The Liverpool Lung Project: a molecular epidemiological study of early lung cancer detection.

Lung cancer is the major cause of death from neoplastic disease in the world, and even with politically-motivated smoking cessation campaigns throughout Europe, the disease remains the major cause of death. The development of molecular epidemiological population-based research into early lung cancer detection, such as the Liverpool Lung Project (LLP), may provide a way forward. This is the first major molecular epidemiological study of detection of early lung cancer. The use of molecular epidemiological risk assessments prior to clinical diagnosis and markers of preclinical carcinogenesis in patients with a high risk of developing lung cancer will reduce the incidence of clinically-detectable lung cancer, given the appropriate intervention strategies. The aims are as follows: 1) to prepare a molecular genetic and epidemiological risk assessment model based on environmental exposures and genetic predisposition; 2) to develop an archive of specimens relating to at-risk individuals and those with lung cancer; 3) to redefine lung cancer based on molecular pathology using the fields of expression profiling, genetic instability and molecular cytogenetics; 4) to identify and assess novel markers of precarcinogenesis in high-risk populations; and 5) to facilitate the development of new treatment strategies (e.g. chemoprevention programmes and targeted drug therapies). The LLP has two components: 1) a case-controlled study of newly-diagnosed cases of lung cancer that will provide a baseline, risk assessment; and 2) a prospective cohort study to be carried out over a 10-yr period that will identify markers of preclinical carcinogenesis. In-depth interviews are carried out using structured and semi-structured questionnaires. Sputum, blood and tumour specimens are collected and will be assessed for specific molecular markers (e.g. genetic instability, mutation and expression profiling, and methylation status). Conclusions from The Liverpool Lung Project will be based around molecular-epidemiological and genotyping risk assessment models, as well as redefining the disease, and ultimately contributing to the development of new early lung cancer detection and treatment strategies.

Genes meet geology: fish phylogeographic pattern reflects ancient, rather than modern, drainage connections.

We used DNA analysis of the freshwater Galaxias vulgaris complex (Pisces: Galaxiidae) to test a geological hypothesis of drainage evolution in South Island, New Zealand. Geological evidence suggests that the presently north-flowing Nevis River branch of the Clutha/Kawarau River system (Otago) once flowed south into the Nokomai branch of the Mataura system (Southland). The flow reversal is thought to have resulted from fault and fold activity associated with post-Miocene uplift. Mitochondrial DNA sequence data (control region and cytochrome b genes; 76 individuals; maximum divergence 7.1%) corroborate this geomorphological hypothesis: The Nevis River retains a freshwater fish species (Galaxias gollumoides; five sites; 10 haplotypes) that is otherwise restricted to Southland (nine sites; 15 haplotypes). There is no indication that the Nevis River lineage of G. gollumoides lives elsewhere in the Clutha/ Kawarau system (> 30 sites). Likewise, two widespread Clutha lineages (G. 'sp D'; G. anomalus-G. pullus) are apparently absent from the Nevis (> 30 sites). In particular, G. 'sp D' lives throughout much of the Clutha (12 sites, 23 haplotypes), including a tributary of the Kawarau, but is absent from the Nevis itself. Conventional molecular clock calibrations (based on a minimum Nevis-Mataura haplotype divergence of 3.0%) indicate that the Nevis flow reversal may have occurred in the early-mid Pleistocene, which is roughly consistent with geological data. The broad phylogeographic structure evident in the Clutha system is consistent with the sedentary nature of nonmigratory galaxiids. Our study reinforces the value of combining biological and geological data for the formulation and testing of historical hypotheses.

Comparison of different scoring systems for immunohistochemical staining.

AIM: To carry out an objective assessment of two systems of scoring immunohistochemical staining, evaluating interobserver and intraobserver error. METHODS: 92 cervical tumours underwent immunohistochemical staining for p53 and epidermal growth factor receptor. Staining was assessed using two methods: a standard 4 point scale and a descriptive method, performed by three observers. Interobserver and intraobserver error were assessed for both scoring methods. RESULTS: In terms of interobserver error between three observers, no difference was found between a simple 4 point scale method of evaluation and the use of a highly circumscribed method. In all evaluations, interobserver error was scored as moderate (kappa w 0.48-0.49). However, evaluation of immunohistochemical staining by a panel of observers led to a marked improvement in the interobserver error scores (kappa w 0.63). CONCLUSIONS: There should be standardisation of immunohistochemical staining and scoring methods. More attention should be paid to measurement of interobserver and intraobserver error in studies. Use of a panel of tissue control slides and consensus scoring by several observers can lead to improvement in reproducibility.

Treatment and survival of lymphoid malignancy in the north-west of England: a population-based study.

Classification of lymphoid malignancy has changed markedly in recent years and advances have been made in therapy. This study investigated the variations in treatment and survival of 1622 patients in a population-based registry. A total of 1009 cases of malignant lymphoma (ML) were classified according to the Kiel classification. Pathology review resulted in major diagnostic changes for 24% of cases. Of the ML cases, 39% had not had full staging procedures. Younger patients were more likely to have been treated with multiagent chemotherapy regimens, as were patients with B symptoms. Median survival for ML patients was 12 months for high-grade patients and more than 60 months for low-grade patients. Significant factors affecting the survival of ML patients were performance status, whether treatment had followed a recognised protocol, whether treatment had been carried out at a specialist oncology centre (SOC), grade of disease, stage, gender and age. The same factors had a significant effect on survival of the leukaemia patients, except for treatment at an SOC, which had a significant favourable effect on survival of acute lymphoblastic leukaemia (ALL) patients only. Median survival for patients with chronic lymphocytic leukaemia was 43 months and 7 months for ALL patients.

A case/control study of adult haematological malignancies in relation to overhead powerlines.

A population based case control study of adult haematological malignancy and distance from, and magnetic fields associated with, overhead (OH) power lines has been carried out in the North West and Yorkshire regions of England. Three-thousand, one hundred and forty-four cases with histologically proven disease were entered into the study. One control per case, matched for age, sex, year of diagnosis and health district of residence, was selected from hospital discharges. Seven per cent of cases and controls lived near to OH power lines as defined by the study protocol. The measure of exposure used was the calculated magnetic field strength at each of these addresses due to maximum load currents carried by OH power lines in the 5 years preceding diagnosis. The odds ratio (OR) for living within 50 m of an OH line was 1.29 with a 95% Confidence Interval (CI) of 0.99-1.68 but a chi 2 test for trend with distance was not statistically significant. The analysis of calculated magnetic fields, did not produce any statistically odds ratios. The OR for magnetic fields greater than or equal to 0.1 mG was 1.03 (95% CI 0.81 1.32). Analysis of magnetic fields greater than or equal to 3.0 mG gave an OR of 1.87 (95% CI 0.79 4.42), but this result is based on small numbers. No evidence was found for confounding by the type of dwelling which was used as a partial surrogate for socio-economic status.