Once-only sigmoidoscopy.
The rationale for infrequent screening for colorectal cancers by sigmoidoscopy of the general population around age 60 is reviewed. A progress report for a trial to evaluate this approach is also presented.
Adenoma↗
Biomedical subjects
J Cuzick
Publications and source records attributed to J Cuzick.
Cervical screening in the United Kingdom.
It has been more than 10 years since the cervical screening system in the United Kingdom was completely overhauled and a computerised call and recall system was introduced. The current programme is very healthy and dramatic improvements have been made over the past decade. The coverage of the screening programme in England has improved, and incidence and mortality rates have been reduced. Further improvements in compliance, rigorous auditing, and new technologies will likely yield more accurate, efficient, and cost-effective screening programmes in the next decade.
Journal Article↗
Effect of early American results on patients in a tamoxifen prevention trial (IBIS). International Breast Cancer Intervention Study.
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Antineoplastic Agents, Hormonal↗
Solar keratoses: a risk factor for melanoma but negative association with melanocytic naevi.
Solar keratoses have been associated with increased risk of squamous-cell and basal-cell carcinomas, but their association with melanoma is less clear. This study investigated solar keratoses as a risk factor for cutaneous melanoma in Australia, also associations between solar keratoses and other host factors associated with melanoma. A total-body naevus count was made of 258 melanoma cases and 281 controls recruited from New South Wales, Australia, and solar keratoses were counted on the left forearm. Solar elastosis was also assessed by clinical examination on the face and the side of the neck. Solar keratoses were a significant risk factor for melanoma in Australia. The presence of 10 or more solar keratoses on the left forearm (compared with none) was associated with an odds ratio of 4.7 (95% CI, 2.0-10.9). A highly significant association was found between number of solar keratoses and a past history of multiple basal-cell carcinomas in cases and controls respectively. Numbers of common and atypical naevi decreased significantly with age, while solar keratoses were more common in older individuals. Solar keratoses were found more commonly in men than women in cases and in controls (p < 0.0001). A negative association was found between numbers of common naevi and numbers of solar keratoses in cases and controls, and this remained significant after stratifying for age, gender and hair colour (p < 0.0001 and p < 0.0016 respectively). Solar keratoses were more common in males with melanoma on the head and neck as compared with melanoma on any other site. Solar keratoses and naevi were independently predictive of increased melanoma risk. The fact that these 2 phenotypes were found to be negatively associated suggests that susceptibility to melanoma may be expressed via 2 distinct cutaneous phenotypes which may be genetically determined.
Adolescent↗
Electropotential measurements as a new diagnostic modality for breast cancer.
BACKGROUND: Proliferative changes in breast epithelium are an intrinsic aspect in the development of breast cancer, and result in regions of epithelial electrical depolarisation within the breast parenchyma, which can extend to the skin surface. Diagnostic information might be obtained from a non-imaging and non-invasive test based on skin-surface electropotentials. METHODS: In 661 women, scheduled for open biopsy at eight European centres, we studied whether measurements of breast electrical activity with surface sensors could distinguish benign from malignant breast disease. A depolarisation index was developed. RESULTS: We found a highly significant trend of progressive electrical changes according to the proliferative characteristics of the biopsied tissue. Discriminatory information was obtained in both premenopausal and postmenopausal women, and the index was not related to age. The best test performances were for women with palpable lesions. The median index was 0.398 for non-proliferative benign lesions, 0.531 for proliferative benign lesions, and 0.644 for cancer (ductal carcinoma-in-situ and invasive). A specificity of 55% was obtained at 90% sensitivity for women with palpable lesions when a discriminant based on age and the depolarisation index was used. INTERPRETATION: This new modality may have diagnostic value, especially in reducing the number of unnecessary diagnostic tests among women with inconclusive findings on physical examination. Understanding and control of the biological variability of these electrical phenomena will be important in the improvement of this test. Studies in populations with a lower cancer prevalence are needed to assess further the diagnostic value of this approach.
Adolescent↗
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.
Adolescent↗
Uptake, yield of neoplasia, and adverse effects of flexible sigmoidoscopy screening.
BACKGROUND: A multicentre randomised controlled trial to evaluate screening by "once only" flexible sigmoidoscopy (FS) for prevention of bowel cancer is in progress. AIMS: To pilot the trial protocol examining rates of attendance, yield of neoplasia, and adverse effects. SUBJECTS: A total of 3540 subjects aged 55-64 years in Welwyn Garden City (WGC) and 19,706 in Leicester (LE). METHODS: Subjects responding positively to an "interest in screening" questionnaire were randomised to invitation for screening or control arms. Small polyps were removed during screening. Colonoscopy was undertaken for high risk polyps (more than two adenomas, size at least 1 cm, villous histology, severe dysplasia, or malignancy). The remainder were discharged. RESULTS: In WGC and LE respectively, 59% and 61% indicated an interest in screening, of which 74% and 75% attended. Adenomas were detected in 10% and 9%, respectively, and cancers in 7 per 1000 (in both centres), 55% at Dukes's stage A. The colonoscopy referral rate was 6% in both centres. Mild, short lived bleeding occurred in 3%. One person died following surgery. CONCLUSIONS: Compliance rates, yield of adenomas, and referral rate for colonoscopy were as expected, but cancer detection rates were higher. Adverse effects following sigmoidoscopy or colonoscopy were mild and transient, but there was one postoperative death. A randomised trial is necessary to evaluate fully the risks and benefits of this intervention.
Adenoma↗
HPV testing in cervical screening.
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Female↗
Low biologic aggressiveness in breast cancer in women using hormone replacement therapy.
PURPOSE: Hormone replacement therapy (HRT) has been associated with an increased risk for breast cancer. Cancers in women who use HRT are often less advanced, and lower mortality has been reported in those who use HRT than in nonusers. We sought to explain this by a comparison of indicators of tumor aggressiveness in patients who received HRT with those in patients who did not. PATIENTS AND METHODS: A population-based cohort of 477 postmenopausal women with breast cancer were interviewed for the use, type, and duration of HRT. Clinical variables and indicators of tumor aggressiveness (histologic grade, hormone receptors, DNA ploidy, S-phase fraction, and c-erbB-2 oncoprotein overexpression) were analyzed. RESULTS: Breast tumors from HRT users were smaller (odds ratio, 0.47; P=.005), had better histologic differentiation (P=.04), and had a lower proliferation rate (S-phase fraction, P=.009) than tumors from nonusers. These differences persisted after adjustments for age and method of diagnosis (mammography screening v self-referral) by multiple logistic regression. No significant differences were observed in the estrogen (ER) or progesterone receptor content, c-erbB-2 oncogene overexpression, or axillary node involvement. A subgroup analysis showed that the tumor proliferation rates among HRT users were significantly lower only if HRT had been used at the time of diagnosis (P=.001). The type of HRT (estrogen v combination of estrogen and progesterone) was not associated with any clinical parameter or tumor phenotype. The association of HRT with lower proliferation rate and smaller tumor size was exclusively caused by ER-positive tumors (P=.0001 and P=.0035 v P > .1, respectively). CONCLUSION: The results indicate that breast cancer in women who receive HRT is biologically less aggressive than those without previous HRT. The lower cell-proliferation rate and smaller tumor size found in ER-positive tumors from current HRT users suggest a direct ER-mediated growth inhibitory effect of HRT on established breast tumors. This may at least partly explain why breast cancer in HRT users has a more favorable clinical course.
Aged↗
Continuation of the International Breast Cancer Intervention Study (IBIS).
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Anticarcinogenic Agents↗
Hormone replacement therapy and biological aggressiveness of breast cancer.
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Breast Neoplasms↗
Analysis of E2 amino acid variants of human papillomavirus types 16 and 18 and their associations with lesion grade and HLA DR/DQ type.
Human papillomavirus (HPV) 16 and HPV 18 E2 amino acid variants and host HLA DR/DQ haplotypes have been identified by direct nucleic acid sequencing from cervical scrapes. HPV16 E2 variants co-segregate with a nucleotide variant at nt350 (in E6), which previously has been associated with persistent infections. Both HPV16 and HPV18 E2 variants occur relatively more frequently in individuals with HLA DR/DQ haplotypes 0401/0301 and 1101/0301 but are not related to lesion grade.
Amino Acids↗
Adjusting for non-compliance and contamination in randomized clinical trials.
A method of analysis is presented for estimating the magnitude of a treatment effect among compliers in a clinical trial which is asymptotically unbiased and respects the randomization. The approach is valid even when compliers have a different baseline risk than non-compliers. Adjustments for contamination (use of the treatment by individuals in the control arm) are also developed. When the baseline failure rates in non-compliers and contaminators are the same as those who accept their allocated treatment, the method produces larger treatment effects than an 'intent-to-treat' analysis, but the confidence limits are also wider, and (even without this assumption) asymptotically the efficiencies are the same. In addition to providing a better estimate of the true effect of a treatment in compliers, the method also provides a more realistic confidence interval, which can be especially important for trials aimed at showing the equivalence of two treatments. In this case the intent-to-treat analysis can give unrealistically narrow confidence intervals if substantial numbers of patients elect to have the treatment they were not randomized to receive.
Adult↗
Germline mutations of the CDKN2 gene in UK melanoma families.
Germline mutations in CDKN2 on chromosome 9p21, which codes for the cyclin D kinase inhibitor p16, and more rarely, mutations in the gene coding for CDK4, the protein to which p16 binds, underlie susceptibility in some melanoma families. We have sequenced all exons of CDKN2 and analysed the CDK4 gene for mutations in 27 UK families showing evidence of predisposition to melanoma. Five different germline mutations in CDKN2 were found in six families. Three of the mutations (Met53Ile, Arg24Pro and 23ins24) have been reported previously. We have identified two novel CDKN2 mutations (88delG and Ala118Thr) which are likely to be associated with the development of melanoma, because of their co-segregation with the disease and their likely functional effect on the CDKN2 protein. In binding assays the protein expressed from the previously described mutation, Met53Ile, did not bind to CDK4/CDK6, confirming its role as a causal mutation in the development of melanoma. Ala118Thr appeared to be functional in this assay. Arg24Pro appeared to bind to CDK6, but not to CDK4. No mutations were detected in exon 2 of CDK4, suggesting that causal mutations in this gene are uncommon. The penetrance of these mutant CDKN2 genes is not yet established, nor is the risk of non-melanoma cancer to gene carriers.
Adult↗
Human papillomavirus genotype as a predictor of persistence and development of high-grade lesions in women with minor cervical abnormalities.
Women referred for colposcopy with mild and moderate dyskaryosis and found to have only minor cervical abnormalities were screened for oncogenic human papilloma virus (HPV) types. The natural development of these abnormalities in 42 HPV-positive women was assessed by cytology and colposcopy at 6-month intervals for up to 2 years. As is the case with cancers and high-grade cervical intra-epithelial neoplasia (CIN), minor cervical abnormalities were frequently found to be associated with HPV16, -18, -31 and -33. Viral persistence and the development of high-grade lesions were found to be closely associated with HPV16; 56% of HPV16 isolates were persistent compared to 7% of other HPV types, and all 4 subsequent CIN 3 lesions were in women with persistent infection. A striking association of persistence with a variant of HPV16 having a base change at nucleotide 350 was observed. Ten of 12 women with this variant had persistent infection compared to only 1 of 16 women infected with the HPV16 prototype.
Adult↗
Susceptibility to human papillomavirus-associated cervical intra-epithelial neoplasia is determined by specific HLA DR-DQ alleles.
Human papillomaviruses (HPV) play a causative role in the aetiology of cervical intra-epithelial neoplasia (CIN) and cervical cancer. Human leukocyte antigens (HLA) are important in the regulation of immune response to foreign antigens. The role of genetic variation at the HLA class II loci (DR and DQ) in CIN (HPV 16, 18, 31 and 33 typed) was investigated by PCR DNA amplification and oligonucleotide probe typing of cervical smears from British Caucasian patients (n = 176) and controls (n = 416). The alleles of the DQB1*03, DRB1*04 and DRB1*11 loci were strongly associated with susceptibility to CIN. Specifically, the haplotypes DRB1*0401-DQB1*0301 and DRB1*1101-DQB1*0301 were significant and indicated susceptibility. The DQB1*03 locus was more contributory to this association than the DRB1 loci. A weak protective effect was shown for the haplotype DRB1*0101-DQB1*0501. Positive correlation was also observed for HPV-positive CIN, suggesting that specific HLA class II alleles may be important in determining the immune response to HPV antigens and the risk for CIN after HPV infection. Our results should help in the rational design of vaccines against HPV.
Alleles↗
Naevi and pigmentary characteristics as risk factors for melanoma in a high-risk population: a case-control study in New South Wales, Australia.
The relationship between risk of cutaneous malignant melanoma and total body and site-specific naevus counts and other host factors was investigated in a Caucasian population aged 15-84 years in New South Wales, Australia. The study sample comprised 244 cases with melanoma diagnosed in 1989-1993, and 276 controls. The strongest relationship was with total body naevus count. Risk of melanoma was raised 12 times in those with more than 100 naevi compared with those with less than 10. There were also strong risks, with odds ratios of 5 or more, associated with having multiple atypical naevi, multiple large naevi, high naevus counts in sun-exposed or sun-protected areas and being unable to tan on repeated sun exposure. The effect of inability to tan was stronger at younger than older ages. Lesser risks, with odds ratios of 2-3, were associated with being prone to burn on sun exposure, having many freckles as a child and having red hair. The site distribution of naevi in males compared with females resembled the distribution of melanoma by sex. Risk of melanoma of the back was significantly more closely related to back naevus count than naevus count for the remainder of the body. For other anatomical sites, naevus count was non-significantly more closely related to naevus counts at that site than counts over the remainder of the body. Naevus count declined with age in both cases and controls. In those aged under 40, having 100 or more naevi was associated with an aetiological fraction (AF) of 41%. In those aged 60 and over, however, the AF associated with this number of naevi was only 5%.
Adolescent↗