Triaging women with human papillomavirus infection and normal cytology or low-grade dyskaryosis: evidence from 10-year follow up of the ARTISTIC trial cohort.

OBJECTIVES: To estimate long-term cervical intraepithelial neoplasia grade 3 (CIN3) risks associated with different triage strategies for human papillomavirus positive (HPV+) women with a view to reducing unnecessary referrals. DESIGN: The ARTISTIC trial cohort was recruited in Manchester in 2001-03 and was followed up for CIN3 and cancer notification through national registration until December 2015. RESULTS: The 10-year cumulative risk of CIN3+ was much higher for women with HPV16/18 infection (19.4%, 95% CI 15.8-23.8% with borderline/low-grade cytology and 10.7%, 95% CI 8.3-13.9% with normal cytology) than for those with other HPV types (7.3%, 95% CI 5.4-9.7% with borderline/low-grade cytology and 3.2%, 95% CI 2.2-4.5% with normal cytology). Among the 379 women with normal to low-grade cytology and new HPV infection, the 10-year cumulative CIN3+ risk was 2.9% (95% CI 1.6-5.2%). CONCLUSIONS: The CIN3 risk is confined to women with persistent type-specific HPV so partial genotyping test assays identifying HPV16/18 as a minimum are essential for efficient risk stratification. Immediate referral to colposcopy for HPV+ women with borderline or low-grade cytology and referral after a year if still HPV+ with normal cytology may be unnecessary. Low-grade lesions can safely be retested to identify those with persistent HPV. Recall intervals of 1 year for HPV16/18 and 2 years for other high-risk HPVs are justified for women with normal cytology and might also be considered for women with borderline/low-grade cytology. The minimal risk of invasive cancer that has progressed beyond stage 1A must be weighed against the advantages for patients and the NHS of reducing the number of referrals to colposcopy. TWEETABLE ABSTRACT: Cervical screening would be better for women and cheaper for the NHS if women with HPV and normal to low-grade cytology were retested after a year or two when many infections will have cleared.

Optimal threshold for a positive hybrid capture 2 test for detection of human papillomavirus: data from the ARTISTIC trial.

We present data on the use of the Hybrid Capture 2 (HC2) test for the detection of high-risk human papillomavirus (HR HPV) with different thresholds for positivity within a primary screening setting and as a method of triage for low-grade cytology. In the ARTISTIC population-based trial, 18,386 women were screened by cytology and for HPV. Cervical intraepithelial neoplasia lesions of grade two and higher (CIN2+ lesions) were identified for 453 women within 30 months of an abnormal baseline sample. When a relative light unit/cutoff (RLU/Co) ratio of > or = 1 was used as the threshold for considering an HC2 result positive, 15.6% of results were positive, and the proportion of CIN2+ lesions in this group was 14.7%. The relative sensitivity for CIN2+ lesion detection was 93.4%. When an RLU/Co ratio of > or = 2 was used as the threshold, there was a 2.5% reduction in positivity, with an increase in the proportion of CIN2+ lesions detected. The relative sensitivity decreased slightly, to 90.3%. Among women with low-grade cytology, HPV prevalences were 43.7% and 40.3% at RLU/Co ratios of > or = 1 and > or = 2, respectively. The proportions of CIN2+ lesions detected were 17.3% and 18.0%, with relative sensitivities of 87.7% at an RLU/Co ratio of > or = 1 and 84.2% at an RLU/Co ratio of > or = 2. At an RLU/Co ratio of > or = 1, 68.3% of HC2-positive results were confirmed by the Roche line blot assay, compared to 77.2% of those at an RLU/Co ratio of > or = 2. Fewer HC2-positive results were confirmed for 35- to 64-year-olds (50.3% at an RLU/Co ratio of > or = 1 and 63.2% at an RLU/Co ratio of > 2) than for 20- to 34-year-olds (78.7% at an RLU/Co ratio of > or = 1 and 83.7% at an RLU/Co ratio of > 2). If the HC2 test is used for routine screening as an initial test or as a method of triage for low-grade cytology, we would suggest increasing the threshold for positivity from the RLU/Co ratio of > or = 1, recommended by the manufacturer, to an RLU/Co ratio of > or = 2, since this study has shown that a beneficial balance between relative sensitivity and the proportion of CIN2+ lesions detected is achieved at this threshold.

ARTISTIC: a randomised trial of human papillomavirus (HPV) testing in primary cervical screening.

OBJECTIVES: Primary cervical screening uses cytology to detect cancer precursor lesions [cervical intraepithelial neoplasia stage 3 or beyond (CIN3+)]. Human papillomavirus (HPV) testing could add sensitivity as an adjunct to cytology or as a first test, reserving cytology for HPV-positive women. This study addresses the questions: Does the combination of cytology and HPV testing achieve a reduction in incident CIN3+?; Is HPV testing cost-effective in primary cervical screening?; Is its use associated with adverse psychosocial or psychosexual effects?; and How would it perform as an initial screening test followed by cytology for HPV positivity? DESIGN: ARTISTIC was a randomised trial of cervical cytology versus cervical cytology plus HPV testing, evaluated over two screening rounds, 3 years apart. Round 1 would detect prevalent disease and round 2 a combination of incident and undetected disease from round 1. SETTING: Women undergoing routine cervical screening in the NHS programme in Greater Manchester. PARTICIPANTS: In total 24,510 women aged 20-64 years were enrolled between July 2001 and September 2003. INTERVENTIONS: HPV testing was performed on the liquid-based cytology (LBC) sample obtained at screening. Women were randomised in a ratio of 3:1 to have the HPV test result revealed and acted upon if persistently positive in cytology-negative cases or concealed. A detailed health economic evaluation and a psychosocial and psychosexual assessment were also performed. MAIN OUTCOME MEASURES: The primary outcome was CIN3+ in round 2. Secondary outcomes included an economic assessment and psychosocial effects. A large HPV genotyping study was also conducted. RESULTS: In round 1 there were 313 CIN3+ lesions, representing a prevalence in the revealed and concealed arms of 1.27% and 1.31% respectively (p = 0.81). Round 2 (30-48 months) involved 14,230 (58.1%) of the women screened in round 1 and only 31 CIN3+ were detected; the CIN3 rate was not significantly different between the revealed and concealed arms. A less restrictive definition of round 2 (26-54 months) increased CIN3+ to 45 and CIN3+ incidence in the arms was significantly different (p = 0.05). There was no difference in CIN3+ between the arms when rounds 1 and 2 were combined. Prevalence of high-risk HPV types was age-dependent. Overall prevalence of HPV16/18 increased with severity of dyskaryosis. Mean costs per woman in round 1 were 72 pounds and 56 pounds for the revealed and concealed arms (p < 0.001); an age-adjustment reduced these mean costs to 65 pounds and 52 pounds. Incremental cost-effectiveness ratio for detecting additional CIN3+ by adding HPV testing to LBC screening in round 1 was 38,771 pounds. Age-adjusted mean cost for LBC primary screening with HPV triage was 39 pounds compared with 48 pounds for HPV primary screening with LBC triage. HPV testing did not appear to cause significant psychosocial distress. CONCLUSIONS: Routine HPV testing did not add significantly to the effectiveness of LBC in this study. No significant adverse psychosocial effects were detected. It would not be cost-effective to screen with cytology and HPV combined but HPV testing, as either triage or initial test triaged by cytology, would be cheaper than cytology without HPV testing. LBC would not benefit from combination with HPV; it is highly effective as primary screening but HPV testing has twin advantages of high negative predictive value and automated platforms enabling high throughput. HPV primary screening would require major contraction and reconfiguration of laboratory services. Follow-up continues in ARTISTIC while maintaining concealment for a further 3-year round of screening, which will help in screening protocol development for the post-vaccination era.

Occupational, domestic and environmental mesothelioma risks in the British population: a case-control study.

We obtained lifetime occupational and residential histories by telephone interview with 622 mesothelioma patients (512 men, 110 women) and 1420 population controls. Odds ratios (ORs) were converted to lifetime risk (LR) estimates for Britons born in the 1940s. Male ORs (95% confidence interval (CI)) relative to low-risk occupations for >10 years of exposure before the age of 30 years were 50.0 (25.8-96.8) for carpenters (LR 1 in 17), 17.1 (10.3-28.3) for plumbers, electricians and painters, 7.0 (3.2-15.2) for other construction workers, 15.3 (9.0-26.2) for other recognised high-risk occupations and 5.2 (3.1-8.5) in other industries where asbestos may be encountered. The LR was similar in apparently unexposed men and women (approximately 1 in 1000), and this was approximately doubled in exposed workers' relatives (OR 2.0, 95% CI 1.3-3.2). No other environmental hazards were identified. In all, 14% of male and 62% of female cases were not attributable to occupational or domestic asbestos exposure. Approximately half of the male cases were construction workers, and only four had worked for more than 5 years in asbestos product manufacture.

HPV testing in routine cervical screening: cross sectional data from the ARTISTIC trial.

To evaluate the effectiveness of human papillomavirus (HPV) testing in primary cervical screening. This was a cross-sectional study from the recruitment phase of a prospective randomised trial. Women were screened for HPV in addition to routine cervical cytology testing. Greater Manchester, attendees at routine NHS Cervical Screening Programme. In all, 24 510 women aged 20-64 screened with liquid-based cytology (LBC) and HPV testing at entry. HPV testing in primary cervical screening. Type-specific HPV prevalence rates are presented in relation to age as well as cytological and histological findings at entry. In all, 24 510 women had adequate cytology and HPV results. Cytology results at entry were: 87% normal, 11% borderline or mild, 1.1% moderate and 0.6% severe dyskaryosis or worse. Prevalence of HPV decreased sharply with age, from 40% at age 20-24 to 12% at 35-39 and 7% or less above age 50. It increased with cytological grade, from 10% of normal cytology and 31% of borderline to 70% mild, 86% moderate, and 96% of severe dyskaryosis or worse. HPV 16 or HPV 18 accounted for 64% of infections in women with severe or worse cytology, and one or both were found in 61% of women with severe dyskaryosis but in only 2.2% of those with normal cytology. The majority of young women in Greater Manchester have been infected with a high-risk HPV by the age of 30. HPV testing is practicable as a primary routine screening test, but in women aged under 30 years, this would lead to a substantial increase in retesting and referral rates. HPV 16 and HPV 18 are more predictive of underlying disease, but other HPV types account for 30% of high-grade disease.

FDG-PET scanning in the management of cancer of the oesophagus and oesophagogastric junction: early experience with 100 consecutive cases.

BACKGROUND: The aim was to evaluate the impact of FDG-PET scan on tumour staging and management decisions in oesophageal cancer. METHODS: One-hundred consecutive patients referred for consideration of surgery underwent a whole body FDG-PET scan in addition to CT imaging. RESULTS: Based on CT scan, a curative approach could be considered in 62 patients. The PET scan altered regional nodal (N) staging in 16 patients overall, but did not alter management decisions. Metastatic status (M) was increased in 14 patients, with altered management in 10/62 (16%). Nine were downstaged, with management changed in 3/38 (8%). Seventeen patients underwent 19 additional tests to clarify findings on PET, in 15 patients (88%) the tests revealed no pathology. CONCLUSION: FDG-PET alters M stage in 23% of patients and may impact on surgical decision-making. The spurious investigations and cost of the high false-positive rate of further tests is of concern.

Day care in infancy and risk of childhood acute lymphoblastic leukaemia: findings from UK case-control study.

OBJECTIVE: To test the hypothesis that reduced exposure to common infections in the first year of life increases the risk of developing acute lymphoblastic leukaemia. Design and setting The United Kingdom childhood cancer study (UKCCS) is a large population based case-control study of childhood cancer across 10 regions of the UK. PARTICIPANTS: 6305 children (aged 2-14 years) without cancer; 3140 children with cancer (diagnosed 1991-6), of whom 1286 had acute lymphoblastic leukaemia (ALL). MAIN OUTCOME MEASURE: Day care and social activity during the first year of life were used as proxies for potential exposure to infection in infancy. RESULTS: Increasing levels of social activity were associated with consistent reductions in risk of ALL; a dose-response trend was seen. When children whose mothers reported no regular activity outside the family were used as the reference group, odds ratios for increasing levels of activity were 0.73 (95% confidence interval 0.62 to 0.87) for any social activity, 0.62 (0.51 to 0.75) for regular day care outside the home, and 0.48 (0.37 to 0.62) for formal day care (attendance at facility with at least four children at least twice a week) (P value for trend < 0.001). Although not as striking, results for non-ALL malignancies showed a similar pattern (P value for trend < 0.001). When children with non-ALL malignancies were taken as the reference group, a significant protective effect for ALL was seen only for formal day care (odds ratio = 0.69, 0.51 to 0.93; P = 0.02). Similar results were obtained for B cell precursor common ALL and other subgroups, as well as for cases diagnosed above and below age 5 years. CONCLUSION: These results support the hypothesis that reduced exposure to infection in the first few months of life increases the risk of developing acute lymphoblastic leukaemia.

Cervical HPV infection and neoplasia in a large population-based prospective study: the Manchester cohort.

Cytology and histology records and cervical samples for HPV assay were obtained from a prospective cohort of 49 655 women attending clinics for routine cervical cytology in or near Manchester between 1988 and 1993. The women were followed up for cytological abnormality and neoplasia through the cytology laboratory's records. HPV at entry was assayed in an age- and period-stratified random sample of 7278 women and in prevalent and incident CIN3 cases. The prevalence of newly diagnosed CIN3 increased with time since last normal smear, indicating that most cases persist for several years. CIN3 prevalence did not increase further for screening intervals exceeding 5 years, however, suggesting that CIN3 eventually regresses cytologically. CIN2 prevalence increased less steeply with screening interval, while the prevalence of lesser abnormality was almost independent of screening interval. The prevalence of oncogenic HPV at entry declined from 19% among women aged under 25 to less than 3% at age 40 or above. Oncogenic HPV infection was strongly predictive of subsequent CIN3 (OR 17.2, 95% CI 10.4-28.4), but only weakly related to CIN2 (OR 2.3, 95% CI 0.5-10.7) and lesser abnormality (OR 1.4, 95% CI 0.8-2.5). At current incidence rates, the lifetime risk of developing CIN3 will be 9% in this population. The cumulative risk of CIN3 diagnosis among cytologically normal women with oncogenic HPV detected at entry was 28% (CI 18-43%) after 14 years. Persistence of oncogenic HPV may be more sensitive and specific than cytology for early detection of CIN3 and invasive cancer.

Contact with farming environment as a major risk factor for Shiga toxin (Vero cytotoxin)-producing Escherichia coli O157 infection in humans.

In a prospective, unmatched case-control study of sporadic Shiga toxin (Vero cytotoxin)-producing Escherichia coli O157 (STEC O157) infection in England, exposure to the farming environment emerged strongly as a risk factor (adjusted odds ratio = 2.45; 95% confidence intervals = 1.49-4.02; p=0.0004) posing further challenges and opportunities for prevention.

An international outbreak of Vero cytotoxin-producing Escherichia coli O157 infection amongst tourists; a challenge for the European infectious disease surveillance network.

In March 1997, an outbreak of Vero cytotoxin-producing Escherichia coli O157 (VTEC) infection occurred amongst holidaymakers returning from Fuerteventura, Canary Islands. For the investigation, a confirmed case was an individual staying in Fuerteventura during March 1997, with either E. coli O157 VTEC isolated in stool, HUS or serological evidence of recent infection; a probable case was an individual with bloody diarrhoea without laboratory confirmation. Local and Europe-wide active case finding was undertaken through national centres, Salm-Net and the European Programme of Intervention Epidemiology, followed by a case-control study. Fourteen confirmed and one probable case were identified from England (7), Finland (5), Wales (1), Sweden (1) and Denmark (1) staying in four hotels. Three of the four hotels were supplied with water from a private well which appeared to be the probable vehicle of transmission. The case-control study showed illness was associated with consumption of raw vegetables (OR 8.4, 95% CI 1-5-48.2) which may have been washed in well water. This investigation shows the importance of international collaboration in the detection and investigation of clusters of enteric infection.

Depressive illness, depressive symptomatology and regional cerebral blood flow in elderly people with sub-clinical cognitive impairment.

BACKGROUND: Depressive illness in dementia is often assumed to be a unitary clinical phenomenon. AIM: To describe changes in patterns of depressive symptomatology with time, and associated changes in cerebral blood flow to the frontal and temporal regions. METHOD AND RESULTS: 397 elderly people with sub-clinical cognitive dysfunction were observed over 3 years. Sixteen percent of them developed dementia during the study The prevalence of depressive symptomatology was higher in this group than in the general population, especially in women, who also had higher recovery rates. A changing profile of depressive symptoms was found in depressed elderly people progressing to dementia, with fewer affective symptoms and increases in agitation and motor slowing. These changes were paralleled by greater reductions in left temporal regional cerebral blood flow than in non-depressed subjects with Alzheimer's disease. CONCLUSION: In dementia, there may be two separate and interacting depressive syndromes whose differentiation may be clinically important.

The most prevalent hepatitis C virus genotypes in England and Wales are 3a and 1a.

Hepatitis C virus (HCV) genotypes were assigned to 567 individuals by restriction fragment length polymorphism analysis of the 5' noncoding region of the HCV genome following reverse transcription-polymerase chain reaction. The groups of individuals in this study included hemophilia patients, injecting drug users (IDUs), blood donors, antenatal patients, those attending genitourinary medicine (GUM) clinics, and patients with chronic liver disease, all from England and Wales. The majority of HCV infections were types 1a (32%), 1b (15%), or 3a (37%). The genotype distribution in individual groups was similar to the overall genotype distribution except for hemophilia patients, in whom the frequencies were 1a (39%), 1b (23%), and 3a (21%). With the exception of hemophilia patients, subpopulations in England and Wales appear to share common modes of HCV transmission. There is a need for continued surveillance to monitor the spread of possibly more virulent or drug-resistant HCV genotypes.

Geographical distribution of tuberculosis notifications in national surveys of England and Wales in 1988 and 1993: report of the Public Health Laboratory Service/British Thoracic Society/Department of Health Collaborative Group.

BACKGROUND: The geographical distribution of tuberculosis in England and Wales and changes since 1983 were examined using data from the 1988 and 1993 national surveys of tuberculosis notifications. METHODS: Notification rates for England and Wales in 1988 and 1993 were calculated for geographical areas using Office for National Statistics (ONS) mid year population estimates. Those for the standard regions and the Greater London boroughs were calculated for the main ethnic groups. Those for the counties and local authorities were calculated for all ethnic groups combined. These were compared using data from the 1983 national survey as a baseline. RESULTS: Wide regional variations in notification rates persist with Greater London having the highest rates. Rates in the ethnic group from the Indian subcontinent (ISC) were high in all regions, whilst those of the white ethnic group varied fourfold. Twenty seven of the 33 London boroughs showed increased rates in 1993 compared with 1988. In general, those local authority areas with high rates had high proportions of notifications in individuals of ISC ethnic origin, emphasising the continuing important contribution of ethnic minority groups to local tuberculosis rates. The number of local authority areas with notification rates four times the national average increased, but the number of areas with low or zero rates increased even more. CONCLUSIONS: The distribution of tuberculosis in England and Wales continues to vary markedly by geographical area. The distribution is becoming increasingly polarised with a growth in the number of areas with very high rates of notifications and a greater increase in the number of areas with very few notifications. Patients from ethnic minorities continued to contribute a substantial and increasing proportion of all reported tuberculosis cases in most regions in 1988 and 1993. These findings have important implications for the provision of tuberculosis services in England and Wales.

A voice against physician-assisted suicide.

In the early hours of November 14, 1996, Card. Joseph Bernardin died of pancreatic cancer. The Archbishop of Chicago approached death not in fear but as a "transition from earthly life to life eternal." One of his last public acts was writing a letter to the U.S. Supreme Court. He asked the justices to reject arguments that the dying have a right to physician-assisted suicide. In two powerful and poignant pages, the cardinal concisely summarizes the legal and policy arguments against legitimizing the purposeful facilitation of death by healthcare providers. CHA attached his letter to the amicus curiae brief it filed with the U.S. Supreme Court in Vacco v. Quill and Washington v. Glucksberg, the two physician-assisted suicide cases to be decided by the Court this term (see "CHA Amicus Curiae Brief on Physician-Assisted Suicide," p. 36). In this article we provide context for the thoughts expressed in Card. Bernardin's letter, excerpted below, and describe how this letter makes a persuasive legal argument against physician-assisted suicide.