Peter Sasieni

Benefit of cervical screening at different ages: evidence from the UK audit of screening histories

While most experts agree that cervical screening is effective, there remains controversy over the most appropriate screening interval. Annual screening is common in North America. In England, some argue for 3-yearly screening while others believe 5-yearly screening is adequate, and the frequency varies from one part of the country to another. Screening histories of 1305 women aged 20–69 years, diagnosed with frankly invasive cervical cancer and 2532 age-matched controls were obtained from UK screening programme databases. Data were analysed in terms of time since last negative, and time since last screening smear. Five-yearly screening offers considerable protection (83%) against cancer at ages 55–69 years and even annual screening offers only modest additional protection (87%). Three-yearly screening offers additional protection (84%) over 5-yearly screening (73%) for cancers at ages 40–54 years, but is almost as good as annual screening (88%). In women aged 20–39 years, even annual screening is not as effective (76%) as 3-yearly screening in older women, and 3 years after screening cancer rates return to those in unscreened women. This calls into question the policy of having a uniform screening interval from age 20 to 64 years and stresses the value of screening in middle-aged women.

Effectiveness of cervical screening with age: population based case-control study of prospectively recorded data

Objective To study the effect of cervical screening on incidence of cervical cancer as a function of age with particular focus on women screened under the age of 25. Design Population based case-control study with prospectively recorded data on cervical screening. Setting Selected centres in the United Kingdom. Participants 4012 women aged 20-69 with invasive cancer diagnosed in participating centres and two controls per case individually matched on age and area of residence. Main outcome measures Odds ratios for strength of association between cervical cancer and screening at particular ages. Results There is no evidence that screening women aged 22-24 reduced the incidence of cervical cancer at ages 25-29 (odds ratio 1.11, 95% confidence interval 0.83 to 1.50). Similar results were seen for cancers restricted to squamous carcinoma or FIGO (International Federation of Gynaecology and Obstetrics) stage IB or worse, but the numbers are insufficient to provide narrow confidence intervals. Screening was associated with a 60% reduction of cancers in women aged 40, increasing to 80% at age 64. Screening was particularly effective in preventing advanced stage cancers. Conclusions Cervical screening in women aged 20-24 has little or no impact on rates of invasive cervical cancer up to age 30. Some uncertainly still exists regarding its impact on advanced stage tumours in women under age 30. By contrast, screening older women leads to a substantial reduction in incidence of and mortality from cervical cancer. These data should help policy makers balance the impact of screening on cancer rates against its harms, such as overtreatment of lesions with little invasive potential.

Promyelocytic leukemia nuclear bodies associate with transcriptionally active genomic regions

The promyelocytic leukemia (PML) protein is aggregated into nuclear bodies that are associated with diverse nuclear processes. Here, we report that the distance between a locus and its nearest PML body correlates with the transcriptional activity and gene density around the locus. Genes on the active X chromosome are more significantly associated with PML bodies than their silenced homologues on the inactive X chromosome. We also found that a histone-encoding gene cluster, which is transcribed only in S-phase, is more strongly associated with PML bodies in S-phase than in G0/G1 phase of the cell cycle. However, visualization of specific RNA transcripts for several genes showed that PML bodies were not themselves sites of transcription for these genes. Furthermore, knock-down of PML bodies by RNA interference did not preferentially change the expression of genes closely associated with PML bodies. We propose that PML bodies form in nuclear compartments of high transcriptional activity, but they do not directly regulate transcription of genes in these compartments.

Prevention of colorectal cancer by colonoscopic surveillance in individuals with a family history of colorectal cancer: 16 year, prospective, follow-up study

Abstract Objective To determine to what extent individuals with various family histories of colorectal cancer (from one to three or more affected first degree relatives) benefit from colonoscopic surveillance. Design Prospective, observational study of high risk families, followed up over 16 years. Setting Tertiary referral family cancer clinic in London. Participants 1678 individuals from families registered with the clinic. Individuals were classified according to the strength of their family history: hereditary non-polyposis colorectal cancer (if they fulfilled the Amsterdam criteria), and one, two, or three affected first degree relatives (moderate risk). Interventions Colonoscopy was initially offered at five year intervals or three year intervals if an adenoma was detected. Main outcome measures The incidence of adenomas with high risk pathological features or cancer. This was analysed by age, the extent of the family history, and findings on previous colonoscopies. The cohort was flagged for cancer and death. Incidence of colorectal cancer and mortality during over 15 000 person years of follow-up were compared with those expected in the absence of surveillance. Results High risk adenomas and cancer were most common in families with hereditary non-polyposis colorectal cancer (on initial colonoscopy 5.7% and 0.9%, respectively). In the families with moderate risk, these findings were particularly uncommon under age 45 (1.1% and 0%) and on follow-up colonoscopy if advanced neoplasia was absent initially (1.7% and 0.1%). The incidence of colorectal cancer was substantially lower—80% in families with moderate risk (P = 0.00004), and 43% in families with hereditary non-polyposis colorectal cancer (P = 0.06)—than the expected incidence in the absence of surveillance when the family history was taken into account. Conclusions Colonoscopic surveillance reduces the risk of colorectal cancer in people with a strong family history. This study confirms that members of families with hereditary non-polyposis colorectal cancer require surveillance with short intervals. Individuals with a lesser family history may not require surveillance under age 45, and if advanced neoplasia is absent on initial colonoscopy, surveillance intervals may be lengthened. This would reduce the demand for colonoscopic surveillance.

APC in the regulation of intestinal crypt fission

The functional effects of APC (adenomatous polyposis coli gene) germ‐line mutations on crypt fission and cell proliferation were investigated in the normal intestine of human familial adenomatous polyposis (FAP) and multiple intestinal neoplasia (MIN) mice. Compared with controls, there was a 19‐fold increase in the proportion of crypts in fission in FAP colon [95 per cent confidence interval (CI):11–32, P<0·0001], and a 75 and 61 per cent increase in MIN colon (95 per cent CI:1·08–2·82, P<0·02) and small bowel, respectively (95 per cent CI:1·31–1·99, P<0·001). In marked contrast, no significant differences in intra‐cryptal epithelial cell proliferation or mitotic distribution were seen. Furthermore, 10·9 per cent of crypts in FAP were in asymmetrical fission as opposed to only 1 per cent in controls (P=0·001). The largest relative increases in MIN crypt fission were in the colon (proximal and distal colon:190 per cent, P=0·02 and 83 per cent, P=0·01), suggesting that Apc mutations exert their maximal influence site‐specifically. However, sites with the highest relative increases were also those with the largest eventual tumour sizes, but not the highest polyp counts. Three‐dimensional serial section reconstruction analysis corroborated that FAP adenomas enlarge by crypt fission, which was frequently both asymmetrical and atypical. It is proposed that the absence of an increase in intestinal cell division infers that APC regulates intestinal crypt differentiation, specifically through the crypt cycle. This role appears analogous to the control of axis re‐duplication in embryonic development, when downstream targets of APC are over‐expressed. It is concluded that in vivo, the major defect in pre‐neoplastic intestine harbouring APC mutations is elevated rates of crypt fission, and that this is also the mode by which micro‐adenomas enlarge.

Changing rates of adenocarcinoma and adenosquamous carcinoma of the cervix in England

BACKGROUNDnA recent analysis showed little or no effect of screening on the incidence of adenocarcinoma of the cervix between 1971 and 1992. We have used additional data on cancers diagnosed in 1993-94 in England and up to 1997 in five English cancer registries to investigate more recent trends.nnnMETHODSnAfter inputing the number of adenocarcinomas in women with unknown histology, we fitted an age-cohort model to 8062 adenocarcinomas of the cervix diagnosed in England between 1971 and 1987. Predictions from this model were applied to the more recent data on 5854 cases. Residual effects were plotted against year of diagnosis in each of four age-groups.nnnFINDINGSnWe estimated the underlying risk of cervical adenocarcinoma to be 14 times (95% CI 11-19) greater in women born in the early 1960s than in cohorts born before 1935. An age-cohort model fitted the data for England well up to 1987, but substantially overestimated the numbers of adenocarcinomas in young women from 1990 onwards. In 1996-97 the incidence rate in women aged 25-54 years was less than 40% of that predicted from the age-cohort model.nnnINTERPRETATIONnThe substantial increase in cervical adenocarcinoma in recent years is largely a birth-cohort effect presumably associated with greater exposure to human papillomavirus after the sexual revolution in the 1960s. The relative decline in younger women observed in more recent years suggests an effect of cervical screening.

Long-term risk of invasive cervical cancer after treatment of squamous cervical intraepithelial neoplasia.

Invasive cancer of the cervix after treatment for cervical intraepithelial neoplasia (CIN) is becoming more important, as screening reduces the incidence of invasive disease. The rate of invasive cervical or vaginal cancer following treatment for CIN in UK remains elevated for at least 8 years. The aim of our study was to determine from international data how long this rate remains elevated and whether the rate of invasive disease reflects the rate of posttreatment CIN. The aim was to determine why the rate of invasive disease does not fall. A search of Medline and a secondary search of cited references identified 1,848 articles referring to the success rate of the treatment of CIN. Only 26 cohorts from 25 articles met all the inclusion criteria. The policy in these was to perform at least annual smears. After the first year following treatment for CIN, the rate of invasive disease remained about 56 per 100,000 woman years until at least 20 years after treatment. This rate is ˜2.8 times greater than expected. In contrast, the risk of posttreatment CIN declined steadily with time to about 190 per 100,000 women in the 10th year. Although the posttreatment rate of CIN falls with time, the rate of invasive disease remains static. It seems likely that this is due to diminishing compliance with follow‐up. Women should be encouraged to persevere with annual smears for at least 10 years after their treatment as this may offer them the best chance of detecting recurrence at a treatable stage.

The association between naevi and melanoma in populations with different levels of sun exposure : a joint case-control study of melanoma in the UK and Australia

Two case-control studies were set up to investigate the relationship between melanocytic naevi and risk of melanoma and to compare the naevus phenotype in two countries exposed to greatly different levels of sun exposure and different melanoma rates. In England 117 melanoma cases and 163 controls were recruited from the North-East Thames Region and 183 melanoma cases and 162 controls from New South Wales, Australia. Each subject underwent a whole-body naevus count performed by the same examiner in each country. Relative risks associated with melanocytic naevi in each country were calculated with comparison of naevus data in controls between Australia and England. Atypical naevi were strong risk factors for melanoma in both countries: the odds ratio (OR) for three or more atypical naevi was 4.6 (95% CI 2.0-10.7) in Australia compared with 51.7 (95% CI 6.5-408.4) in England. Common naevi were also significant risk factors in Australia and England with similar odds ratios in the two countries. Prevalence of atypical naevi was greater in Australian controls than in English controls: OR 9.7 (95% CI 1.2-81.7) for three or more atypical naevi in Australia compared with England. For young age groups, the median number of common naevi was greater in Australia than in the UK, whereas for older individuals this difference in naevi number between the two countries disappeared. The prevalence of naevi on non-sun-exposed sites in controls was not significantly different between the two countries. The atypical mole syndrome (AMS) phenotype was more prevalent in Australian controls (6%) than in English controls (2%). The results of this study support the role of sun exposure in the induction of atypical naevi in adults. There was a trend towards stronger risk factors associated with atypical naevi in England compared with Australia. The atypical mole syndrome, usually associated with a genetic susceptibility to melanoma, was more common in Australia than in England, suggesting genetic environmental interactions with the possibility of phenocopies induced by sunlight.

Cervical screening by visual inspection, HPV testing, liquid‐based and conventional cytology in Amazonian Peru

Cervical cancer is an important public health problem in many developing countries, where cytology screening has been ineffective. We compared four tests to identify the most appropriate for screening in countries with limited resources. Nineteen midwives screened 5,435 women with visual inspection (VIA) and collected cervical samples for HPV testing, liquid‐based cytology (LBC) and conventional cytology (CC). If VIA was positive, a doctor performed magnified VIA. CC was read locally, LBC was read in Lima and HPV testing was done in London. Women with a positive screening test were offered colposcopy or cryotherapy (with biopsy). Inadequacy rates were 5% and 11% for LBC and CC respectively, and less than 0.1% for VIA and HPV. One thousand eight hundred eighty‐one women (84% of 2,236) accepted colposcopy/cryotherapy: 79 had carcinoma in situ or cancer (CIS+), 27 had severe‐ and 42 moderate‐dysplasia on histology. We estimated a further 6.5 cases of CIS+ in women without a biopsy. Sensitivity for CIS+ (specificity for less than moderate dysplasia) was 41.2% (76.7%) for VIA, 95.8% (89.3%) for HPV, 80.3% (83.7%) for LBC, and 42.5% (98.7%) for CC. Sensitivities for moderate dysplasia or worse were better for VIA (54.9%) and less favourable for HPV and cytology. In this setting, VIA and CC missed the majority of high‐grade disease. Overall, HPV testing performed best. VIA gives immediate results, but will require investment in regular training and supervision. Further work is needed to determine whether screened‐positive women should all be treated or triaged with a more specific test.

Predicted impact of vaccination against human papillomavirus 16/18 on cancer incidence and cervical abnormalities in women aged 20-29 in the UK

Background:Human papillomavirus (HPV) vaccination has been approved in more than 90 countries and is being implemented in many of these. In the UK, vaccination for girls aged 12–13 with catch-up for girls up to age 18 was introduced in 2008, using the bivalent GSK vaccine (Cervarix).Methods:We modelled the proportion of abnormal smears, cervical intraepithelial neoplasia grade 3 (CIN3) and invasive cancer, which will be prevented in women aged 20–29 in the UK as a result of HPV vaccination.Results:It will take many years for the full benefit of vaccination to be achieved. The earliest effects will be seen in women aged 20–29. With 80% coverage in women aged 12–13, we project an eventual 63% reduction in invasive cancer, a 51% reduction in CIN3 and a 27% reduction in cytological abnormalities before age 30. The full effect in this age group will not be seen until 2025, although half of the benefit will be seen by 2019 in England, where screening starts at age 25. However in Scotland and Wales, where screening starts at age 20, 50% of the benefit for CIN3 and abnormal smears (but not cancer) will be seen earlier.Conclusion:Substantial reductions in disease can be anticipated by vaccination, but most of the benefit will not be apparent for at least another decade. High vaccine coverage is the key factor for achieving these benefits.