C H Pui

The University of Tennessee Health Science Center, Memphis, Tennessee, United States

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Publications (357)3848.9 Total impact

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    ABSTRACT: Abstract BACKGROUND: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is characterized by a gene-expression profile similar to that of BCR-ABL1-positive ALL, alterations of lymphoid transcription factor genes, and a poor outcome. The frequency and spectrum of genetic alterations in Ph-like ALL and its responsiveness to tyrosine kinase inhibition are undefined, especially in adolescents and adults. METHODS: We performed genomic profiling of 1725 patients with precursor B-cell ALL and detailed genomic analysis of 154 patients with Ph-like ALL. We examined the functional effects of fusion proteins and the efficacy of tyrosine kinase inhibitors in mouse pre-B cells and xenografts of human Ph-like ALL. RESULTS: Ph-like ALL increased in frequency from 10% among children with standard-risk ALL to 27% among young adults with ALL and was associated with a poor outcome. Kinase-activating alterations were identified in 91% of patients with Ph-like ALL; rearrangements involving ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B, TSLP, or TYK2 and sequence mutations involving FLT3, IL7R, or SH2B3 were most common. Expression of ABL1, ABL2, CSF1R, JAK2, and PDGFRB fusions resulted in cytokine-independent proliferation and activation of phosphorylated STAT5. Cell lines and human leukemic cells expressing ABL1, ABL2, CSF1R, and PDGFRB fusions were sensitive in vitro to dasatinib, EPOR and JAK2 rearrangements were sensitive to ruxolitinib, and the ETV6-NTRK3 fusion was sensitive to crizotinib. CONCLUSIONS: Ph-like ALL was found to be characterized by a range of genomic alterations that activate a limited number of signaling pathways, all of which may be amenable to inhibition with approved tyrosine kinase inhibitors. Trials identifying Ph-like ALL are needed to assess whether adding tyrosine kinase inhibitors to current therapy will improve the survival of patients with this type of leukemia. (Funded by the American Lebanese Syrian Associated Charities and others.).
    New England Journal of Medicine 09/2014; 371(11):1005-1015. · 54.42 Impact Factor
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    ABSTRACT: Minimal residual disease (MRD) is a strong prognostic factor in children and adolescents with acute myeloid leukaemia (AML) but nearly one-quarter of patients who achieve MRD-negative status still relapse. The adverse prognostic factors among MRD-negative patients remain unknown. We analysed the AML02 study cohort to identify demographic and genetic prognostic factors. Among the presenting features, certain 11q23 abnormalities, such as t(6;11) and t(10;11), acute megakaryoblastic leukaemia without the t(1;22), and age ≥10 years were associated with inferior outcome in patients who had MRD-negative status after either remission induction I or II. By contrast, those with rearrangement of CBF genes had superior outcome. Our study identifies patient populations for whom close post-remission MRD monitoring to detect and treat emerging relapse and adjustment in treatment intensity might be indicated.
    British Journal of Haematology 08/2014; · 4.94 Impact Factor
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    ABSTRACT: With improved contemporary therapy, we re-assess long-term outcome in patients completing treatment for childhood acute lymphoblastic leukemia to determine when cure can be declared with a high degree of confidence. In 6 successive clinical trials between 1984 and 2007, 1291(84.5%) patients completed all therapy in continuous complete remission. The post-therapy cumulative risk of relapse or development of a second neoplasm and the event-free survival rate and overall survival were analyzed according to the presenting features and the three treatment periods defined by relative outcome. Over the three treatment periods, there has been progressive increase in the rate of event-free survival (65.2% vs 74.8% vs 85.1% [P<0.001]) and overall survival (76.5% vs 81.1% vs 91.7% [P<0.001]) at 10 years. The most important predictor of outcome after completion of therapy was the type of treatment. In the most recent treatment period, which omitted the use of prophylactic cranial irradiation, the post-treatment cumulative risk of relapse was 6.4%, death in remission 1.5%, and development of a second neoplasm 2.3% at 10 years, with all relapses except one occurring within 4 years off therapy. None of the 106 patients with the t(9;22)/BCR-ABL1, t(1;19)/TCF3-PBX1 or t(4;11)/MLL-AFF1 had relapsed after 2 years from completion of therapy. These findings demonstrate that with contemporary effective therapy that excludes cranial irradiation, approximately 6% of children with acute lymphoblastic leukemia may relapse after completion of treatment, and those who remain in remission at 4 years post-treatment may be considered cured (i.e., less than 1% chance of relapse).Leukemia accepted article preview online, 30 April 2014; doi:10.1038/leu.2014.142.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 04/2014; · 10.16 Impact Factor
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    ABSTRACT: Asparaginase is an essential component of pediatric acute lymphoblastic leukemia (ALL) therapy. However, asparaginase-induced hypersensitivity reactions can compromise its efficacy either by directly influencing the pharmacokinetics of asparaginase or by leading to a discontinuation of asparaginase treatment. Here, we report successful challenges using native Escherichia coli asparaginase after previous hypersensitivity reactions to both PEGylated E. coli asparaginase and Erwinia asparaginase. The two patients included in this case report were diagnosed with B-precursor ALL at St. Jude Children's Research Hospital and were treated with a common regimen. Both patients developed hypersensitivity reactions to PEGylated E. coli asparaginase and Erwinia asparaginase early in treatment, and they were challenged with native E. coli asparaginase. Serum samples were collected for estimating the pharmacokinetic parameters of each patient during native E. coli asparaginase therapy. Challenges with native E. coli asparaginase were successful, and asparaginase serum concentrations above therapeutic levels were attained in both patients. These two cases suggest that some patients can be given native E. coli asparaginase after hypersensitivity reactions to PEGylated asparaginase and achieve therapeutic concentrations of the drug in serum.
    Cancer Chemotherapy and Pharmacology 04/2014; · 2.80 Impact Factor
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    ABSTRACT: BACKGROUNDA better understanding of when cure can be declared in childhood acute myeloid leukemia (AML) would reduce anxiety and improve quality of life of AML survivors. The authors determined the likelihood that patients with AML would maintain long-term remission after the completion of therapy.METHODS The cumulative risk of relapse, the time to relapse, event-free survival, and overall survival were analyzed for 604 patients with AML who were enrolled in 7 successive clinical trials divided into 3 treatment eras (1976-1991, 1991-1997, and 2002-2008).RESULTSThe median time to relapse did not change over time (0.93 years vs 0.76 years vs 0.8 years, respectively, for each consecutive era; P = .22), but the risk of relapse decreased significantly (5-year cumulative incidence of relapse: 52.6% ± 3.1% vs 31.5% ± 3.9% vs 22% ± 3%, respectively, for each consecutive era; P < .001). Among patients who were in remission 4 years from diagnosis, the probabilities of relapse were 1.7%, 2.9%, and 0.9%, respectively, for each consecutive era. In the most recent era, all but 1 of 44 relapses occurred within 4 years of diagnosis.CONCLUSIONS Children with AML who receive treatment with contemporary therapy and remain in remission 4 years from diagnosis probably are cured. Although late relapses and late deaths from other causes are rare, long-term follow-up of survivors is necessary for the timely management of late adverse effects. Cancer 2014. © 2014 American Cancer Society.
    Cancer 04/2014; · 5.20 Impact Factor
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    ABSTRACT: BACKGROUND Intensive chemotherapy for pediatric acute myeloid leukemia incurs the risk of infectious complications, but the benefits of antibiotic prophylaxis remain unclear.METHODS In the current study, among 103 children treated on the AML02 protocol between October 2002 and October 2008 at St. Jude Children's Research Hospital, the authors retrospectively assessed the effect of antibiotic prophylaxis on the frequency of febrile neutropenia, clinically or microbiologically confirmed infections (including bacteremia), and antibiotic resistance, as well as on the results of nasal and rectal surveillance cultures. Initially, patients received no prophylaxis or oral cephalosporin (group A). The protocol was then amended to administer intravenous cefepime alone or intravenous vancomycin plus either oral cephalosporin, oral ciprofloxacin, or intravenous cefepime (group B).RESULTSThere were 334 infectious episodes. Patients in group A had a significantly greater frequency of documented infections and bacteremia (both P < .0001) (including gram-positive and gram-negative bacteremia; P = .0003 and .001, respectively) compared with patients in group B, especially viridans streptococcal bacteremia (P = .001). The incidence of febrile neutropenia without documented infection was not found to be different between the 2 groups. Five cases of bacteremia with vancomycin-resistant enterococci (VRE) occurred in group B (vs none in group A), without related mortality. Two of these cases were preceded by positive VRE rectal surveillance cultures.CONCLUSIONS Outpatient intravenous antibiotic prophylaxis is feasible in children with acute myeloid leukemia and reduces the frequency of documented infection but not of febrile neutropenia. Despite the emergence of VRE bacteremia, the benefits favor antibiotic prophylaxis. Creative approaches to shorten the duration of prophylaxis and thereby minimize resistance should be explored. Cancer 2014. © 2014 American Cancer Society.
    Cancer 03/2014; · 5.20 Impact Factor
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    ABSTRACT: Background We investigated the effects of demographic, lifestyle (self-reported smoking status and physical activity levels), cancer-related treatment factors (radiation and chemotherapy), and diet (calcium and vitamin D intake) on bone turnover and the relationship of bone turnover to lumbar spine bone mineral density (BMD) Z-scores (LS-BMD Z-scores) determined by quantitative computed tomography (QCT) in 418 ≥5-year survivors of childhood acute lymphoblastic leukemia (ALL).ProcedureBone turnover was assessed by biomarkers including serum bone-specific alkaline phosphatase (BALP), osteocalcin (OC), and urinary N-telopeptide of type I collagen indexed to creatinine (NTX/Cr). The 215 males ranged in age from 9 to 36 years (median age 17 years).ResultsAge and tanner score were inversely associated with all biomarkers (BALP, OC, NTX/Cr) (P < 0.001). Males had higher BALP and OC than females (P < 0.001). Body mass index (BMI) was inversely associated with OC and NTX/Cr (P < 0.001). There was no significant association of biomarkers with lifestyle related factors, ALL treatment-related factors, dietary calcium, vitamin D, or LS-BMD Z-score.Conclusions In this population of long-term survivors of ALL, bone turnover was significantly associated with age, gender, tanner stage, and BMI. ALL-related treatments did not influence bone turnover and bone turnover was not predictive of volumetric LS-BMD Z-score. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 03/2014; · 2.35 Impact Factor
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    ABSTRACT: We sought to improve lumbar spine bone mineral density (LS-BMD) in long-term survivors of childhood acute lymphoblastic leukemia (ALL) using calcium and cholecalciferol supplementation. This double-blind, placebo-controlled trial randomized 275 participants (median age, 17 [9-36.1] years) with age- and gender-specific LS-BMD Z-scores <0 to receive nutritional counseling with supplementation of 1,000 mg/day calcium and 800 International Unit cholecalciferol or placebo for 2 years. The primary outcome was change in LS-BMD assessed by quantitative computerized tomography (QCT) at 24 months. Linear regression models were employed to identify the baseline risk factors for low LS-BMD and to compare LS-BMD outcomes. Pre-randomization LS-BMD below the mean was associated with male gender (P = 0.0024), White race (P = 0.0003), lower body mass index (P < 0.0001), and cumulative glucocorticoid doses of ≥5,000 mg (P = 0.0012). One hundred eighty-eight (68%) participants completed the study; 77% adhered to the intervention. Mean LS-BMD change did not differ between survivors randomized to supplements (0.33 ± 0.57) or placebo (0.28 ± 0.56). Participants aged 9-13 years and those 22-35 years had the greatest mean increases in LS-BMD (0.50 ± 0.66 and 0.37 ± 0.23, respectively). Vitamin D insufficiency (serum 25[OH]D <30 ng/ml) found in 296 (75%), was not associated with LS-BMD outcomes (P = 0.78). Cholecalciferol and calcium supplementation provides no added benefit to nutritional counseling for improving LS-BMD among adolescent and young adult survivors of ALL (93% of whom had LS-BMD Z-scores above the mean at study entry). Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 01/2014; · 2.35 Impact Factor
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    ABSTRACT: Reliable prognostic factors have not been established for advanced-stage pediatric lymphoblastic lymphoma (LL). We analyzed treatment outcomes and potential risk factors in children and adolescents with advanced-stage LL treated over a 40-year period. From 1962 through 2002, 146 patients (99 boys and 47 girls) with stage III (n = 111) or stage IV (n = 35) LL were treated at St Jude Children's Research Hospital. The five treatment eras were 1962-1975 (no protocol), 1975-1979 (NHL-75), 1979-1984 (Total 10 High), 1985-1992 (Pediatric Oncology Group protocol), and 1992-2002 (NHL13). Age at diagnosis was <10 years in 65 patients and ≥10 years in 81. Outcomes improved markedly over successive treatment eras. NHL13 produced the highest 5-year event-free survival (EFS) estimate (82.9% ± 6.1% [SE]) compared with only 20.0% ± 8.0% during the earliest era. Treatment era (P < 0.0001) and age at diagnosis (<10 years versus ≥10 years, P = 0.0153) were independent prognostic factors, whereas disease stage, lactate dehydrogenase level, and presence of a pleural effusion were not. Treatment era and age were the most important prognostic factors for children with advanced-stage LL. We suggest that a better assessment of early treatment response may help to identify patients with drug-resistant disease who require more intensive therapy.
    Annals of Oncology 06/2013; · 7.38 Impact Factor
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    JNCI Journal of the National Cancer Institute 03/2013; · 14.34 Impact Factor
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    ABSTRACT: Background Treatment of acute lymphoblastic leukemia (ALL) has included the use of prophylactic cranial irradiation in up to 20% of children with high-risk disease despite known cognitive risks of this treatment modality. Methods Patients enrolled on the St Jude ALL Total Therapy Study XV, which omitted prophylactic cranial irradiation in all patients, were assessed 120 weeks after completion of consolidation therapy (n = 243) using a comprehensive cognitive battery. χ(2) analysis was used to compare the percentage of below-average performers among the entire ALL patient group to the expected rate based on the normative sample. Univariate logistic regression was used to estimate the effect of intensity of chemotherapy (treatment arm), age at diagnosis, and sex on the probability of below-average performance. All statistical tests were two-sided. Results Overall, the ALL group had a statistically significantly higher risk for below-average performance on a measure of sustained attention (67.31% more than 1 SD below the normative mean for omission errors, P < .001) but not on measures of intellectual functioning, academic skills, or memory. Patients given higher intensity chemotherapy were at greater risk for below-average performance compared with those given lower intensity therapy on measures of processing speed (27.14% vs 6.25%, P = .009) and academic abilities (Math Reasoning: 18.60% vs 3.90%, P = .008; Word Reading: 20.00% vs 2.60%, P = .007; Spelling: 27.91% vs 3.90%, P = .001) and had higher parent-reported hyperactivity (23.00% vs 9.84%, P = .018) and learning problems (35.00% vs 16.39%, P = .005). Neither age at diagnosis nor sex was associated with risk for below-average cognitive performance. Conclusions Omitting cranial irradiation may help preserve global cognitive abilities, but treatment with chemotherapy alone is not without risks. Caregiver education and development of interventions should address both early attention deficits and cognitive late effects.
    CancerSpectrum Knowledge Environment 08/2012; 104(18):1386-95. · 14.07 Impact Factor
  • Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 08/2012; · 10.16 Impact Factor
  • Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 02/2010; 24(2):253-4. · 10.16 Impact Factor
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    ABSTRACT: We analyzed the long-term outcome of 1011 patients treated in five successive clinical trials (Total Therapy Studies 11, 12, 13A, 13B, and 14) between 1984 and 1999. The event-free survival improved significantly (P=0.003) from the first two trials conducted in the 1980s to the three more recent trials conducted in the 1990s. Approximately 75% of patients treated in the 1980s and 80% in the 1990s were cured. Early intensive triple intrathecal therapy, together with more effective systemic therapy, including consolidation and reinduction treatment (Studies 13A and 13B) as well as dexamethasone (Study 13B), resulted in a very low rate of isolated central nervous system (CNS) relapse rate (<2%), despite the reduced use of cranial irradiation. Factors consistently associated with treatment outcome were age, leukocyte count, immunophenotype, DNA index, and minimal residual disease level after remission induction treatment. Owing to concerns about therapy-related secondary myeloid leukemia and brain tumors, in our current trials we reserve the use of etoposide for patients with refractory or relapsed leukemia undergoing hematopoietic stem cell transplantation, and cranial irradiation for those with CNS relapse. The next main challenge is to further increase cure rates while improving quality of life for all patients.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 12/2009; 24(2):371-82. · 10.16 Impact Factor
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    ABSTRACT: An international childhood acute lymphoblastic leukemia (ALL)working group was formed during the 27th annual meeting of the International Society of Pediatric Oncology in 1995. Since then, 10 workshops have been held to address many issues that help advance treatment outcome of childhood ALL but require international collaboration (Table 1). The group was fondly named after 'Ponte di Legno,' a place in Lombardy, Italy, because the first major workshop was held there. In celebration of the 10th anniversary of the first major meeting, the group returned to Ponte di Legno on 6 and 7 May 2009 for its 11th meeting (Figure 1). During the meeting, Professor Giuseppe Masera was honored for his vision and contributions to further develop the International-BFM study group and to co-found the Ponte di Legno working group. The meeting began with greetings by Professor Andrea Biondi. This report summarizes the data presented and the discussion in the meeting.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 11/2009; 23(12):2318-24. · 10.16 Impact Factor
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    ABSTRACT: Asparaginase (ASP) is used routinely in frontline clinical trials for the treatment of childhood acute lymphoblastic leukemia (ALL). The goals of this study were to assess the pharmacokinetics and pharmacodynamics of ASP and to mathematically model the dynamics between ASP and asparagine (ASN) in relapsed ALL. Forty children were randomized to receive either native or polyethylene glycolated (PEG) Escherichia coli ASP during reinduction therapy. Serial plasma ASP and ASN, cerebrospinal fluid (CSF) ASN, and serum anti-ASP antibody samples were collected. The ASP clearance was higher (P = 0.001) for native vs. PEG ASP. Patients with antibodies to PEG ASP had faster PEG ASP clearance (P = 0.004) than did antibody-negative patients. Patients who were positive for antibodies had higher CSF ASN concentrations than did those who were negative (P = 0.04). The modeling suggests that by modifying dosages, comparable ASN depletion is achievable with both preparations. At relapse, there were significant pharmacokinetic and pharmacodynamic differences attributable to ASP preparation and antibody status.
    Clinical Pharmacology &#38 Therapeutics 10/2009; 86(6):651-8. · 6.85 Impact Factor
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    ABSTRACT: We measured baseline serum mannose binding lectin (MBL) levels in 91 patients with childhood leukemia to determine their predictive value for the development of febrile neutropenia or specific infections. Median MBL levels did not differ significantly between patients who developed febrile neutropenia, bacterial infection, or disseminated fungal infection and those who did not. In addition, low MBL levels were not associated with an increased cumulative incidence of infection or with a shorter time to first infection. This preliminary study suggests that baseline MBL levels may not be clinically useful to identify pediatric leukemia patients who are at increased risk of infection. Additional studies are required to determine whether serial MBL measurements may be valuable for this purpose. Pediatr Blood Cancer 2008;50:866–868. © 2007 Wiley-Liss, Inc.
    Pediatric Blood & Cancer 03/2008; 50(4):866 - 868. · 2.35 Impact Factor
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    ABSTRACT: BACKGROUND.Dexamethasone improves the cure rate of childhood acute lymphoblastic leukemia (ALL) but causes physical and behavioral adverse events. The objective of the current study was to determine the effect of dexamethasone exposure on sleep and fatigue in pediatric patients with ALL.METHODS.One hundred pediatric patients with low-risk or standard-risk ALL were enrolled on 1 of 3 protocols (St. Jude Total XV, Children's Oncology Group [COG] 9904, or COG 9905) at 3 institutions. The mean age of the cohort was 9.24 ± 3.23 years (range, 5.03-18.14 years). The majority of patients were white (79%) males (62%) with standard-risk ALL (63%). The cohort was divided into 4 subgroups: St. Jude low-risk, St. Jude standard-risk, COG low-risk, and COG standard-risk. Patients wore a wrist actigraph to monitor sleep activity during 2 consecutive 5-day periods: During the first period, they did not receive dexamethasone; and, during the second period, they did. Patients and their parents completed fatigue instruments on Days 2 and 5 of each period, and parents completed sleep diaries.RESULTS.Actual sleep minutes, sleep duration, total daily nap minutes, and fatigue increased significantly during the dexamethasone treatment for 3 to 4 of the subgroups. Total daily nap minutes increased significantly for both standard-risk groups during the dexamethasone treatment. Parents reported significant increases in their child's nighttime awakenings, restless sleep, and nap time during dexamethasone treatment.CONCLUSIONS.Dexamethasone treatment during continuation therapy for childhood ALL significantly and adversely altered sleep and fatigue, confirming that sleep and fatigue are behavioral responses to dexamethasone. 2007. © 2007 American Cancer Society.
    Cancer 11/2007; 110(10):2321 - 2330. · 5.20 Impact Factor
  • Leukemia Research - LEUK RES. 01/2007; 31.

Publication Stats

15k Citations
3,848.90 Total Impact Points

Institutions

  • 2014
    • The University of Tennessee Health Science Center
      Memphis, Tennessee, United States
  • 1980–2014
    • St. Jude Children's Research Hospital
      • • Division of Translational Imaging Research
      • • Department of Pharmaceutical Sciences
      • • Department of Oncology
      • • Division of Leukemia/Lymphoma
      • • Department of Pathology
      Memphis, Tennessee, United States
  • 2010
    • University Medical Center Schleswig-Holstein
      • Department of Pediatrics
      Kiel, Schleswig-Holstein, Germany
  • 2009
    • Azienda Ospedaliera San Gerardo
      Monza, Lombardy, Italy
  • 2006
    • St Anna's Kinderspital
      Wien, Vienna, Austria
  • 1988–2001
    • University of Tennessee
      • • College of Medicine
      • • Division of Hematology and Oncology
      • • Department of Medicine
      • • Department of Pediatrics
      Knoxville, Tennessee, United States
  • 2000
    • Università degli Studi di Milano-Bicocca
      Milano, Lombardy, Italy
  • 1998
    • United States Environmental Protection Agency
      Cincinnati, Ohio, United States
  • 1997
    • University of Pavia
      Ticinum, Lombardy, Italy
  • 1996
    • Chang Gung Memorial Hospital
      • Division of Hematology and Oncology
      Taipei, Taipei, Taiwan
  • 1994
    • Medical University of South Carolina
      • Department of Pediatrics
      Charleston, SC, United States
  • 1993
    • University of Florida
      Gainesville, Florida, United States