J L Spivak

Johns Hopkins University, Baltimore, MD, United States

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Publications (129)982.01 Total impact

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    ABSTRACT: Disease-specific induced pluripotent stem cells (iPSCs) provide an unprecedented opportunity to establish novel disease models and accelerate drug development using distinct tissue target cells generated from isogenic iPSC lines with and without disease-causing mutations. To realize the potential of iPSCs in modeling acquired diseases which are usually heterogeneous, we have generated multiple iPSC lines including two lines that are JAK2-wild type and four lines homozygous for JAK2-V617F somatic mutation from a single polycythemia vera patient blood. In vitro differentiation of the same patient-derived iPSC lines have demonstrated the differential contributions of their parental hematopoietic clones to the abnormal erythropoiesis including the formation of endogenous erythroid colonies. This iPSC approach thus may provide unique and valuable insights into the genetic events responsible for disease development. To examine the potential of iPSCs in drug testing, we generated isogenic hematopoietic progenitors and erythroblasts from the same iPSC lines derived from PV patients and normal donors. Their response to three clinical JAK inhibitors, INCB018424 (Ruxolitinib), TG101348 (SAR302503) and the more recent CYT387 was evaluated. All three drugs similarly inhibited erythropoiesis from normal and PV iPSC lines containing the wild-type JAK2 genotype, as well as those containing a homozygous or heterozygous JAK2-V617F activating mutation that showed increased erythropoiesis without a JAK inhibitor. However, the JAK inhibitors had less inhibitory effect on the self-renewal of CD34+ hematopoietic progenitors. The iPSC-mediated disease modeling thus underlies the ineffectiveness of the current JAK inhibitors, and provides a modeling system to develop better targeted therapies for the JAK2 mutated hematopoiesis. Stem Cells 2013.
    Stem Cells 09/2013; · 7.70 Impact Factor
  • Jerry L Spivak
    Hematology (Amsterdam, Netherlands) 07/2013; 18(4):244-5. · 1.33 Impact Factor
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    ABSTRACT: Thromboses represent a major cause of morbidity and mortality in polycythemia vera but the contributing mechanisms are not fully described. To evaluate whether environmental conditions such as altitude/hypoxia could impact thrombosis history, we retrospectively analyzed thrombosis history in 71 polycythemia vera patients living at an elevation of 5000 feet or more in the Salt Lake City (SLC) area and 166 polycythemia vera patients living near sea level in the Baltimore (BLM) area. The SLC cohort was older with a longer disease duration. No significant differences in type of anticoagulation therapy or prothrombotic factors were present between the two cohorts. After adjusting for age, sex and disease duration, SLC patients experienced an estimated 3.9-fold increase in the odds of a history of thrombosis compared with BLM patients (95% confidence interval 1.8-7.6; P = 0.0004). A history of a cardiovascular event was present in 58% of the SLC patients compared with 27% of the BLM patients (P < 0.0001). Before diagnosis, thrombosis occurred in 18 and 4% of the SLC and BLM groups, respectively (P = 0.003). No correlation between the JAK2 allele burden and thrombosis was observed in this study. This retrospective study suggests that even moderate hypoxia associated with 5000 feet elevation should be considered as an independent prothrombotic risk factor. This observation needs to be confirmed by prospective studies.
    Blood coagulation & fibrinolysis: an international journal in haemostasis and thrombosis 02/2013; · 1.25 Impact Factor
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    ABSTRACT: Polycythemia vera (PV) and essential thrombocythemia (ET) are the two most common myeloproliferative neoplasms. The same JAK2(V617F) mutation can be found in both disorders and is able to recapitulate many of the phenotypic abnormalities of these diseases in the murine models. The disease phenotype is also influenced by other unknown genetic or epigenetic factors. MicroRNAs (miRNA) are 18-24 nucleotides single-stranded non-protein-coding RNAs that function primarily as gene repressors by binding to their target messenger RNAs. We performed miRNA expression profiling by oligonucleotide microarray analysis in purified peripheral blood CD34+ cells from eight JAK2(V617F)-positive PV patients and six healthy donors. A quantitative reverse-transcription polymerase chain reaction assay was used to verify differential miRNA expression. Since erythrocytosis is the only feature that distinguishes PV from ET, we also compared specific miRNA expression in the nucleated erythroid cells directly descended from the early erythroid progenitor cells of PV and ET patients. Our data indicate that significant miRNA deregulation occurs in PV CD34+ cells and confirm a genetic basis for the gender-specific differences that characterize PV with respect to miRNA. The results of our study also suggest that deregulated miRNAs may represent an important mechanism by which the PV erythrocytosis and ET thrombocytosis phenotypes are determined.
    Blood Cells Molecules and Diseases 12/2012; · 2.26 Impact Factor
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    ABSTRACT: Summary The natural history and prognosis for young patients with polycythemia vera (PV) in the post-JAK2 V617F era is not well defined; therefore, we retrospectively analyzed disease characteristics and clinical outcomes in 120 patients ≤45 years and 84 patients ≥65 years at diagnosis. Despite lower white blood counts (9.2 vs. 13.4 x 10(9)/L, p=0.004) and a lower JAK2 V617F allele burden (51% vs. 66%, p=0.015), younger PV patients had comparable rates of vascular complications compared to older patients (27% vs. 31%, p=0.64). However, splanchnic vein thrombosis occurred more frequently in younger patients (13% vs. 2%, p=0.0056). Myelofibrotic and leukemic transformation, the most serious complications of myeloproliferative neoplasms (MPN), occurred with similar frequencies in young vs. older patients (15% vs. 10%, p=0.29). Prevention or delay of these complications is currently the most urgent challenge in the care of younger patients with PV.
    Leukemia & lymphoma 12/2012; · 2.40 Impact Factor
  • Jerry L Spivak
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    ABSTRACT: Marchioli et al.(1) report in the Journal that a hematocrit target of less than 45% for therapeutic phlebotomy reduces the risk of thrombosis in patients with polycythemia vera. In the genomic era, readers may question attention given to a measurement as mundane as the hematocrit, but this study resolves a half-century of debate about the role of phlebotomy in polycythemia vera and has ramifications for diagnosis and management. Polycythemia vera is a unique myeloproliferative disorder in which there is overproduction of morphologically normal erythrocytes, granulocytes, and platelets, a phenotype that is caused by a mutation (V617F) in JAK2, encoding . . .
    New England Journal of Medicine 12/2012; · 51.66 Impact Factor
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    ABSTRACT: We treated 37 patients with polycythemia vera with imatinib mesylate (IM). The overall response rate was 49%. Thirty percent had a complete response, and 19%, a partial response. Thirty-one patients were treated for >120 days. Frequent side effects included nausea, diarrhea, edema, and skin rash. Whereas IM was effective in controlling erythropoiesis and reducing spleen size it was ineffective in controlling thrombocytosis. Normocellular marrow developed in 4 patients who had a complete response. Progression to overt myelofibrosis occurred in 3. Nevertheless, 6 patients have had a sustained complete response while on IM for >6 years. These patients were young, had high phlebotomy requirements, and only slightly elevated platelet counts. Therefore, we believe there may be a role for IM in patients with these characteristics whose disease cannot be controlled by, or as an alternative to, other myelosuppressive treatments.
    Leukemia research 02/2012; 36(2):156-62. · 2.36 Impact Factor
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    Jerry L Spivak, Richard T Silver
    Blood 07/2011; 118(4):1179-80; author reply 1180-1. · 9.06 Impact Factor
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    ABSTRACT: The myeloproliferative neoplasms, essential thrombocytosis, polycythemia vera and primary myelofibrosis, share the same acquired genetic lesion, but the concept of JAK2 V617F serving as the sole lesion responsible for these neoplasms is under question, and there has been interest in identifying additional mutations that may contribute to disease pathogenesis. Because ASXL1 lesions have been increasingly identified in myeloid neoplasms, we examined the relationships of ASXL1 mutation or deletion to both clinical phenotype and associated molecular features in 166 patients with myeloproliferative neoplasms. Exon 12 of ASXL1 was amplified from neutrophil genomic DNA and bidirectionally sequenced in 77 patients with myelofibrosis (including patients with primary and post-essential thrombocytosis or post-polycythemia myelofibrosis), 42 patients with polycythemia vera, 41 with essential thrombocytosis and 6 with post-myelofibrosis acute myeloid leukemia. Pyrosequencing assays were designed to determine the allele percentages of JAK2 V617F (G5073770T), ASXL1 2475dupA, and ASXL1 2846_2847del in neutrophil genomic DNA samples. Clinical and laboratory characteristics of patients with wild-type and ASXL1 mutations were then compared. We identified nonsense mutations or hemizygous deletion of ASXL1 in 36% of the patients with myelofibrosis, but very rarely among those with polycythemia vera or essential thrombocytosis. Among the patients with myelofibrosis, those with ASXL1 lesions were not distinguished from their wild-type counterparts with regard to JAK2 V617F status, exposure to chemotherapy or evolution to leukemia. Myelofibrosis patients with ASXL1 lesions were more likely to have received anemia-directed therapy compared to those without lesions [15/26 (58%) versus 11/39 (23%); P=0.02]. Using serial banked samples and quantitative ASXL1 mutant allele burden assays, we observed the acquisition and accumulation of ASXL1 mutations over time in two patients with post-essential thrombocytosis myelofibrosis. ASXL1 haploinsufficiency is associated with a myelofibrosis phenotype in the context of other known and unknown lesions, and disruption of ASXL1 function may contribute to the disease pathogenesis of myelofibrosis.
    Haematologica 06/2011; 96(10):1462-9. · 5.94 Impact Factor
  • Jerry L Spivak
    Oncology (Williston Park, N.Y.) 04/2011; 25(5):421-3. · 3.19 Impact Factor
  • Jerry L Spivak, Hans Hasselbalch
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    ABSTRACT: Hydroxycarbamide is a nonalkylating antiproliferative and antiviral agent that has been used for over 40 years to treat a variety of neoplastic and non-neoplastic conditions. Hydroxycarbamide is readily absorbed and widely distributed throughout the body. It acts primarily to inhibit DNA synthesis, which underpins its use in solid tumors, viral infections and chronic myeloproliferative disorders. Hydroxycarbamide is an effective treatment for preventing transient ischemic attacks associated with thrombocytosis in chronic myeloproliferative disorders because it is a nitric oxide donor. While its mechanism of action and side-effect profile are well defined, its potential for leukemic transformation as a single agent is still a matter of controversy. Based on a search of the Medline database, this article encompasses the pharmacokinetics, pharmacodynamics, clinical use and tolerability of hydroxycarbamide, plus its potential for mutagenicity with special reference to the chronic myeloproliferative disorders. The toxicity profile of hydroxycarbamide is also discussed to enable clinicians to balance potential risks with therapeutic benefits.
    Expert Review of Anti-infective Therapy 03/2011; 11(3):403-14. · 2.07 Impact Factor
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    ABSTRACT: We previously found that gender influenced the JAK2 V617F allele burden, but it is unknown whether this gender difference in molecular epidemiology influences complications in the myeloproliferative neoplasms (MPNs). Historically, vascular complications represented the most common cause of mortality in polycythemia vera and essential thrombocytosis and contributed to morbidity in primary myelofibrosis. To determine the influence of gender on vascular complications, we retrospectively analyzed associations between gender and vascular complications. Despite their younger age, less prevalent dyslipidemia or smoking history, lower white blood counts, and lower JAK2 V617F allele burden, women had higher rates of abdominal venous thrombosis and comparable rates of all vascular complications. Vascular risk is currently not easily stratified by MPN-disease burden or traditional risk factors. Our analysis contributes to growing literature emphasizing gender differences in the MPN and further supports the important impact of individual and host variation on MPN clinical manifestations, and especially vascular risk.
    Thrombosis. 01/2011; 2011:874146.
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    ABSTRACT: Purpose: To update American Society of Hematology/American Society of Clinical Oncology recommendations for use of erythropoiesis-stimulating agents (ESAs) in patients with cancer. Methods: An Update Committee reviewed data published between January 2007 and January 2010. MEDLINE and the Cochrane Library were searched. Results: The literature search yielded one new individual patient data analysis and four literature-based meta-analyses, two systematic reviews, and 13 publications reporting new results from randomized controlled trials not included in prior or new reviews. Recommendations: For patients undergoing myelosuppressive chemotherapy who have a hemoglobin (Hb) level less than 10 g/dL, the Update Committee recommends that clinicians discuss potential harms (eg, thromboembolism, shorter survival) and benefits (eg, decreased transfusions) of ESAs and compare these with potential harms (eg, serious infections, immune-mediated adverse reactions) and benefits (eg, rapid Hb improvement) of RBC transfusions. Individual preferences for assumed risk should contribute to shared decisions on managing chemotherapy-induced anemia. The Committee cautions against ESA use under other circumstances. If used, ESAs should be administered at the lowest dose possible and should increase Hb to the lowest concentration possible to avoid transfusions. Available evidence does not identify Hb levels ≥ 10 g/dL either as thresholds for initiating treatment or as targets for ESA therapy. Starting doses and dose modifications after response or nonresponse should follow US Food and Drug Administration-approved labeling. ESAs should be discontinued after 6 to 8 weeks in nonresponders. ESAs should be avoided in patients with cancer not receiving concurrent chemotherapy, except for those with lower risk myelodysplastic syndromes. Caution should be exercised when using ESAs with chemotherapeutic agents in diseases associated with increased risk of thromboembolic complications. Table 1 lists detailed recommendations.
    Blood 10/2010; 116(20):4045-59. · 9.06 Impact Factor
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    ABSTRACT: Suppression of normal hematopoiesis by the neoplastic clone (clonal dominance) is a feature of the myeloproliferative neoplasms, but the determinants that predict clonal dominance are unknown. The objective of this study was to identify clinical and laboratory variables that associate with the JAK2 V617F CD34(+) progenitor allele burden and clonal dominance, which was defined by congruence of the JAK2 V617F CD34(+) progenitor and neutrophil allele burdens. A cross-sectional analysis was performed on 164 consecutive JAK2 V617F-positive patients: 30 with essential thrombocytosis (ET), 100 with polycythemia vera (PV), and 34 with myelofibrosis (MF), including 8 post-ET MF and 3 post-PV MF. The JAK2 V617F CD34(+) progenitor and neutrophil allele burdens were measured using an allele-specific, quantitative real-time polymerase chain reaction assay. After adjusting for genotype, sex, age at diagnosis, and disease duration, disease type was the strongest predictor of clonal dominance, with the odds ratio being nearly 61.9 times higher for MF patients when compared with ET patients (p < 0.001), and 9.7 times higher when compared with PV patients (p = 0.002). Additionally, clonal dominance was associated with a clinical phenotype of an increased spleen size (p = 0.006), increased white blood cell count (p = 0.009), and lower hemoglobin (p < 0.001), even after adjusting for disease type and duration. These data indicate that loss of wild-type clones at the progenitor level is a feature of MF (primary MF, post-ET MF, and post-PV MF), presumably due to expansion of the JAK2 V617F clone and that this characteristic is surprisingly independent of JAK2 V617F homozygosity, suggesting that additional genomic lesions may contribute to this unique molecular process that distinguishes MF from ET and PV.
    Experimental hematology 09/2010; 39(1):95-101. · 3.11 Impact Factor
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    ABSTRACT: The JAK2(V617F) allele burden is a variable measure, determined by the frequency of mitotic recombination events and the expansion of JAK2(V617F) clones. Since variability in the JAK2(V617F) allele burden is partly responsible for the distinct phenotypes seen in the myeloproliferative disorders, the objective of this study was to identify modifiers of the allele burden. Blood samples were obtained between May 2005 and January 2009 from 272 patients with essential thrombocytosis, polycythemia vera, and myelofibrosis. The JAK2(V617F) allele burden was measured by an allele-specific quantitative polymerase chain reaction using DNA from purified neutrophils. Repeated measures, on average 2 years apart, were available for 104 patients. Sex, age at diagnosis, and disease duration all independently influenced the JAK2(V617F) allele burden. When considering all patients with myeloproliferative disorders, women had significantly lower allele burdens than men (P=0.04). In those patients with repeated measures, the increase in allele burden per year between the first and second evaluations was significantly less in females than in males. Among those who experienced disease evolution, females were 4.5 times more likely to have evolution from essential thrombocytosis to polycythemia vera, but 0.23 times as likely to have evolution from essential thrombocytosis to myelofibrosis. Sex is an independent factor accounting for variability in the JAK2(V617F) allele burden. We speculate that lower allele burdens in females reflect a lower frequency of mitotic recombination events in females than in males, and should be considered when evaluating the relationship of allele burden to disease phenotype and also in evaluating responses to JAK2(V617F)-inhibitors. Because sex may influence genotype and/or clonal expansion, underpinning the variability in JAK2(V617F) allele burden, it will be important to explore factors that determine susceptibility to mitotic recombination events.
    Haematologica 07/2010; 95(7):1090-7. · 5.94 Impact Factor
  • Jerry L Spivak
    Blood 04/2010; 115(14):2727-8. · 9.06 Impact Factor
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    Jerry L Spivak
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    ABSTRACT: The myeloproliferative disorders polycythemia vera, essential thrombocytosis, and primary myelofibrosis are clonal disorders arising in a pluripotent hematopoietic stem cell, causing an unregulated increase in the number of erythrocytes, leukocytes, or platelets, alone or in combination; eventual marrow dominance by the progeny of the involved stem cell; and a tendency to arterial or venous thrombosis, marrow fibrosis, splenomegaly, or transformation to acute leukemia, albeit at widely varying frequencies. The discovery of an activating mutation (V617F) in the gene for JAK2 (Janus kinase 2), a tyrosine kinase utilized by hematopoietic cell receptors for erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor, provided an explanation for the shared clinical features of these 3 disorders. Constitutive JAK2 activation provides a growth and survival advantage to the hematopoietic cells of the affected clone. Because signaling by the mutated kinase utilizes normal pathways, the result is overproduction of morphologically normal blood cells, an often indolent course, and (in essential thrombocytosis) usually a normal life span. Because the erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor receptors are all constitutively activated, polycythemia vera is the potential ultimate clinical phenotype of the JAK2 V617F mutation and, as a corollary, is the most common of the 3 disorders. The number of cells expressing the JAK2 V617F mutation (the allele burden) seems to correlate with the clinical phenotype. Preliminary results of clinical trials with agents that inhibit the mutated kinase indicate a reduction in splenomegaly and alleviation of night sweats, fatigue, and pruritus.
    Annals of internal medicine 03/2010; 152(5):300-6. · 13.98 Impact Factor
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    ABSTRACT: Human induced pluripotent stem (iPS) cells derived from somatic cells hold promise to develop novel patient-specific cell therapies and research models for inherited and acquired diseases. We and others previously reprogrammed human adherent cells, such as postnatal fibroblasts to iPS cells, which resemble adherent embryonic stem cells. Here we report derivation of iPS cells from postnatal human blood cells and the potential of these pluripotent cells for disease modeling. Multiple human iPS cell lines were generated from previously frozen cord blood or adult CD34(+) cells of healthy donors, and could be redirected to hematopoietic differentiation. Multiple iPS cell lines were also generated from peripheral blood CD34(+) cells of 2 patients with myeloproliferative disorders (MPDs) who acquired the JAK2-V617F somatic mutation in their blood cells. The MPD-derived iPS cells containing the mutation appeared normal in phenotypes, karyotype, and pluripotency. After directed hematopoietic differentiation, the MPD-iPS cell-derived hematopoietic progenitor (CD34(+)CD45(+)) cells showed the increased erythropoiesis and gene expression of specific genes, recapitulating features of the primary CD34(+) cells of the corresponding patient from whom the iPS cells were derived. These iPS cells provide a renewable cell source and a prospective hematopoiesis model for investigating MPD pathogenesis.
    Blood 10/2009; 114(27):5473-80. · 9.06 Impact Factor
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    Huichun Zhan, Jerry L Spivak
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    ABSTRACT: The chronic myeloproliferative disorders, polycythemia vera, essential thrombocythemia, and primary myelofibrosis, are clonal stem cell disorders that occur at a low frequency and mimic not only each other clinically, but also many benign and malignant hematopoietic disorders as well. The discovery that many patients with polycythemia vera, essential thrombocythemia, and primary myelofibrosis express a mutation in the Janus Kinase 2 gene (JAK2 V617F), a kinase essential for the normal development of erythrocytes, granulocytes, and platelets, provided a molecular explanation for the unregulated hematopoiesis typical of these disorders, a diagnostic test that distinguishes them from other types of myeloproliferative disorders, and an opportunity to develop targeted therapy that could potentially avoid the toxicities associated with the conventional chemotherapeutic agents currently employed in their treatment. In this review, we discuss the molecular basis of polycythemia vera, essential thrombocythemia, and primary myelofibrosis, their diagnosis and their management in the context of the JAK2 V617F mutation.
    Clinical advances in hematology & oncology: H&O 06/2009; 7(5):334-42.
  • Ashkan Emadi, Jerry L Spivak
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    ABSTRACT: Thrombocytosis is a common feature of chronic myeloproliferative disorders (MPD) and may be asymptomatic or associated with transient microvascular vaso-occlusive symptoms or large vessel arterial or venous thrombosis. Failure of either the hematocrit or the platelet count to correlate with thrombotic events is a peculiar conundrum of the MPDs. Asymptomatic thrombocytosis in young MPD patients with no cardiovascular risk factors does not require treatment. It is also undisputed that lowering the platelet count reduces the incidence of microvascular events in MPD patients. At the same time, no study to date has demonstrated that platelet count reduction prolongs survival in MPD patients. Agents such as hydroxyurea, busulfan, IFN-alpha and anagrelide, have been used to reduce an elevated platelet count and decrease thrombohemorrhagic events in at-risk patients with thrombocytosis associated with an MPD. When treatment is required, it makes sense to use drugs that are not myelotoxic or mutagenic. Based on the Primary Thrombocythaemia 1 study, hydroxyurea is the treatment of choice for thrombocytosis-associated transient ischemic attacks. However, hydroxyurea does not prevent venous thrombosis, is not more effective in preventing arterial thrombosis than anagrelide and its long-term safety is not established. Therefore, unless curative therapy is planned, one should use the least myelotoxic agent when platelet count reduction is required. In this regard, anagrelide can be considered a first-line drug. With regard to long-term safety of anagrelide, the EMEA has required close monitoring of the safety points identified in future Periodic Safety Update Reports and in a Post Authorisation Safety Study in the EU, which will focus especially on cardiovascular events and acute leukemia. In this article, we review anagrelide pharmacology, the physiology of thrombopoiesis, the differential diagnosis of thrombocytosis and the management of patients with an elevated platelet count.
    Expert Review of Anti-infective Therapy 02/2009; 9(1):37-50. · 2.07 Impact Factor

Publication Stats

3k Citations
174 Downloads
982.01 Total Impact Points

Institutions

  • 1981–2013
    • Johns Hopkins University
      • Department of Medicine
      Baltimore, MD, United States
  • 2012
    • James J. Peters VA Medical Center
      New York City, New York, United States
  • 2011
    • Northwestern University
      • Division of Hematology/Oncology
      Evanston, IL, United States
  • 1985–2011
    • Johns Hopkins Medicine
      • • Department of Medicine
      • • Division of Hematology
      Baltimore, Maryland, United States
  • 2009
    • Institut Multidisciplinaire d'Oncologie - Clinique de Genolier
      Vaud, Switzerland
  • 2005
    • Mayo Clinic - Rochester
      Rochester, Minnesota, United States
  • 2004
    • Weill Cornell Medical College
      New York City, New York, United States
    • Pacific Northwest Diabetes Research Institute
      Seattle, Washington, United States
  • 2003
    • Mount Sinai Medical Center
      New York City, New York, United States
  • 1990
    • University of Maryland, Baltimore
      • Department of Medicine
      Baltimore, MD, United States