Faculty Bibliography

This study described the haplotypic structure across a region of chromosome 6 including the tumour necrosis factor (TNF) gene, and investigated its influence on the aetiology of myeloma. A total of 181 myeloma cases from the Medical Research Council Myeloma VII trial and 233 controls from the Leukaemia Research Fund Case Control Study of Adult Acute Leukaemia were included in the analysis. Genotyping by induced heteroduplex generator analysis was carried out for single nucleotide polymorphisms (SNP) located at positions -1031, -863, -857, -308 and -238 of the 5' promoter region of TNF-alpha gene, and 252 in the LT-alpha gene; and five microsatellites, TNFa, b, c, d and e. Haplotypes were inferred statistically using the phase algorithm. A limited diversity of haplotypes was observed, with the majority of variation described by 12 frequent haplotypes. Detailed characterization of the haplotype did not provide greater determination of disease risk beyond that described by the TNF-alpha-308 SNP. Some evidence was provided for a decreased risk of myeloma associated with the TNF-alpha-308 variant allele A, odds ratio, 0.57; 95% confidence interval, 0.38-0.86. The results of this study did not support our starting hypothesis; that high producer haplotypes at the TNF locus are associated with an increased risk of developing myeloma.

Induction chemotherapy followed by high-dose melphalan (HDM) is the standard treatment for fitter patients with myeloma. The place of bortezomib and the thalidomide analogues within this treatment paradigm is yet to be established. We sought to identify patients who may benefit from the introduction of novel agents during their initial management. An intention-to-treat analysis was performed on 383 patients with newly diagnosed myeloma eligible for HDM to determine whether the extent of response to induction therapy and HDM correlated with long-term survival. Early response [complete response (CR) and partial response (PR)] to induction therapy was predictive of overall survival (OS) [median OS, 7.47 years for responders (CR and PR) versus 4.89 years for non-responders; P = 0.035]. The attainment of CR at 3 months post-HDM correlated with a prolonged progression-free survival (PFS) (median PFS, 7.4 years in CR group versus 5.3 years in non-CR group; P = 0.023). This data suggests that, at every stage of treatment, the aim should be to achieve CR. Patients with suboptimal responses could be offered alternative therapy. We propose a multiparametric risk-adapted model that includes response to induction chemotherapy and HDM, for identifying patients who may benefit from novel approaches to treatment.

Broad cross-talk exists between the endocrine and immune systems. Estrogen receptor expression in lymphocytes suggests that hormonal modulation may influence lymphoma risk. Analysis of genetic polymorphisms that affect oestrogen production, such as cytochrome P450 17A1 (CYP17A1) -34T>C, may provide insight into oestrogen's role in lymphomagenesis. CYP17A1-34T>C and CYP17A1 IVS2 105A>C polymorphisms were analyzed in a non-Hodgkin lymphoma (NHL) population-based case-control study. The CYP17A1-34CC genotype was positively associated with NHL [odds ratio (OR) = 1.44, 95% confidence interval (CI) 1.02-2.03], particularly diffuse large B-cell lymphoma (OR = 1.76, CI 1.14-2.71). Associations of CYP17A1 polymorphisms with increased risk of NHL suggest a role for oestrogen in lymphomagenesis.

The emerging understanding of the biology of the hemopoietic stem cell is beginning to shed light on the mechanisms by which benzene gives rise to acute myeloid leukaemia. These mechanisms are complex, affecting not only the DNA, but also the complex intercellular interactions present in the bone marrow microenvironment. The toxic effects of benzene are mediated within the bone marrow and we are beginning to understand the contributions of inter-individual variation in xenobiotic metabolisms and DNA repair to the definition of risk following exposure to benzene in the environment. This process is likely to be accelerated by recent advances in high throughput genotyping. Until now, research has focussed directly on mutation and chromosomal translocations, but we are beginning to understand more how environmental exposures can modify chromatin structure giving rise to heritable changes not affecting DNA. These epigenetic studies are likely to give important further insights into the mode of action of benzene as are studies of its effect on the immune system.

Genetic instability, including chromosomal imbalance, is important in the pathogenesis of lymphoproliferative disorders such as non-Hodgkin lymphoma (NHL). DNA synthesis and methylation, which are closely linked to folate metabolism and transport, may be affected by polymorphisms in genes involved in these pathways. Folate metabolism polymorphisms have been linked to acute lymphoblastic leukemia and colorectal cancer. To evaluate whether genetic variation in folate metabolism and transport may have a role in determining the risk of developing NHL, we analyzed several polymorphisms using DNA obtained as part of a large U.K. population-based case-control study of lymphoma. Polymorphisms studied include methylenetetrahydrofolate reductase (MTHFR) 677 C >T and 1298 A >C, methionine synthase (MTR) 2756 A>G, serine hydroxymethyltransferase (SHMT1) 1420 C >T, thymidylate synthase (TYMS) 1494del6 and 28-bp repeat, and reduced folate carrier (RFC) 80 G >A. Increased risks for NHL [odds ratio (OR), 1.48; 95% confidence intervals (CI), 1.12-1.97], and marginal zone lymphoma (OR, 3.38; 95% CI, 1.30-8.82) were associated with the TYMS 2R/3R variant. Marginal increased risks were also observed for diffuse large B cell lymphoma with the TYMS homozygous 6 bp deletion (OR, 1.61; 95% CI, 0.99-2.60) and for follicular lymphoma with RFC 80AA (OR, 1.44; 95% CI, 0.94-2.22) and TYMS 28-bp repeat 2R/3R (OR, 1.45; 95% CI, 0.96-2.2). We observed no association between NHL and haplotypes for MTHFR or TYMS. These findings are somewhat inconsistent with those of others, but may reflect differences in circulating folate levels between study populations. Thus, further investigations are warranted in larger series with dietary information to determine the roles that genetics and folic acid status play in the etiology of lymphoma.

PURPOSE/OBJECTIVE:We have developed and evaluated a CNS-targeted chemotherapy regimen based on the pharmacokinetic properties of the individual drugs in the combination. PATIENTS AND METHODS/METHODS:In a twin-track study, 16 patients with secondary CNS lymphoma (SCNSL) and 8 with primary CNS lymphoma (PCNSL) were treated with IDARAM which comprised idarubicin 10 mg/m(2) i.v., days 1 and 2; dexamethasone 100 mg, 12-h infusion, days 1, 2 and 3; cytosine arabinoside (ARA-C) 1.0 g/m(2), 1-h infusion, days 1 and 2; methotrexate 2.0 g/m(2), 6-h infusion, day 3 (with folinic acid rescue); and cytosine arabinoside 70 mg plus methotrexate 12 mg, intrathecally, days 1 and 8. Two cycles were delivered at 3-weekly intervals. After response assessment, patients received adjuvant cranial radiotherapy (40 Gy over 20 fractions). RESULTS:The series comprised 24 patients, 11 male and 13 female. Their median age was 53 years (range 21 to 73 years). Grade 4 neutropenia and thrombocytopenia occurred in the majority of patients treated. Of the eight PCNSL patients, seven achieved complete remission (CR). Four remained in CR at the time of this report with a median duration of follow-up of 25 months (range 11 to 42 months). Of the 16 SCNSL patients, 12 achieved CR. Seven patients remained in CR at the time of this report with a median duration of follow-up of 24 months (range 18 to 57 months). CONCLUSION/CONCLUSIONS:This study suggests that IDARAM is an effective regimen in both PCNSL and SCNSL and is suitable for further development and evaluation.

Understanding haematological malignancies at the protein level is important as the development of targeted treatments must be based on knowledge regarding the molecular pathogenesis of the tumour, inherited genetic variation and the mode of action of drugs. 'Proteomics' describes the analysis of the entire proteome of a cell or tissue and incorporates multiple technologies including Western blotting, two-dimensional gel electrophoresis, mass spectrometry, and ProteinChip-based technology. Although there are a limited number of studies to date in haematology those performed highlight the potential future impact of these technologies in the discovery of novel markers, proteins associated with drug resistance and the identification of tumour biomarkers which may facilitate the development of a rapid diagnostic test easily applicable in the clinical setting. Rapid large-scale analysis of the proteome in normal pathways and disease offers the opportunity of identification of potential diagnostic/prognostic markers and proteins associated with the malignant phenotype. This review discusses the current situation regarding the use of these technologies and the potential opportunities their future use may offer in the field of haematology.