S Richards

University of Oxford, Oxford, England, United Kingdom

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Publications (85)608.18 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: AIMS: In children with acute lymphoblastic leukaemia (ALL) bone marrow activity can influence red blood cell (RBC) kinetics, the surrogate tissue for thiopurine methyltransferase (TPMT) measurements. The aim of this study was to investigate TPMT phenotype-genotype concordance in ALL, and the influence of TPMT on thiopurine metabolite formation. METHODS: We measured TPMT (activity as units/ml packed RBCs, and genotype) at diagnosis (n=1150) and TPMT and thioguanine nucleotide (TGN) and methylmercaptopurine nucleotide (MeMPN) metabolites (pmol/8x10(8) RBCs) during chemotherapy (n=1131) in children randomised to thioguanine or mercaptopurine on the United Kingdom trial ALL97. RESULTS: Median TPMT activity at diagnosis (8.5units) was significantly lower than during chemotherapy (13.8units, median difference 5.1units, 95% confidence interval, CI, 4.8 to 5.4, P<0.0001). At diagnosis genotype-phenotype was discordant. During chemotherapy the overall concordance was 92%, but this fell to 55% in the intermediate activity cohort (45% had wild-type genotypes). For both thiopurines TGN concentrations differed by TPMT status. For mercaptopurine, median TGNs were higher in TPMT heterozygous genotype (754pmol) than wild-type (360pmol) patients; median difference 406pmol, 95% CI 332 to 478, P<0.0001, whilst median MeMPNs, products of the TPMT reaction, were higher in wild-type (10,650pmol) than heterozygous patients (3,868pmol); P<0.0001. In TPMT intermediate activity patients with a wild-type genotype, TGN (median 366pmol) and MeMPN (median 8590pmol) concentrations were similar to those in wild-type, high activity patients. CONCLUSIONS: In childhood ALL, TPMT activity should not be used to predict heterozygosity particularly in blood samples obtained at disease diagnosis. Genotype is a better predictor of TGN accumulation during chemotherapy.
    British Journal of Clinical Pharmacology 12/2012; 76(1). DOI:10.1111/bcp.12066 · 3.69 Impact Factor
  • 54th Annual Meeting and Exposition of the American Society of Hematology (ASH); 12/2012
  • 54th Annual Meeting and Exposition of the American Society of Hematology (ASH), Atlanta; 12/2012
  • Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 07/2012; DOI:10.1038/leu.2012.199 · 9.38 Impact Factor
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    ABSTRACT: Activating mutations in the NOTCH1 pathway are frequent in pediatric T-cell acute lymphoblastic leukemia (T-ALL) but their role in refining risk stratification is unclear. We screened 162 pediatric T-ALL patients treated on the MRC UKALL2003 trial for NOTCH1/FBXW7 gene mutations and related genotype to response to therapy and long-term outcome. Overall, 35% were wild-type (WT) for both genes (NOTCH1(WT)FBXW7(WT)), 38% single NOTCH1 mutant (NOTCH1(Single)FBXW7(WT)), 3% just FBXW7 mutant (NOTCH1(WT)FBXW7(MUT)) and 24% either double NOTCH1 mutant (NOTCH1(Double)FBXW7(WT)) or mutant in both genes (NOTCH1(MUT)FBXW7(MUT)), hereafter called as NOTCH1±FBXW7(Double). There was no difference between groups in early response to therapy, but NOTCH1±FBXW7(Double) patients were more likely to be associated with negative minimal residual disease (MRD) post-induction than NOTCH1(WT)FBXW7(WT) patients (71% versus 40%, P=0.004). Outcome improved according to the number of mutations, overall survival at 5 years 82%, 88% and 100% for NOTCH1(WT)FBXW7(WT), NOTCH1(Single)FBXW7(WT) and NOTCH1±FBXW7(Double) patients, respectively (log-rank P for trend=0.005). Although 14 NOTCH1±FBXW7(Double) patients were classified as high risk (slow response and/or MRD positive), only two had disease progression and all remain alive. Patients with double NOTCH1 and/or FBXW7 mutations have a very good outcome and should not be considered for more intensive therapy in first remission, even if slow early responders or MRD positive after induction therapy.Leukemia advance online publication, 20 July 2012; doi:10.1038/leu.2012.176.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 07/2012; DOI:10.1038/leu.2012.176 · 9.38 Impact Factor
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    ABSTRACT: We previously reported that children in the UKALL XI ALL trial with HLA-DP 1 and -DP 3 supertypes had significantly worse event-free survival (EFS) than children with other DP supertypes. As DP 1 and DP 3 share two of four key antigen-binding amino-acid polymorphisms (aspartic acid84-lysine69), we asked whether Asp84-Lys69 or Asp84 alone were independent prognostic indicators in childhood acute lymphoblastic leukemia (ALL). We analysed EFS in 798 UKALL XI patients, stratified by Asp84-Lys69 vs non-Asp84-Lys69, for a median follow-up of 12.5 years. Asp84-Lys69 was associated with a significantly worse EFS than non-Asp84-Lys69 (5-year EFS: Asp84-Lys69: 58.8% (95% CI (confidence of interval): 52.7-64.9%); non-Asp84-Lys69: 67.3% (63.4-71.2%); 2P=0.007). Post-relapse EFS was 10% less in Asp84-Lys69 than non-Asp84-Lys69 patients. EFS was significantly worse (P=0.03) and post-relapse EFS marginally worse (P=0.06) in patients with Asp84 compared with Gly84. These results suggest that Asp84-Lys69 predicted adverse EFS in the context of UKALL XI because of Asp84, and may have influenced post-relapse EFS. We speculate that this may be due to the recruitment of Asp84-Lys69-restricted regulatory T cells in the context of this regimen, leading to the re-emergence of residual disease. However, functional and molecular studies of the prognostic value of this and other HLA molecular signatures in other childhood ALL trials are needed.
    Blood Cancer Journal 07/2012; 2(7):e80. DOI:10.1038/bcj.2012.25 · 2.88 Impact Factor
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    ABSTRACT: Children with Down's syndrome (DS) have an increased risk of developing acute lymphoblastic leukemia (ALL) and have a low frequency of established genetic aberrations. We aimed to determine which genetic abnormalities are involved in DS ALL. We studied the frequency and prognostic value of deletions in B-cell development genes and aberrations of janus kinase 2 (JAK2) and cytokine receptor-like factor 2 (CRLF2) using array-comparative genomic hybridization, and multiplex ligation-dependent probe amplification in a population-based cohort of 34 Dutch Childhood Oncology Group DS ALL samples. A population-based cohort of 88 DS samples from the UK trials was used to validate survival estimates for IKZF1 and CRLF2 abnormalities. In total, 50% of DS ALL patients had 1 deletion in the B-cell development genes: PAX5 (12%), VPREB1 (18%) and IKZF1 (35%). JAK2 was mutated in 15% of patients, genomic CRLF2 rearrangements in 62%. Outcome was significantly worse in patients with IKZF1 deletions (6-year event-free survival (EFS) 45±16% vs 95±4%; P=0.002), which was confirmed in the validation cohort (6-year EFS 21±12% vs 58±11%; P=0.002). This IKZF1 deletion was a strong independent predictor for outcome (hazard ratio EFS 3.05; P=0.001). Neither CRLF2 nor JAK2 were predictors for worse prognosis. If confirmed in prospective series, IKZF1 deletions may be used for risk-group stratification in DS ALL.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 03/2012; 26(10):2204-11. DOI:10.1038/leu.2012.84 · 9.38 Impact Factor
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    ABSTRACT: Although the incidence rate of acute lymphoblastic leukaemia (ALL) is slightly higher in older than in younger adults, response rates to induction chemotherapy and survival rates are poorer. The contribution of disease-related versus treatment-related factors remains unclear. We analysed 100 older patients (aged 55-65 years) treated on the UKALLXII/ECOG2993 trial compared with 1814 younger patients (aged 14-54 years). Baseline characteristics, induction chemotherapy course, infections, drug reductions and survival outcomes were compared. There were more Philadelphia-positive (Ph+) patients in the older group (28% vs. 17%, P = 0·02), and a trend towards higher combined cytogenetic risk score (46% vs. 35%, P = 0·07). The complete remission rate in older patients was worse (73% vs. 93%, P < 0·0001) as was 5-year overall survival (21% vs. 41%, P < 0·0001) and event-free survival (EFS) (19% vs. 37%, P < 0·0001). Older patients had more infections during induction (81% vs. 70%, P = 0·05), and drug reductions (46% vs. 28%, P = 0·0009). Among older patients, Ph+ and cytogenetic risk category as well as infection during induction predicted for worse EFS. Poorer outcomes in these patients are partly due to cytogenetic risk, but there is significant morbidity and mortality during induction chemotherapy with frequent delays and drug reductions. New approaches, including better risk stratification and use of targeted therapies, could improve treatment for these patients.
    British Journal of Haematology 03/2012; 157(4):463-71. DOI:10.1111/j.1365-2141.2012.09095.x · 4.96 Impact Factor
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    Blood 09/2011; 118(9):2632-3. DOI:10.1182/blood-2011-05-355206 · 10.43 Impact Factor
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    ABSTRACT: The biology and outcome of adult T-cell acute lymphoblastic leukemia are poorly understood. We present here the clinical and biologic features of 356 patients treated uniformly on the prospective trial (UKALL XII/ECOG 2993) with the aim of describing the outcome and identifying prognostic factors. Complete remission was obtained in 94% of patients, and 48% survived 5 years. Positivity of blasts for CD1a and lack of expression of CD13 were associated with better survival (P = .01 and < .001, respectively). NOTCH1 and CDKN2A mutations were seen in 61% and 42% of those tested. Complex cytogenetic abnormalities were associated with poorer survival (19% vs 51% at 5 years, P = .006). Central nervous system involvement at diagnosis did not affect survival (47% vs 48%, P = not significant). For 99 patients randomized between autograft and chemotherapy, 5-year survival was 51% in each arm. Patients with a matched sibling donor had superior 5-year survival to those without donors (61% vs 46%, chi(2), P = .02); this was the result of less relapse (25% vs 51% at 5 years, P < .001). Only 8 of 123 relapsed patients survive. This study provides a baseline for trials of new drugs, such as nelarabine, and may allow risk-adapted therapy in patients with poor-prognosis T-cell ALL.
    Blood 10/2009; 114(25):5136-45. DOI:10.1182/blood-2009-08-231217 · 10.43 Impact Factor
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    ABSTRACT: The molecular mechanisms involved in disease progression and relapse in T-cell acute lymphoblastic leukemia (T-ALL) are poorly understood. We used single nucleotide polymorphism array analysis to analyze paired diagnostic and relapsed T-ALL samples to identify recurrent genetic alterations in T-ALL. This analysis showed that diagnosis and relapsed cases have common genetic alterations, but also that relapsed samples frequently lose chromosomal markers present at diagnosis, suggesting that relapsed T-ALL emerges from an ancestral clone different from the major leukemic population at diagnosis. In addition, we identified deletions and associated mutations in the WT1 tumor suppressor gene in 2 of 9 samples. Subsequent analysis showed WT1 mutations in 28 of 211 (13.2%) of pediatric and 10 of 85 (11.7%) of adult T-ALL cases. WT1 mutations present in T-ALL are predominantly heterozygous frameshift mutations resulting in truncation of the C-terminal zinc finger domains of this transcription factor. WT1 mutations are most prominently found in T-ALL cases with aberrant rearrangements of the oncogenic TLX1, TLX3, and HOXA transcription factor oncogenes. Survival analysis demonstrated that WT1 mutations do not confer adverse prognosis in pediatric and adult T-ALL. Overall, these results identify the presence of WT1 mutations as a recurrent genetic alteration in T-ALL.
    Blood 07/2009; 114(5):1038-45. DOI:10.1182/blood-2008-12-192039 · 10.43 Impact Factor
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    ABSTRACT: Prospective data on the value of allogeneic hematopoietic stem cell transplantation (alloHSCT) in Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL) are limited. The UKALLXII/ECOG 2993 study evaluated the outcome of assigning alloHSCT with a sibling (sib) or matched unrelated donor (MUD) to patients younger than 55 years of age achieving complete remission (CR). The CR rate of 267 patients, median age 40, was 82%. Twenty-eight percent of patients proceeded to alloHSCT in first CR. Age older than 55 years or a pre-HSCT event were the most common reasons for failure to progress to alloHSCT. At 5 years, overall survival (OS) was 44% after sib alloHSCT, 36% after MUD alloHSCT, and 19% after chemotherapy. After adjustment for sex, age, and white blood count and excluding chemotherapy-treated patients who relapsed or died before the median time to alloHSCT, only relapse-free survival remained significantly superior in the alloHSCT group (odds ratio 0.31, 95% confidence interval 0.16-0.61). An intention-to-treat analysis, using the availability or not of a matched sibling donor, showed 5-year OS to be nonsignificantly better at 34% with a donor versus 25% with no donor. This prospective trial in adult Ph(+) ALL indicates a modest but significant benefit to alloHSCT. This trial has been registered with clinicaltrials.gov under identifier NCT00002514 and as ISRCTN77346223.
    Blood 02/2009; 113(19):4489-96. DOI:10.1182/blood-2009-01-199380 · 10.43 Impact Factor
  • Blood 06/2008; 111(12):5755-5755. DOI:10.1182/blood-2008-04-149088 · 10.43 Impact Factor
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    ABSTRACT: The effect of randomly allocated testicular irradiation on the subsequent incidence of testicular infiltration and disease-free survival was assessed in two Medical Research Council Childhood Leukaemia Trials, UKALL VI and UKALL VII. None of the 83 boys who actually received testicular radiotherapy subsequently developed gonadal disease, whereas 18 of the 163 who were not irradiated did. Despite this there is no apparent difference in disease-free survival for those randomized to receive testicular irradiation compared to those who were not. after a minimum of 8 years follow up. Although prophylactic testicular irradiation appears to prevent subsequent gonadal relapse there is no evidence that it improves overall prognosis when adequate systemic chemotherapy is used. As it has considerable long-term side effects it cannot be recommended as routine therapy.
    British Journal of Haematology 03/2008; 75(4):496 - 498. DOI:10.1111/j.1365-2141.1990.tb07788.x · 4.96 Impact Factor
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    ABSTRACT: Blast cell morphology of children with lymphoblastic leukaemia (ALL) entering two national multicentre trials was prospectively reviewed by three haematologists to define the clinical importance of (a) French–American–British (FAB) classification, (b) the presence of cytoplasmic vacuoles, and (c) the presence of ‘hand-mirror’cells.Of 2135 evaluable children, 1907 (89%) had FAB L1 morphology and 228 (11%) L2. (L3 patients were not eligible for the trials in question). L2 patients more frequently had residual disease 14 d after starting treatment and had a significantly inferior disease-free survival, but not if the analysis was stratified for age, sex and diagnostic white cell count (WBC), 627 (29%) had blast cells with cytoplasmic vacuoles, and showed a significant survival advantage over the remainder. Vacuoles were positively associated with a low WBC, age range 1–6 years and blast cell positivity for CD10, but their benign influence was apparent even when these variables were taken into account. ‘Hand-mirror’(HM) cells were only studied in UKALL X, and were noted in 316/1402 (23%) children. There appeared to be an inverse correlation between HM cells and cytoplasmic vacuoles and a weak association with T-cell immunophenotype, but no prognostic significance was evident.FAB classification appears to be of less prognostic importance than has previously been supposed, though L2 disease is more resistant to current remission induction regimens. Hand-mirror cells may be more common in T-ALL, but are seen in all types and are not related to prognosis. Cytoplasmic vacuoles are predictive of a good response to current therapeutic schedules even allowing for other prognostic variables, and are the single most important morphological feature relating to prognosis in childhood ALL.
    British Journal of Haematology 03/2008; 81(1):52 - 57. DOI:10.1111/j.1365-2141.1992.tb08170.x · 4.96 Impact Factor
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    ABSTRACT: An international collaboration was set up to prospectively evaluate the role of allogeneic transplantation for adults with acute lymphoblastic leukemia (ALL) and compare autologous transplantation with standard chemotherapy. Patients received 2 phases of induction and, if in remission, were assigned to allogeneic transplantation if they had a compatible sibling donor. Other patients were randomized to chemotherapy for 2.5 years versus an autologous transplantation. A donor versus no-donor analysis showed that Philadelphia chromosome-negative patients with a donor had a 5-year improved overall survival (OS), 53% versus 45% (P = .01), and the relapse rate was significantly lower (P < or = .001). The survival difference was significant in standard-risk patients, but not in high-risk patients with a high nonrelapse mortality rate in the high-risk donor group. Patients randomized to chemotherapy had a higher 5-year OS (46%) than those randomized to autologous transplantation (37%; P = .03). Matched related allogeneic transplantations for ALL in first complete remission provide the most potent antileukemic therapy and considerable survival benefit for standard-risk patients. However, the transplantation-related mortality for high-risk older patients was unacceptably high and abrogated the reduction in relapse risk. There is no evidence that a single autologous transplantation can replace consolidation/maintenance in any risk group. This study is registered at http://clinicaltrials.gov as NCT00002514.
    Blood 03/2008; 111(4):1827-33. DOI:10.1182/blood-2007-10-116582 · 10.43 Impact Factor
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    ABSTRACT: Avascular necrosis (AVN) is a serious complication of acute lymphoblastic leukaemia (ALL) therapy. Little is known of the scope and magnitude of this problem among adults with ALL. We analysed the incidence and risk factors for AVN in 1053 patients on the UKALLXII/ECOG2993 study. AVN affected 99 joints in 42 patients at a median of 2.2 years post-diagnosis, giving a crude incidence rate of 4.0%. Statistically significant risk factors for the development of AVN were age and treatment with chemotherapy. Patients receiving prolonged chemotherapy without stem cell transplant were at significantly greater risk of developing AVN than stem cell transplant recipients (P<0.00005). The actuarial incidence of AVN was 29% at 10 years in patients <20 years old compared to 8% at 10 years in those >20 years old; P=0.0004; odds ratio 0.28 (95% CI=0.14-0.56).
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 02/2008; 22(2):308-12. DOI:10.1038/sj.leu.2405032 · 9.38 Impact Factor
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    ABSTRACT: Patients with acute lymphoblastic leukemia (ALL) and an intrachromosomal amplification of chromosome 21 (iAMP21) comprise a novel and distinct biological subgroup. We prospectively screened 1630 (84%) patients treated on the UK MRC ALL97 protocol for iAMP21 and herein present demographic, clinical, and survival data on the 28 (2%) children found to harbor this abnormality. They had a common or pre-B ALL immunophenotype, were significantly older (median 9 years vs 5 years), and had a lower white cell count (median 3.9 vs 12.4) compared with children without this abnormality. Notably, patients with iAMP21 had a significantly inferior event-free and overall survival at 5 years compared with other patients: 29% (95% confidence interval [CI], 13%-48%) versus 78% (95% CI, 76%-80%) and 71% (95% CI, 51%-84%) versus 87% (95% CI, 85%-88%), respectively. As a result of this 3-fold increase in relapse risk, newly diagnosed patients with iAMP21 recruited to the current UK MRC ALL2003 trial are being treated on the high-risk arm and are considered for bone marrow transplantation in first remission.
    Blood 04/2007; 109(6):2327-30. DOI:10.1182/blood-2006-08-040436 · 10.43 Impact Factor
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    ABSTRACT: Most adults with acute lymphoblastic leukemia (ALL) who achieve complete remission (CR) will relapse. We examined the outcome of 609 adults with recurring ALL, all of whom were previously treated on the Medical Research Council (MRC) UKALL12/ECOG2993 study, where the overall survival (OS) of newly diagnosed patients is 38% (95% confidence interval [CI]=36%-41%) at 5 years. By contrast, OS at 5 years after relapse was 7% (95% CI=4%-9%). Factors predicting a good outcome after salvage therapy were young age (OS of 12% in patients younger than 20 years vs OS of 3% in patients older than 50 years; 2P<.001) and short duration of first remission (CR1) (OS of 11% in those with a CR1 of more than 2 years versus OS of 5% in those with a CR1 of less than 2 years; 2P<.001). Treatment received in CR1 did not influence outcome after relapse. In a very highly selected subgroup of patients who were able to receive HSCT after relapse, some were long-term survivors. We conclude from a large, unselected series with mature follow-up that most adults with recurring ALL, whatever their prior treatment, cannot be rescued using currently available therapies. Prevention of recurrence is the best strategy for long-term survival in this disease.
    Blood 03/2007; 109(3):944-50. DOI:10.1182/blood-2006-05-018192 · 10.43 Impact Factor
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    ABSTRACT: Outcome of acute lymphoblastic leukemia (ALL) in adults with central nervous system (CNS) disease at diagnosis is unclear. We treated 1508 de novo ALL patients with 2-phase induction and then high-dose methotrexate with l-asparaginase. Patients up to 50 years old in first remission (CR1) with a matched related donor (MRD) underwent an allogeneic stem cell transplantation (SCT); the remainder in CR1 were randomized to an autologous SCT or intensive consolidation followed by maintenance chemotherapy. Philadelphia chromosome (Ph)-positive patients were offered a matched unrelated donor (MUD) allogeneic SCT. Seventy-seven of 1508 (5%) patients a median age of 29 years had CNS leukemia at presentation; 13 of the 77 (17%) had Ph-positive ALL. Sixty-nine of 77 (90%) patients attained CR1. Thirty-six patients underwent transplantation in CR1 (25 MRD, 5 MUD, and 6 autografts). Eleven of 25 patients with MRD transplantation remain alive at 21 to 102 months, 2 of 5 with MUD at 42 and 71 months, and 1 of 6 with autologous SCT at 35 months. Seven of 27 treated with consolidation/maintenance remain in CR1 56 to 137 months after diagnosis. Overall survival at 5 years was 29% in those with CNS involvement at diagnosis versus 38% (P = .03) for those without. CNS leukemia in adult ALL is uncommon at diagnosis. Adult Ph-negative ALL patients, however, can attain long-term disease-free survival using SCT as well as conventional chemotherapy.
    Blood 08/2006; 108(2):465-72. DOI:10.1182/blood-2005-11-4666 · 10.43 Impact Factor

Publication Stats

4k Citations
608.18 Total Impact Points


  • 1999–2012
    • University of Oxford
      • Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU)
      Oxford, England, United Kingdom
  • 2006–2007
    • Case Western Reserve University
      • Case Comprehensive Cancer Center
      Cleveland, Ohio, United States
    • Technion - Israel Institute of Technology
      • Rambam Medical Center
      Haifa, Haifa District, Israel
  • 1998–2005
    • The Clinical Trial Center, LLC
      Jenkintown, Pennsylvania, United States
  • 2003
    • University of Milan
      Milano, Lombardy, Italy
  • 2001
    • Medical Research Council (UK)
      Londinium, England, United Kingdom
  • 2000
    • Great Ormond Street Hospital for Children NHS Foundation Trust
      • Department of Haematology and Oncology
      Londinium, England, United Kingdom
  • 1995–1997
    • Institute for Child Health Policy (ICHP)
      London, Ohio, United States
    • UK Department of Health
      Londinium, England, United Kingdom
  • 1994
    • The University of Sheffield
      Sheffield, England, United Kingdom
  • 1993–1994
    • SickKids
      • Division of Hematology/Oncology
      Toronto, Ontario, Canada
  • 1992
    • Children's Hospital of Richmond
      Ричмонд, Virginia, United States