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Prolyl hydroxylase domain (PHD) proteins play a major role in regulating the hypoxia-inducible factor (HIF) that induces expression of genes involved in angiogenesis, erythropoiesis, and cell metabolism, proliferation, and survival. Germ-line mutations in the prolyl hydroxylase domain 2 gene (PHD2) have been reported in patients with familial erythrocytosis but not in association with tumors. We describe a patient with erythrocytosis and recurrent paraganglioma who carries a newly discovered PHD2 mutation. This mutation affects PHD2 function and stabilizes HIF-alpha proteins. In addition, we demonstrate loss of heterozygosity of PHD2 in the tumor, suggesting that PHD2 could be a tumor-suppressor gene.

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IntroductionImmune thrombocytopenic purpura (ITP) is an autoimmune disease characterized by low platelet counts and may be responsible for mucocutaneous bleeding of variable severity. 1 ITP is usually chronic (Ͼ 6 months) in adults and, after this time, the probability of spontaneous remission is low. Standard management is to initiate steroids, anti-Rh 0 (D) immune globulins, and/or intravenous immunoglobulins (IVIgs) for the more severe forms. [2][3][4][5] The response rate is high but most often transient. That the spleen plays a major role in the removal of damaged platelets has long been known and, to date, splenectomy is still considered the "gold standard" treatment in many countries for the management of chronic ITP with platelet counts less than 30 ϫ 10 9 /L, especially when hemorrhagic complications are present. Approximately two thirds of chronic ITP patients who undergo splenectomy achieve lasting responses. 6 As suggested in the guidelines of the American Society of Hematology (ASH) 7 and the British Committee for Standards in Hematology (BCSH), 8 splenectomy should be considered the main second-line therapy for patients who fail to respond durably to first-line therapy, with persistent platelet counts less than 30 ϫ 10 9 /L. However, increasing numbers of patients are reluctant to undergo splenectomy and physicians are hesitant to recommend it. 9,10 In addition, the risk of overwhelming postsplenectomy infections, although rare, is not predictable and represents a major concern. 11-13 Moreover, some authors reported that, despite initial good responses to splenectomy, the risk of late relapse persists during long-term follow-up 14,15 and severe morbidity resulting from surgery is associated with 11% to 30% postoperative complications requiring prolonged hospitalization or readmission. 11,16 For these reasons, an effective and safe alternative to splenectomy would improve management of chronic ITP.Rituximab is a chimeric, humanized monoclonal antibody directed against the CD20 determinant on B cells. It was initially developed for the treatment of malignant lymphoma but has also been used in autoantibody-mediated disorders, such as rheumatoid arthritis, 17 systemic lupus erythematosus, 18 autoimmune hemolytic anemia, 19 or thrombotic thrombocytopenic purpura. 20 Case reports and several uncontrolled studies described its promising results in ITP patients. Arnold et al 21 conducted a systematic review of published reports on rituximab use in adults with chronic ITP. A complete response, usually observed 3 to 8 weeks after the first infusion, was obtained in 46% of patients. The median response duration was 10.5 months (interquartile range [IQR]: 6.3-17.8 months), but long-term For personal use only. on May 10, 2018. by guest www.bloodjournal.org From responses were not mentioned in all published studies. Arnold et al 21 pointed out the heterogeneity of patients' prior rituximab use and particularly their splenectomy status. Moreover, the short follow-up in some reports and the possible bias due to th...

One hundred and twenty-nine patients with chronic lymphocytic leukemia (CLL) followed in our outpatient department for periods ranging from 6 months to 13 years were divided into five anatomico-clinical stages: stage 0 (peripheral and bone marrow lymphocytosis); stage I (stage 0 + lymph node enlargement); stage I1 (stage 0 + palpable spleen); stage 111 (stage I + 11); and stage IV (anemia or thrombocytopenia) . Analysis of actuarial survival curves revealed the following: 1) median survival of the entire population exceeded 114 months; 2) there was no difference between the curves of stage 0 and stage I patients, 3) there was a significant difference between survival for stage 111 and IV patients as compared with stages 0, I and I1 (p < 0.01); and 4) median survival for stage I11 and stage IV was 70 months; and 23 months, respectively. Age did not appear to be a prognostic factor. Prognosis was poorer in male patients and in those with a high initial lymphocyte count (50,000/mma), but this was due to the higher incidence of stages 111 and IV in this population ( p <