Updated investigations of cancer excesses in individuals born or resident in the vicinity of Sellafield and Dounreay.

BACKGROUND: Earlier studies have shown raised risks of leukaemia and non-Hodgkin lymphoma in children, teenagers and young adults resident either at birth or diagnosis in Seascale. Some increases in cancer risk in these age groups have also been noted among those living around Dounreay. We aimed to update previous analyses relating to areas close to these nuclear installations by considering data from an additional 16 years of follow-up. METHODS: Cross-sectional analyses compared cancer incidence rates for 1963-2006 among those aged 0-24 years at diagnosis living in geographically specified areas around either Sellafield or Dounreay with general population rates. Cancer incidence for the period 1971-2006 among the cohort of Cumbrian births between 1950 and 2006 was compared to national incidence for 1971-2006 using person-years analysis. Cancer among those born in the postcode sector closest to Dounreay was compared with that among those born in the three adjoining postcode sectors. Analyses considered both cancer overall and ICD-O-3 defined diagnostic subgroups including leukaemia, central nervous system tumours and other malignancies. RESULTS: Apart from previously reported raised risks, no new significantly increased risks for cancer overall or any diagnostic subgroup were found among children or teenagers and young adults living around either nuclear installation. Individuals born close to the installations from 1950 to 2006 were not shown to be at any increased risk of cancer during the period 1971 to date. CONCLUSIONS: Analysis of recent data suggests that children, teenagers and young adults currently living close to Sellafield and Dounreay are not at an increased risk of developing cancer. Equally, there is no evidence of any increased cancer risk later in life among those resident in these areas at birth.

Risk of cancer following primary total hip replacement or primary resurfacing arthroplasty of the hip: a retrospective cohort study in Scotland.

BACKGROUND: Release and dispersion of particles arising from corrosion and wear of total hip arthroplasty (THA) components has raised concerns about a possible increased risk of cancer. Concerns have been heightened by a recent revival in the use of metal-on-metal (MoM) hip prostheses. METHODS: From a linked database of hospital discharge, cancer registration, and mortality records, we selected a cohort of patients who underwent primary THA (1990-2009) or primary resurfacing arthroplasty (mainly 2000-2009) in Scotland, with follow-up to the end of 2010. Available operation codes did not enable us to distinguish MoM THAs. Indirectly standardised incidence ratios (SIRs) were calculated for selected cancers with standardisation for age, sex, deprivation, and calendar period. RESULTS: The study cohort included 71 990 patients yielding 547 001 person-years at risk (PYAR) and 13 946 cancers diagnosed during follow-up. For the total period of observation combined, the risks of all cancers (SIR: 1.05; 95% CI: confidence interval 1.04-1.07), prostate cancer (SIR: 1.07; 95% CI: 1.01-1.14), and multiple myeloma (SIR: 1.22; 95% CI: 1.06-1.41) were increased. These modest increases in risk emerged in the context of effectively multiple tests of statistical significance, and may reflect inadequate adjustment for confounding factors. For 1317 patients undergoing primary resurfacing arthroplasty between 2000 and 2009 (PYAR=5698), the SIR for all cancers (n=39) was 1.23 (95% CI: 0.87-1.68). CONCLUSION: In the context of previous research, these results do not suggest a major cause for concern. However, the duration of follow-up of patients receiving recently introduced, new-generation MoM prostheses is too short to rule out a genuinely increased risk of cancer entirely.

The impact of population-based faecal occult blood test screening on colorectal cancer mortality: a matched cohort study.

BACKGROUND: Randomised trials show reduced colorectal cancer (CRC) mortality with faecal occult blood testing (FOBT). This outcome is now examined in a routine, population-based, screening programme. METHODS: Three biennial rounds of the UK CRC screening pilot were completed in Scotland (2000-2007) before the roll out of a national programme. All residents (50-69 years) in the three pilot Health Boards were invited for screening. They received a FOBT test by post to complete at home and return for analysis. Positive tests were followed up with colonoscopy. Controls, selected from non-pilot Health Boards, were matched by age, gender, and deprivation and assigned the invitation date of matched invitee. Follow-up was from invitation date to 31 December 2009 or date of death if earlier. RESULTS: There were 379 655 people in each group (median age 55.6 years, 51.6% male). Participation was 60.6%. There were 961 (0.25%) CRC deaths in invitees, 1056 (0.28%) in controls, rate ratio (RR) 0.90 (95% confidence interval (CI) 0.83-0.99) overall and 0.73 (95% CI 0.65-0.82) for participants. Non-participants had increased CRC mortality compared with controls, RR 1.21 (95% CI 1.06-1.38). CONCLUSION: There was a 10% relative reduction in CRC mortality in a routine screening programme, rising to 27% in participants.

Systemic lupus erythematosus: presence in human serum of an unusual acid-labile leukocyte interferon.

A previously undescribed species of human leukocyte, or alpha, interferon is present in the serum of many patients with systemic lupus erythematosus. It was shown to be alpha-interferon by neutralization with specific antiserums, affinity column chromatography, and antiviral activity on bovine cells. However, 23 of 30 interferon samples tested were inactivated by incubation at pH 2, a characteristic of human "immune," or gamma, interferon. Multiple samples of interferon from the same patient had similar biological properties, but samples from different patients were not all identical, suggesting that several variants of this species of human alpha-interferon may exist.

Risk of leukaemia among children living near the Solway coast of Dumfries and Galloway Health Board area, Scotland, 1975-2002.

OBJECTIVE: To investigate allegations of an excess risk of leukaemia among children living near the Solway Firth coast of Dumfries and Galloway Health Board area in Scotland, UK. METHODS: Incident cases of childhood leukaemia (International Classification of Diseases, 10th revision, C91-C95, patients aged 0-14 years) for two almost equal calendar periods of diagnosis (1975-89 and 1990-2002) were selected from the Scottish Cancer Registry database and allocated to predetermined study areas, on the basis of proximity of residence to the Solway coast. Expected numbers of childhood leukaemia cases for the study areas were calculated by applying Scotland's age-specific, sex-specific and calendar period-specific rates to estimates of the person-years at risk in each study area. The ratios of observed to expected cases or standardised incidence ratios (SIRs) were calculated overall and for each sex and calendar period category. Exact 95% confidence intervals (CIs) for the SIRs were calculated assuming a Poisson distribution for the observed number of cases of childhood leukaemia. RESULTS: No statistically significantly increased SIRs were found in boys, girls or both combined for any of the areas or periods of diagnosis studied. For the total period of observation (1975-2002), and the more immediate coastal area studied, the SIR for both sexes combined was 1.22 (95% CI 0.53 to 2.40). CONCLUSION: No statistically significant evidence was found of an excess risk of childhood leukaemia in the vicinity of the Solway Firth coast of Dumfries and Galloway Health Board area in Scotland.

Antagonism of 2-5 A-mediated inhibition of protein synthesis in intact cells by 2',5'-(pA)3.

In vitro studies have shown that the translational inhibitory activity of 2-5 A can be blocked by the oligoribonucleotide 2',5'-(pA)3. We have examined the effect of simultaneous introduction of inhibitor and antagonist into intact mouse cells using calcium phosphate coprecipitation. Upon introduction of 10(-4) M 2',5'-(pA)3 and 10(-6) M 2-5 A, inhibition of protein synthesis was prevented. Efficiency of calcium phosphate precipitation of 2-5 A in the presence or absence of 2',5'-(pA)3 was comparable. Introduction of 2',5'-(pA)3 analogs showed that nucleotides which do not bind well to the 2-5 A dependent endonuclease do not prevent 2-5 A inhibitory activity. Thus, 2',5'-(pA)3 functions as an antagonist of 2-5 A in vivo.

Cancer incidence and mortality in the European Union: cancer registry data and estimates of national incidence for 1990.

Members of the European Network of Cancer Registries (ENCR) provide population-based data on cancer incidence for some countries and regions of Europe. These were supplemented by estimates in order to provide comparable information on cancer incidence and mortality in the 15 member states of the European Union (EU). The estimated numbers of new cases of cancer (excluding nonmelanoma skin cancer) in 1990 were approximately 706,900 in men and 644,200 in women. Approximately 497,500 men and 398,200 women died of cancer in the same year. The main sites of incident cases in men were lung (21%), large bowel (13%), prostate (12%), bladder (7%) and stomach (7%). For women, the predominant sites were breast (28%), large bowel (15%), lung (6%), uterine corpus (5%) and stomach (5%). The overall incidence rates for males were highest in continental Western Europe (France, The Netherlands, Austria, Luxembourg, Belgium, Germany and Italy) while the rates of Greece, Portugal, Sweden, Ireland, Spain, Finland, the U.K. and Denmark were below the average value for the EC. Rates for females were highest in Northern and Western Europe, with the exception of France, which had a relatively low rate for females, in common with Greece, Spain and Portugal. The geographical variations in incidence of the major cancers are discussed in relation to risk factors. The estimates show the substantial burden of cancer in European Union populations, but there are also indications of effects of past preventive measures and there is scope for further intervention. Cancer registries are an important source of information for cancer control since they provide population-based incidence and survival statistics. These, along with mortality data, are required to obtain a full picture of the frequency of cancer and its effects at the population level. Some 44% of the EU population is covered by registries. The European Network of Cancer Registries aims to standardise the information provided by existing registries and to provide practical assistance to those in development.

Incidence of non-Hodgkin's lymphoma in children between 1970 and 1990 in nine European countries.

Data from population-based cancer registries in Europe (nine countries) were used to monitor the incidence of non-Hodgkin's lymphoma in children aged 0-14 years over the 20 year period 1970-1990. The overall annual change in incidence was small--an increase of 0.76% annually, and there was no change at all in infants under one year of age. This differs markedly from the pattern in adults, where quite large increases have occurred.

Animal studies of prophylaxis.

Antiviral and immune-based intervention strategies have been evaluated in vivo in animal models based on infections with lentiviruses and other retroviruses to explore their effect on preventing or limiting de novo virus infection. Variables that can be experimentally manipulated to address specific questions relevant to postexposure prophylaxis (PEP) include timing of initiation of treatment, duration of treatment, dosing regimen, virus strain, and virus inoculum. Prevention of the establishment of infection by PEP has been documented under defined experimental conditions. However, in the event that early intervention is not effective in preventing infection, evidence supporting control of viral replication and disease progression mediated by early intervention has also been reported. Thus, PEP may have a significant impact in preventing or altering viral replication in vivo and disease course.

Frontiers in HIV-1 Therapy: fourth conference of the NIAID National Cooperative Drug Discovery Groups-HIV.

This summary describes current studies in antiviral targeting as reported at the Frontiers in HIV Therapy conference, November 3-7, 1991, in San Diego, California. In parallel with the progressive steps in HIV-1 replication, the meeting covered potential antiviral targets starting from the time HIV-1 docks with the CD4 receptor to virus release. The summary concludes with current research trends to block HIV-1 growth.

Conference summary: novel HIV therapies--from discovery to clinical proof of concept.

In this report we have highlighted only a few examples of the extensive efforts underway to better understand the process of HIV pathogenesis, to develop new therapeutic agents to inhibit virus replication, and to identify strategies to restore damage done to the immune system during HIV disease progression. It is expected that progress in these areas will continue to advance, and that development of more effective therapies will lead to comprehensive multifaceted, multipronged treatment regimens.

Complications associated with free jejunal graft reconstruction of the pharyngoesophagus--a multiinstitutional experience with 52 cases.

Fifty-two patients who underwent reconstruction of the pharynx and esophagus using the free jejunal graft were retrospectively reviewed. The complications were categorized into those associated with the resection, those associated with the harvesting of the graft, and those related to the reconstruction per se. In this series, the graft failure rate was 7.6% with an overall success rate of 90.3%. Graft necrosis was found to be the most serious complication occurring in four patients. Methods of detection of graft necrosis and management of these complications are discussed.

Cancer incidence and mortality in France in 1975-95.

The aims of the European Network of Cancer Registries (ENCR) are to improve the quality, comparability and availability of cancer registry data in Europe. This paper on cancer incidence and mortality in France presents the most recent available data, with short-term projections to 1995, and a commentary based, where possible, on epidemiological research carried out in France. Cancer incidence in men in France increased throughout the study period 1975 to 1995, from 92,000 new cases in 1975 to about 135,000 in 1995. This increase was partly due to the ageing of the French population, but incidence rates have also increased, particularly from 1975 to 1985. The trend appears to be levelling off in the 1990s, with an incidence rate in 1995 of about 482 per 100,000 (this and subsequent rates quoted are standardized to the European Standard Population). Among women, the all-cancer incidence rates also increased during the 1970s and 1980s. Although the rate of increase was less pronounced than in men, the trend is continuing in the 1990s. The estimated age standardized rate in 1995 was 309 per 100,000, representing 104,000 new cases. The main components of these changes in the last decade were, for men, increases in large bowel and prostate cancer, which have been partly compensated for by decreases in oral cavity, larynx and stomach cancer. For women the trend was dominated by the continuing increase in breast cancer with increases also in large bowel and lung cancers. Of the numerically important cancers in women, only stomach cancer has shown a clear decline. The situation in 1995 was that breast cancer remained the predominant cancer affecting women in France, accounting for almost one third of all new cases of cancer diagnosed and one fifth of cancer deaths. The next most frequent cancers in women were those of the large bowel. Regrettably, incidence rates of both breast and bowel cancer are increasing in women. For men in France the most frequent cancers in 1995 were those of the prostate, large bowel and lung, all of which increased in incidence since 1975. Although it is estimated that there will be more newly diagnosed cases of prostate cancer than lung cancer in 1995, the latter will cause many more deaths, particularly of young men.

Leukaemia and non-Hodgkin's lymphoma: incidence in children and young adults resident in the Dounreay area of Caithness, Scotland in 1968-91.

STUDY OBJECTIVE: To review the incidence of leukaemia and non-Hodgkin's lymphoma in children and young adults in the area less than 25 km from the Dounreay nuclear installation and the remainder of the Kirkwall postcode area in the full time period for which data are now available (1968-91), and to determine whether the excess incidence reported in the period up to 1984 has continued in subsequent years. DESIGN: Geographical incidence study. SETTING: The Kirkwall postcode area of Scotland. SUBJECTS: Children and young adults resident in the area in the period 1968-91. MAIN RESULTS: Observed numbers of cases of leukaemia and non-Hodgkin's lymphoma and observed to expected ratios with expected numbers based on Scottish national rates were determined. In 1968-91, 12 cases were observed compared with 5.2 expected in the zone < 25 km from the Dounreay plant (p = 0.007). In the latest period, 1985-91, which has not previously been examined, four cases were observed compared with 1.4 expected (p = 0.059). CONCLUSION: The observation of an excess of borderline statistical significance in 1985-91 following the substantial excess incidence which occurred in the early 1980s suggests that the incidence of leukaemia and non-Hodgkin's lymphoma in this area should continue to be a matter of concern. The phenomenon of high incidences of childhood and young adult leukaemia and lymphoma near some nuclear installations in isolated areas is yet to be explained, but certain aspects of the data examined in the present report are consistent with the hypothesis of an infectious aetiology for leukaemia in very young children.

Prognostic factors in women with breast cancer: distribution by socioeconomic status and effect on differences in survival.

STUDY OBJECTIVE: To quantify and investigate differences in survival from breast cancer between women resident in affluent and deprived areas and define the contribution of underlying factors to this variation. DESIGN: Analysis of two datasets relating to breast cancer patients in Scotland: (1) population-based cancer registry data; (2) a subset of cancer registration records supplemented by abstraction of prognostic variables (stage, node status, tumour size, oestrogen receptor (ER) status, type of surgery, use of radiotherapy and use of adjuvant systemic therapy) from medical records. SETTING: Scotland. PATIENTS: (1) Cancer registration data on 21,751 women aged under 85 years diagnosed with primary breast cancer between 1978 and 1987; (2) national clinical audit data on 2035 women aged under 85 years diagnosed with primary breast cancer during 1987 for whom adequate medical records were available. MAIN RESULTS: Survival differences of 10% between affluent and deprived women were observed in both datasets, across all age groups. In the audit dataset, the distribution of ER status varied by deprivation group (65% ER positive in affluent group v 48% ER positive in deprived group; under 65 age group). Women aged under 65 with non-metastatic disease were more likely to have breast conservation than a mastectomy if they were affluent (45%) than deprived (32%); the affluent were more likely to receive endocrine therapy (65%) than the deprived (50%). However, these factors accounted for about 20% of the observed difference in survival between women resident in affluent and deprived areas. CONCLUSIONS: Deprived women with breast cancer have poorer outcomes than affluent women. This can only partly be explained by deprived women having more ER negative tumours than affluent women. Further research is required to identify other reasons for poorer outcomes in deprived women, with a view to reducing these survival differences.

Cancer registry data based estimation of regional cancer incidence: application to breast and colorectal cancer in French administrative regions.

STUDY OBJECTIVE: In many countries, cancer registries cover only a small part of the national population. Cancer incidence for the rest of the country has therefore to be estimated. This can be done from mortality data using the relation between incidence and mortality observed in the cancer registry areas. Such an approach was used to study geographical variation and trend of colorectal and breast cancer incidence in France where 10% of the national population is covered by cancer registries. DESIGN: This study applies the incidence/mortality ratios of cancer registry areas to regional mortality data to obtain an estimation of cancer incidence at a given point in time. Age and period effects are included in the statistical models. MAIN RESULTS: The incidence estimations are given for 21 administrative regions and three time points (1985, 1990, 1995). The European standardised incidence rates for breast cancer ranged from 86.8 to 128.8. For colorectal cancer, these rates ranged from 48.2 to 79.6 for men, and from 32.5 to 48.8 for women. Breast cancer incidence has increased considerably between 1985 and 1995 with a higher increase in the north than in the south of France. The incidence of colorectal cancer has also increased, albeit to a lesser extent. CONCLUSION: The incidence estimation method proposed leads to regional incidence rates that are useful for planning health care services on a regional basis and may also be used to study regional differences in incidence. This method is useful when only partial incidence data are available.

Modulation of oncogene expression by epidermal growth factor and gamma-interferon in A431 squamous carcinoma cells.

Epidermal growth factor (EGF) acts, in a dose dependent manner, as both a mitogen and an inhibitor of growth of the A431 squamous carcinoma cell line. gamma-interferon (IFN) also inhibits A431 cell growth. The dual effects of EGF on A431 growth and expression of the oncogenes, EGF receptor (EGFR) and Ha-ras, were evaluated with or without gamma-IFN. A mitogenic level (10pM) of EGF had no effect on expression of EGFR 10 kb mRNA or protein. gamma-IFN combined with 10pM EGF caused an initial drop in EGFR mRNA not reflected at the protein level; at 72 hours, the level of EGFR 10kb mRNA rose and inhibition of cell growth was observed. Treatment with a cytostatic amount (10nM) of EGF resulted in decreased expression of EGFR 10kb mRNA and protein within 24 hours; combined treatment with gamma-IFN caused rapid cell death. Expression of Ha-ras mRNA paralleled that of EGFR mRNA upon treatment with 10pM EGF and/or gamma-IFN, but differed with 10nM EGF.

Association of interferon-gamma induced growth inhibition and modulation of epidermal growth factor receptor gene expression in squamous cell carcinoma cell lines.

Interferons (IFN) possess the ability to inhibit proliferation of certain transformed cell lines. Down modulation of the abnormal expression of certain oncogenes by IFN has been associated with phenotypic reversion of src, myc, or ras transformed cells. It has already been shown that some squamous cell carcinoma (SCCa) cell lines express elevated levels of the epidermal growth factor receptor (EGFR). Previously, in A431, an SCCa cell line, it was shown that IFN-gamma-induced growth inhibition was associated with both enhanced expression of EGFR and terminal differentiation. This study examines the effect of IFN-beta or IFN-gamma on five additional cervical SCCa cell lines. One cell line was shown to have amplification of the EGFR gene. An IFN-gamma induced antiproliferative response, observed in four of the five cell lines, was associated with increased expression of EGFR mRNA and induction of the IFN-inducible genes, HLA-A3 class I antigen and 2-5 oligoadenylate synthetase. These data suggest that the increased expression of the EGFR gene in a particular SCCa may predict response to IFN-gamma.

Partial vs total esophagectomy for advanced carcinoma of the hypopharynx.

Cancer of the hypopharynx is an aggressive disease with a poor prognosis irrespective of the therapeutic regimen instituted. Controversy centers around the extent of surgery required to adequately ablate the advanced cancers, particularly related to the role of esophagectomy. A literature review and analysis of 43 cases of advanced hypopharyngeal cancer treated with total laryngopharyngectomy and partial esophagectomy support the argument that in carefully selected situations, a partial esophagectomy is oncologically an adequate operation.

Silicone gel-filled breast implants and connective tissue diseases.

Recent worldwide press and media speculation that silicone implants may be linked to an increased incidence of breast cancer, other cancers, and connective tissue diseases-particularly systemic sclerosis-is a current cause for concern to the medical profession and public alike. We conducted a cross-sectional study of the prevalence of connective tissue diseases, as well as signs and symptoms associated with these conditions, in women who had received a silicone gel-filled breast implant for either breast augmentation or breast reconstruction following mastectomy for breast cancer compared with women without implants in South East Scotland. We compared 317 patients who had had a silicone gel-filled breast implant inserted with matched controls. We found no increased incidence of antinuclear antibodies or rheumatoid factor in the study groups. We detected one case of rheumatoid arthritis in the reconstruction group and one in matched controls, but no cases of any other connective tissue disease. No cases were found among the augmentation patients or their controls. No differences were found in symptoms or physical signs of connective tissue diseases between the study patients and their controls. This study has failed to find any case for a link between silicone gel-filled breast implants and connective tissue diseases.