Mark C Walters

Indiana Blood and Marrow Transplantation, Indianapolis, Indiana, United States

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Publications (68)306.07 Total impact

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    ABSTRACT: Background It is well established that umbilical cord blood and bone marrow are biologically different stem cell sources.Patients and Methods We analyzed the feasibility and outcome of hematopoietic stem cell transplantation (HSCT) in 13 children (median age 5.9 years) with hemoglobinopathies after the co- infusion of cord blood (CB) and bone marrow (BM) from the same human leucocyte antigen (HLA) identical sibling donor. We also compared outcomes of children with co-transplantation to outcomes in children with hemoglobinopathies who had received a BM (n = 21) or CB (n = 22) transplant alone.ResultsCompared to CB transplant (CBT) recipients, the co-transplant group had more rapid neutrophil (17 vs. 25 days, P = 0.013) and platelet (29 vs. 48 days, P = 0.009) recovery and less transplant related mortality. Patients who received a co-transplant had a lower incidence of ≥grade II acute (0% vs. 26.3%) and chronic (0% vs. 21%) graft versus host disease (GVHD) compared to BM transplant (BMT) recipients (P = 0.055 and 0.045, respectively). With a median follow-up of >60 months in each treatment group, the 5-year probability of event free survival (EFS) was 100% in the co-transplant group, 90% after BMT and 86% after CBT (P = 0.42).Conclusion Co-transplantation of CB and BM from HLA-identical sibling donors appears to be a feasible and effective strategy to further optimize outcomes of HSCT for hemoglobinopathies. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 05/2014; · 2.35 Impact Factor
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    ABSTRACT: Graft-versus-host disease (GVHD) is a common complication of allogeneic bone marrow transplantation (BMT). Upregulation of inflammatory cytokines precedes the clinical presentation of GVHD and predicts its severity. In this report, thiol/redox metabolomics was used to identify metabolic perturbations associated with early preclinical (Day+4) and clinical (Day+10) stages of GVHD by comparing effects in Syngeneic (Syn; major histocompatibility complex- identical) and allogeneic transplant recipients (Allo BMT) in experimental models. While most metabolic changes were similar in both groups, plasma glutathione (GSH) was significantly decreased, and GSH disulfide (GSSG) was increased after allogeneic compared to syngeneic recipient and non-transplant controls. The early oxidation of the plasma GSH/GSSG redox couple was also observed irrespective of radiation conditioning treatment and was accompanied by significant rise in hepatic protein oxidative damage and ROS generation. Despite a significant rise in oxidative stress, compensatory increase in hepatic GSH synthesis was absent following Allo BMT. Early shifts in hepatic oxidative stress and plasma GSH loss preceded a statistically significant rise in TNF-α. To identify metabolomic biomarkers of hepatic GVHD injury, plasma metabolite concentrations analyzed at Day+10 were correlated with hepatic organ injury. GSSG (oxidized GSH) and β-alanine, were positively correlated, and plasma GSH cysteinylglycine, and branched chain amino acids were inversely correlated with hepatic injury. Although changes in plasma concentrations of cysteine, cystathionine (GSH precursors) and cysteinylglycine (a GSH catabolite) were not significant by univariate analysis, principal component analysis (PCA) indicated that accumulation of these metabolites after Allo BMT contributed significantly to early GVHD in contrast to Syn BMT. In conclusion, thiol/redox metabolomic profiling implicates that early dysregulation of host hepatic GSH metabolism and oxidative stress in sub-clinical GVHD before elevated TNF-α levels is associated with GVHD pathogenesis. Future studies will probe the mechanisms for these changes and examine the potential of antioxidant intervention strategies to modulate GVHD.
    PLoS ONE 01/2014; 9(2):e88868. · 3.73 Impact Factor
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    ABSTRACT: We analyzed the outcomes of 485 patients with thalassemia major (TM) or sickle cell disease (SCD) receiving HLA-identical sibling cord blood transplantation (CBT, n=96) or bone marrow transplantation (BMT, n=389). Compared to patients given BMT, CBT recipients were significantly younger (median age 6 versus 8 years, p=0.02), and were treated more recently (median year 2001 versus 1999, p<0.01). A higher proportion of patients with TM belonging to classes II-III of the Pesaro classification received BMT (44%) compared to CBT (39%, p<0.01). In comparison with patients receiving BMT (n=259, TM; n=130, SCD), those given CBT (n=66, TM; n=30, SCD) had slower neutrophil recovery, less acute graft-versus-host disease (GVHD) and none had extensive chronic GVHD. With a median follow-up of 70 months, the 6-year overall survival was 95% and 97% after BMT and CBT, respectively (p=0.92). The 6-year disease-free survival (DFS) was 86% and 80% in TM patients after BMT and CBT, respectively, while DFS in SCD patients was 92% and 90%, respectively. The cell dose infused did not influence outcome of patients given CBT. In multivariate analysis, DFS did not differ between CBT and BMT recipients. Patients with TM or SCD have excellent outcomes after both HLA-identical sibling CBT and BMT.
    Blood 05/2013; · 9.06 Impact Factor
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    ABSTRACT: The Sickle Cell Unrelated Donor Transplant Trial (SCURT trial) of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) is a phase II study of the toxicity and efficacy of unrelated donor hematopoietic cell transplantation in children with severe sickle cell disease (SCD) using a reduced-intensity conditioning regimen. Here we report the results for the cord blood cohort of this trial. Eight children with severe SCD underwent unrelated donor cord blood transplantation (CBT) following alemtuzumab, fludarabine, and melphalan. Cyclosporine or tacrolimus and mycophenolate mofetil were administered for graft-versus-host disease (GVHD) prophylaxis. Donor/recipient HLA match status was 6 of 6 (n = 1) or 5 of 6 (n = 7), based on low/intermediate-resolution molecular typing at HLA -A, -B, and high-resolution typing at -DRB1. Median recipient age was 13.7 years (range: 7.4-16.2 years), and median weight was 35.0 kg (range: 25.2-90.2 kg). The median pre-cryopreservation total nucleated cell dose was 6.4 × 10(7) /kg (range: 3.1-7.6), and the median postthaw infused CD34 cell dose was 1.5 × 10(5) /kg (range: 0.2-2.3). All patients achieved neutrophil recovery (absolute neutrophil count >500/mm(3)) by day 33 (median: 22 days). Three patients who engrafted had 100% donor cells by day 100, which was sustained, and 5 patients had autologous hematopoietic recovery. Six of 8 patients had a platelet recovery to >50,000/mm(3) by day 100. Two patients developed grade II acute GVHD. Of these, 1 developed extensive chronic GVHD and died of respiratory failure 14 months posttransplantation. With a median follow-up of 1.8 years (range: 1-2.6), 7 patients are alive with a 1-year survival of 100%, and 3 of 8 are alive without graft failure or disease recurrence. Based upon the high incidence of graft rejection after unrelated donor CBT, enrollment onto the cord blood arm of the SCURT trial was suspended. However, because this reduced-intensity regimen has demonstrated a favorable safety profile, this trial remains open to enrollment for unrelated marrow donor transplants. Novel approaches aimed at improving engraftment will be needed before unrelated CBT can be widely adopted for transplanting patients with severe SCD.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 02/2012; 18(8):1265-72. · 3.15 Impact Factor
  • Jakub Tolar, Parinda A Mehta, Mark C Walters
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    ABSTRACT: Hereditary disorders that trace their origin to the hematopoietic stem cell have been targeted for allogeneic therapy and were among the first human diseases cured by successful hematopoietic cell transplantation (HCT). More recently, the possibility of treating nonhematopoietic hereditary disorders in which engraftment of hematopoietic cells might ameliorate tissue damage in target organs has also been investigated with encouraging results. As in the malignant hematological disorders, transplantation results have improved over the past 3 decades as a consequence of more refined donor selection and patient risk stratification with modifications to the conditioning regimen. The application of these principles is described in this update about HCT for hereditary marrow failure syndromes and hemoglobin disorders. In addition, a novel indication of HCT for epidermolysis bullosa is presented. Together, these representative disorders illustrate the potential for an expanding role of HCT for nonmalignant disorders.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 01/2012; 18(1 Suppl):S166-71. · 3.15 Impact Factor
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    ABSTRACT: There is a significant risk of severe graft-versus-host disease (GVHD) and graft failure after unrelated umbilical cord blood transplantation (CBT) if donor-recipient pairs are mismatched at major histocompatibility complex (MHC) loci. To mitigate these risks after MHC-mismatched CBT, we infused psoralen-treated, photochemically inactivated, mature donor T-lymphocytes with MHC (H2-haplotype) mismatched murine donor fetal near-term peripheral blood (FNPB) cells after sublethal irradiation. We analyzed the rates of donor engraftment, GVHD and long-term survival in H2 haplotype disparate (C57BL/6 [H-2(b)/Thy1.1] → AKR [H-2(k)/Thy1.2]) recipient mice. We observed inconsistent donor engraftment after transplantation with cord blood alone, but superior engraftment and long-term survival after FNPB transplantation supplemented with psoralen-treated donor T-lymphocytes. Additionally, there was fatal GVHD after FNPB co-infusion with untreated donor T-lymphocytes, but minimal GVHD after FNPB supplemented with psoralen-treated donor T-lymphocytes transplantation. Donor MHC(high)/c-Kit(+)/lineage(-)/CD34(-) stem cells were noted in the recipient bone marrow compartment following co-infusion of photochemically inactivated T-cells with FNPB. Despite the non-myeloablative preparation before FNPB infusion, complete hematological recovery was delayed until 50-60 d after transplantation. We observed that co-transplantation of psoralen-treated donor T-lymphocytes with FNPB facilitated durable engraftment of donor hematopoietic stem cells in the marrow and splenic compartments with complete but delayed recovery of all hematopoietic lineages. This CBT model establishes the possibility of ensuring donor engraftment across a MHC barrier without severe GVHD.
    Experimental Biology and Medicine 03/2011; 236(4):492-504. · 2.80 Impact Factor
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    ABSTRACT: We describe outcomes after human leukocyte antigen-matched sibling bone marrow transplantation (BMT) for 179 patients with β-thalassemia major. The median age at transplantation was 7 years and the median follow-up was 6 years. The distribution of Pesaro risk class I, II, and III categories was 2%, 42%, and 36%, respectively. The day 30 cumulative incidence of neutrophil recovery and day 100 platelet recovery were 90% and 86%, respectively. Seventeen patients had graft failure, which was fatal in 11. Six of 9 patients with graft failure are alive after a second transplantation. The day 100 probability of acute graft-versus-host disease and 5-year probability of chronic graft-versus-host disease was 38% and 13%, respectively. The 5-year probabilities of overall- and disease-free survival were 91% and 88%, respectively, for patients with Pesaro risk class II, and 64% and 62%, respectively, for Pesaro risk class III. In multivariate analysis, mortality risks were higher in patients 7 years of age and older and those with hepatomegaly before BMT. The leading causes of death were interstitial pneumonitis (n = 7), hemorrhage (n = 8), and veno-occlusive disease (n = 6). Proceeding to BMT in children younger than 7 years before development of end-organ damage, particularly in the liver, should improve results after BMT for β-thalassemia major.
    Blood 02/2011; 117(5):1745-50. · 9.06 Impact Factor
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    ABSTRACT: We examined the efficacy of unrelated cord blood (CB) transplantation in children with thalassemia (n = 35) and sickle cell disease (n = 16), using data reported to 3 registries. Donor-recipient pairs were matched at HLA-A and -B (antigen level) and DRB1 (allele level) in 7 or HLA mismatched at 1 (n = 18), 2 (n = 25), or 3 loci (n = 1). Transplant conditioning was myeloablative (n = 39) or reduced intensity (n = 12). Neutrophil recovery with donor chimerism was documented in 24 patients; 11 patients developed grade II-IV acute graft-versus-host disease (aGVHD) and 10 patients, chronic GVHD (cGVHD). Overall survival (OS) and disease-free survival (DFS) were 62% and 21% for thalassemia and 94% and 50% for sickle cell disease (SCD), respectively. In multivariate analysis, engraftment rate (hazard ratio [HR] 2.2, P = .05) and DFS (HR 0.4, P = .01) were higher with cell dose >5 × 10(7)/kg. The 2-year probability of DFS was 45% in patients who received grafts with cell dose >5 × 10(7)/kg and 13% with lower cell dose. Primary graft failure was the predominant cause of treatment failure occurring in 20 patients with thalassemia and 7 patients with SCD. Primary graft failure was fatal in 5 patients with thalassemia. These results suggest that only CB units containing an expected infused cell dose >5 × 10(7)/kg should be considered for transplantation for hemoglobinopathy.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 01/2011; 17(9):1375-82. · 3.15 Impact Factor
  • Biology of Blood and Marrow Transplantation - BIOL BLOOD MARROW TRANSPLANT. 01/2011; 17(2).
  • Biology of Blood and Marrow Transplantation - BIOL BLOOD MARROW TRANSPLANT. 01/2011; 17(2).
  • Bindu Kanathezhath, Mark C Walters
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    ABSTRACT: Hematopoietic cell transplantation is curative therapy for thalassemia major. Although the clinical application of hematopoietic cell transplantation has relied on marrow collected from related and unrelated donors as the primary source of donor hematopoietic cells, umbilical cord blood (UCB) is an alternative source of hematopoietic cells and represents a suitable allogeneic donor pool in the event that a marrow donor is not available. Progress in developing UCB transplantation for thalassemia is reviewed and the most likely areas of future clinical investigation are discussed.
    Hematology/oncology clinics of North America 12/2010; 24(6):1165-77. · 2.05 Impact Factor
  • Mark C Walters, Keith M Sullivan
    New England Journal of Medicine 03/2010; 362(10):955-6; author reply 956. · 51.66 Impact Factor
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    ABSTRACT: Abstract 2245 BackgroundHigh dose chemo/radiotherapy followed by autologous hematopoietic stem cell (HSC) transplantation (HSCT) is indicated in several pediatric malignant disorders such as neuroblastoma and relapsed Hodgkin's disease. Ideally, 2-5 x 106 CD34+ cells/kg should be infused during autologous peripheral blood (PB) HSCT to support timely and durable engraftment and improve transplant outcomes. In patients who have received repetitive cycles of intensive chemotherapy, this target is not always achieved with standard mobilization regimens. Plerixafor, a novel CXCR4 antagonist, when combined with granulocyte colony-stimulating factor (G-CSF), can safely and predictably mobilize adequate numbers of CD34+ HSC to support transplantation in adult patients with myeloma and lymphoma. We report on the safety and efficacy of PB HSC mobilization with plerixafor + G-CSF in pediatric patients with cancer. MethodsThis is a retrospective analysis of all children with various malignant disorders who were enrolled in the US plerixafor compassionate use program (CUP; NCT00291811). Patients who had previously failed HSC mobilization (defined as the inability to collect [≥]2 x106 CD34+ cells/kg or achieve an adequate PB CD34+ cell count, typically [≥]10 CD34+ cells/{micro}l) with growth factor +/- chemotherapy were treated with plerixafor + G-CSF. The goal was to collect [≥]2 x 106 CD34+ cells/kg for autologous HSCT. G-CSF (10{micro}g/kg SC) was administered daily for 5 days. Plerixafor (0.24 mg/kg SC) was given in the evening on Day 4, ~11 hours prior to apheresis. Plerixafor, G-CSF and apheresis were repeated daily until [≥]2 x 106 CD34+ cells/kg had been collected. ResultsA total of 16 patients with non Hodgkin's lymphoma (3), Hodgkin's disease (1), CNS tumors (4), Ewing's sarcoma (4), neuroblastoma (2), osteogenic sarcoma (1) and desmoplastic small cell tumor (1) underwent the procedure. The median age was 14 years and 7 (44%) patients were male. In previous mobilization attempts, 5 patients failed to collect the minimum transplantable cell dose with a median yield of 0.44 x106 (range: 0.17-2.2 x 106) CD34+ cells/kg. Apheresis was never attempted in11 patients due to low PB CD34+ cell levels; median cells/{micro}l was 1.0 (range, 0.01-12) in 9 patients with available data. Initial mobilization regimens included growth factor alone in 6 patients and growth factor + chemotherapy in 9 patients (data unavailable for 1 patient). When re-challenged for mobilization with plerixafor + G-CSF, 14 (88%) patients successfully collected [≥]2 x 106 CD34+ cells/kg; this included all 4 (100%) patients with lymphoma and 10 (83%) patients with solid tumors. The median time to collect the target cell dose was 1.5 days (range 1-5 days). The median CD34+ cell yield from all patients was 3.5 x 106 cells/kg (range 0.96 - 9.80 x 106); patients with lymphoma and solid tumors collected a median of 7.2 (range 3.2 - 7.9) x 106 and 3.3 (range 0.96 -9.8) x 106 CD34+ cells/kg, respectively. Eleven (69%) patients proceeded to transplant including all 4 (100%) patients with lymphoma and 7 (58%) patients with solid tumors. One patient with neuroblastoma received a tandem transplant. The median infused cell dose was 4.18 x 106 CD34+ cells/kg (range 1.7 - 7.6 x 106). The median time to neutrophil and platelet engraftment was 14 and 33 days, respectively. Plerixafor-related adverse events were mostly mild, and observed in 5 (31%) patients. They included administration site reactions (4), vomiting (2), nausea (1) and oral paraesthesia (1). No patient experienced a serious adverse event. ConclusionsTreatment with plerixafor + G-CSF safely and effectively mobilized HSC in the majority of pediatric patients with malignant disorders after failure of standard mobilization with growth factor {+/-} chemotherapy. Successful stem cell mobilization allowed consideration of autologous HSCT when indicated. Mobilization with plerixafor was safe and resulted in prompt engraftment. Many of these patients could not have proceeded to transplant without this ntervention. View this table: TU1500400TU1 Outcomes of plerixafor+ G-CSF remobilization in children DisclosuresOff Label Use: Plerixafor (Mozobil(R)), a hematopoietic stem cell mobilizer, is approved by the US FDA in combination with granulocyte-colony stimulating factor (G-CSF) to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma and multiple myeloma. McCarty: Genzyme, Amgen: Honoraria, Research Funding. Angell: Genzyme Corporation: Employment, Equity Ownership. Huebner: Genzyme Corporation: Employment, Equity Ownership.
    Blood (ASH Annual Meeting Abstracts). 01/2010; 116(21):2245-.
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    ABSTRACT: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only potential cure for most bone marrow (BM) failure syndromes and hemoglobinopathies. Over the past decade, umbilical cord blood (UCB) has been used more frequently as a stem cell source in patients who lack a suitable BM donor. Although graft failure remains a significant problem, UCB transplantation (UCBT) using the optimal conditioning regimen can be a salvage treatment for patients without a suitable BM donor and warrants evaluation in further prospective studies.
    Seminars in Hematology 01/2010; 47(1):37-45. · 3.36 Impact Factor
  • Biology of Blood and Marrow Transplantation - BIOL BLOOD MARROW TRANSPLANT. 01/2010; 16(2).
  • Biology of Blood and Marrow Transplantation - BIOL BLOOD MARROW TRANSPLANT. 01/2010; 16(2).
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    ABSTRACT: We conducted a prospective, multicenter investigation of human-leukocyte antigen (HLA) identical sibling bone marrow transplantation (BMT) in children with severe sickle cell disease (SCD) between 1991 and 2000. To determine if children were protected from complications of SCD after successful BMT, we extended our initial study of BMT for SCD to conduct assessments of the central nervous system (CNS) and of pulmonary function 2 or more years after transplantation. In addition, the impact on gonadal function was studied. After BMT, patients with stroke who had stable engraftment of donor cells experienced no subsequent stroke events after BMT, and brain magnetic resonance imaging (MRI) exams demonstrated stable or improved appearance. However, 2 patients with graft rejection had a second stroke after BMT. After transplantation, most patients also had unchanged or improved pulmonary function. Among the 11 patients who had restrictive lung changes at baseline, 5 were improved and 6 had persistent restrictive disease after BMT. Of the 2 patients who had obstructive changes at baseline, 1 improved and 1 had worsened obstructive disease after BMT. There was, however, significant gonadal toxicity after BMT, particularly among female recipients. In summary, individuals who had stable donor engraftment did not experience sickle-related complications after BMT, and were protected from progressive CNS and pulmonary disease.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 10/2009; 16(2):263-72. · 3.15 Impact Factor
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    M C Walters
    Gene therapy 07/2009; 16(8):943. · 4.75 Impact Factor
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    ABSTRACT: The main barrier to a broader clinical application of umbilical cord blood (UCB) transplantation is its limiting cellular content. Thus, the discovery of hematopoietic progenitor cells in murine placental tissue led us investigate whether the human placenta contains hematopoietic cells, sites of hematopoiesis, and to develop a procedure of processing and storing placental hematopoietic cells for transplantation. Here we show that the human placenta contains large numbers of CD34-expressing hematopoietic cells, with the potential to provide a cellular yield several-fold greater than that of a typical UCB harvest. Cells from fresh or cryopreserved placental tissue generated erythroid and myeloid colonies in culture, and also produced lymphoid cells after transplantation in immunodeficient mice. These results suggest that human placenta could become an important new source of hematopoietic cells for allogeneic transplantation.
    Experimental Biology and Medicine 06/2009; 234(7):813-23. · 2.80 Impact Factor
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    ABSTRACT: We examined transplantation outcomes after a second HLA-matched sibling transplantation for primary (16%) or secondary (84%) graft failure in 166 patients with severe acquired aplastic anemia (AA). Two-thirds of these patients has a performance score < 90. In most cases (88%), the same donor was used for both transplants, for both transplantations, and 84% of the second transplantations used bone marrow grafts. We identified 2 prognostic factors: intertransplantation interval (surrogate for primary graft failure and early secondary graft failure) and performance status. Shorter intertransplantation interval (<or= 3 months) and poor performance score (< 90) at second transplantation were associated with high mortality. In patients with a performance score of 90% to 100%, the 8-year probability of overall survival (OS) after second transplantation <or= 3 and > 3 months from first transplantation was 56% and 76%, respectively. The corresponding probabilities in patients with lower performance scores were 33% and 61%. The predominant cause of failure after second transplantation was nonengraftment (in 72 of 166 patients), most commonly in patients with primary or early secondary graft failure (51 of 72; 71%). Our data indicate that novel approaches, including conditioning regimens with greater immunosuppression, should be explored for these patients.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 05/2009; 15(5):626-31. · 3.15 Impact Factor

Publication Stats

1k Citations
306.07 Total Impact Points

Institutions

  • 2012
    • Indiana Blood and Marrow Transplantation
      Indianapolis, Indiana, United States
  • 2001–2012
    • Children's Hospital & Research Center Oakland
      Oakland, California, United States
  • 2008
    • University of British Columbia - Vancouver
      Vancouver, British Columbia, Canada
  • 2007
    • Childrens Hospital of Pittsburgh
      Pittsburgh, Pennsylvania, United States
  • 2006
    • Children's Hospital Oakland Research Institute
      Oakland, California, United States
  • 2003
    • Johns Hopkins Medicine
      • Department of Pediatrics
      Baltimore, MD, United States
  • 2002
    • University of California, San Francisco
      San Francisco, California, United States
  • 1994–2000
    • Fred Hutchinson Cancer Research Center
      • Division of Clinical Research
      Seattle, Washington, United States