A V Hoffbrand

University College London, London, ENG, United Kingdom

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Publications (512)3981.06 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: We have analysed and compared the applicability of mRNA quantitation and immunocytochemistry to the detection of the multidrug resistant gene mdr1 and its protein product P-glycoprotein (PGP) in patients with acute leukaemia. Elevated mdr1 mRNA was detected in 12 of 55 patients and PGP expression by immunocytochemistry in 10 of 27. Raised mdr1 transcript was associated with immunocytochemical positivity in 6 of 8 cases studied. 4 of 10 cases of immunocytochemical positivity were not associated with elevated mdr1 mRNA. Immunocytochemistry showed PGP expression to be heterogeneous within blast populations. In 4 cases PGP positivity was most marked in differentiated leukaemic subpopulations. PGP expression was increased in secondary acute myeloid leukaemia (AML) compared to other disease groups. No association with disease stage was detected except within the secondary leukaemias. In 40 patients studied mdr3 mRNA was raised in one patient with AML and in two remission marrows. These results indicate that further prospective studies in acute leukaemias are required using combined immunocytochemical and RNA quantitation of PGP expression.
    06/2009; 5(5-6):357-364.
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    ABSTRACT: : The incidence of endocrine dysfunction in relation to the detailed genotype of β-thalassaemia is investigated in this study. In addition, the association of genotype to specific clinical features of β-thalassaemia is examined, together with the relationship between serum ferritin levels and endocrine complications. Ninety-seven patients were included, all with transfusion dependent β-thalassaemia. Patients were divided into 2 categories; group 1 consisted of patients with a β0/β0 genotype with or without a concomitant α-globin gene deletion as well as patients with β0/β+ or β+/β+ genotype and normal α-globin chain synthesis. Group 2 included patients with β+/β+ or β+/β0 genotype and one α-globin chain deletion and those with a moderate amount of β-globin chain synthesis (β++) and normal α-globin chain synthesis. The results showed that group 1 patients were more likely to have severe clinical disease (p = 0.005). Sixty-four patients (66%) had at least 1 endocrine disorder and 39 (40%) had multiple endocrinopathies; the most common abnormality was hypogonadotrophic hypogonadism (HH). There was a significant association between patients with group 1 genotypes and the presence of HH and impaired glucose tolerance or diabetes. A positive correlation was demonstrated between serum ferritin concentrations and the presence of thyroid or parathyroid dysfunction.
    European Journal Of Haematology 01/2009; 59(2):76-81. · 2.55 Impact Factor
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    ABSTRACT: Clinically latent myeloproliferative disorders (MPDs) are important causes of what would otherwise be considered idiopathic hepatic (HVT) or portal vein thrombosis (PVT). They may be difficult to diagnose initially because the peripheral blood count may be normal at the time of thrombosis. A strong association between an activating mutation of the gene encoding one of the Janus kinase family of tyrosine kinases (JAK2(V617F)) and the Philadelphia chromosome-negative MPDs has been identified. We have studied 19 patients with unexplained HVT or PVT and tested for JAK2(V617F). Fourteen (74%) of the 19 patients were heterozygous for JAK2(V617F) but did not meet diagnostic criteria for a MPD at the time of presentation with thrombosis. Prolonged follow-up established the presence of an overt MPD in 13 of the 14 patients after a median duration of 38 months. We recommend testing for JAK2(V617F) in all patients with unexplained HVT or PVT, to identify latent MPDs and prevent potential complications.
    International Journal of Laboratory Hematology 11/2008; 30(5):415-9. · 1.29 Impact Factor
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    ABSTRACT: The incidence of histocompatibility antigens HL-A, 4a and 4b was studied in thirty-eight patients with dermatitis herpetiformis (DH) and thirty-six patients with adult coeliac disease (ACD). The 4b antigen was found in all the DH and ACD patients. HL-A 8 was found in 89% of patients with ACD similar to the incidence reported in previous studies—and in 79% of patients with DH, a higher incidence than in previous studies which may be due to stricter criteria being used here to diagnose DH. There was no significant difference in the incidence of HL-A 8 between those patients with DH whose small intestinal biopsies appeared macroscopically abnormal and those with a normal macroscopic appearance. These findings suggest that patients with DH form a single disease group and do not support the concept previously postulated that there are two groups of patients with DH, one with an increased incidence of HL-A 8 antigen similar to that in ACD who have a gluten sensitive enteropathy (GSE), and another with a normal incidence of HL-A 8 antigen and without enteropathy.
    British Journal of Dermatology 07/2006; 94(2):131 - 138. · 3.76 Impact Factor
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    ABSTRACT: We have studied the in vitro actions of the sesquiterpene lactone parthenolide (PTL) on cells isolated from patients with chronic lymphocytic leukemia (CLL). Dye reduction viability assays showed that the median LD(50) for PTL was 6.2 muM (n=78). Fifteen of these isolates were relatively resistant to the conventional agent chlorambucil but retained sensitivity to PTL. Brief exposures to PTL (1-3 h) were sufficient to induce caspase activation and commitment to cell death. Chronic lymphocytic leukemia cells were more sensitive towards PTL than were normal T lymphocytes or CD34(+) haematopoietic progenitor cells. The mechanism of cell killing was via PTL-induced generation of reactive oxygen species, resulting in turn in a proapoptotic Bax conformational change, release of mitochondrial cytochrome c and caspase activation. Parthenolide also decreased nuclear levels of the antiapoptotic transcription factor nuclear factor-kappa B and diminished phosphorylation of its negative regulator IkappaB. Killing of CLL cells by PTL was apparently independent of p53 induction. This is the first report showing the relative selectivity of PTL towards CLL cells. The data here warrant further investigation of this class of natural product as potential therapeutic agents for CLL.
    Leukemia 07/2006; 20(6):1073-9. · 10.16 Impact Factor
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    Journal of Clinical Pathology 04/2005; 58(3):334. · 2.44 Impact Factor
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    A V Hoffbrand
    British Journal of Haematology 11/2003; 123(2):207-18. · 4.94 Impact Factor
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    ABSTRACT: We report the characterization of a new gene (E4.5) that maps at chromosome band 13q14.3, a chromosomal area frequently deleted in chronic lymphocytic leukemia (CLL) and in other lymphoid malignancies. E4.5 gene encodes for a 4 kb mRNA expressed in various tissues and has an open reading frame of 531 amino acids. The predicted E4.5 protein shows strong homology with the human regulator of chromosome condensation (RCC1) protein, the principal GTP exchange factor for Ran protein. The E4.5 protein contains a BTB domain in its N-terminus, a protein-protein interaction motif. Therefore, we propose that E4.5 is a new member of the RCC1-related guanine nucleotide exchange factor (GEF) family with potent interaction with other proteins and unknown function. Until now, no tumor suppressor genes have been mapped in the 13q14.3 minimal deleted region (MDR) in patients with CLL. It has been proposed that loss of the 13q14.3 MDR may contribute to lymphoid neoplasia by altering the expression/function of genes located on 13q14.3 outside the MDR. The E4.5 is one of these genes with a potential role in the pathogenesis of CLL.
    Leukemia and Lymphoma 10/2003; 44(9):1579-85. · 2.61 Impact Factor
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    ABSTRACT: Heterozygous and homozygous deletions of chromosome 13q14.3 are found in 50% of patients with B cell CLL, suggesting the presence of one or more tumour suppressor genes within the deleted region. To identify candidate genes from the region, we constructed a map of 13q14.3 using a combination of genomic and cDNA library screening. The incidence of deletions in CLL patients was 51.5% encompassing a 265 kb region of minimal deletion (RMD) telomeric to markers D13S319. Two CpG islands were identified within the RMD, the telomeric of which is fully methylated whilst the more centromeric is unmethylated. A novel transcript was identified within the RMD that represents an alternative splice version of Leu1. The nine exons of this transcript span a genomic of 436 kb with exon 1 of Leu1 being the common first exon. The remaining exons were shown to be more frequently deleted than Leu1 itself. All splice forms of this transcript were detectable by RT-PCR but Leu1 detected the most abundant message on Northern blotting. Sequence analysis failed to reveal inactivating mutations in patients with heterozygous deletion of 13q14.3, although a polymorphic T to A variant was identified within exon 1 of Leu1 in leukemic and normal controls. As no mutations have been detected for Leu1 or any other transcript so far described, we cannot exclude the existence of control elements within the RMD that may regulate expression of genes lying in this region.
    Leukemia 08/2002; 16(7):1267-75. · 10.16 Impact Factor
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    A V Hoffbrand
    European Heart Journal 01/2002; 22(23):2140-1. · 14.72 Impact Factor
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    ABSTRACT: Ligation of the cell-surface Fas molecule by its ligand (Fas-L) or agonistic anti-Fas monoclonal antibodies results in the cleavage and activation of the cysteine protease procaspase 8 followed by the activation of procaspase 3 and by apoptosis. In some leukemia cell lines, cytotoxic drugs induce expression of Fas-L, which may contribute to cell killing through the ligation of Fas. The involvement of Fas, Fas-L, and caspase 8 was studied in the killing of B-cell chronic lymphocytic leukemia (B-CLL) cells by chlorambucil, fludarabine, or gamma radiation. Spontaneous apoptosis was observed at 24-hour incubation, with additional apoptosis induced by each of the cytotoxic treatments. Although Fas mRNA expression was elevated after exposure to chlorambucil, fludarabine, or gamma radiation, Fas protein levels only increased after irradiation. Therefore, Fas expression may be regulated by multiple mechanisms that allow the translation of Fas mRNA only in response to restricted cytotoxic stimuli. None of the cytotoxic stimuli studied here induced Fas-L expression. An agonistic anti-Fas monoclonal antibody (CH-11) did not significantly augment apoptosis induction by any of the death stimuli. A Fas-blocking antibody (ZB4) did not inhibit spontaneous, chlorambucil-, fludarabine-, or radiation-induced apoptosis. However, procaspase 8 processing was induced by all cytotoxic stimuli. These data suggest that the Fas/Fas-L signaling system does not play a major role in the induction of apoptosis in B-CLL cells treated with cytotoxic drugs or radiation. However, Fas-independent activation of caspase 8 may play a crucial role in the regulation of apoptosis in these cells.
    Blood 12/2001; 98(9):2800-7. · 9.78 Impact Factor
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    ABSTRACT: Oligoclonal B cell proliferation, as defined by the presence of more than one leukemic clone, has been detected in approximately 20% to 30% of patients with acute lymphoblastic leukemia (ALL) using PCR or Southern blotting. An accurate assessment of these populations is required to avoid false negative measurements of minimal residual disease (MRD) in follow-up bone marrow (BM) samples of ALL patients. In this study, we analysed 29 ALL patients with two or more immunoglobulin heavy (IGH) chain gene rearrangements in the presentation samples using IGH fingerprinting PCR and sequence analysis. Thirty-nine (51%) of 76 sequences (from 15 patients), shared no VNDNJ homology (ie different CDR3 regions). In the remaining 14 patients, at least two related VH sequences were identified in each patient (identical DNJ sequences). Numerical abnormalities of chromosome 14 was detected in 10 patients. Eight patients were analysed at presentation and relapse. In four of them, expansion of a minor presentation-clone was detected at relapse while the major presentation clone disappeared, confirming 'subclonal evolution'. Finally, in our cohort of patients, the presence of related or unrelated IGH clones did not influence overall survival.
    Leukemia 11/2001; 15(10):1527-36. · 10.16 Impact Factor
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    ABSTRACT: We have studied the actions of autologous plasma on both basal and DNA damage-induced apoptosis in B-chronic lymphocytic leukaemia (B-CLL) cells. Apoptosis was quantified using morphological criteria and Western blot analysis for the apoptosis-specific p85 fragment of poly(ADP ribose) polymerase. Cell viability was estimated using the methyl thiazol tetrazolium bromide dye reduction assay. Plasma cultures showed lower rates of basal apoptosis as well as a decreased cytotoxic response to chlorambucil and gamma-radiation compared with cultures in fetal calf serum. Experiments using neutralizing antibodies suggested that the protective actions of plasma could not be accounted for by interleukin 4, the interferons alpha or gamma or stromal cell-derived factor 1, each of which have been shown to protect B-CLL cells from apoptosis in vitro. Plasma addition to B-CLL cells resulted in rapid activation of the Akt protein kinase, a key signalling enzyme that has been implicated in anti-apoptotic signalling. LY294002, an inhibitor of phosphatidylinositol 3'-kinase, blocked Akt activation by plasma. To the best of our knowledge, this is the first report to show that factors present in plasma promote basal survival of B-CLL cells and resistance to cytotoxic drugs via stimulation of the Akt cytoprotective-signalling pathway. Pharmacological blockade of this pathway may have potential in the development of novel therapeutic strategies for B-CLL treatment.
    British Journal of Haematology 10/2001; 114(3):608-15. · 4.94 Impact Factor
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    A V Hoffbrand, D G Weir
    British Journal of Haematology 07/2001; 113(3):579-89. · 4.94 Impact Factor
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    ABSTRACT: Detection of PML-RAR alpha transcripts by RT-PCR is now established as a rapid and sensitive method for diagnosis of acute promyelocytic leukemia (APL). Although the majority of patients in long-term clinical remission are negative by consecutive reverse transcription polymerase chain reaction (RT-PCR) assays, negative tests are still observed in patients who ultimately relapse. Conversion from negative to positive PCR has been observed after consolidation and found to be a much stronger predictor of relapse. This study reports on 47 APL patients to determine the correlation between minimal residual disease (MRD) status and clinical outcome in our cohort of patients. The presence of PML-RAR alpha t transcripts was investigated in 47 APL patients (37 adults and 10 children) using a semi-nested reverse transcriptase-polymerase chain reaction to evaluate the prognostic value of RT-PCR tests. All patients achieved complete clinical remission (CCR) following induction treatment with all-trans retinoic acid (ATRA) and chemotherapy (CHT) or ATRA alone. Patients were followed up between 2 and 117.6 months (median: 37 months). Relapses occurred in 11 patients (9 adults and 2 children) between 11.4 and 19 months after diagnosis (median: 15.1 months) while 36 patients (28 adults and 8 children) remained in CCR. Seventy-five percent of patients carried the PML-RAR alpha long isoform (bcr 1/2) which also predominated among the relapsed cases (9 of 11) but did not associate with any adverse outcome (p= 0.37). For the purpose of this analysis, minimal residual disease tests were clustered into four time-intervals: 0-2 months, 3-5 months, 6-9 months and 10-24 months. Children showed persisting disease for longer than adults during the first 2 months of treatment. At 2 months, 10 (50%) of 20 patients who remained in CCR and 4 (80%) of 5 patients who subsequently relapsed were positive. Patients who remained in CCR had repeatedly negative results beyond 5.5 months from diagnosis. A positive MRD test preceded relapse in 3 of 4 tested patients. The ability of a negative test to predict CCR (predictive negative value, PNV) was greater after 6 months (>83%), while the ability of a positive test to predict relapse (predictive positive value, PPV) was most valuable only beyond 10 months (100%). This study (i) highlights the prognostic value of RT-PCR monitoring after treatment of APL patients but only from the end of treatment, (ii) shows an association between conversion to a positive test and relapse and (iii) suggests that PCR assessments should be carried out at 3-month intervals to provide a more accurate prediction of hematologic relapses but only after the end of treatment.
    Haematologica 06/2001; 86(6):577-85. · 5.94 Impact Factor
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    ABSTRACT: The aim of this study was to characterize individual-segment and overall patterns of V(H) gene usage in adult B-lineage acute lymphoblastic leukemia (ALL). Theoretical values of V(H) segment usage were calculated with the assumption that all V(H) segments capable of undergoing rearrangement have an equal probability of selection for recombination. Leukemic clones from 127 patients with adult B-lineage acute leukemias were studied by fingerprinting by means of primers for the framework 1 and joining segments. Clones from early preimmune B cells (245 alleles identified) show a predominance of V(H)6 family rearrangements and, consequently, do not conform to this hypothesis. However, profiles of V(H) gene family usage in mature B cells, as investigated in peripheral blood (6 samples), B-cell lymphomas (36 clones) and chronic lymphocytic leukemia (56 clones), are in agreement with this theoretical profile. Sequence analyses of 64 V(H) clones in adult ALL revealed that the rate of V(H) usage is proportional to the proximity of the V(H) gene to the J(H) locus and that the relationship can be mathematically defined. Except for V(H)6, no other V(H) gene is excessively used in adult ALL. V(H) pseudogenes are rarely used (n = 2), which implies the existence of early mechanisms in the pathway to B-cell maturation to reduce wasteful V(H)-(D(H))-J(H) recombination. Finally, similar to early immunoglobulin-H rearrangement patterns in the mouse, B cells of ALL derive from a pool of cells more immature than the cells in chronic lymphoid B-cell malignancies.
    Blood 06/2001; 97(9):2716-26. · 9.78 Impact Factor
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    ABSTRACT: The t(12;21)(p13;q22) translocation, resulting in the fusion of the ETV6 and AML1 genes, occurs in 20-25% of paediatric B-lineage acute lymphoblastic leukaemias (ALL). The identification of the fusion product has important prognostic and therapeutic implications as the translocation has been associated with a favourable clinical outcome. The aim of this study was threefold: (i) to assess the frequency and clinical association of the fusion gene in patients with and without a cytogenetically detectable chromosome 12 and/or 21 abnormality or failed cytogenetic results, (ii) to characterize alternative forms of ETV6/AML1 transcripts, and (iii) to use ETV6/AML1 as a molecular marker for the investigation of minimal residual disease (MRD). ETV6/AML1 fusion was detected in 22 (39%) of 56 cases studied by reverse transcriptase polymerase chain reaction (RT-PCR). ETV6/AML1 fusion was found in nine out of 16 (56%) cases with a cytogenetically visible chromosome 12 abnormality, but also in nine out of 29 patients (31%) without a chromosome 12 abnormality or patients with failed cytogenetics (four out of 11 patients, 36%), making this the most common cytogenetic abnormality in childhood ALL. Alternatively spliced ETV6/AML1 forms were investigated in 14 of the positive patients. Exon 5 of ETV6 was fused in frame to all AML1 exons, except exon 4. Fusion to exon 6 of AML1 resulted in one amino acid change. The presence of ETV6/AML1 was associated with a lower white blood cell count (Student's t-test; P = 0.009) and common (c)ALL phenotype (chi(2) test; P > 0.001), but no better disease-free survival. Our study shows that (i) RT-PCR is the most effective approach for the detection of t(12;21) in childhood ALL, (ii) the association of ETV6/AML1 and chromosome 12 and/or 21, seen in 56% of our cases, further confirms existing data, (iii) overall survival of patients with t(12;21) was not better than other cytogenetics groups, and (d) MRD analysis using ETV6/AML1 fusion is specific, but not sensitive enough to avoid false negative results.
    British Journal of Haematology 12/2000; 111(4):1071-9. · 4.94 Impact Factor
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    ABSTRACT: Clinical complications of transfusional iron overload are still common in patients with thalassaemia major (TM) and it is not clear how best to monitor body iron stores during long-term follow-up to anticipate tissue damage. In this study, we have reviewed a group of 32 patients who underwent liver biopsy between 1984 and 1986. We developed a method of assessing the trend in serum ferritin (TSF) during long-term monitoring and compared this with mean serum ferritin (MSF) and initial liver iron (LI) concentration to determine whether, individually or in combination, they were accurate in predicting clinical outcome. LI levels were low (< 7 mg/g), medium (7-15 mg/g) and high (> 15 mg/g dry weight) in 15, 7 and 10 patients respectively. MSF was low (< 1500 microg/l), medium (1500-2500 microg/l) and high (> 2500 microg/l) in 10, 14 and 8 patients. TSF was low, medium and high risk in 9, 9 and 11 out of 29 evaluable patients. During a median follow-up of 13.6 years (range 2.3-14.8 years) after biopsy, nine patients died and an additional three patients developed heart failure. Hypothyroidism developed in five, hypoparathyroidism in four, and diabetes mellitus in seven patients. Cirrhosis developed in four of 10 evaluable patients. The clinical end-point of death or cardiac failure was significantly associated with increasing iron load using all three means of assessment. Although numbers were insufficient for statistical analysis, MSF or TSF were more closely associated with complications of iron overload than LI. There was no clear additional value in combining LI with MSF or TSF. The data show that quantitation of liver iron from a single liver biopsy has little value in long-term monitoring of iron stores. Most complications can be avoided if ferritin levels can be brought down to <1500 microg/l.
    British Journal of Haematology 10/2000; 110(4):971-7. · 4.94 Impact Factor
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    R G Wickremasinghe, A V Hoffbrand
    Blood 07/1999; 93(11):3587-600. · 9.78 Impact Factor
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    ABSTRACT: Ceramide induces apoptosis in leukemia cell lines and has been proposed as a potential therapeutic agent in malignancies refractory to conventional treatment. Here we show that synthetic N-acetyl-d-erythro-sphingosine (C2 ceramide) kills normal human T lymphocytes by a caspase-independent nonapoptotic mechanism. By contrast, T cells were induced to caspase-dependent apoptosis by okadaic acid. Furthermore, C2 ceramide treatment of the Jurkat leukemia cell line induced killing by apoptosis. Activation of T lymphocytes by phytohemagglutinin abrogated killing by C2 ceramide. The data here suggest that ceramide triggers caspase-dependent apoptosis in leukemia cells lines, but activates caspase-independent nonapoptotic killing of resting T lymphocytes which is abrogated following mitogenic activation.
    Experimental Cell Research 06/1999; 249(1):116-22. · 3.56 Impact Factor

Publication Stats

11k Citations
3,981.06 Total Impact Points

Institutions

  • 1988–2001
    • University College London
      • Department of Haematology
      London, ENG, United Kingdom
  • 1982–2001
    • Royal Free London NHS Foundation Trust
      • Department of Haematology
      Londinium, England, United Kingdom
  • 1999
    • Norfolk and Norwich University Hospitals NHS Foundation Trust
      • Haematology Unit
      Norwich, England, United Kingdom
  • 1998
    • University College London Hospitals NHS Foundation Trust
      • Department of Obstetrics and Gynaecology
      London, ENG, United Kingdom
    • UK Department of Health
      Londinium, England, United Kingdom
  • 1979–1997
    • The Whittington Hospital NHS Trust
      Londinium, England, United Kingdom
  • 1993
    • University of London
      Londinium, England, United Kingdom
  • 1991–1993
    • St. Jude Children's Research Hospital
      Memphis, Tennessee, United States
  • 1992
    • Imperial College Healthcare NHS Trust
      Londinium, England, United Kingdom
  • 1989
    • Medsol Clinical Research Center
      Florida, United States
  • 1985–1989
    • Universität Heidelberg
      Heidelburg, Baden-Württemberg, Germany
  • 1981
    • Uniformed Services University of the Health Sciences
      Maryland, United States
  • 1980
    • Mount Sinai Hospital, Toronto
      Toronto, Ontario, Canada
  • 1976
    • London School of Hygiene and Tropical Medicine
      Londinium, England, United Kingdom
  • 1971
    • Cancer Research Institute
      New York City, New York, United States
  • 1970
    • British Medical Journal
      Londinium, England, United Kingdom
  • 1968
    • Boston Medical Center
      Boston, Massachusetts, United States
  • 1967
    • Lund University
      Lund, Skåne, Sweden