Evaluation of mammographic surveillance services in women aged 40-49 years with a moderate family history of breast cancer: a single-arm cohort study.

BACKGROUND: Women with a significant family history of breast cancer are often offered more intensive and earlier surveillance than is offered to the general population in the National Breast Screening Programme. Up to now, this strategy has not been fully evaluated. OBJECTIVE: To evaluate the benefit of mammographic surveillance for women aged 40-49 years at moderate risk of breast cancer due to family history. The study is referred to as FH01. DESIGN: This was a single-arm cohort study with recruitment taking place between January 2003 and February 2007. Recruits were women aged < 50 years with a family history of breast or ovarian cancer conferring at least a 3% risk of breast cancer between ages 40 and 49 years. The women were offered annual mammography for at least 5 years and observed for the occurrence of breast cancer during the surveillance period. The age group 40-44 years was targeted so that they would still be aged < 50 years after 5 years of surveillance. SETTING: Seventy-four surveillance centres in England, Wales, Scotland and Northern Ireland. PARTICIPANTS: A total of 6710 women, 94% of whom were aged < 45 years at recruitment, with a family history of breast cancer estimated to imply at least a 3% risk of the disease between the ages of 40 and 50 years. INTERVENTIONS: Annual mammography for at least 5 years. MAIN OUTCOME MEASURES: The primary study end point was the predicted risk of death from breast cancer as estimated from the size, lymph node status and grade of the tumours diagnosed. This was compared with the control group from the UK Breast Screening Age Trial (Age Trial), adjusting for the different underlying incidence in the two populations. RESULTS: As of December 2010, there were 165 breast cancers diagnosed in 37,025 person-years of observation and 30,556 mammographic screening episodes. Of these, 122 (74%) were diagnosed at screening. The cancers included 44 (27%) cases of ductal carcinoma in situ. There were 19 predicted deaths in 37,025 person-years in FH01, with an estimated incidence of 6.3 per 1000 per year. The corresponding figures for the Age Trial control group were 204 predicted deaths in 622,127 person-years and an incidence of 2.4 per 1000 per year. This gave an estimated 40% reduction in breast cancer mortality (relative risk = 0.60; 95% confidence interval 0.37 to 0.98; p = 0.04). CONCLUSIONS: Annual mammography in women aged 40-49 years with a significant family history of breast or ovarian cancer is both clinically effective in reducing breast cancer mortality and cost-effective. There is a need to further standardise familial risk assessment, to research the impact of digital mammography and to clarify the role of breast density in this population. TRIAL REGISTRATION: National Research Register N0484114809. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 17, No. 11. See the HTA programme website for further project information.

Effect of diindolylmethane supplementation on low-grade cervical cytological abnormalities: double-blind, randomised, controlled trial.

BACKGROUND: Cervical screening identifies many women with low-grade abnormalities. In vitro and in vivo studies have shown that diindolylmethane (DIM) could potentially halt (cervical) carcinogenesis. We report on a randomised controlled trial of the effect of DIM in women with low-grade cervical cytological abnormalities. METHODS: We conducted a pragmatic double-blind, randomised controlled trial of 150 mg DIM (from BioResponse DIM) or placebo daily for 6 months in women with newly diagnosed, low-grade cytological abnormalities. Randomisation was in the ratio 2 (DIM) to 1 (placebo). All women were invited for colposcopy at 6 months with biopsy of any abnormality. RESULTS: Of the 551 randomised women available for analysis, 9% on DIM and 12% on placebo had cervical intraepithelial neoplasia-2 (CIN2) or worse after 6-month supplementation (risk ratio (RR) 0.7 (95% confidence interval (CI): 0.4-1.2)), whereas 4.6% and 5.1%, respectively, had CIN3 or worse (RR 0.9 (95% CI: 0.4-2.0)). A total of 27.3% of women on DIM and 34.3% on placebo had no sign of disease (negative cytology, colposcopy and human papilloma virus (HPV) tests) at 6 months (RR 0.8 (95% CI: 0.6-1.0)). Of those HPV-positive at baseline, 69% (114 out of 166) of the DIM group were positive at 6 months compared with 61% (43 out of 71) of the placebo group: RR 1.1 (95% CI: 0.9-1.4). Diindolylmethane supplementation was well tolerated. CONCLUSION: The results suggest that short-term DIM supplementation (150 mg day(-1)) is well tolerated, but is unlikely to have an effect on cytology or HPV infection. Uncertainty remains regarding its effect on CIN2+.

Birth outcomes following treatment for precancerous changes to the cervix: a population-based record linkage study.

OBJECTIVE: To examine whether treatments for precancerous changes to the cervix are associated with adverse birth outcomes in subsequent pregnancies. DESIGN: Population-based retrospective cohort study using electronic linkage of data from the Welsh cervical screening programme and a national routine child health database. SETTING: Wales. POPULATION: A total of 174,325 women aged 20-39 years who received cervical screening between April 2001 and March 2004. METHODS: Logistic regression was used to compare the odds of each birth outcome between women who had negative cervical smears and women who received either colposcopy ± punch biopsy only or colposcopy and excisional or ablative treatments, adjusted for confounding factors (e.g. age, social deprivation and smoking). MAIN OUTCOME MEASURES: Preterm birth (before 37, 32 and 28 weeks of gestation), and low birthweight (<2500 g). RESULTS: Compared with women who had negative cervical smears, the odds ratio for preterm birth (<37 weeks) was significantly increased in women who had colposcopy only (adjusted odds ratio 1.54, 95% CI 1.32-1.80) and single excisional treatment (adjusted odds ratio 1.77, 95% CI 1.47-2.13). Similar results were observed for preterm birth at <32 weeks of gestation. There was no increased risk of preterm birth or low birthweight for women who had treatment compared with women who had colposcopy only. CONCLUSION: Women who were referred for colposcopy had an increased risk of preterm births regardless of whether or not they received treatment to the cervix. This increased risk could be the result of common risk factors for abnormal smears and preterm birth.

Human papillomavirus prevalence in women attending routine cervical screening in South Wales, UK: a cross-sectional study.

In this cross-sectional population-based study we determine human papillomavirus (HPV) prevalence in South Wales to provide comprehensive baseline data for future assessment of the impact of prophylactic HPV vaccination and to help inform future screening strategies. Liquid-based cytology samples from women attending routine cervical screening were collected (n=10 000: mean age 38 years, 93% cytology negative, and 64.8% from the 50% least deprived LSOA according to social deprivation score (SDS)). High-Risk (HR) and Low-Risk HPV screening was performed using HPV PCR-EIA with genotyping of HR positives and data correlated with age, SDS and cytology. Overall HPV prevalence was 13.5% (9.3% age standardised) and the most frequent HR types were HPV 16, 31, 18 and 58. In HR HPV-positive cases 42.4% had a single HR type and they were predominant in women with severe cytological abnormalities. Here, 66% of all HR HPV cases were in women aged 30 years of age or less and SDS had no significant effect on HPV status. HPV prevalence increased significantly with degree of dyskaryosis from 7% in cytology negative samples to 80% in samples with severe cytological abnormalities (P-value <0.0001). Overall, 46% of HR HPV cases were positive for the two HR types targeted by the prophylactic vaccines (HPV 16 and HPV 18). The data presented represents the largest type-specific investigation of HPV prevalence in an unselected UK population.

A comparison of variability in Papanicolaou and liquid-based cytology inadequacy rates using Shewhart control charts.

OBJECTIVE: To use Shewhart control charts to compare variability in inadequacy rates from Papanicolaou (Pap) and liquid-based cytology (LBC). DESIGN: Retrospective analysis of quality assurance data. SETTING: Eleven Welsh cytology laboratories. METHODS: Shewhart 'p' charts were plotted for proportions of slides reported as inadequate. Charts were compared for statistical control. MAIN OUTCOME MEASURES: Evidence of statistical control in the processes. RESULTS: Control charts allowed easy interpretation of patterns in the data. Variability in inadequacy rates was much lower for LBC than for Pap cytology. CONCLUSION: Monitoring inadequate rates with Shewhart charts provides more information than tabular monitoring reports, assisting in quality improvement. With respect to inadequacy rates, LBC is less variable than Pap cytology.

Cervical screening in 20-24-year olds.

BACKGROUND: In 2003 the NHS Cervical Screening Programme in England changed the age at which women are first invited for cervical screening from 20 to 25 years. The aim of this review was to assess the evidence for benefit and harm of undertaking cervical screening in Wales for women aged 20-24 years. METHOD: A literature review looking for evidence of the effectiveness and potential harmful effects of cervical screening was undertaken. Welsh data for the number of cases of high-grade cervical intraepithelial neoplasia (CIN3) were examined and rates of invasive cervical cancer (1981-2003) for young women calculated. The medical notes of women less than 25 years old diagnosed with cervical cancer were reviewed and a cost analysis was performed. RESULTS: The literature review failed to identify any randomized controlled studies of the effectiveness of cervical screening in young women, but demonstrated that organized screening programmes result in a decrease in the incidence of cervical carcinoma. Following the introduction of the Welsh organized call/recall cervical screening programme in 1988, cervical cancer has been reduced by 58% in women aged 20-24 years and 45% in women aged 25-29 years (mean age-specific rate per 100,000 women aged 20-24 years: 4.2 in 1981-88 compared with 2.2 in 1989-2003). If these changes can be attributed to the screening of women aged 20-24, then the costs of at least pound sterling 82,500 are estimated to prevent one cervical cancer in this age group. CONCLUSIONS: The incidence of cervical cancer in young women has halved since the introduction of the Welsh-organized call-recall cervical screening programme. In Wales we recommend that women continue to be invited for cervical screening from 20 years of age. This will provide the information required to compare the incidence and stage at diagnosis of cervical cancer in young women invited for first time cervical screening at different ages across the UK.

Two-view mammography at the incident round has improved the rate of screen-detected breast cancer in Wales.

AIM: To investigate whether pre-invasive and invasive cancer detection rates were improved in Wales after the introduction of two views at incident screens. METHODS: The records of women attending follow-up screening for 2 years before and 2 years after the introduction of two-view incident screening were analysed. Cancer detection rates were compared before and after introduction of two view screening. RESULTS: At the incident round 98,752 women had one and 95,464 had two views. Five hundred and fifty-five cancers were detected with one view and 744 with two, an increased detection rate from 5.6 to 7.8 cancers per 1000 women screened (p=0.01). Two hundred and thirty-nine small cancers were detected with one view and 323 with two, increasing the detection rate from 2.4 to 3.4 per 1000 women screened (p=0.05). CONCLUSIONS: Two-view mammography at incident rounds detects more cancers and more favourable prognosis small cancers than single-view mammograms.

Patient demographics and treatment for early breast cancer: an observational study.

This study aims to examine relationships between demographic factors and treatment choice for early breast cancer (T2/N<1). Two hundred and two patients were offered modified radical mastectomy (MRM), breast conserving therapy (BCT) or MRM and reconstruction and interviewed at a University Hospital and oncology centre in South Wales. Median age at treatment was 57 (32-90) years. Seventy-one patients (35%) choose MRM, 10 (5%) MRM and reconstruction and 121 (60%) BCT. Median age of women choosing MRM was 61 and 55 for BC (P<0.0001). Single women (P=0.009) and those with no family history of breast cancer (P=0.02) were more likely to choose MRM. There was no difference between treatment choice and method of cancer detection and the age at which the patient left education (P=0.065). Mean histological tumour diameter was smaller for women choosing BC (15 mm) than for women choosing mastectomy (17 mm; P=0.014). There was no association between tumour grade and treatment choice.

A case-control study to estimate the impact on breast cancer death of the breast screening programme in Wales.

OBJECTIVES: The aim of this study was to estimate the effect of service screening, as provided by the NHS breast screening programme, on breast cancer mortality in Wales. Furthermore, we wished to ascertain whether a reduction in breast cancer mortality consistent with that observed in the randomised screening trials was being achieved. SETTING: The NHS Breast Screening Programme in Wales, managed by Breast Test Wales, with headquarters in Cardiff. METHODS: A case-control study design with 1:2 matching. The cases were deaths from breast cancer in women aged 50-75 years at diagnosis who were diagnosed after the instigation of screening in 1991 and who died after 1998. The controls were women who had not died of breast cancer or any other condition during the study period. One was from the same GP practice and the other from a different GP practice within the same district, matched by year of birth. RESULTS: Based on 419 cases, the odds ratio for risk of death from breast cancer for women who have attended at least one routine screen compared to those never screened was 0.62 (95% confidence interval [CI] 0.47-0.82, p=0.001). After excluding cases diagnosed prior to 1995 and adjusting for self-selection bias, the estimated mortality reduction was 25% (odds ratio=0.75, 95% CI 0.49-1.14, p=0.09). CONCLUSION: The Breast Test Wales screening programme is achieving a reduction in breast cancer mortality of 25% in women attending for screening, which is consistent with the results of the randomized controlled trials of mammographic screening.

The inadequate smear: does it matter?

The objective of this study was to quantify the incidence of underlying cervical intraepithelial neoplasia (CIN) among women referred for colposcopy with three consecutive inadequate smears. The design was a retrospective cohort study analysing data from a regional colposcopy database at Cervical Screening Wales. Women who were referred to all the colposcopy clinics in Wales with three consecutive inadequate smears, the third inadequate smear being taken between 1 April 2001 and 31 March 2002 constituted the study population. The results of the fourth smear taken at the colposcopy clinic after three consecutive inadequate smears, the worst biopsy results from any of the subsequent colposcopies and the relationship between the result of the fourth smear taken at colposcopy clinic and any histology result were the main outcome measures. The accuracy of the colposcopic opinion was also examined. Of the 433 women identified as having been referred because of three consecutive inadequate smears, 302 were linked to either a subsequent smear and/or a biopsy result. An adequate smear result was available for 85% of these women when the smear was taken in the colposcopy clinic; 77% were reported as negative and 8% were abnormal. Of the 347 women seen in the colposcopy clinic, high-grade CIN was seen in 3% and low-grade lesion in 8%. The sensitivity and specificity of the fourth inadequate smear test in predicting underlying CIN were 15% and 84% respectively, with a positive predictive value of 8%. The sensitivity and specificity of colposcopy in predicting histological CIN among patients with three inadequate smears was 70% and 49%, respectively, and the positive predictive value was 44%. This study raises the question as to whether three consecutive inadequate smears should be considered as an indication for colposcopy, or merely for a further smear to be taken in circumstances where there is a greater likelihood getting an adequate result.

Results from 10 years of breast screening in Wales.

OBJECTIVE: To present results from 10 years of breast screening in Wales, including rates of interval cancers. SETTING: All women aged 50-64 years in Wales; approximately 250,000 in each screening round. METHODS: Breast Test Wales (BTW) began mammographic screening in 1989 as part of the National Breast Screening Programme. Two view mammography was introduced at the inception of the Welsh programme for all prevalent screens. Single view mammography was subsequently performed for incident screens. Interval cancers were identified by matching details from the BTW administrative screening database with the BTW database of all incident breast cancers for residents in Wales. RESULTS: For the first and second round prevalent screens, the cancer detection rate was 8.6 per 1000 and 7.4 per 1000 screened, respectively. The interval cancer rates following round one were 4.9 per 10,000 in the first 12 months, 9.0 per 10,000 between 12 and 24 months, and 11.6 per 10,000 between 24 and 36 months after screening. For the second round incident screens the detection rate was 4.6 per 1000 and the standardised detection ratio was 0.89, but the interval cancer rates in the first year after incident screens were not statistically different from those following prevalent screens. There was no change in the proportion of invasive breast cancers which were < 15 mm in diameter, or in the grades of invasive cancer between the first and second rounds, prevalent or incident screens. CONCLUSIONS: Breast Test Wales has achieved the standards set by the National Health Service Breast Screening Programme. Taking two views at the prevalent screen gave high sensitivity and may have resulted in the low standardised detection ratio at subsequent incident screens.

Addressing environmental health concerns near Trecatti landfill site, United Kingdom.

Residents near the Trecatti landfill site located in South Wales, United Kingdom, expressed concern about odors and health effects they attributed to site emissions. The authors compared routinely collected, population-based, health data from potentially exposed electoral wards (i.e., United Kingdom electoral tracts) with data from both wards nearby, matched for socioeconomic deprivation scores, and with wards where residents were likely to attend the same hospital. Mortality rates were higher for all causes and neoplastic diseases (but not respiratory disease) in the exposed wards, but there was no change in rates after the site opened. Hospital data revealed a transient increase in admissions for asthma during the 3 yr that preceded the peak in odor complaints. The birth prevalence of congenital malformations was raised in the exposed wards, but the authors could not exclude a possible artifact resulting from differences in reporting practices between hospitals. The absence of environmental monitoring in the community during the period of public concern was a significant weakness of this study.

Development of a protocol for evaluation of mammographic surveillance services in women under 50 with a family history of breast cancer.

BACKGROUND: Preliminary retrospective data suggest it is possible to identify impalpable breast cancer in women presenting with a family history of breast cancer under the age of 50, by using regular mammography. In consequence, this service is offered in a number of centres in the UK. The effectiveness of such a service, however, has not been fully evaluated. METHODS: We propose to perform such an evaluation in a cohort of 20000 women under the age of 50 with a significant family history of breast cancer, given regular mammographic surveillance over 5 years. Comparison of surgical and pathological data with completed and ongoing population screening trials using analysis techniques of varying complexity will be performed to obtain an accurate prediction of future breast-cancer mortality reduction. The formal aims are: i) to estimate the difference in breast-cancer mortality in women under the age of 50 with a significant family history of breast cancer having regular mammography, compared with those not being screened; ii) to estimate the cost-effectiveness of regular mammography in this group of women, compared with no screening. The increase in health service resource use attributable to such a policy will be compared with no screening, and costed. Incremental cost-effectiveness ratios of implementing the standardised mammography strategy compared with no screening will be presented in terms of the additional cost per cancer detected, per life saved and per life-year saved.

Community exposures to chemical incidents: development and evaluation of the first environmental public health surveillance system in europe.

OBJECTIVE: To describe the frequency, nature and location of acute chemical incidents in Wales, and the morbidity in employees, emergency responders and the general public who were exposed. DESIGN: Active multi-agency community-based surveillance system. SETTING: Wales, 1993-5. MAIN OUTCOME MEASURES: Frequency, nature and location of incidents, populations potentially exposed and with symptoms. RESULTS: Most of the 402 incidents identified were not associated with sites governed by the Control of Industrial Major Accident Hazard Regulations but with smaller industrial sites and commercial premises. About two in every thousand of the estimated 236 000 members of the public considered to be at risk from exposure reported symptoms, which were mainly nausea, headaches, and irritation of the eye, skin and respiratory tract. The most commonly reported chemicals that members of the public were exposed to were smoke toxins, miscellaneous organics, toxic gases and flammable gases. A health authority was reported to be involved in only 34 (8%) of the incidents and in only 3 of the 29 incidents where more than 100 members of the public were exposed. CONCLUSION: A geographically defined, multi-agency surveillance system can identify high risk locations and types of incidents, together with the chemicals most likely to be involved. Such ongoing surveillance information is essential for appropriate policy making, emergency planning, operational management and training.

Investigation of an acute chemical incident: exposure to fluorinated hydrocarbons.

OBJECTIVES: To assess whether attendance at the site after an incident in a sewer was associated with symptoms in emergency personnel and whether the prevalence of symptoms was associated with estimated levels of exposure to any chemical hazard. METHODS: Symptoms experienced by people attending an incident involving two dead sewer workers suggested the presence of a chemical hazard, before environmental sampling confirmed any toxic agent. Self reported symptoms, estimated exposures, and biomarkers of exposure for likely agents from all 254 people who attended the incident and a referent occupational group matching the 83 emergency personnel who went to the Accident and Emergency department (A and E) in the first 48 hours were recorded. The prevalence of symptoms and concentrations of creatine phosphokinase in serum of the 83 early patients at A and E were compared with their referent occupational group. In all workers who attended the incident, the trends in symptom prevalences and concentrations of creatine phosphokinase in serum were examined by distance from the site and predefined exposure category. RESULTS: Among all workers who attended the incident, symptoms of shortness of breath and sore throat were significantly associated with indirect estimates of exposure but not associated with concentrations of creatine phosphokinase. Freon was detected in two blood samples. The early patients at A and E reported more symptoms than their matched reference group and their median concentrations of creatine phosphokinase were higher. CONCLUSIONS: The association between symptoms and concentrations of creatine phosphokinase with attendance at the site indicated the presence of a continuing hazard at the site and led to extra precautions being taken. Comparison values from the referent occupational group prevented unnecessary medical follow up.

Assessment of impact on health of residents living near the Nant-y-Gwyddon landfill site: retrospective analysis.

OBJECTIVES: To compare indices of health in a population living near a landfill site with a population matched for socioeconomic status and to review environmental monitoring data. DESIGN: Ecological study with small area statistics and environmental reports. SETTING: Electoral wards in valleys of South Wales. SUBJECTS: Populations in the five wards near the landfill site who had formally complained of odours (exposed population), and comparison populations in 22 wards in the same unitary authority within the same fifth of Townsend score. OUTCOME MEASURES: Mortality, rates of hospital admission, measures of reproductive health (proportion of all births and stillbirths of infants weighing <2500 g; rates of admissions for spontaneous abortion; rates of all reported congenital malformations). Environmental data on site emissions. RESULTS: There were no consistent differences in mortality, rates of hospital admissions, or proportion of low birthweight infants between the two populations. There was an increased maternal risk of having a baby with a congenital abnormality in residents near the site, both before its opening (relative risk 1.9; 95% confidence interval 1.3 to 2.85; P<0.001) and after (1.9; 1.23 to 2.95; P=0.003). Environmental monitoring showed that hydrogen sulphide from the site was probably responsible for odours. CONCLUSIONS: The area surrounding the landfill site has an increased rate of reported congenital malformations, which predated the opening of the landfill, although the cluster of cases of gastroschisis post-dated its opening. Several chemicals emitted from the site, including hydrogen sulphide and benzene, were found in air samples in the nearby community. Further studies of the reproductive risk in such communities are needed to examine the safety of waste disposal sites.

An international outbreak of Salmonella enteritidis associated with lasagne; lessons on the need for cross-national co-operation in investigating food-borne outbreaks.

We investigated an outbreak of Salmonella enteritidis involving at least 19 British tourists returning from one hotel in another European country. A retrospective cohort study of 47 hotel guests identified lasagne as the most likely vehicle of transmission (RR 11.5; 95% CI 3.0-44.1; P < 0.0001). However, difficulties in information exchange and lack of formal mechanisms to agree on the aims of the cross-national investigation hampered efficient management of the outbreak. The factors leading to contamination of the food vehicle were not identified and therefore specific action to prevent reoccurrence could not be taken. There is need to develop protocols for cross-national investigations of outbreaks in Europe which should include specifying objectives, roles and responsibilities of investigators and control agencies, with formal reporting of the outcome of the investigation.

A study of postoperative fever following paediatric tonsillectomy.

The aetiology of post-tonsillectomy fever is obscure. Bacteraemia during surgery, anaesthetic agents and the inflammatory response of tissue to injury have been implicated. A prospective study was undertaken in 100 consecutive children to evaluate the occurrence and severity of fever in the 24 h after tonsillectomy and its relationship to bacteraemia during surgery and qualitative and quantitative cultures (colony counts) of organisms in tonsil core tissue. Fifty-four patients had a fever (> 37.5 degrees C) postoperatively, of whom, 30 had a fever greater than 38 degrees C. Blood cultures during tonsillectomy were positive in 22 patients. There was no statistically significant difference between the occurrence of fever and the techniques of tonsillectomy and haemostasis. There was also no association between positive blood, core or surface cultures and the incidence or severity of fever nor any association between colony count in core cultures and fever. Our results suggest that postoperative fever in the 24 h following tonsillectomy is not caused by infection.

Effect of environmental tobacco smoke on peak flow variability.

This study was undertaken to determine whether exposure to various indoor pollutants is associated with a higher prevalence of respiratory symptoms, a diagnosis of asthma, or more variable peak flow rates. Four hundred and twenty-six children aged 8-11 years in four junior schools at three locations recorded respiratory symptoms and diagnosis of asthma using the ISAAC questionnaire. Daily peak flow measurements were taken during two six-week periods (winter and summer). Symptoms in children with and without asthma were not related to gas fires, cookers, smokers, or pets in the home. However, the variability of lung function, expressed as the coefficient of variation, in all children was increased with a household smoker. Environmental tobacco smoke increases airways variability in children with and without asthma. Its effects were not apparent from a questionnaire completed by parents, and the coefficient of variation of serially measured peak flows was a more sensitive indicator of lung function.