistent with ET, group II comprised 21 patients revealing prefibrotic and early fibrotic chronic idiopathic myelofibrosis (CIMF) and finally 11 patients (group III) displayed myelodysplastic syndromes (MDS). Follow-up studies revealed that no patient with ET showed a fiber increase but eight CIMF patients developed overt myelofibrosis and four patients of the MDS group developed secondary acute myeloid leukemia. In comparison with a control group of 39 patients with true ET, prognosis was significantly different because our cohort showed a median survival of 100 months that contrasted significantly with the 170 months in the patients with true ET. INTERPRETATION AND CONCLUSIONS: Ringed sideroblasts are not a pathognomonic feature of MDS, but may indicate a dysplasia probably associated with a primary or secondary disturbance of iron metabolism in a variety of disorders. For this reason, a more accurate classification of so-called ET/RS patients is warranted by evaluation of smears and in particular bone marrow biopsy specimens. According to our findings these patients should be classified as having either ET, CIMF or MDS and show a significantly different survival pattern.

3
UI - 11694412
AU - Billio A; Venturi R; Morello E; Rosanelli C; Pescosta N; Coser P
TI - Chronic neutrophilic leukemia evolving from polycythemia vera with multiple chromosome rearrangements: a case report.
SO - Haematologica 2001 Nov;86(11):1225-6

4
UI - 11963240
AU - Scherer A; Strupp C; Wittsack HJ; Engelbrecht V; Willers R; Germing U;
TI - Gattermann N; Haas R; Modder U [Dynamic contrast-enhanced MRI for evaluating bone marrow microcirculation in malignant hematological diseases before and after thalidomide therapy]
SO - Radiologe 2002 Mar;42(3):222-30
AD - Institut fur Diagnostische Radiologie, Heinrich-Heine Universitat, Moorenstrasse 5, 40225 Dusseldorf. scherera@uni-duesseldorf.de
PURPOSE: The aim of the study was to measure microcirculation parameters by dynamic contrast-enhanced MRI (d-MRI) and to evaluate the anti-angiogentic effects during treatment with thalidomide in different hematologic malignancies. METHODS: In 20 healthy normal persons, 20 patients with myelodysplastic syndromes (MDS), 10 patients with multiple myeloma (MM) and 10 with myelofibrosis (MF) a fast gradient echo sequence (Turbo fast low angle shot 2D) with a pump controlled bolus infusion of gadolinium-DTPA was performed before and in 18 of these after beginning (average of 4.3 months) of a thalidomide therapy. Two pharmacokinetic parameters--the amplitude and exchange-rate-constant--were calculated and a statistical comparison of these values between healthy persons and patients as well as a correlation with the clinical course was executed. RESULTS: Compared with the normal controls the patients showed a higher amplitude (normal persons 14.4 +/- 5.2, MDS 24.8 +/- 8.1, MF 35.9 +/- 4.3, MM 23.4 +/- 3.6) and exchange-rate-constant (normal persons 0.124 +/- 0.042, MDS 0.136 +/- 0.036, MF 0.144 +/- 0.068, MM 0.131 +/- 0.034). In the d-MRI-follow-up examinations a significant (p < 0.005) reduction of the amplitude and exchange rate constant values was evident in 14 of 18 patients undergoing a thalidomide therapy. Clinically all of these patients showed a therapy responding with complete or partial diseases remission. CONCLUSIONS: In patients with hematologic malignancies significantly higher d-MRI-microcirculation parameters of the lumbar spine can be demonstrated than in normal persons. During anti-angiogenetic treatment with thalidomide a decrease of these values was observed in case of a responding to therapy.

5
UI - 12094244
AU - Cross NC; Reiter A
TI - Tyrosine kinase fusion genes in chronic myeloproliferative diseases.
SO - Leukemia 2002 Jul;16(7):1207-12
AD - Wessex Regional Genetics Laboratory, Salisbury, UK.
With the exception of chronic myeloid leukemia (CML), chronic myeloproliferative disorders (CMPDs) are a heterogeneous spectrum of conditions for which the molecular pathogenesis is not well understood. Most cases have a normal or aneuploid karyotype, but a minority present with a reciprocal translocation that disrupts specific tyrosine kinase genes, most commonly PDGFRB or FGFR1. These translocations result in the production of constitutively active tyrosine kinase fusion proteins that deregulate hemopoiesis in a manner analogous to BCR-ABL. With the advent of targeted signal transduction therapy, an accurate clinical and molecular diagnosis of CMPDs has become increasingly important. Currently, patients with PDGFRB or ABL fusion genes are candidates for treatment with Imatinib (STI571), but it is likely that alternative strategies will be necessary for the treatment of most other patients.

6
UI - 12096352
AU - Solberg LA Jr
TI - Therapeutic options for essential thrombocythemia and polycythemia vera.
SO - Semin Oncol 2002 Jun;29(3 Suppl 10):10-5
AD - Mayo Medical School, Mayo Clinic and Foundation, Jacksonville, FL 32224, USA.
Several options exist for treating essential thrombocythemia and polycythemia vera. One approach is to assign the patient to a risk category from which treatment recommendations follow. The principal risks of essential thrombocythemia include thrombosis, major hemorrhage, and conversion to leukemia or myelofibrosis. Risk factors for thrombosis include age and prior thrombosis. Smoking and obesity have been implicated in isolated series. High-risk patients with essential thrombocythemia can be defined as those 60 years of age or older or those who have had a thrombosis at any age. These patients should be treated with hydroxyurea. If hydroxyurea cannot be tolerated, anagrelide and interferon-alpha (IFN-alpha) are alternatives. Low-dose aspirin (40 to 325 mg) can be used for patients whose platelet counts are < 1,500 x10(9)/L. Low-risk patients are those less than 60 years old who have not had thrombosis, who have no cardiovascular risk factors, and whose platelet counts are < 1,500 x 10(9)/L. These patients can be observed or placed on low-dose aspirin. Intermediate-risk patients are those less than 60 years who have not had thromboses, but who have platelet counts > 1,500 x 10(9)/L or who have significant cardiovascular risk factors. These patients should have their risk factors treated and may be given low-dose aspirin if the platelet count is < 1,500 x 10(9)/L. They can be observed or treated with anagrelide, hydroxyurea, or IFN-alpha. The Mayo Clinic experience suggests that no specific treatment affects outcomes of pregnancies. In high-risk pregnant women who need treatment, IFN-alpha is used. The principal risks of polycythemia vera are thrombosis, postpolycythemia myeloid metaplasia, and acute leukemia. Risk factors for thrombosis include age, the use of phlebotomies, the rate of phlebotomies, and a prior history of thrombosis. Platelet counts have not been definitively linked to an increased risk of thrombosis. High-risk polycythemia vera patients are those 60 years of age or older (some groups use 70 years) or those of any age who have had thrombosis. They should be treated with phlebotomy and hydroxyurea or IFN-alpha. Selected patients may be treated with anagrelide. A typical target range for phlebotomy is a hematocrit of < 42% for women and < 45% for men. Low-dose aspirin can be used if the platelet count is < 1,500 x 10(9)/L. Low-risk patients are those less than 60 years old who have had no thrombosis, no cardiovascular risk factors, and whose platelets are < 1,500 x 10(9)/L. These patients can be managed with phlebotomy alone or phlebotomy and low-dose aspirin. Intermediate-risk patients are those who are less than 60 years old, who have not had thrombosis, but who have platelet counts > 1,500 x 10(9)/L or who have cardiovascular risk factors. The cardiovascular risk factors should be treated, along with phlebotomy alone or with IFN-alpha. Low-dose aspirin is reasonable for those with platelet counts < 1,500 x 10(9)/mL. Anagrelide can be used with phlebotomy in selected patients. Women of childbearing age who are in the low-risk or intermediate-risk group can be treated with phlebotomy alone and low-dose aspirin if the platelet count is < 1,500 x 10(9)/L. For high-risk patients or pregnant patients, IFN-alpha can be added. Copyright 2002, Elsevier Science (USA). All rights reserved.

7
UI - 12096354
AU - Gilbert HS
TI - Other secondary sequelae of treatments for myeloproliferative disorders.
SO - Semin Oncol 2002 Jun;29(3 Suppl 10):22-7
AD - Albert Einstein College of Medicine, Bronx, NY, USA.
Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic disorders for which there are no medical cures. Clinical sequelae of PV and ET fall into three categories: primary, such as thrombosis and hemorrhage; secondary, resulting from disease progression or treatment. The decision whether to treat the patient is based on the sequelae of no treatment versus short- and long-term toxicities of the three classes of drugs available for treatment: hydroxyurea, interferon-alpha, and anagrelide. Thrombosis is the most common short-term sequelae of untreated disease; the risk increases with age and after the first thrombotic complication. Hydroxyurea, a nonalkylating myelosuppressive agent, is mutagenic and probably leukemogenic over 5 to 15 years, which makes it unsuitable for treating most younger patients. Interferon-alpha, a cytokine that is myelosuppressive and immunomodulatory, has been shown to have a therapeutic effect in both PV and ET. Tolerance to the initial flu-like symptoms of interferon-alpha is usually developed, but dose-limiting symptoms of anorexia, asthenia, and neuropsychiatric disease can occur, along with exacerbation or development of autoimmune diseases. Anagrelide, a quinazoline that inhibits cyclic nucleotide phosphodiesterase, inhibits platelet aggregation and has an idiosyncratic effect of inhibiting megakaryocyte maturation and platelet budding at doses below those that affect platelet function. This agent is a vasodilator with positive inotropic activity and a side-effect profile that may include palpitations, forceful heartbeat, tachycardia, and headache. One in four patients develop fluid retention and/or edema that are controllable with diuretic therapy. Dizziness is frequent, but mild. Because these side effects usually abate in 2 to 4 weeks, successful management of patients taking anagrelide depends on encouraging them to maintain therapy. The availability of these three classes of drugs with differing modes of action suggests that combination therapy may offer the opportunity to achieve better control of proliferation while reducing short-term side effects as well as the risks of dose-related cumulative sequelae. Copyright 2002, Elsevier Science (USA). All rights reserved.

8
UI - 12096355
AU - Golub R; Adams J; Dave S; Bennett CL
TI - Cost-effectiveness considerations in the treatment of essential thrombocythemia.
SO - Semin Oncol 2002 Jun;29(3 Suppl 10):28-32
AD - Department of Medicine, Northwestern University Fernberg School of Medicine, Chicago, IL, USA.
Factors that influence the choice of anagrelide, hydroxyurea, or interferon-alfa (IFN-alpha) for treatment of essential thrombocythemia include efficacy, toxicity, and cost. Anagrelide has the US Food and Drug Administration's approval to be used for treating patients with thrombocythemia secondary to chronic myeloproliferative disorders. In contrast, the use of IFN-alpha and hydroxyurea are considered "off-label." We performed an incremental cost-effectiveness analysis to compare anagrelide, hydroxyurea, and IFN-alpha for treating essential thrombocythemia, in terms of estimated impact on life expectancy. The case used for this analysis was of a 40-year-old man with essential thrombocythemia. Clinical assumptions were based on information obtained from nonrandomized clinical trials, and the economic assumptions were derived from information abstracted from observational studies. Lifelong treatment use of anagrelide versus hydroxyurea would cost approximately $72,000 per additional year of life gained, while the use of IFN-alpha was found to be both more costly and less effective than anagrelide. The results were very sensitive to the risk of leukemia caused by hydroxyurea, with an incremental cost-effectiveness of anagrelide compared with hydroxyurea of $156,969 per additional year of life gained if the lifetime leukemia risk drops from a baseline of .08 to.05. Given that many commonly used medical interventions cost in the range of $50,000 to $100,000 per year of life gained, and the generally poor outcome associated with treatment-related leukemia that can result from hydroxyurea, anagrelide could be considered a therapeutic alternative that is clinically effective at an acceptable cost. Copyright 2002, Elsevier Science (USA). All rights reserved.

9
UI - 12071939
AU - Damaj G; Lefrere F; Canioni D; Rubio MT; Radford-Weiss I; Valensi F;
TI - Varet B; Hermine O Remission of transformed myelodysplastic syndrome with fibrosis after danazol therapy.
SO - Eur J Haematol 2002 Apr;68(4):233-5
AD - Department of Clinical Hematology, Hopital Necker Enfants-Malades, Paris, France. damajg@marseille.fnclcc.fr
Danazol has been used with success in some hematological diseases, but there is no report of this treatment in acute leukemia. We report here a case of remission of myelodysplastic syndrome with myelofibrosis in transformation after danazol therapy in a 72-yr-old man. The role of danazol in remission induction is briefly discussed.

10
UI - 12096716
AU - Abu-Duhier FM; Goodeve AC; Wilson GA; Carr RS; Peake IR; Reilly JT
TI - FTL3 internal tandem duplication mutations are rare in agnogenic myeloid metaplasia.
SO - Blood 2002 Jul 1;100(1):364

11
UI - 11735160
AU - Tefferi A; Murphy S
TI - Current opinion in essential thrombocythemia: pathogenesis, diagnosis, and management.
SO - Blood Rev 2001 Sep;15(3):121-31
AD - Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA. tefferi.ayalew@mayo.edu
A working diagnosis of essential thrombocythemia (ET) is made in the presence of nonreactive thrombocytosis and after the exclusion of another chronic myeloid disorder that may mimic ET in its presentation. Clinically, ET is characterized by vasomotor symptoms, thrombohemorrhagic complications, recurrent fetal loss, and transformation of the disease into either myelofibrosis with myeloid metaplasia or acute myeloid leukemia. Median survival in the majority of patients is close to that of an age-adjusted normal population, and current therapy has not been shown to either retard or hasten leukemic transformation, which is reported to occur in 1% to 20% of patients. The use of hydroxyurea in high-risk patients with ET has reduced the incidence of thrombosis, and recent studies have suggested the value of keeping the platelet count below 400 x 10(9)/L in such cases. The incidence of thrombosis in low-risk patients may not be high enough to warrant the use of cytoreductive therapy. Although effective in controlling vasomotor symptoms, aspirin therapy has not been shown to influence the risk of either recurrent thrombosis or first-trimester miscarriage in ET. Recent laboratory studies have suggested that hematopoiesis in ET may not always be clonal. Similarly, there is substantial heterogeneity in both megakaryocyte/platelet surface expression of the thrombopoietin receptor (c-Mpl) and bone marrow microvessel density. Clinicopathologic correlates to these biologic parameters are currently being defined. Copyright 2001 Harcourt Publishers Ltd.

12
UI - 12111780
AU - Lev PR; Marta RF; Vassallu P; Molinas FC
TI - Variation of PDGF, TGFbeta, and bFGF levels in essential thrombocythemia patients treated with anagrelide.
SO - Am J Hematol 2002 Jun;70(2):85-91
AD - Seccion Hematologia Investigacion, Instituto de Investigaciones Medicas Alfredo Lanari, Facultad de Medicina, Universidad de Buenos Aires, Combatientes de Malvinas 3150, 1427 Buenos Aires, Argentina.
We studied 15 patients with essential thrombocythemia (ET) before treatment and after normalization of platelet count by anagrelide. Significantly increased plasma levels of PDGF, TGFbeta, and bFGF were found. Patients with mild reticulin fibrosis in bone marrow had higher PDGF levels. During treatment, plasma TGFbeta and bFGF levels remained elevated in most patients (P < 0.0001 and P < 0.01, respectively). Intraplatelet PDGF levels were low before treatment (P < 0.006) and normal on hematological remission, without relation with the presence or absence of reticulin fibrosis in bone marrow. Intraplatelet TGFbeta levels were normal regardless of the platelet count. Intraplatelet bFGF levels were raised before (P < 0.001) and during treatment (P < 0.01). By immunostaining, TGFbeta and bFGF were seen in megakaryocytes and lymphocytes with a similar pattern of intensity in patients and controls, suggesting that other cells might also contribute to the raised plasma values. We believe that the plasma increment of these cytokines suggests that they play a role in the pathogenesis of ET. The normal PDGF plasma level found during treatment may be in relation with the platelet count. However, the persistent increase of TGF-beta in plasma and bFGF both in plasma and platelets may indicate dysregulation of cytokine synthesis in TE. Copyright 2002 Wiley-Liss, Inc.

13
UI - 12111781
AU - Hasselbalch HC; Clausen NT; Jensen BA
TI - Successful treatment of anemia in idiopathic myelofibrosis with recombinant human erythropoietin.
SO - Am J Hematol 2002 Jun;70(2):92-9
AD - Department of Hematology L, Rigshospitalet, Copenhagen, Denmark.
Thirteen patients with idiopathic myelofibrosis (5 osteomyelosclerosis) were treated with recombinant human erythropoietin (rHuEpo) for transfusion-dependent anemia. All but 7 patients were concomitantly treated with alpha interferon, and 5 patients also received a interferon before the start of erythropoietin (EPO) treatment. All but two patients became transfusion independent. The highly positive results of the present study of transfusion-dependent patients with idiopathic myelofibrosis calls for further studies to delineate more precisely in larger series those patients who are likely to respond to rHuEpo. Copyright 2002 Wiley-Liss, Inc.

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