Guillermo Garcia-Manero

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

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Publications (448)2942.82 Total impact

  • [Show abstract] [Hide abstract]
    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 : an official journal of the United States and Canadian Academy of Pathology, Inc. 09/2014;
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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 & lymphoma. 08/2014;
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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 & lymphoma. 08/2014;
  • 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 & lymphoma. 07/2014;
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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 & lymphoma. 07/2014;
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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 & leukemia. 06/2014;
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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; · 4.94 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 & lymphoma. 05/2014;
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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 & leukemia. 05/2014;
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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: The outcome of patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) post clofarabine is unknown. We reviewed 109 patients with MDS or CMML with a median age of 67 years, treated with a clofarabine-based chemotherapy as frontline (n = 38) or salvage (n = 71) therapy. A total of 58 (53%) patients received salvage therapy after clofarabine failure: 13 allogeneic stem cell transplant (ASCT), 18 high-dose cytarabine-containing regimen, 10 hypomethylating agents and 17 investigational treatments. Eight patients achieved complete remission (CR) and three had stable disease for an overall response rate of 19%. With a median follow-up of 3 months from clofarabine failure, 12 patients (11%) remained alive, 5 remain in CR, 4 of them after ASCT. The median overall survival post clofarabine failure was 4 months with a 1-year survival rate of 23%. This outcome is predictable, with patients with high-risk disease at the time of clofarabine failure having the worse survival. To date, patients with MDS continue to have a short survival after failure of all available therapies. Ultimately, patients who are candidates for additional treatments should be offered novel approaches. In conclusion, the outcome of patients with MDS and CMML post clofarabine failure is poor. The pattern is similar to patients with MDS post hypomethylating agent failure and predictable using University of Texas M. D. Anderson Cancer Center global scoring system.
    Therapeutic advances in hematology. 04/2014; 5(2):29-34.
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    Shilpan Shah, Sanam Loghavi, Guillermo Garcia-Manero, Joseph D Khoury
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    ABSTRACT: The FIP1L1-PDGFRA rearrangement results in constitutive activation of the tyrosine kinase PDGFRA. Neoplasms harboring this rearrangement are responsive to imatinib mesylate at doses much lower than those recommended for the treatment of chronic myelogenous leukemia. Only a single report has described the identification of FIP1L1-PDGFRA in chronic myelomonocytic leukemia (CMML). Herein, we present a case report of a patient in whom the FIP1L1-PDGFRA was discovered as he evolved from CMML to acute myeloid leukemia (AML). The presence of a dominant neoplastic clone with FIP1L1-PDGFRA rearrangement was suspected on the basis of sudden onset of peripheral and bone marrow eosinophilia and confirmed by fluorescence in situ hybridization and molecular diagnostic tests. Whereas the patient was initially refractory to chemotherapy before the rearrangement was detected, subsequent therapy with imatinib led to complete remission.
    Journal of Hematology & Oncology 03/2014; 7(1):26. · 4.46 Impact Factor
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    ABSTRACT: Previous studies have suggested that many patients with myelodysplastic syndromes (MDS) have an incomplete understanding of their disease, which may influence adherence to prescribed regimens and outcomes. To better understand physician and patient perceptions about MDS and MDS therapy, the authors conducted 2 surveys in February 2012: 1 for patients with MDS and 1 for health care professionals (HCPs) who cared for patients with MDS. Patient and HCP surveys consisted of 57 and 49 questions, respectively, assessing understanding of MDS, perceptions of specific treatments, barriers to treatment adherence, and treatment experience. In total, 477 complete patient responses and 120 complete HCP responses were received. Among patient responders, 63% were aged ≥60 years, and 42% had received at least 1 disease-modifying therapy. Of the 61 physician responders, 57% practiced in an academic setting, and 43% practiced in the community; 71% of the 59 nonphysician HCPs worked in the community setting. Only 10% of patients agreed that MDS represented "cancer" compared with 59% of physicians and 46% of nonphysician HCPs (P < .001). Only 29% of patients reported that MDS was ever "curable" compared with 52% of physicians (P < .001). Physicians viewed the potential benefits of active therapy as greater than patients, but patients perceived the actual treatment experience more positively than physicians and differed from physicians in perceived reasons for stopping therapy. Physicians, nonphysician HCPs, and patients with MDS have disparate views of MDS characteristics and the value and limitations of treatments for MDS. Improved communication and education may increase understanding and achieve better treatment adherence and patient outcomes. Cancer 2014. © 2014 American Cancer Society.
    Cancer 02/2014; · 5.20 Impact Factor
  • Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 02/2014; · 10.16 Impact Factor
  • Kplola Y Elhor Gbito, Guillermo Garcia-Manero, Sara S Strom
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    ABSTRACT: Myelodysplastic syndromes (MDS) prognosis is currently based solely on clinical parameters. The identification of additional factors associated with MDS outcome could be used to further improve the current scoring system such as the International Prognostic Scoring System (IPSS). The present study evaluates the role of epidemiological markers as predictors of survival for 365 adult de novo MDS patients. Multivariable Cox regression analysis was used to estimate overall survival. Median follow-up time was 22 months. At the time of last follow-up, 271 patients (74.3 %) had died. For all MDS patients, medium-high lifetime occupational agrochemical exposure (HR 1.85, CI 1.19-2.89) remained as an independent predictor of MDS survival. Stratified analysis by gender showed that ≥25 pack-years smoked (HR 1.44, CI 1.001-2.09) and medium-high lifetime occupational agrochemical exposure (HR 1.84, CI 1.15-2.97) were independent predictors of MDS survival in men, but not in women. For MDS patients stratified by IPSS categories, ≥25 pack-years smoked (HR 1.75, CI 1.005-3.06) was an independent predictor for intermediate 1 IPSS risk group only, and medium-high lifetime occupational agrochemical exposure was associated with increased mortality (HR 4.36, CI 1.20-15.8) in the high IPSS risk group. Smoking and lifetime occupational agrochemical exposure may play a role in MDS survival. Incorporating relevant epidemiological markers with known clinical predictors of outcome may help physician stratify patients and customize treatment strategies to improve the outcome of MDS.
    Cancer Causes and Control 01/2014; · 3.20 Impact Factor
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    ABSTRACT: Background: Comorbidities significantly affect the prognosis and outcomes of patients with hematological malignancies. We have previously reported the impact of comorbidities on the IPSS score. The aim of this study was to determine whether comorbidities continued to have a significant impact when patients were reclassified according to the Revised-International Prognostic Scoring System (IPSS-R). Methods: The medical records of 600 consecutive MDS patients who presented to MD Anderson Cancer Center between January 2002 and June 2004 were reviewed. The Adult Comorbidity Evaluation-27 (ACE-27) was used to assess the severity of comorbid conditions. Results: Four hundred and two (67%) patients were male. Median age at presentation was 66.6 years (17 - 94). Mean duration of follow-up was 54 months (1 - 100). Five hundred and two (84%) patients died, and 54 (9%) patients underwent SCT. Overall median survival was 16.8 months (1 - 100). Median survival by IPSS-R was 47, 34, 21, 16, and 6 months for patients in very low, low, intermediate, high and very high-risk groups, respectively (P<0.001). The ACE-27 comorbidity score significantly impacted the median survival of patients in the intermediate (P<0.001), high (P=0.045), and very high (P=0.004) IPSS-R groups; but did not significantly impact the median survival in the low (P=0.11) and very low (P=0.49) IPSS-R groups. The ACE-27 comorbidity score significantly impacted the median survival of patients ≤ 65 years (P<0.001) but did not significantly impact those > 65 years (P=0.18). Conclusion: Assessment of comorbidity may enhance the prognostic ability of the IPSS-R.
    American Journal of Hematology 01/2014; · 4.00 Impact Factor
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    ABSTRACT: Chromosome 17 abnormalities are associated with poor outcome in leukemias including AML. Recently, MK was introduced as an independent predictor of dismal outcome in AML. The additional prognostic effect of C17 abns in patients with MK in a CK background is not clear. We conducted a retrospective analysis of 1086 patients with newly diagnosed AML treated between January 1998 and December 2007. Patients received treatment with one of the institution's first-line protocols. Four hundred eighty-three patients had CK. Among them, 370 patients (77%) had CK-MK, and 195 patients (53%) had CK-MK-C17 abns. Patients with CK-MK had significantly shorter OS rates compared with patients with CK without MK (4.4 vs. 8 months, respectively; P = .002). The median OS for patients with CK-C17 abns was shorter than for patients without C17 abns (4 vs. 6.1 months, respectively; P = .004). In a multivariate analysis, the presence of MK among patients with CK was identified as an independent prognostic marker for OS. In addition, presence of C17 abns had a significant negative effect on OS among patients with CK-MK (P = .04). Among patients with CK-AML, MK was associated with poor outcomes. Additional presence of C17 abns further worsens the outcome in these particularly poor-risk patients with AML.
    Clinical lymphoma, myeloma & leukemia 01/2014;
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    ABSTRACT: The frequency of RAS mutations in chronic myelomonocytic leukemia (CMML) suggests that activation of the MAPK pathway is important in CMML pathogenesis. Accordingly, we hypothesized that mutations in other members of the MAPK pathway might be overrepresented in RAS(wt) CMML. We performed targeted next generation sequencing analysis on 70 CMML patients with known RAS mutation status. The study group included 37 men and 33 women with a median age of 67.8 years (range, 28-86 years). Forty patients were RAS(wt) and 30 were RAS(mut) ; the latter included KRAS=17; NRAS=12; KRAS+NRAS=1. Five patients (7.1% of total group; 12.5% of RAS(wt) group) with RAS(wt) had kinase domain BRAF mutations. The BRAF mutations were of missense type and involved exon 11 in 1 patient and exon 15 in 4 patients. All BRAF(mut) patients had CMML-1 with low-risk cytogenetic findings. Two (40%) of the 5 patients with BRAF(mut) patients transformed to acute myeloid leukemia during follow up. In summary, we demonstrate that a subset of patients with RAS(wt) CMML harbors BRAF kinase domain mutations that are potentially capable of activating the MAPK signaling pathway.
    American Journal of Hematology 01/2014; · 4.00 Impact Factor
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    ABSTRACT: Anti-angiogenic agents combined with histone deacetylase inhibitors act synergistically in vitro and in vivo. We conducted a phase I study of the combination of the anti-VEGF monoclonal antibody bevacizumab and histone deacetylase inhibitor valproic acid in patients with advanced cancers. Bevacizumab was administered at escalating dosages of 2.5-11 mg/kg on days 1 and 15, and oral valproic acid at dosages of 5.3-10 mg/kg on days 1-28 every 28 days to determine the maximum tolerated dose. Pharmacodynamic parameters were assessed in peripheral blood mononuclear cells (histone H3 acetylation) and serum (valproic acid levels). Fifty-seven patients were enrolled. Dose-limiting toxicities were grade 3 altered mental status (n = 2), related to valproic acid. Bevacizumab 11 mg/kg given on days 1 and 15 and valproic acid 5.3 mg/kg daily were the recommended phase II dosages. Stable disease (SD) ≥6 months was reported in 4/57 (7 %) of patients, including two patients with colorectal cancer who had progressed previously on bevacizumab. Of the 39 patients evaluated for histone acetylation, 2 of 3 (67 %) patients with SD ≥6 months showed histone acetylation, while 8 of 36 (22 %) without SD ≥6 months demonstrated histone acetylation (p = 0.16). Patients with any grade of hypertension, compared to others, had a prolonged median survival (11.1 vs. 5.8 months; p = 0.012). The combination of bevacizumab 11 mg/kg and valproic acid 5.3 mg/kg is safe in patients with advanced malignancies, with activity in colorectal, gastroesophageal junction, and prostate cancer. Patients with hypertension had improved overall survival.
    Cancer Chemotherapy and Pharmacology 01/2014; · 2.80 Impact Factor

Publication Stats

15k Citations
2,942.82 Total Impact Points


  • 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