G B McDonald

Fred Hutchinson Cancer Research Center, Seattle, Washington, United States

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Publications (171)1117.8 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The 2005 National Institutes of Health (NIH) Consensus Conference proposed new criteria for diagnosing and scoring the severity of chronic GVHD. The 2014 NIH consensus maintains the framework of the prior consensus with further refinement based on new evidence. Revisions have been made to address areas of controversy or confusion, such as the overlap chronic GVHD subcategory and the distinction between active disease and past tissue damage. Diagnostic criteria for involvement of mouth, eyes, genitalia, and lungs have been revised. Categories of chronic GVHD should be defined in ways that indicate prognosis, guide treatment, and define eligibility for clinical trials. Revisions have been made to focus attention on the causes of organ-specific abnormalities. Attribution of organ-specific abnormalities to chronic GVHD has been addressed. This paradigm shift provides greater specificity, more accurately measures the global burden of disease attributed to GVHD, and will facilitate biomarker association studies. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 12/2014; · 3.15 Impact Factor
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    ABSTRACT: Development of liver disease after hematopoietic cell transplantation is common and the causes diverse. Infection by hepatitis C virus (HCV) can be seen in patients who are chronically infected before transplant or from passage of virus from an infected donor; the normal 10-year course of hepatitis C after transplant is one of waxing and waning of serum aminotransferase enzymes, with little morbidity. In the series of 3 patients reported here, the course of hepatitis C was rapidly fatal, with the onset of jaundice at day 60 to 80 after transplant and liver histology typical of fibrosing cholestatic hepatitis (marked bile ductular proliferation, ballooned hepatocytes, and associated collagenous fibrosis centered around ductules). The bile ductular reaction pattern varied from elongated structures without a recognizable lumen to a pattern of cuboidal cells with a clear lumen. There was significant cholestasis with bile within hepatocytes and canalicular bile plugs. In situ HCV RNA hybridization studies from 1 patient showed a robust infection with high levels of HCV-infected hepatocytes and active viral replication. All 3 patients were on immunosuppressive drugs after transplant, including mycophenolate mofetil (MMF), which irreversibly inhibits inosine monophosphate dehydrogenase, on which T and B lymphocytes are dependent. We speculate that fatal fibrosing cholestatic hepatitis C in these cases was related to the immunosuppressive effects of MMF, as we had not recognized this presentation of HCV infection before the introduction of MMF.
    The American journal of surgical pathology. 12/2014;
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    ABSTRACT: Graft-versus-host disease (GVHD) is associated with kidney injury after hematopoietic cell transplantation (HCT). Because plasma elafin levels correlate with skin GVHD, this study examined urinary elafin as a potential marker of renal inflammation and injury.
    Clinical journal of the American Society of Nephrology : CJASN. 11/2014;
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    ABSTRACT: To determine risk factors for the development of gallstones and the prevalence of related cholecystectomy in children following hematopoietic cell transplantation (HCT).
    Journal of Pediatric Hematology/Oncology 07/2014; · 0.97 Impact Factor
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    ABSTRACT: Cord colitis syndrome after umbilical cord blood transplantation (UCBT) is late-onset diarrhea, absence of infection or GVHD, chronic active colitis and granulomatous inflammation, responding to antibiotics. We tested the hypothesis that Seattle recipients of UCBT had late-occurring colitis distinct from GVHD and colitis in other allograft recipients. We conducted a blinded histologic review of 153 colon biopsies obtained between days 70-365 from 45 UCBT recipients and 45 matched allograft controls. Diarrhea was the primary indication for biopsy in 10 UCBT and 11 controls. No histological differences were seen between UCBT patients and controls with diarrhea or between the entire cohort of UCBT patients and their controls. Distorted mucosal architecture and apoptotic crypt cells typical of GVHD were common in both groups; Paneth cell metaplasia and granulomas were rare findings. Chronic active colitis was present in 58% of UCBT recipients and in 62% of controls. No UCBT recipient with diarrhea was treated with antibiotics and all responded to systemic corticosteroids. Allograft recipients with colitis after day 70 had acute GVHD as the explanation, independent of the source of donor cells. We could not identify a histologically distinct cord colitis syndrome in either UCBT or non-cord blood allograft recipients.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 04/2014; · 3.15 Impact Factor
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    ABSTRACT: We compared urinary levels of cytokines in patients with and without albuminuria, proteinuria and kidney disease (glomerular filtration rate<60 mL/min per 1.73 m(2)) after HCT. Plasma and urine were collected at baseline and weekly through day 100 and monthly through year 1, for measurement of IL-6, gp130, sIL6r, IL-10, IL15, MCP-1 and urine albumin-to-creatinine ratios (ACRs). Cox-proportional hazards modeling examined associations between urinary cytokine levels and development of these renal end points. The association of ACR with the hazard of overall mortality was assessed using Cox regression. Increasing urinary IL-6 and IL-15 were associated with an increased risk of developing proteinuria. Urinary MCP-1 during the first 100 days post HCT was associated with kidney disease at 1 year. The degree of albuminuria at any time point in the first 100 days post transplant was related to the subsequent risk of death (for ACR 30-299, hazard ratio (HR)=1.91; 95% confidence interval (CI): 1.27-2.87; for ACR >300, HR=2.82; 95% CI: 1.60-4.98). After HCT, elevated urinary levels of pro-inflammatory cytokines are associated with development of albuminuria and proteinuria, suggesting early intra-renal inflammation as an important pathogenetic mechanism. Albuminuria and proteinuria within the first 100 days post HCT are associated with decreased overall survival.Bone Marrow Transplantation advance online publication, 9 December 2013; doi:10.1038/bmt.2013.197.
    Bone marrow transplantation 12/2013; · 3.00 Impact Factor
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    ABSTRACT: The Tim-3 receptor has been implicated as a negative regulator of adaptive immune responses. We have utilized a proteomic strategy to identify novel proteins associated with graft vs host disease (GVHD) following allogeneic hematopoietic cell transplantation (HCT). Mass spectrometry analysis of plasmas from subjects with mid-gut and upper-gut GVHD compared to those without GVHD identified increased levels of a protein identified with high confidence as Tim-3. A followup validation study using an immunoassay to measure Tim-3 levels in individual plasma samples from 127 patients demonstrated significantly higher plasma Tim-3 concentrations in patients with the more severe mid-gut, compared to those with upper gut GVHD (p=0.005), patients without GVHD (p=0.002), and normal controls (p<0.0001). Surface expression of Tim-3 was increased on CD8(+) T cells from patients with grade II-IV acute GVHD (p=0.01). Mass spectrometry based profiling of plasmas from multiple subjects diagnosed with common diseases provided evidence for restricted release of soluble Tim-3 in the context of GVHD. These findings have mechanistic implications for the development of novel strategies for targeting the Tim-3 immune regulatory pathway as an approach to improving control of GVHD.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 06/2013; · 3.15 Impact Factor
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    ABSTRACT: Targeted busulfan/cyclophosphamide ((T)BU/CY) for allogeneic hematopoietic cell transplantation (HCT) carries a high risk of sinusoidal obstruction syndrome (SOS) in patients transplanted for myelofibrosis. We tested the hypothesis that reversing the sequence of administration (from (T)BU/CY to CY/(T)BU) will reduce SOS and day +100 non-relapse mortality (NRM). We enrolled 51 patients with myelofibrosis (n=20), acute myeloid leukemia (AML, n=20), or myelodysplastic syndrome (MDS, n=11) in a prospective trial of CY/(T)BU conditioning for HCT. Cyclophosphamide 60 mg/kg/day IV for two days was followed by daily IV BU for four days, targeted to a concentration at steady state (Css) of 800-900 ng/mL. CY/(T)BU-conditioned patients had higher exposure to CY (p<0.0001) and lower exposure to 4-hydroxyCY (p<0.0001) compared to (T)BU/CY-conditioned patients. Clinical outcomes were compared with controls (n=271) conditioned with (T)BU/CY for the same indications. In patients with myelofibrosis, CY/(T)BU conditioning was associated with a significantly reduced incidence of SOS (0% vs. 30% after (T)BU/CY, p=0.006), while SOS incidence was low in both cohorts with AML/MDS. Day +100 mortality was significantly lower in the CY/(T)BU cohort (2% vs. 13%, p=0.01). CY/(T)BU conditioning markedly impacted CY pharmacokinetics and was associated with significantly lower incidences of SOS and day +100 mortality, suggesting that CY/(T)BU is superior to (T)BU/CY as conditioning for patients with myelofibrosis.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 04/2013; · 3.15 Impact Factor
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    ABSTRACT: The purpose of this prospective observational study was to determine the incidence of hepatic sinusoidal obstruction syndrome (SOS), following gemtuzumab ozogamicin (GO) therapy in routine clinical practice. Patients receiving GO for acute myeloid leukemia (AML) were eligible. Assessments were requested to be performed weekly for 6 weeks after the start of GO therapy or 4 weeks after the last dose (whichever was later), and after 6 months. The primary outcome variable was the incidence of SOS as judged by a panel of independent experts. A total of 512 patients were enrolled at 54 US centers and 482 were evaluable. The incidence of SOS in this study population was 9.1 % (44/482; 95 % confidence interval 6.9-12.0 %). Of the 44 patients classified as having SOS, 8 were mild, 17 moderate, and 19 severe; 33 died within 6 months (20 of disease progression and 13 of SOS and multiorgan failure). Most (68 %) patients in the study died within 6 months; most of these deaths (73 %) were due to progression of AML. Serious adverse events occurred in 85 % of patients, most (81 %) due to AML, febrile neutropenia, pyrexia, and sepsis. GO administered in routine clinical practice carries an overall 9.1 % risk of SOS and a 2.7 % risk of death from SOS and multiorgan failure. No risk factors were identified for the development of SOS.
    International journal of hematology 03/2013; · 1.17 Impact Factor
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    ABSTRACT: Existing standards for screening and management of late effects occurring in children who have undergone hematopoietic cell transplantation (HCT) include recommendations from pediatric cancer networks and consensus guidelines from adult-oriented transplantation societies applicable to all HCT recipients. Although these approaches have significant merit, they are not pediatric HCT-focused, and they do not address post-HCT challenges faced by children with complex nonmalignant disorders. In this article we discuss the strengths and weaknesses of current published recommendations and conclude that pediatric-specific guidelines for post-HCT screening and management would be beneficial to the long-term health of these patients and would promote late effects research in this field. Our panel of late effects experts also provides recommendations for follow-up and therapy of selected post-HCT organ and endocrine complications in pediatric patients.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 03/2012; 18(3):334-47. · 3.15 Impact Factor
  • Aiko Kida, George B McDonald
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    ABSTRACT: Gastrointestinal and hepatobiliary problems in the second year after allogeneic hematopoietic cell transplant (HCT) are usually a continuation of symptoms of protracted acute graft-versus-host disease (GVHD), chronic GVHD, medication side effects, and infection related to immune suppression. As time passes, as tolerance develops, and as immunity improves, the frequency and severity of these problems wane, but new problems involving the gut and liver may arise, sometimes insidiously and sometimes decades after the transplant. Examples are esophageal strictures related to chronic GVHD, gallstones, cirrhosis caused by chronic hepatitis C, secondary malignancy, and rare cases of pancreatic atrophy. One very common complication of transplantation, iron overload, is often associated with substantial iron accumulation in the liver; however, the most troublesome complications are not hepatic but cardiac and endocrine-related.
    Seminars in Hematology 01/2012; 49(1):43-58. · 3.36 Impact Factor
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    ABSTRACT: Long-term complications after hematopoietic cell transplantation (HCT) have been studied in detail. Although virtually every organ system can be adversely affected after HCT, the underlying pathophysiology of these late effects remain incompletely understood. This article describes our current understanding of the pathophysiology of late effects involving the gastrointestinal, renal, cardiac, and pulmonary systems, and discusses post-HCT metabolic syndrome studies. Underlying diseases, pretransplantation exposures, transplantation conditioning regimens, graft-versus-host disease, and other treatments contribute to these problems. Because organ systems are interdependent, long-term complications with similar pathophysiologic mechanisms often involve multiple organ systems. Current data suggest that post-HCT organ complications result from cellular damage that leads to a cascade of complex events. The interplay between inflammatory processes and dysregulated cellular repair likely contributes to end-organ fibrosis and dysfunction. Although many long-term problems cannot be prevented, appropriate monitoring can enable detection and organ-preserving medical management at earlier stages. Current management strategies are aimed at minimizing symptoms and optimizing function. There remain significant gaps in our knowledge of the pathophysiology of therapy-related organ toxicities disease after HCT. These gaps can be addressed by closely examining disease biology and identifying those patients at greatest risk for adverse outcomes. In addition, strategies are needed for targeted disease prevention and health promotion efforts for individuals deemed at high risk because of their genetic makeup or specific exposure profile.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 09/2011; 17(11):1573-84. · 3.15 Impact Factor
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    ABSTRACT: Biomarkers capable of predicting the onset and severity of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation (HCT) would enable preemptive and risk-stratified therapy. Severe aGVHD leads to gastrointestinal protein loss, resulting in hypoalbuminemia. We hypothesized that decreases in serum albumin at onset of aGVHD would predict the risk of progression to severe aGVHD. We identified 401 patients who developed aGVHD grades II-IV after reduced-intensity allogeneic HCT and reviewed all available serum albumin values from 30 days before HCT to 45 days after initiation of treatment for aGVHD. A ≥0.5 g/dL decrease in serum albumin concentration from pretransplantation baseline to the onset of treatment for aGVHD predicted the subsequent development of grade III/IV aGVHD (versus grade II aGVHD) with a sensitivity of 69% and a specificity of 73%. Overall mortality at 6 months after initiation of aGVHD treatment was 36% versus 17% for patients with and without ≥0.5 g/dL decreases in serum albumin, respectively (P = .0009). We conclude that change in serum albumin concentration from baseline to initiation of aGVHD treatment is an inexpensive, readily available, and predictive biomarker of GVHD severity and mortality after reduced-intensity allogeneic HCT.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 07/2011; 17(11):1594-601. · 3.15 Impact Factor
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    ABSTRACT: Daily intravenous (i.v.) busulfan is increasingly being used in hematopoietic cell transplantation (HCT) conditioning regimens. Intravenous busulfan doses administered at the traditional frequency of every 6 hours can be targeted ((T)Bu) to a patient-specific concentration at steady state (C(ss)) using therapeutic drug monitoring (TDM). In this report, we describe our experiences with TDM of daily i.v. busulfan in an adult population, with the specific aims of (1) evaluating covariates associated with busulfan clearance, and (2) assessing the feasibility of TDM for outpatient administration of daily (T)Bu with pharmacokinetic sampling over 6 hours. A retrospective pharmacokinetic analysis was conducted in 87 adults receiving daily (T)Bu as part of cyclophosphamide followed by (T)BU (CY/(T)BU), fludarabine monophosphate (fludarabine) followed by (T)BU, or (T)BU concurrent with fludarabine conditioning. The desired C(ss) was achieved in 85% of patients receiving daily i.v. busulfan. Busulfan clearance was not associated with sex or age, but was associated with the day of dosing and conditioning regimen (P = .0016). In patients receiving CY/(T)BU, no differences in clearance were found between dosing days (P > .36); however, clearance decreased significantly in patients receiving fludarabine-based regimens (P = .0016). Busulfan clearance and C(ss) estimates from pharmacokinetic sampling over 8, 11, or 24 hours were comparable (P > .4). However, pharmacokinetic modeling of individual patient concentration-time data over 6 hours could not reliably estimate busulfan clearance or C(ss).
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 07/2011; 18(2):265-72. · 3.15 Impact Factor
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    ABSTRACT: Previous studies suggest regulatory T cells (Tregs) inhibit graft-versus-host disease (GVHD) in mouse and human hematopoietic cell transplant (HCT) recipients. As the gastrointestinal tract represents one of the most common and severe sites of GVHD-related tissue damage, we sought to determine whether a deficit in circulating or gastric mucosal Treg numbers correlates with the clinical onset of gastric GVHD. We used the marker FOXP3 to quantify Tregs in blood and in gastric antral biopsies in a cohort of 60 allogeneic HCT recipients undergoing endoscopy at a single center to evaluate symptoms suspicious for gastrointestinal GVHD. We show for the first time in the gastric mucosa and, contrary to existing reports, in the blood, that the percent of T cells expressing FOXP3 is at least as high in the presence as in the absence of GVHD involving the upper gut. There was no correlation of Treg frequency with the histologic or clinical severity of gastrointestinal GVHD. We conclude that Treg depletion is not a central feature in the pathogenesis of gastric GVHD in humans.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 04/2011; 17(4):486-96. · 3.15 Impact Factor
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    ABSTRACT: When assessing liver iron content using relaxometry, an average relaxation rate (R1, R2 or R2*) is usually determined from a region of interest or the entire liver. This is commonly performed by fitting the signal decay in individual voxels to an appropriate relaxation function. The voxel-level parameters resulting from the fits are combined to determine the average relaxation rate, and an empirically derived calibration curve is used to convert this single value to iron content. The goal of this study was to compare the precision and accuracy of this voxel-wise fitting to an alternative method that relies on first averaging the signals from all voxels within the region of interest and then determining the relaxation rate from a single fit. Systematic differences were observed when both methods were applied to clinical images. Mathematical simulations were employed to determine which method provided more robust estimates of the true relaxation rate. The mathematical simulations were then expanded to include a range of conditions expected in typical relaxometry images. The results show that voxel-wise fitting skews the relaxation rate estimates and increases variance, particularly when the true relaxation rate is moderate to fast, as it would be in liver with high iron content. The potential impact of these results on clinical decisions is discussed.
    Magnetic Resonance Imaging 02/2011; 29(4):497-506. · 2.06 Impact Factor
  • George B. McDonald
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    ABSTRACT: Toxic injury to hepatic sinusoids may be caused by specific drugs and irradiation that are used to prepare patients for transplantation. The clinical disease resulting from sinusoidal injury is sinusoidal obstruction syndrome (SOS), which presents within 1–3 weeks of the completion of conditioning therapy. The frequency of SOS as a complication of transplant has declined markedly in recent years, following the recognition that only certain conditioning regimens (notably those containing cyclophosphamide or total body irradiation) caused SOS and that patients with underlying necroinflammatory and fibrotic liver diseases were at highest risk for fatal SOS. Avoiding the toxins that cause sinusoidal injury prevents SOS, a more promising approach than treatment of patients with severe liver dysfunction and multiorgan failure. Other hepatic vascular pathology can be seen after transplant, including reversed portal venous flow, portal venous thrombosis, and rarely occlusion of hepatic veins. Nodular regenerative hyperplasia and focal nodular hyperplasia can be seen in long-term transplant survivors, usually as incidental findings. KeywordsToxic liver injury-Sinusoidal obstruction syndrome-Venocclusive disease-Nodular regenerative hyperplasia-Focal nodular hyperplasia
    12/2010: pages 149-163;
  • Richard A Nash, George B McDonald
    Blood 12/2010; 116(26):5790-1. · 9.78 Impact Factor
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    ABSTRACT: Over the past decade, advances have been made in the care of patients undergoing transplantation. We conducted a study to determine whether these advances have improved the outcomes of transplantation. We analyzed overall mortality, mortality not preceded by relapse, recurrent malignant conditions, and the frequency and severity of major complications of transplantation, including graft-versus-host disease (GVHD) and hepatic, renal, pulmonary, and infectious complications, among 1418 patients who received their first allogeneic transplants at our center in Seattle in the period from 1993 through 1997 and among 1148 patients who received their first allogeneic transplants in the period from 2003 through 2007. Components of the Pretransplant Assessment of Mortality (PAM) score were used in regression models to adjust for the severity of illness at the time of transplantation. In the 2003-2007 period, as compared with the 1993-1997 period, we observed significant decreases in mortality not preceded by relapse, both at day 200 (by 60%) and overall (by 52%), the rate of relapse or progression of a malignant condition (by 21%), and overall mortality (by 41%), after adjustment for components of the PAM score. The results were similar when the analyses were limited to patients who received myeloablative conditioning therapy. We also found significant decreases in the risk of severe GVHD; disease caused by viral, bacterial, and fungal infections; and damage to the liver, kidneys, and lungs. We found a substantial reduction in the hazard of death related to allogeneic hematopoietic-cell transplantation, as well as increased long-term survival, over the past decade. Improved outcomes appear to be related to reductions in organ damage, infection, and severe acute GVHD. (Funded by the National Institutes of Health.).
    New England Journal of Medicine 11/2010; 363(22):2091-101. · 54.42 Impact Factor
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    George B McDonald
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    ABSTRACT: Liver problems caused by infection, cholestasis and sinusoidal liver injury in the months following HCT have become less frequent because of preventive and pre-emptive strategies. When patients develop jaundice after transplant, the time to search for treatable causes is early in the course of jaundice, as the risk of mortality rises steeply with small increments of serum bilirubin above normal. Chronic hepatitis C, persistent GVHD, cirrhosis and hepatocellular carcinoma are significant liver problems in the longest-lived survivors of HCT.
    Hepatology 04/2010; 51(4):1450-60. · 12.00 Impact Factor

Publication Stats

9k Citations
1,117.80 Total Impact Points

Institutions

  • 1984–2014
    • Fred Hutchinson Cancer Research Center
      • • Division of Clinical Research
      • • Division of Public Health Sciences
      Seattle, Washington, United States
  • 1992–2013
    • University of Washington Seattle
      • • Department of Pediatrics
      • • Department of Medicine
      • • Division of Cardiology
      • • Division of General Internal Medicine
      • • Department of Pharmaceutics
      • • Division of Gastroenterology
      • • Department of Radiology
      Seattle, Washington, United States
  • 2012
    • University of Utah
      • Primary Children's Medical Center
      Salt Lake City, UT, United States
  • 2005
    • Harvard Medical School
      • Department of Medicine
      Boston, MA, United States
  • 2004
    • University of Florida
      Gainesville, Florida, United States
  • 2002
    • University of Southern California
      • Division of Gastrointestinal and Liver Diseases
      Los Angeles, CA, United States
  • 2001
    • Emory University
      Atlanta, Georgia, United States
  • 1998
    • Swedish Medical Center
      Englewood, Colorado, United States