P G Isaacson

University College London, Londinium, England, United Kingdom

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Publications (200)1560.23 Total impact

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    ABSTRACT: To evaluate the status of the immune regulation and homeostasis mechanisms in Celiac Disease (CD), and its progression toward Refractory Celiac Disease (RCD) and transformation to EATL type 1 focusing on FOXP3+Tregs, ITGAX+DCs, BTLA+cell, PDCD1+TFH subpopulations. The series was comprised of 69 cases consisting on 50 samples of CD and 19 samples of EATL type 1. Protein expression was analyzed and quantified by digital image analysis. Histological compartmentalization included lamina propria, isolated lymphoid follicles and tumoral lymphoid area. In comparison to physiological conditions, CD was characterized by higher numbers of FOXP3+Tregs and ITGAX+DCs, but lower BTLA+cells and PDCD1+TFH cells. Progression from CD to RCD1, RCD2 and transformation to EATL was characterized by decreasing trends of FOXP3+Tregs and BTLA+cell. ITGAX+DCs showed a similar decreasing trend from CD to RCD stages but transformation to EATL was characterized with a striking increase. The RCD progression and EATL transformation stages show a defect in inhibitory pathways of FOXP3 and BTLA. Those results pinpoint the role of immune homeostasis and tolerance in CD and in the generation of cancer.
    No preview · Article · Jan 2012 · Japanese Journal of Clinical Immunology
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    ABSTRACT: Splenic marginal zone lymphoma is characterised by 7q32 deletion, but the target genes of the deletion remain unknown. The minimally deleted region contains a cluster of 6 microRNAs. We investigated whether these miRNAs are the target of 7q32 deletion. High resolution array comparative genomic hybridisation showed no evidence of cryptic or homozygous deletions of the microRNAs. Quantitative polymerase chain reaction showed reduced expression of the miRNA cluster in splenic marginal zone lymphoma relative to other lymphomas, with cases bearing the 7q deletion showing downregulation compared to those without the deletion. Sequencing of these microRNAs revealed a single recurrent somatic mutation in miR-182 in 22% of splenic marginal zone lymphomas. The mutation was also seen frequently in follicular lymphoma (20%), hairy cell leukaemia (13%), mucosa associated lymphoid tissue lymphoma (13%) and peripheral T cell lymphoma (11%), but infrequently in other lymphomas. This microRNA cluster, and miR-182 in particular, may be the target of the 7q32 deletion in SMZL.
    Preview · Article · Sep 2010 · Haematologica
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    ABSTRACT: Mucosa-associated lymphoid tissue (MALT) lymphoma is characterized by t(11;18)(q21;q21)/API2-MALT1, t(1;14)(p22;q32)/BCL10-IGH and t(14;18)(q32;q21)/IGH-MALT1, which commonly activate the nuclear factor (NF)-kappaB pathway. Gastric MALT lymphomas harboring such translocations usually do not respond to Helicobacter pylori eradication, while most of those without translocation can be cured by antibiotics. To understand the molecular mechanism of these different MALT lymphoma subgroups, we performed gene expression profiling analysis of 21 MALT lymphomas (13 translocation-positive, 8 translocation-negative). Gene set enrichment analysis (GSEA) of the NF-kappaB target genes and 4394 additional gene sets covering various cellular pathways, biological processes and molecular functions have shown that translocation-positive MALT lymphomas are characterized by an enhanced expression of NF-kappaB target genes, particularly toll like receptor (TLR)6, chemokine, CC motif, receptor (CCR)2, cluster of differentiation (CD)69 and B-cell CLL/lymphoma (BCL)2, while translocation-negative cases were featured by active inflammatory and immune responses, such as interleukin-8, CD86, CD28 and inducible T-cell costimulator (ICOS). Separate analyses of the genes differentially expressed between translocation-positive and -negative cases and measurement of gene ontology term in these differentially expressed genes by hypergeometric test reinforced the above findings by GSEA. Finally, expression of TLR6, in the presence of TLR2, enhanced both API2-MALT1 and BCL10-mediated NF-kappaB activation in vitro. Our findings provide novel insights into the molecular mechanism of MALT lymphomas with and without translocation, potentially explaining their different clinical behaviors.
    Full-text · Article · Aug 2010 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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    ABSTRACT: Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.
    Full-text · Article · Feb 2010 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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    ABSTRACT: An aberrant immunophenotype and monoclonality of intraepithelial lymphocytes (IELs) are frequently found in refractory coeliac disease (RCD). However, the utility of continual monitoring of IEL immunophenotype and clonality in the surveillance of RCD remains to be studied. The diagnostic and follow-up biopsies from 33 patients with CD, 7 with suspected RCD, 41 with RCD and 20 with enteropathy-associated T cell lymphoma (EATL) (including 11 evolved from RCD) were investigated by CD3epsilon/CD8 double immunohistochemistry and PCR-based clonality analysis of the rearranged T cell receptor (TCR) genes. An aberrant immunophenotype (CD3epsilon(+)CD8(-) IELs > or =40%) and monoclonality were detected occasionally in CD biopsies, either transiently in patients with CD not compliant with a gluten-free diet or in those who subsequently developed suspected RCD, RCD or EATL. In contrast, the aberrant immunophenotype and monoclonality were found in 30 of 41 (73%) and 24 of 37 (65%) biopsies, respectively, at the time of RCD diagnosis. Among the patients with RCD who did not show these abnormalities in their diagnostic biopsies, 8 of 10 (80%) and 5 of 11 (45%) cases gained an aberrant immunophenotype and monoclonality, respectively, during follow-up. Irrespective of whether detected in diagnostic or follow-up biopsies, persistence of both abnormalities was characteristic of RCD. Importantly, the presence of concurrent persistent monoclonality and aberrant immunophenotype, especially > or =80% CD3epsilon(+)CD8(-) IELs, was a strong predictor of EATL development in patients with RCD (p=0.001). Continual monitoring of both immunophenotype and clonality of IELs is more important than snapshot analysis for RCD diagnosis and follow-up, and could provide a useful tool for surveillance of patients at risk of EATL.
    Full-text · Article · Dec 2009 · Gut
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    ABSTRACT: The genetic basis of MALT lymphoma is largely unknown. Characteristic chromosomal translocations are frequently associated with gastric and pulmonary cases, but are rare at other sites. We compared the genetic profiles of 33 ocular adnexal and 25 pulmonary MALT lymphomas by 1 Mb array-comparative genomic hybridization (CGH) and revealed recurrent 6q23 losses and 6p21.2-6p22.1 gains exclusive to ocular cases. High-resolution chromosome 6 tile-path array-CGH identified NF-kappaB inhibitor A20 as the target of 6q23.3 deletion and TNFA/B/C locus as a putative target of 6p21.2-22.1 gain. Interphase fluorescence in situ hybridization showed that A20 deletion occurred in MALT lymphoma of the ocular adnexa (8/42=19%), salivary gland (2/24=8%), thyroid (1/9=11%) and liver (1/2), but not in the lung (26), stomach (45) and skin (13). Homozygous deletion was observed in three cases. A20 deletion and TNFA/B/C gain were significantly associated (p<0.001) and exclusively found in cases without characteristic translocation. In ocular cases, A20 deletion was associated with concurrent involvement of different adnexal tissues or extraocular sites at diagnosis (p=0.007), a higher proportion of relapse (67% versus 37%) and a shorter relapse-free survival (p=0.033). A20 deletion and gain at TNFA/B/C locus may thus play an important role in the development of translocation-negative MALT lymphoma.
    Full-text · Article · Nov 2008 · The Journal of Pathology
  • S-S Chuang · Y-L Liao · H Liu · S-H Lin · P-P Hsieh · W-T Huang · H-K Chen · P G Isaacson

    No preview · Article · Aug 2008 · Histopathology
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    M-Q Du · C M Bacon · P G Isaacson
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    ABSTRACT: Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV8), is a recent addition to the list of human viruses that are directly associated with lymphoproliferative disorders. KSHV was first shown to be involved in multicentric Castleman disease and primary effusion lymphoma (PEL). Subsequently, the virus was identified in solid lymphomas, often of extranodal sites, with morphological and immunophenotypic characteristics similar to those of PEL, and in other lymphoproliferative disorders with heterogeneous clinicopathological presentations. The recent advances in our understanding of the histology, immunophenotype and pathogenesis of these KSHV-associated lymphoproliferative disorders are reviewed.
    Preview · Article · Jan 2008 · Journal of clinical pathology
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    Full-text · Article · Oct 2007 · Arthritis Research & Therapy
  • P G Isaacson
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    ABSTRACT: Although not specifically recognized as a subspecialty of histopathology, haematopathology has a long history of specialist practice in the UK, with a few centres attracting large numbers of referred cases. The specialist nature of haematopathology has been enhanced by the advent of immunohistochemistry and, more recently, molecular genetics, which now play a major role in the diagnosis of haematopoietic and lymphoid neoplasms. Problems encountered by non-specialist pathologists, and reflected in those cases submitted for consultation, include difficulties in the differential diagnosis of certain benign lymphoproliferative disorders from lymphoma and the precise classification of lymphomas which may have an impact on therapeutic decisions. Lymphomas that frequently pose problems include common lesions such as follicular lymphoma and more esoteric disorders such as T-cell/histiocyte-rich large B-cell lymphoma. This review is an attempt to clarify a logical approach to the differential diagnosis of these lesions.
    No preview · Article · Jul 2007 · Histopathology
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    ABSTRACT: We reviewed 45 pulmonary B-cell non-Hodgkin's lymphomas to determine whether their morphology and immunohistochemical features were those of lymphomas arising from mucosa-associated lymphoid tissue (MALT), as described in other sites. The polymerase chain reaction was used to provide further information on clonality. We found that these lymphomas infiltrate the pulmonary interstitium along bronchovascular bundles and interlobular septa, subsequently spilling out into airspaces and finally destroying the alveolar architecture of the lung. Central hyaline sclerosis and vascular infiltration were common features. All lymphomas stained CD20 positive and were accompanied by variable numbers of reactive CD3 positive T-cells. Cytokeratin staining with CAM 5.2 was useful in identifying lymphoepithelial lesions. CD21 staining of follicular dendritic cells revealed germinal centres where they were not recognizable on H & E staining. The polymerase chain reaction was performed on paraffin tissue from 28 patients. Twenty were low grade, of which 12 showed a clonal band and eight stiowed a polyclonal smear pattern. Eight were high grade, of which one revealed a clonal band. Three produced polyclonal smear patterns and four cases were inadequate samples. In one patient who had lymphoma at a second extranodal site, identical bands were identified, evidence for ‘homing’ of lymphoid cells towards mucosal epithelium.
    No preview · Article · Apr 2007 · Histopathology
  • A.D. Attygalle · S-S Chuang · T.C. Diss · M-Q Du · P.G. Isaacson · A Dogan
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    ABSTRACT: To identify distinguishing histological, immunophenotypic and molecular genetic features between angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma (PTL). Nodal T-cell lymphomas examined (n =137), included AITL (n = 89), PTL (n = 22), anaplastic large cell lymphoma (n = 16) and 'AITL/PTL indeterminate' (n = 10) with overlapping features between AITL and PTL, showing morphology typical of AITL but lacking follicular dendritic cell expansion. Immunohistochemistry for CD3, CD20, CD21 and CD10, in situ hybridization for Epstein-Barr virus encoded RNA (EBER) and polymerase chain reaction for T-cell and B-cell clonality analysis were performed. Of the AITLs, 74/89 showed typical morphology, whereas 15/89 showed hyperplastic follicles. AITL and 'AITL/PTL indeterminate' showed a polymorphous infiltrate and prominent vascularity in all cases. In both groups, CD10 was present in the majority and clear cells and EBER positivity were specific (but not universal) features lacking in PTL. Detection of T-cell clonality was significantly higher in AITL (90%) compared with PTLu (59%). Clear cells and EBV infection (when present) are useful distinguishing features and CD10 a sensitive and specific marker of AITL. Hyperplastic follicles are present in a significant minority of AITL. AITL/PTL indeterminate probably falls within the spectrum of AITL rather than PTL.
    No preview · Article · Apr 2007 · Histopathology
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    A Dogan · M Du · P G Isaacson

    Preview · Article · Jan 2005
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    ABSTRACT: Occurrence of an aggressive lymphoma in patients with chronic lymphocytic leukemia (CLL), clinically referred to as Richter's syndrome, occasionally manifests as a lymphoproliferation resembling Hodgkin's lymphoma (HL) and often containing the Epstein-Barr virus (EBV). Only a limited number of HL variants have been subject to informative analysis regarding their clonal relationship to the CLL, with evidence of a same clonal origin in some cases and of clonally unrelated neoplasms in other cases. In this paper, we performed a detailed pathologic, virologic, and molecular analysis of two cases of Richter's syndrome with HL features. The first case occurred in a 65-year-old man with a 5-year history of CLL as a mediastinal and supraclavicular mass histologically diagnosed as lymphocyte depleted HL with no background CLL. The second case occurred in a 78-year-old woman with a 4-year history of CLL as an inguinal mass with a composite histologic appearance comprising areas of CLL, areas of CLL with Hodgkin Reed-Sternberg cells, and areas of HL. Both patients had received fludarabine therapy. The HRS cells were CD20-/CD30+/CD15-/J-chain- in case no. 1 and CD20+/-/CD30+/CD15-/J-chain- in case no. 2. In both cases, the Hodgkin's Reed-Sternberg cells (HRS) were positive for type A EBV, and a 30-bp deletion of the LMP-1 gene was detected in case no. 2. Using microdissection and polymerase chain reaction amplification of the immunoglobulin heavy chain gene (IgH) complementarity determining region III of each cell type, we demonstrated a distinct clonal origin for the CLL cells and the HRS in both cases. These cases bring support to the hypothesis that EBV+ HL in CLL patients occurs as unrelated secondary neoplasms most likely as the result of the immune depression associated with CLL and also raise the question of a possible causal role of fludarabine.
    No preview · Article · Jun 2004 · American Journal of Surgical Pathology
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    ABSTRACT: Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with three distinct lymphoproliferative disorders: primary effusion lymphoma (PEL), multicentric Castleman's disease (MCD) and germinotropic lymphoproliferative disorder (GLD). KSHV positive lymphocytes in GLD and in most cases of PEL are co-infected by Epstein-Barr virus (EBV) and these viral double positive cells harbour mutated rearranged immunoglobulin (Ig) genes, suggesting that they originate from germinal centre or post-germinal centre B-cells. In contrast, KSHV positive cells in MCD are invariably negative for EBV, do not carry Ig gene mutation and are believed to originate from naïve IgMlambda expressing B-cells. Interestingly, one EBV negative PEL (BC3) also lacks Ig gene mutation, raising the question whether KSHV preferentially targets naïve B-cells in the absence of EBV. We compared the cellular origin of PEL with and without EBV infection by analysis of Ig gene mutation. High molecular weight DNA from 17 PELs was subjected to PCR of the rearranged Ig heavy and light chain genes. Successful amplification was achieved from eight cases (four EBV positive and four EBV negative) and the PCR products were sequenced. All four EBV positive PEL showed variable levels of mutation in their rearranged V(H) or V(L) genes, ranging from 4 to 7%. In contrast, two of the four EBV negative PELs including BC3 displayed absence of mutation in their rearranged Ig genes. Our results indicate that EBV positive PELs are derived from germinal centre or post-germinal centre B-cells, whereas EBV negative PELs may originate from either germinal/post-germinal centre or naïve B-cells.
    No preview · Article · May 2004 · Leukemia Research
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    ABSTRACT: Enteropathy-type T-cell lymphoma (ETL) and ulcerative jejunitis (UJ) are rare disorders often occurring in patients with coeliac disease. The genetic events associated with the accumulation of intraepithelial lymphocytes in coeliac disease and tumour development are largely unknown. Deletions at chromosome 9p21, which harbours the tumour suppressor genes p14/ARF, p15/INK4b, and p16/INK4a, and 17p13, where p53 is located, are associated with the development and progression of lymphomas. To examine whether deletions at 9p21 and 17p13 play a role in ETL, 22 cases of ETL and seven cases of UJ were screened for loss of heterozygosity (LOH) by tissue microdissection and polymerase chain reaction (PCR) analysis for microsatellite markers. Furthermore, p53 and p16 protein expression was examined by immunohistochemistry. In addition, polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) analysis for detection of mutations in exons 5-8 of the p53 gene was performed in five cases of ETL and three cases of UJ. LOH was found in at least one microsatellite marker at the 9p21 locus in 8 of 22 (36%) ETLs, but not in UJ. Five of nine (56%) tumours composed of large cells showed LOH at 9p21, as opposed to two of eight (25%) tumours with small- or medium-sized cell morphology. The region spanning the p14/p15/p16 gene locus was most frequently affected (five cases); LOH at these markers coincided with loss of p16 protein expression in all of these cases. p53 overexpression was demonstrated in all ETLs examined and in four of seven cases of UJ. However, no alterations of the p53 gene were detected by LOH or PCR-SSCP analysis. The results of this study show that LOH at chromosome 9p21 is frequent in ETL, especially in tumours with large cell morphology; this finding suggests that gene loss at this locus may play a role in the development of ETL.
    Full-text · Article · Mar 2004 · The Journal of Pathology
  • LA Baginsky · TC Diss · HT Ye · B Wren · MQ du · PG Isaacson · A Dogan

    No preview · Article · Jan 2004 · Blood

  • No preview · Article · Dec 2003 · Pathology - Research and Practice
  • P G Isaacson · M Q Du
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    ABSTRACT: Gastric mucosa associated lymphoid tissue (MALT) lymphoma is a histologically distinct tumour derived from MALT acquired as a result of Helicobacter pylori infection. Eradication of H. pylori causes clinical regression of the lymphoma n 75 % of cases. In seeking to identify those cases resistant to this therapy, and in the interests of further understanding the biology of MALT lymphoma, genetic alterations of MALT lymphomas have been investigated. Three translocations, t(11;18)(q21; q21), t(1;14)(p22;q32) and t(14;18)(q32;q21) are specifically associated with MALT lymphoma and the genes involved have been identified. T(11;18) results in a chimeric fusion between the API2 and MALT1 genes and is specifically associated with gastric MALT lymphomas that do not respond to eradication of H. pylori. T(1; 14) and t(14; 18) deregulate bcl-10 and MALT1 expression respectively. These three chromosomal translocations that involve different genes appear to share common oncogenic properties by targeting the to target the same NFkappaB oncogenic pathway.
    No preview · Article · Feb 2003 · Verhandlungen der Deutschen Gesellschaft für Pathologie
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    ABSTRACT: Neoplasms of histiocytes and dendritic cells are rare, and their phenotypic and biological definition is incomplete. Seeking to identify antigens detectable in paraffin-embedded sections that might allow a more complete, rational immunophenotypic classification of histiocytic/dendritic cell neoplasms, the International Lymphoma Study Group (ILSG) stained 61 tumours of suspected histiocytic/dendritic cell type with a panel of 15 antibodies including those reactive with histiocytes (CD68, lysozyme (LYS)), Langerhans cells (CD1a), follicular dendritic cells (FDC: CD21, CD35) and S100 protein. This analysis revealed that 57 cases (93%) fit into four major immunophenotypic groups (one histiocytic and three dendritic cell types) utilizing six markers: CD68, LYS, CD1a, S100, CD21, and CD35. The four (7%) unclassified cases were further classifiable into the above four groups using additional morphological and ultrastructural features. The four groups then included: (i) histiocytic sarcoma (n=18) with the following phenotype: CD68 (100%), LYS (94%), CD1a (0%), S100 (33%), CD21/35 (0%). The median age was 46 years. Presentation was predominantly extranodal (72%) with high mortality (58% dead of disease (DOD)). Three had systemic involvement consistent with 'malignant histiocytosis'; (ii) Langerhans cell tumour (LCT) (n=26) which expressed: CD68 (96%), LYS (42%), CD1a (100%), S100 (100%), CD21/35 (0%). There were two morphological variants: cytologically typical (n=17) designated LCT; and cytologically malignant (n=9) designated Langerhans cell sarcoma (LCS). The LCS were often not easily recognized morphologically as LC-derived, but were diagnosed based on CD1a staining. LCT and LCS differed in median age (33 versus 41 years), male:female ratio (3.7:1 versus 1:2), and death rate (31% versus 50% DOD). Four LCT patients had systemic involvement typical of Letterer-Siwe disease; (iii) follicular dendritic cell tumour/sarcoma (FDCT) (n=13) which expressed: CD68 (54%), LYS (8%), CD1a (0%), S100 (16%), FDC markers CD21/35 (100%), EMA (40%). These patients were adults (median age 65 years) with predominantly localized nodal disease (75%) and low mortality (9% DOD); (iv) interdigitating dendritic cell tumour/sarcoma (IDCT) (n=4) which expressed: CD68 (50%), LYS (25%), CD1a (0%), S100 (100%), CD21/35 (0%). The patients were adults (median 71 years) with localized nodal disease (75%) without mortality (0% DOD). In conclusion, definitive immunophenotypic classification of histiocytic and accessory cell neoplasms into four categories was possible in 93% of the cases using six antigens detected in paraffin-embedded sections. Exceptional cases (7%) were resolvable when added morphological and ultrastructural features were considered. We propose a classification combining immunophenotype and morphology with five categories, including Langerhans cell sarcoma. This simplified scheme is practical for everyday diagnostic use and should provide a framework for additional investigation of these unusual neoplasms.
    No preview · Article · Aug 2002 · Histopathology

Publication Stats

17k Citations
1,560.23 Total Impact Points


  • 1983-2010
    • University College London
      • • Department of Pathology
      • • Division of Medicine
      Londinium, England, United Kingdom
  • 2007
    • University of Birmingham
      Birmingham, England, United Kingdom
    • University College London Hospitals NHS Foundation Trust
      • Department of Histopathology
      Londinium, England, United Kingdom
  • 1998
    • The Hillingdon Hospitals NHS Foundation Trust
      अक्सब्रिज, England, United Kingdom
  • 1996
    • Royal Brompton and Harefield NHS Foundation Trust
      • Respiratory Medicine
      Harefield, England, United Kingdom
  • 1995
    • Great Ormond Street Hospital for Children NHS Foundation Trust
      • Department of Histopathology
      Londinium, England, United Kingdom
  • 1994
    • Medical University of Graz
      • Institute of Pathology
      Gratz, Styria, Austria
  • 1988-1994
    • Middlesex University, UK
      Londinium, England, United Kingdom
  • 1983-1993
    • University of Southampton
      • Faculty of Medicine
      Southampton, England, United Kingdom
  • 1992
    • Karl-Franzens-Universität Graz
      • Institute of Psychology
      Graz, Styria, Austria
  • 1990
    • The Courtauld Institute of Art
      Londinium, England, United Kingdom
    • Queen Elizabeth Hospital
      Hong Kong, Hong Kong
  • 1987
    • Oxford University Hospitals NHS Trust
      Oxford, England, United Kingdom