scholarly journals Management of Polycythemia Vera and Essential Thrombocythemia

Hematology ◽  
2005 ◽  
Vol 2005 (1) ◽  
pp. 201-208 ◽  
Author(s):  
Peter J. Campbell ◽  
Anthony R. Green
Keyword(s):  
Clinical Trials ◽  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Randomized Clinical Trials ◽  
Randomized Study ◽  
Myeloproliferative Disorders ◽  
Optimal Management ◽  
Jak2 Mutation ◽  
The Past ◽  
Therapeutic Decisions

Abstract The optimal management of patients with polycythemia vera (PV) and essential thrombocythemia (ET) continues to be controversial. Both diseases present diagnostic challenges and there is a paucity of data from randomized clinical trials to guide therapeutic decisions. However, the past two years have seen major advances in our understanding of these myeloproliferative disorders (MPD). First, the ECLAP study demonstrated the anti-thrombotic efficacy of aspirin in patients with PV.1 Second, the PT-1 trial, the largest randomized study of any MPD, has provided much needed guidance on the optimal management of patients with ET.2 Third, the identification of a single JAK2 mutation in most patients with PV, and in some of those with ET, illuminates the pathogenesis of these diseases and raises questions about the boundary between them.3–7 For the purpose of management decisions, it remains appropriate to consider them as separate entities for the time being. However, as we learn more about the clinical significance of the JAK2 mutation, it seems likely that the coming years will see major changes in the way we classify and manage these disorders.

Methylation of Progesterone Receptor Promoter-Associated CpG Island in Polycythemia Vera and Related Myeloproliferative Disorders.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3507-3507
Author(s):  
Jaroslav Jelinek ◽  
Srdan Verstovsek ◽  
Carlos E. Bueso-Ramos ◽  
Josef T. Prchal ◽  
Jean-Pierre J. Issa
Keyword(s):  
Progesterone Receptor ◽  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Cpg Island ◽  
Cpg Islands ◽  
Myeloproliferative Disorders ◽  
Receptor Expression ◽  
Quantitative Detection ◽  
Jak2 Mutation ◽  
A Genome

Abstract Polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (MF) are clonal myeloproliferative disorders (MPD). A recently discovered activating mutation of JAK2 tyrosine kinase has been found in most patients with polycythemia vera (PV), in about half of those with essential thrombocythemia (ET) and myelofibrosis (MF), and in 10–20% patients with chronic myelomonocytic leukemia, Philadelphia-negative CML, atypical or unclassified MPD and megakaryocytic leukemia. It is not known what other factors determine the disease phenotype of PV, MF, and other MPD, and what factors other than JAK2 lead to disease progression. Very little is known about epigenetic changes in PV. DNA methylation of promoter-associated CpG islands is a well-recognized mechanism of epigenetic silencing used by tumors for evasion from regulatory mechanisms, and it is an alternative to genetic lesions in cancer causation. Using a genome-wide screen for differentially methylated CpG islands, we found methylation of progesterone receptor promoter region (PGR) in PV granulocytes. We then developed pyrosequencing assays for quantitative detection of PGR methylation in bisulfite-treated PCR-amplified DNA. The PGR methylation above normal control levels was observed in ET (2/12 patients, 17%), PV (10/22 patients, 45%), MF (8/12 patients, 67%), and patients with acute myeloid leukemia and antecedent PV (6/7 patients, 86%). We compared the levels of PGR methylation in MPD with the mutation status of JAK2. The 1849G>T JAK2 mutation was present in 16/27 (59%) MPD patients with unmethylated PGR and 21/26 (80%) patients with methylated PGR; the difference not statistically significant; p=0.135. The role of progesterone receptor signaling in hematopoiesis is not known. Using real time quantitative RT-PCR assay for progesterone receptor expression we found detectable levels in granulocytes from 4/5 normal individuals while the expression in granulocytes from 5/5 PV patients was not detectable. To assess the functional significance of progesterone receptor silencing, we explored the effect of mifepristone, a progesterone receptor antagonist, on the response of BFU-E progenitors to erythropoietin. Mifepristone increased the sensitivity of BFU-E progenitors from normal blood to low concentrations of erythropoietin (60–250 mU/ml) suggesting that disabling of progesterone receptor may increase the response of hematopoietic cells to proliferative stimuli. In conclusion, our data show that PGR methylation is present in half of PV patients and it is even more frequent in MF and PV transformed to AML. Silencing of progesterone receptor by methylation may be an epigenetic change contributing to MPD phenotype and transformation to leukemia.

Molecular basis of the diagnosis and treatment of polycythemia vera and essential thrombocythemia

Blood ◽  
2006 ◽  
Vol 107 (11) ◽  
pp. 4214-4222 ◽  
Author(s):  
Andrew I. Schafer
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Molecular Mechanisms ◽  
Randomized Clinical Trials ◽  
Great Majority ◽  
Jak2 V617f ◽  
Myeloproliferative Disorders ◽  
Erythropoietin Receptor ◽  
Bleeding Tendency ◽  
Clinical Complications

Abstract Recent insights into the molecular mechanisms of polycythemia vera (PV) and essential thrombocythemia (ET) are challenging the traditional diagnostic classification of these myeloproliferative disorders (MPDs). Clonality analysis using X-chromosome inactivation patterns has revealed apparent heterogeneity among the MPDs. The recently discovered single somatic activating point mutation in the JAK2 gene (JAK2-V617F) is found in the great majority of patients with PV, but also in many patients with phenotypically classified ET and other MPDs. In contrast to the acquired MPDs, mutations of the erythropoietin receptor and thrombopoietin receptor have been identified in familial forms of nonclonal erythrocytosis and thrombocytosis, respectively. The mechanisms of major clinical complications of PV and ET remain poorly understood. Quantitative or qualitative abnormalities of red cells and platelets do not provide clear explanations for the thrombotic and bleeding tendency in these MPDs, suggesting the need for entirely new lines of research in this area. Recently reported randomized clinical trials have demonstrated the efficacy and safety of low-dose aspirin in PV, and an excess rate of arterial thrombosis, major bleeding, and myelofibrotic transformation, but decreased venous thrombosis, in patients with ET treated with anagrelide plus aspirin compared to hydroxyurea plus aspirin.

Analysis of JAK2 V617F Mutation and Its Clinical Significance in Patients with Thrombocythemia and Other Myeloproliferative Neoplasms in Chinese

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4687-4687
Author(s):  
Yue Xu ◽  
Changxin Yin ◽  
Han He ◽  
Lingling Shu ◽  
Fuqun Wu ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Jak2 V617f ◽  
Jak2 V617f Mutation ◽  
Jak2 Mutation ◽  
Western Countries ◽  
Arms Pcr ◽  
V617f Mutation

Abstract Abstract 4687 JAK2 mutation is commonly found in Philadelphia-negative myeloproliferative neoplasms (MPNs). In Western countries, this mutation is found in approximately 96 percent of people with polycythemia vera, half of individuals with essential thrombocythemia or primary myelofibrosis. We used the method of amplification refractory mutation PCR (ARMS-PCR) to investigate MPN patients in China. We focused our study on patients with essential thrombocythemia (ET). ARMS-PCR was used to detect JAK2 V617F mutation in the bone barrow (BM) or peripheral blood of 37 MPN patients, which consisting of 7 ET, 5 polycythemia vera (PV), 5 chronic myeloid leukemia (CML), 5 chronic idiopathic myelofibrosis (CIMF), as well as 15 suspected MPNs. 17 cases of JAK2 V617F mutation (45.9%) were found in 37 patients, including 4 ET (57.1%), 4 PV (80.0%), 3 CIMF (60.0%), 6 suspected MPNs (40.0%). We did not find JAK2 V617F in the patients with CML. Our results indicated that the frequency of JAK2 V617F mutation in bcr/abl-negative MPNs in Chinese is similar to that in MPN patients in Western countries. At the same time, ARMS-PCR can distinguish the mutation is heterozygous or homozygous. Most patients were heterozygous for JAK2 but only a few were homozygous. In conclusion, our study showed that JAK2 V617F mutation frequency in Chinese MPN patients is similar to that in patients with this disorder in the West. It is the major molecular genetic abnormality in bcr-abl negative MPN and it can be used for diagnosis of MPN in China. Disclosures: No relevant conflicts of interest to declare.

Retrospective analysis of second malignancies in patients with multiple myeloma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8090-8090
Author(s):  
Giampaolo Talamo ◽  
W. Christopher Ehmann ◽  
Nathan G Dolloff ◽  
Jozef Malysz ◽  
Joseph J. Drabick ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Retrospective Analysis ◽  
Medical Records ◽  
Randomized Clinical Trials ◽  
Myeloproliferative Disorders ◽  
Second Malignancy ◽  
Second Malignancies ◽  
Penn State

8090 Background: Recent data from patients with multiple myeloma (MM) enrolled in randomized clinical trials have shown an increased incidence of second malignancies after treatment with lenalidomide, but the prevalence of second malignancies in the overall MM population is uncertain. Methods: We retrospectively analyzed the medical records of 320 consecutive MM patients followed at the Penn State Hershey Cancer Institute between 2006 and 2010. We excluded from the analysis basocellular and squamocellular carcinomas of the skin. Results: Forty-three patients (13%) were found to have second malignancies, and 5 of them had a third cancer. One pt had 4 cancers. They included cancers of the prostate (8 pts), breast (8), MDS/leukemia (6), colon/rectum (5), melanoma (5), lung (4), uterus (4), bladder (3), kidneys (2), pancreas (2), testicle (1), myeloproliferative disorders (1), and sarcoma (1). Of 50 cancers, 36 (72%) developed before the diagnosis of MM, at a median of 65 months (range, 1-372), and 14 after that, at a median of 37 months (range, 3-104). Lenalidomide was used in 239 (75%) patients, and in 9 of 14 cases of post-MM second malignancies. Conclusions: Second malignancies usually develop before the diagnosis of MM, i.e., MM is the second malignancy for the majority of patients. The use of lenalidomide could not be indicated as a possible carcinogenic factor for the majority of MM patients with second malignancies.

scholarly journals Transgenic expression of JAK2V617F causes myeloproliferative disorders in mice

Blood ◽  
2008 ◽  
Vol 111 (10) ◽  
pp. 5109-5117 ◽  
Author(s):  
Shu Xing ◽  
Tina Ho Wanting ◽  
Wanming Zhao ◽  
Junfeng Ma ◽  
Shaofeng Wang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Transgenic Mice ◽  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Gene Promoter ◽  
Primary Myelofibrosis ◽  
Myeloproliferative Disorders ◽  
Transgenic Expression ◽  
Cell Counts

Abstract The JAK2V617F mutation was found in most patients with myeloproliferative disorders (MPDs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. We have generated transgenic mice expressing the mutated enzyme in the hematopoietic system driven by a vav gene promoter. The mice are viable and fertile. One line of the transgenic mice, which expressed a lower level of JAK2V617F, showed moderate elevations of blood cell counts, whereas another line with a higher level of JAK2V617F expression displayed marked increases in blood counts and developed phenotypes that closely resembled human essential thrombocythemia and polycythemia vera. The latter line of mice also developed primary myelofibrosis-like symptoms as they aged. The transgenic mice showed erythroid, megakaryocytic, and granulocytic hyperplasia in the bone marrow and spleen, displayed splenomegaly, and had reduced levels of plasma erythropoietin and thrombopoietin. They possessed an increased number of hematopoietic progenitor cells in peripheral blood, spleen, and bone marrow, and these cells formed autonomous colonies in the absence of growth factors and cytokines. The data show that JAK2V617F can cause MPDs in mice. Our study thus provides a mouse model to study the pathologic role of JAK2V617F and to develop treatment for MPDs.

scholarly journals Bias and unclear outcomes in clinical trials of diabetic retinopathy: a cross-sectional analysis of literature

2021 ◽  
Vol 3 ◽  
Author(s):  
Vania Mozetic ◽  
Valéria Mozetic de Barros ◽  
Lucas Denadai ◽  
Matheus Ferreira Santos da Cruz ◽  
Natasha Ferreira Santos da Cruz ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Diabetic Retinopathy ◽  
Adverse Events ◽  
Publication Bias ◽  
Randomized Clinical Trials ◽  
Cross Sectional ◽  
Know How ◽  
The Past ◽  
Sectional Analysis ◽  
Subjective Outcomes

BACKGROUND: Clinical trials are well-designed papers that aim to answer questions in the real world. However, sometimes they present missing, dubious and unclear outcomes that make it difficult to apply in practice. OBJECTIVE: The objective of this work is to evaluate the way and the frequency with which the outcomes in randomized clinical trials of intervention in diabetic retinopathy can be presented in an unclear way to readers. Make an analysis of how these dubious presentations can lead to misinterpretations, why this happens and how they can be remedied. METHODS AND MATERIALS: We conducted a search for RCT about DR intervention in PubMed published over the past five years. RESULTS: Seventy RCT were included, 27 in peripheral diabetic retinopathy (PDR) and 43 in diabetic macular edema (DME). In the DME group we found 25.6% reporting and publication bias; 34.9% subjective outcomes, 44.1% presented a lack of presentation of the baseline and 51.1% underreporting adverse events. In the PDR group we found 29.6% reporting and publication bias; 44.4% subjective outcomes, 14.8% presented a lack of presentation of the baseline and 62.9% underreporting adverse events. CONCLUSION: In addition to the result bias, we found other forms of publication of unclear outcomes in RCT on DR. Most of them occurred due to disrespect for CONSORT parameters. The reader must be attentive to recognize them and know how they can influence the interpretation of the data.

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