Guillermo Garcia-Manero

University of Texas MD Anderson Cancer Center, Houston, Texas, United States

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Publications (453)2974.19 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Correlative and functional studies support the involvement of the RUNX gene family in haematological malignancies. To elucidate the role of epigenetics in RUNX inactivation, we evaluated promoter DNA methylation of RUNX1, 2, and 3 in 23 leukaemia cell lines and samples from acute myeloid leukaemia (AML), acute lymphocytic leukaemia (ALL) and myelodysplatic syndromes (MDS) patients. RUNX1 and RUNX2 gene promoters were mostly unmethylated in cell lines and clinical samples. Hypermethylation of RUNX3 was frequent among cell lines (74%) and highly variable among patient samples, with clear association to cytogenetic status. High frequency of RUNX3 hypermethylation (85% of the 20 studied cases) was found in AML patients with inv(16)(p13.1q22) compared to other AML subtypes (31% of the other 49 cases). RUNX3 hypermethylation was also frequent in ALL (100% of the six cases) but low in MDS (21%). In support of a functional role, hypermethylation of RUNX3 was correlated with low levels of protein, and treatment of cell lines with the DNA demethylating agent, decitabine, resulted in mRNA re-expression. Furthermore, relapse-free survival of non-inv(16)(p13.1q22) AML patients without RUNX3 methylation was significantly better (P = 0·016) than that of methylated cases. These results suggest that RUNX3 silencing is an important event in inv(16)(p13.1q22) leukaemias. © 2015 John Wiley & Sons Ltd.
    British Journal of Haematology 01/2015; · 4.94 Impact Factor
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    ABSTRACT: We investigated the combination of midostaurin and azacitidine (AZA) in patients with AML and high risk MDS. Patients received AZA 75mg/m(2) on days 1-7 and midostaurin 25mg bid (in cohort 1 of phase I) or 50mg bid (in cohort 2 of Phase I and in Phase II) orally on day 8-21 during the first cycle and continuously thereafter. Fourteen patients were enrolled in the phase I and 40 in the phase II. Overall response rate was 26%. The median remission duration (RD) was 20 weeks and was significantly longer in patients with FLT3 mutations not previously exposed to other FLT3 inhibitors (p=0.05) and in patients not previously transplanted (p=0.01). Thirty-two (59%) patients have died, all of complications related to disease progression. G3-4 non-hematological toxicity was reported in 38 (70%) patients, most frequently infections (56%), ejection fraction reduction (11%), and diarrhea or nausea/vomiting (9% each). The combination of midostaurin and AZA is an effective and safe regimen in patients with AML and high-risk MDS. Patients with FLT3 mutations but not previously exposed to other FLT3 inhibitors and patients not previously transplanted derived the greatest benefit. Further studies with this combination are warranted. This article is protected by copyright. All rights reserved. © 2014 Wiley Periodicals, Inc.
    American Journal of Hematology 12/2014; · 3.48 Impact Factor
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    ABSTRACT: In this study we used a next generation sequencing-based approach to profile gene mutations in therapy-related myelodysplastic syndromes (t-MDS) and acute myeloid leukemia (t-AML); and compared these findings with de novo MDS/AML. Consecutive bone marrow samples of 498 patients, including 70 therapy-related (28 MDS and 42 AML) and 428 de novo (147 MDS and 281 AML) were analyzed using a modified-TruSeq Amplicon Cancer Panel (Illumina) covering mutation hotspots of 53 genes. Overall, mutation(s) were detected in 58.6% of t-MDS/AML and 56.8% of de novo MDS/AML. Of therapy-related cases, mutations were detected in 71.4% of t-AML versus 39.3% t-MDS (p = 0.0127). TP53 was the most common mutated gene in t-MDS (35.7%) as well as t-AML (33.3%), significantly higher than de novo MDS (17.7%) (p = 0.0410) and de novo AML (12.8%) (p = 0.0020). t-AML showed more frequent PTPN11 but less NPM1 and FLT3 mutations than de novo AML. In summary, t-MDS/AML shows a mutation profile different from their de novo counterparts. TP53 mutations are highly and similarly prevalent in t-MDS and t-AML but mutations in genes other than TP53 were more frequent in t-AML than t-MDS. The molecular genetic profiling further expands our understanding in this group of clinically aggressive yet heterogeneous myeloid neoplasms.
    Leukemia Research 12/2014; · 2.69 Impact Factor
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    ABSTRACT: Purpose: Data suggest that activity of p38 MAPK and Tie2 kinase are dysregulated in MDS and may be targets for novel therapies. A Phase 1 study of ARRY 614, an oral dual inhibitor of p38 MAPK and Tie2, was conducted in patients with low or intermediate-1 International Prognostic Scoring System risk MDS to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary responses by IWG 2006 criteria. Experimental Design: Forty-five patients received ARRY-614 either QD or BID in dose escalation (400, 600, 900 or 1200 mg QD; 200 or 300 mg BID) or expansion cohorts. Results: The 300 mg BID schedule was not tolerated, and a maximum tolerated dose was not reached for QD dosing. Treatment-related adverse events were primarily grade 1-2, with the most common being rash, diarrhea, dry skin, fatigue and anorexia. Inter-patient PK variability was high, although exposure was sufficient to achieve reduction in p38 MAPK activation in bone marrow and in the levels of circulating biomarkers. Disease responses were observed in 14 of 44 (32%) evaluable patients, 13 (93%) of whom had previously been treated with a hypomethylating agent. Responses were observed in all lineages, with 5 patients experiencing bilineage responses. Three of 25 RBC transfusion-dependent (TD) patients achieved transfusion independence (TI) and 5 of 7 platelet TD patients achieved TI. Conclusions: ARRY-614 was well tolerated with sufficient activity to warrant further evaluation in this patient population. We recommend 1200 mg QD as the optimal dose for further study. This study was registered at http://www.clinicaltrials.gov as NCT00916227. Copyright © 2014, American Association for Cancer Research.
    Clinical Cancer Research 12/2014; · 8.19 Impact Factor
  • British Journal of Haematology 11/2014; · 4.96 Impact Factor
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    ABSTRACT: Background Ruxolitinib is a potent and specific JAK1/JAK2 inhibitor recently approved for the treatment of myelofibrosis. Patients and Methods We conducted a single-center phase I/II clinical study testing 3 dose levels (50 mg BID [n=4], 100 mg BID [n=5], and 200 mg BID [n=18]). We enrolled 27 patients older than 14 years with relapsed or refractory acute myeloid leukemia (n=26) or acute lymphoid leukemia (n=1). Results Median age was 66 years (range, 25-88). Thirteen patients were evaluable for dose-limiting toxicities. The most common grade 3 or 4 non-hematologic event was infection (n= 26 events; most frequently pneumonia; 15/26, 58%). One patient with multiple relapses after 7 lines of therapy had a CRp at ruxolitinib dose of 200 mg BID. Conclusion In this cohort of heavily pre-treated patients with relapsed or refractory acute leukemias, ruxolitinib was overall reasonably well tolerated, with one patient achieving CRp.
    Clinical Lymphoma, Myeloma and Leukemia 09/2014; · 1.93 Impact Factor
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    ABSTRACT: Only a minority of myelodysplastic syndrome (MDS) patients respond to hypomethylating agents, but strong predictors of response are not known. We sequenced 40 recurrently mutated myeloid malignancies genes in tumor DNA from 213 MDS patients collected prior to treatment with azacitidine or decitabine. Mutations were examined for association with response and overall survival. The overall response rate of 47% was not different between agents. Clonal TET2 mutations predicted response (odds ratio [OR] 1.99, p = 0.036) when subclones unlikely to be detected by Sanger sequencing (allele fraction <10%) were treated as wildtype. Response rates were highest in the subset of TET2 mutant patients without clonal ASXL1 mutations (OR 3.65, p = 0.009). Mutations of TP53 (hazard ratio [HR] 2.01, p = 0.002) and PTPN11 (HR 3.26, p = 0.006) were associated with shorter overall survival but not drug response. Murine competitive bone marrow transplantation followed by treatment with azacitidine demonstrated that Tet2-null cells have an engraftment advantage over Tet2-WT cells. Azacitidine significantly decreased this advantage for Tet2-null cells (p=0.002) but not Tet2-WT cells (p=0.212). Overall, Tet2 loss appears to sensitize cells to treatment with azacitidine in vivo and TET2 mutations can identify patients more likely to respond to hypomethylating agents.
    Blood 09/2014; · 9.78 Impact Factor
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    ABSTRACT: Myelodysplastic syndromes are a heterogeneous group of clonal bone marrow hematopoietic stem cell disorders characterized by ineffective hematopoiesis and peripheral cytopenias. Chromosomal abnormalities and gene mutations have been shown to have essential roles in pathogenesis and correlate with prognosis. Molecular markers, however, are not integrated into currently used prognostic systems. The goal of this study is to identify plasma microRNAs useful for classification and risk stratification of myelodysplastic syndromes. We applied a novel, high-throughput digital quantification technology (NanoString) to profile microRNA expression in plasma samples of 72 patients with myelodysplastic syndromes and 12 healthy individuals. We correlated these results with overall survival. In patients with myelodysplastic syndromes associated with a diploid karyotype, we identified and validated a 7-microRNA signature as an independent predictor of survival with a predictive power of 75% accuracy (P=0.008), better than those of the International Prognostic Scoring Systems and the MD Anderson Prognostic Lower Risk Prognostic Model. We also identified differentially expressed plasma microRNAs in patients with myelodysplastic syndromes versus healthy individuals and between patients with myelodysplastic syndromes associated with different cytogenetic features. These results validate the utility of circulating-microRNA levels as noninvasive biomarkers that can inform the management of patients with myelodysplastic syndromes. Our findings also shed light on interactions of gene regulation pathways that are likely involved in the pathogenesis of myelodysplastic syndromes.Modern Pathology advance online publication, 12 September 2014; doi:10.1038/modpathol.2014.108.
    Modern Pathology 09/2014; · 6.36 Impact Factor
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    ABSTRACT: Abstract The incidence and pattern of secondary neoplasms in patients with acute promyelocytic leukemia (APL) treated with ATRA-containing regimens is not well-described. We compared secondary neoplasms in 160 patients with APL treated with ATRA plus idarubicin (n=54), or ATRA plus arsenic trioxide (ATO) (n=106) for the incidence of secondary cancers per unit time of follow-up. Median follow-up times for the two cohorts were 136 and 29 months, respectively. Nine patients developed secondary cancers in the chemotherapy group. These included two breast cancers, three myelodysplastic syndromes/acute myeloid leukemia, one vulvar cancer, one prostate cancer, one colon cancer and one soft tissue sarcoma. A melanoma and one pancreatic cancer developed in the ATO group. We conclude that treatment of patients with APL using the non-chemotherapy regimen of ATRA plus ATO is not associated with a higher incidence of secondary cancers (p=0.29) adjusted for unit time of exposure.
    Leukemia and Lymphoma 08/2014; · 2.61 Impact Factor
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    ABSTRACT: Abstract It is thought that the low incidence of central nervous system (CNS) involvement in acute myeloid leukemia (AML) does not justify routine CNS prophylaxis, as high-dose cytarabine eliminates CNS disease. To test whether chemotherapy that does not include high-dose cytarabine increases the risk of CNS involvement, the medical records of 1,412 newly diagnosed AML patients were reviewed. In 1,370 patients, lumbar puncture (LP) was performed only if clinically indicated, and CNS disease was detected in 45 (3.3%) patients. Another 42 patients underwent routine LP as part of an investigational protocol, and in 8 (19%) CNS disease was detected (P<0.0001). Risk factors included high LDH, African-American ethnicity, and young age. Patients receiving high-dose cytarabine and those that did not had similar rates of CNS involvement. Disease free survival (DFS) and overall survival were shorter in patients with CNS involvement. It remains to be determined whether routine CNS prophylaxis would improve DFS.
    Leukemia and Lymphoma 08/2014; · 2.61 Impact Factor
  • Elias Jabbour, Guillermo Garcia-Manero
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    ABSTRACT: Abstract Myelodysplastic syndromes (MDS) are a diverse group of myeloid disorders, with patients being at risk for cytopenias or progression to acute myeloid leukemia. Several classification and prognostic scoring systems have been developed. High-intensity treatments are not appropriate for all patients. Two demethylating agents, azacitidine and decitabine, are approved for treatment of MDS, though many patients do not derive long-term benefit and eventually progress. Deacetylase inhibitors have emerged as novel treatment candidates based on mechanistic rationale and preliminary data. This article reviews existing data on MDS treatment and discusses the rationale and potential for combination with deacetylase inhibitors.
    Leukemia and Lymphoma 07/2014; · 2.61 Impact Factor
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    ABSTRACT: Summary Two hundred thirty-five consecutive patients presenting to a single center with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after breast cancer treatment were compared with matched patients with de novo AML or MDS. There was no significant difference in median OS times between patients with therapy related AML and those with de novo AML (8.7 months vs.10.2 months; P = .17). Patients with therapy related MDS had slightly lower median baseline platelet counts and a higher frequency of poor cytogenetics than those with de novo MDS, but the two groups had similar OS times (13.6 months vs. 18.9 months; P = .06). Multivariate analysis revealed that cytogenetic risk, baseline white blood cell count, age, and performance status were predictive for OS time in AML and that cytogenetic risk and performance status were predictive for OS time in MDS. Having therapy-related disease is not an independent risk factor in patients with myeloid neoplasms and with a history of breast cancer. Clinical trials should be designed to serve both populations.
    Leukemia and Lymphoma 07/2014; · 2.61 Impact Factor
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    ABSTRACT: Background Patients with multiple myeloma (MM) have had significant improvements in outcomes. An increased risk of therapy-related myeloid neoplasms (t-MNs) has also developed. Little is known about the characteristics and outcomes of these patients. Patients and Methods Patients with MM treated at our institution from 1993 to 2011 were reviewed. Forty-seven patients were diagnosed with t-MN. Our primary objective was to evaluate the interval to t-MN, response to treatment, and overall survival (OS). Results The median patient age at the MM diagnosis was 65 years. Of the 47 patients, 32 (68.0%) initially received conventional chemotherapeutic agents, 7 (14.9%), novel agents (eg, lenalidomide, thalidomide, bortezomib), and 8 (17.0%), a combination. Twenty patients (42.6%) underwent high-dose chemotherapy and autologous hematopoietic stem cell transplantation. The median interval from the MM diagnosis to t-MN was 7 years (95% CI, 5.0-28.0). Of the 47 patients, 33 (70.2%) developed therapy-related myelodysplastic syndrome (t-MDS), 11 (23.4%) acute myeloid leukemia (t-AML), and 3 (6.4%) chronic myelomonocytic leukemia (t-CMML). The median age at the t-MN diagnosis was 65 years. Of the 47 patients, 26 (78.8%) with t-MDS, 9 (81.8%) with t-AML, and 1 (33.3%) with t-CMML had complex/high-risk cytogenetics. The median OS for all 47 patients after the t-MN diagnosis was 6.3 months (95% CI, 4.0-8.7). Conclusion The development of t-MN in patients with MM is associated with poor outcomes. These patients, in general, have complex cytogenetic abnormalities and short complete remission and OS times. A better understanding of the disease biology and novel therapeutic approaches are warranted.
    Clinical Lymphoma, Myeloma and Leukemia 07/2014; · 1.93 Impact Factor
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    ABSTRACT: Acute myeloid leukemias with MLL rearrangements are frequently associated with myelomonocytic and monoblastic/monocytic morphology, with an increased risk of leukocytosis and leukostasis-related complications. Yet, little is known regarding the clinical presentation of adult AML patients with MLL translocations based on the specific translocation partner.
    Clinical Lymphoma, Myeloma and Leukemia 06/2014; · 1.93 Impact Factor
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    ABSTRACT: The myelodysplastic syndromes (MDS) are a group of clonal diseases characterized by inefficient haematopoiesis, increased apoptosis and risk of evolution to acute myeloid leukaemia. Alterations in epigenetic processes, including DNA methylation, histone modifications, miRNA and splicing machinery, are well known pathogenical events in MDS. Although many advances have been made in determining the mutational frequency, distribution and association affecting these epigenomic regulators, functional integration to better understand pathogenesis of the disease is a challenging and expanding area. Recent studies are shedding light on the molecular basis of myelodysplasia and how mutations and epimutations can induce and promote this neoplastic process through aberrant transcription factor function (RUNX1, ETV6, TP53), kinase signalling (FLT3, NRAS, KIT, CBL) and epigenetic deregulation (TET2, IDH1/2, DNMT3A, EZH2, ASXL1, SF3B1, U2AF1, SRSF2, ZRSR2). In this review we will try to focus on the description of these mutations, their impact on prognosis, the functional connections between the different epigenetic pathways, and the existing and future therapies targeting these processes.
    British Journal of Haematology 06/2014; · 4.96 Impact Factor
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    ABSTRACT: Patients with newly diagnosed AML (n = 360) including 137 (38%) with normal karyotype (NK) were evaluated. Overall, 60 (16.6%) patients, including 46 of the 137 (33.5%) NK patients, had NPM1 mutation at baseline. Thirty-nine patients (30 NK) had available NPM1 status at the time of complete remission (CR) and all (100%) were negative for mutated NPM1. Among the patients with mutated NPM1 at baseline, 10/39 overall (25%) and 7/30 NK (23%) patients relapsed. NPM1 status was available for eight patients (six with NK) at the time of relapse. Among them, 7/8 overall (87%) and 5/6 NK (83%) patients had mutated NPM1, while 1/8 overall (12%) and 1/6 NK (16%) patients remained NPM1 wild type. Among the 300 patients (including 91 with NK) with wild type NPM1 at diagnosis, none acquired a mutated NPM1 clone, either at CR or at relapse. We conclude that mutated NPM1 is a stable and reliable prognostic marker in AML and can be used to assess MRD.
    Leukemia and Lymphoma 06/2014; 55(6). · 2.61 Impact Factor
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    ABSTRACT: Abstract Myelosuppression in myelodysplastic syndromes (MDS) is associated with the hypomethylating agent decitabine. A retrospective pooled analysis of 2 decitabine clinical trials in patients with MDS conducted Cox regression analyses of red blood cell or platelet dependence, myelosuppression, dose modification, cycle delay or dose reduction, and survival effects. In 182 patients, baseline platelet dependence was a predictor for dose modification, reduction, or delay, and death (modification: P = .006, hazard ratio [HR] = 2.04; reduction/delay: P = .011, HR = 2.00; death: P = .003, HR = 1.94). Patients with dose modifications had significantly higher overall response rates versus those with none (22% vs 10%; P = .015). Patients with no dose modifications had faster progression to AML versus patients with dose modifications (P = .004). Without dose modifications, patients tended to drop out due to disease progression or other reasons. Decitabine dose modifications on treatment may indicate response to treatment.
    Leukemia and Lymphoma 05/2014; · 2.61 Impact Factor
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    ABSTRACT: We evaluated the characteristics of a cohort of patients with myelodysplastic syndrome (MDS) related to therapy (t-MDS) to create a prognostic model.
    Clinical Lymphoma, Myeloma and Leukemia 05/2014; · 1.93 Impact Factor
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    ABSTRACT: Exact mechanism of action of umbilical cord blood (CB)-derived regulatory T cells (Tregs) in the prevention of GVHD remains unclear. On the basis of selective overexpression of peptidase inhibitor 16 in CB Tregs, we explored the related p53 pathway, which has been shown to negatively regulate miR15a/16 expression. Significantly lower levels of miR15a/16 were observed in CB Tregs when compared with conventional CB T cells (Tcons). In a xenogeneic GVHD mouse model, lower levels of miR15a/16 were also found in Treg recipients, which correlated with a better GVHD score. Forced overexpression of miR15a/16 in CB Tregs led to inhibition of FOXP3 and CTLA4 expression and partial reversal of Treg-mediated suppression in an allogeneic mixed lymphocyte reaction that correlated with the reversal of FOXP3 demethylation in CB Tregs. On the other hand, miR15a/16 knockdown in CB Tcons led to expression of FOXP3 and CTLA4 and suppression of allogeneic lymphocyte proliferation. Using a luciferase-based mutagenesis assay, FOXP3 was determined to be a direct target of miR15a and miR16. We propose that miR15a/16 has an important role in mediating the suppressive function of CB Tregs and these microRNAs may have a 'toggle-switch' function in Treg/Tcon plasticity.Bone Marrow Transplantation advance online publication, 7 April 2014; doi:10.1038/bmt.2014.57.
    Bone marrow transplantation 04/2014; · 3.00 Impact Factor
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    ABSTRACT: Myelodysplastic syndromes (MDS) are characterized by impaired proliferation and differentiation of hematopoietic stem cells. The participation of toll-like receptor (TLR)-mediated signaling in MDS is well documented. Increased TLR signaling leads to the constitutive activation of NF-κB, which mediates inflammation, cell proliferation and apoptosis. In addition, the TLR pathway induces the expression of miRNAs which participate in the fine-tuning of the inflammatory response. miRNAs also regulate other biological processes, including hematopoiesis. miR-125a and miR-125b are known modulators of hematopoiesis and are abnormally expressed in several hematologic malignancies. However, little is known about their role in MDS. NF-κB-activating ability has been described for both miRNAs. We studied the role of miR-125a/miR-125b in MDS and their relationship with TLR signaling and hematopoietic differentiation. Our results indicate that miR-125a is significantly overexpressed in MDS patients and correlates negatively with patient survival. Expression of miR-99b, which is clustered with miR-125a, is also directly correlated with prognosis of MDS. Both miR-125a and miR-99b activated NF-κB in vitro; however, we observed a negative correlation between miR-99b expression and the levels of TLR2, TLR7 and two downstream genes, suggesting that NF-κB activation by the miRNA cluster occurs in the absence of TLR signaling. We also show that TLR7 is negatively correlated with patient survival in MDS. In addition, our data suggest that miR-125a may act as an NF-κB inhibitor upon TLR stimulation. These results indicate that miR-125a is involved in the fine-tuning of NF-κB activity and that its effects may depend on the status of the TLR pathway. Furthermore, we observed that miR-125a inhibits erythroid differentiation in leukemia and MDS cell lines. Therefore, this miRNA could serve as a prognostic marker and a potential therapeutic target in MDS.
    PLoS ONE 04/2014; 9(4):e93404. · 3.53 Impact Factor

Publication Stats

16k Citations
2,974.19 Total Impact Points

Institutions

  • 2002–2014
    • University of Texas MD Anderson Cancer Center
      • • Department of Hematopathology
      • • Department of Leukemia
      Houston, Texas, United States
  • 2013
    • University of Texas Health Science Center at Houston
      Houston, Texas, United States
    • University of Alcalá
      Cómpluto, Madrid, Spain
    • Nanjing Medical University
      Nan-ching, Jiangsu Sheng, China
    • US Oncology
      The Woodlands, Texas, United States
    • Kolling Institute of Medical Research
      Sydney, New South Wales, Australia
    • Kyoto University
      Kioto, Kyōto, Japan
  • 2012
    • University of Michigan
      • Life Sciences Institute
      Ann Arbor, MI, United States
  • 2011–2012
    • Brigham and Women's Hospital
      • • Center for Brain Mind Medicine
      • • Department of Medicine
      Boston, MA, United States
    • Hospital Israelita Albert Einstein
      San Paulo, São Paulo, Brazil
    • Universitätsmedizin Göttingen
      • Department of Hematology and Oncology
      Göttingen, Lower Saxony, Germany
    • Emory University
      • Department of Hematology and Medical Oncology
      Atlanta, GA, United States
  • 2009
    • Mayo Clinic - Rochester
      Rochester, Minnesota, United States
  • 2008
    • Medical College of Wisconsin
      • Department of Surgery
      Milwaukee, WI, United States
  • 2004
    • University of Arkansas for Medical Sciences
      Little Rock, Arkansas, United States
  • 1999
    • Thomas Jefferson University
      • Division of Hematology
      Philadelphia, PA, United States