Ciaran Woodman

Natural history of cervical human papillomavirus infection in young women: a longitudinal cohort study

BACKGROUND Laboratory and epidemiological research suggests an association between human papillomavirus (HPV) and cervical intraepithelial neoplasia (CIN). We studied the natural history of incident cervical HPV infection and its relation to the development of CIN. METHODS We recruited 2011 women aged 15-19 years who had recently become sexually active. We took a cervical smear every 6 months and stored samples for virological analysis. We immediately referred all women with any cytological abnormality for colposcopic assessment, but postponed treatment until there was histological evidence of progression to high-grade CIN. FINDINGS In 1075 women who were cytologically normal and HPV negative at recruitment, the cumulative risk at 3 years of any HPV infection was 44% (95% CI 40-48): HPV 16 was the most common type. The cumulative risk at 3 years of detecting an HPV type not present in the first positive sample was 26% (20-32). 246 women had an abnormal smear during follow-up, of whom 28 progressed to high-grade CIN. The risk of high-grade CIN was greatest in women who tested positive for HPV 16 (risk ratio 8.5 [3.7-19.2]); this risk was maximum 6-12 months after first detection of HPV 16. All HPV types under consideration were associated with cytologically abnormal smears. Although abnormality was significantly less likely to be associated with low-viral-load samples, the cumulative risk at 3 years of a high-viral-load sample after a low-viral-load sample was 45% (95% CI 35-56). Five women who progressed to high-grade CIN consistently tested negative for HPV. INTERPRETATION Our findings suggest that attempts to exploit the association between cervical neoplasia and HPV infection to improve effectiveness of cervical screening programmes might be undermined by the limited inferences that can be drawn from the characterisation of a womans HPV status at a single point in time, and the short lead time gained by its detection.

The polymerase chain reaction: a new epidemiological tool for investigating cervical human papillomavirus infection.

The polymerase chain reaction is an in vitro method for primer directed enzymatic amplification of specific target DNA sequences. The technique was used to detect human papillomavirus types 11 and 16 simultaneously in cellular DNA recovered from cervical smears in 38 women referred for colposcopy to evaluate cytological abnormality and 10 women with no history of cytological abnormality. The polymerase chain reaction was shown to be both specific and sensitive in detecting human papillomavirus DNA such that a single human papillomavirus molecule was detected in 10(5) cells. Of the 38 women with cytological abnormality, all were positive for human papillomavirus on testing with the polymerase chain reaction; 36 were infected with human papillomavirus type 16 and 22 dually infected with human papillomavirus types 11 and 16. Seven of the 10 women with no cytological abnormality were also infected with human papillomavirus type 11 or 16. The use of the polymerase chain reaction will facilitate epidemiological investigation of the aetiological role of human papillomavirus in cervical neoplasia. This preliminary analysis suggests that the prevalence of human papillomavirus infection is greater than previously reported.

High incidence of cervical human papillomavirus infection in women during their first sexual relationship

The prevalence of cervical human papillomavirus increases with increasing numbers of sexual partners, leaving the impression that this infection is acquired only as a result of high risk sexual behaviour. Using longitudinal data from 242 women who had only had one sexual partner, we found that the risk of acquiring cervical human papillomavirus infection was 46% (95% CI 28–64) at three years after first intercourse and that the median time from first intercourse to first detection of human papillomavirus was only three months.

Follow up policy after treatment for Hodgkin's disease: too many clinic visits and routine tests? A review of hospital records.

Abstract Objective: To examine the effectiveness of routine clinic review in detecting relapse after treatment for Hodgkins disease. Design: Review of hospital records. Setting: Regional centre for cancer treatment and research. Subjects: 210 patients with Hodgkins disease recruited to a chemotherapy trial protocol between 1984 and the end of 1990 who had achieved a complete or partial remission after treatment. Main outcome measures: The number of clinic visits made by patients over the period of observation, the number of relapses occurring during that time, and the route by which relapse was detected. Results: The 210 patients generated 2512 outpatient reviews, and 37 relapses were detected. Thirty relapses (81%) were diagnosed in patients who described symptoms, which in 15 cases had resulted in an earlier appointment being arranged. In only four cases (11%; 95% confidence interval 4% to 25%) was relapse detected as a result of routine physical examination or investigation of a patient who did not have symptoms. Conclusions: Relapse of Hodgkins disease after treatment is usually detected as a result of the investigation of symptoms rather than by routine screening of asymptomatic patients. It is therefore proposed that the frequency of routine follow up visits should be reduced and greater emphasis placed on patient education. This should underline the importance of symptoms and encourage patients to arrange an earlier appointment if these develop. Key messages Follow up after treatment for Hodgkins disease has several functions but detection of relapse is probably the most important In Hodgkins disease the relapse rate is maximal 12-18 months after the start of treatment but declines rapidly thereafter Relapse is usually identified as a result of the investigation of symptoms rather than by routine screening of asymptomatic patients Routine clinic visits should be reduced in frequency and far greater emphasis placed on patient education; this should underline the importance of symptoms and encourage patients to arrange earlier appointments if these develop

Cost effectiveness of shortening screening interval or extending age range of NHS breast screening programme: computer simulation study

Abstract Objective : To compare the cost effectiveness of two possible modifications to the current UK screening programme: shortening the screening interval from three to two years and extending the age of invitation to a final screen from 64 to 69. Design : Computer simulation model which first simulates life histories for women in the absence of a screening programme for breast cancer and then assesses how these life histories would be changed by introducing different screening policies. The model was informed by screening and cost data from the NHS breast screening programme. Setting : North West region of England. Main outcome measures : Numbers of deaths prevented, life years gained, and costs. Results : Compared with the current breast screening programme both modifications would increase the number of deaths prevented and the number of life years saved. The current screening policy costs £2522 per life year gained; extending the age range of the programme would cost £2612 and shortening the interval £2709 per life year gained. The marginal cost per life year gained of extending the age range of the screening programme is £2990 and of shortening the screening interval is £3545. Conclusions : If the budget for the NHS breast screening programme were to allow for two more invitations per woman, substantial mortality reductions would follow from extending the age range screened or reducing the screening interval. The difference between the two policies is so small that either could be chosen.

Human papillomavirus type 18 and rapidly progressing cervical intraepithelial neoplasia

BACKGROUND Human papillomavirus type 18 (HPV-18) is the second most frequent of the HPV types detected when squamous-cell cancer is diagnosed and the type most strongly associated with adenocarcinoma of the cervix. However, in cross-sectional studies, HPV-18 is rarely detected at the time of diagnosis of high-grade cervical intraepithelial neoplasia (CIN). We used a longitudinal study design to describe the occurrence of cytological abnormality after incident HPV-18 and HPV-16 infections. METHODS The analysis was based on 1075 women aged 15-19 years, who had normal cytology and were negative for HPV at recruitment from a single family-planning clinic, and who had further follow-up. The women reattended every 6 months, and samples were taken for cytological and virological examination. FINDINGS The relative risk of a cytological diagnosis of borderline nuclear abnormality after exposure to HPV-18 was 2.06 (95% CI 1.24-3.43) and that after exposure to HPV-16 was 1.99 (1.32-3.01). The relative risks of mild dyskaryosis were 3.11 (1.86-5.18) and 4.76 (3.15-7.18), and the relative risks of moderate or severe dyskaryosis were 0.80 (0.24-2.65) and 2.85 (1.36-5.97). Time to acquisition of cytological abnormality was unrelated to the infecting type (p=0.88). INTERPRETATION Our findings do not support the long-held view that the reason why HPV-18 infection is under-represented at the time of diagnosis of high-grade CIN is because HPV-18-associated disease rapidly progresses through the preinvasive stages of neoplasia. We suggest that the cytological changes detected after HPV-18 infection might understate the severity of underlying disease. This feature could compromise the effectiveness of screening programmes in reducing the frequency of HPV-18-associated cancers.

What changes in the organisation of cancer services will improve the outcome for women with ovarian cancer

Objective To examine the influence of operator specialty, volume of work and referral to an oncologist on the survival of women with ovarian cancer.

Analysis of human papillomavirus type 16 E6-E7 transcription in cervical carcinomas and normal cervical epithelium using the polymerase chain reaction.

Cervical biopsies were collected from Birmingham women having cervical intraepithelial neoplasia or invasive cervical carcinoma and normal controls, and examined for the presence of human papillomavirus type 16 (HPV-16) E6-E7 DNA and mRNA using an adaptation of the polymerase chain reaction. HPV-16 E6-E7 sequences were detected in all abnormal biopsies and in 90% of the normal biopsies examined, confirming previous studies describing the high prevalence of cervical HPV-16 infection. While we were unable to identify any qualitative differences in RNA transcripts from the p97 promoter, substantial quantitative differences in HPV-16-specific early region transcripts between normal and cytologically abnormal cervices were observed. These results suggest that although the level of E6-E7 transcription may contribute to the malignant phenotype, additional factors are likely to be important in the development of cervical neoplasia.

Low prevalence of Epstein-Barr virus in incident gastric adenocarcinomas from the United Kingdom.

Epstein–Barr virus has been associated with a proportion of typical gastric adenocarcinomas. Here we report that the prevalence of Epstein–Barr virus in gastric adenocarcinomas from the United Kingdom is one of the lowest in the World. Gastric adenocarcinoma is another tumour whose association with Epstein–Barr virus varies with the population studied.

Adequacy of cervical cytology sampling with the Cervex brush and the Aylesbury spatula : a population based randomised controlled trial

Abstract Objective: To compare the adequacy of cervical cytology sampling with two sampling instruments commonly used in primary care—namely, the Aylesbury spatula and the Cervex brush. Design: Pair matched, population based randomised controlled trial. Setting: 86 general practices and family planning clinics in Greater Manchester. Subjects: 15 882 cervical smears taken from women aged 20-64 years as part of the national cervical screening programme. Interventions: Participating centres were allocated to sample with either the Cervex brush or the Aylesbury spatula. Main outcome measure: Inadequate smear rate. Results: 5.4% and 5.5% (433/8086 and 426/7796) of smears taken with the Cervex brush and the Aylesbury spatula respectively were reported as inadequate (odds ratio 0.95; 95% confidence interval 0.74 to 1.22). Conclusion: The Cervex brush offers no advantage over the Aylesbury spatula in reducing inadequate smear rates in the primary care setting. Key messages Cervical sampling instruments have rarely been formally evaluated in population based settings Group randomisation is useful when evaluating community based interventions but requires modified statistical techniques The Cervex brush offers no advantage over the Aylesbury spatula in reducing rates of inadequate smears when used in primary care