Evaluating cytology for the detection of invasive cervical cancer.

OBJECTIVE: To assess the sensitivity, the number needed to screen (NNS) and the positive predictive value (PPV) of cervical cytology for the diagnosis of cancer by age in a screening population. METHODS: A retrospective cohort of women with invasive cervical cancer nested within a census of cervical cytology. All (c. 8 million) women aged 20-64 years with cervical cytology (excluding tests after an earlier abnormality). From April 2007 to March 2010, 3372 women had cervical cancer diagnosed within 12 months of such cytology in England. The sensitivity of cervical cytology to cancer, NNS to detect one cancer and predictive values of cytology were calculated for various 'referral' thresholds. These were calculated for ages 20-24, 25-34, 35-49 and 50-64 years. RESULTS: The sensitivity of at least moderate dyskaryosis [equivalent to a high-grade squamous intraepithelial lesion (HSIL) or worse] for cancer of 89.4% [95% confidence interval (CI) 88.3-90.4%] in women offered screening was independent of age. At all ages, women with borderline-early recall or mild dyskaryosis on cytology (equivalent to ASC-US and LSIL, respectively, in the Bethesda system) had a similar risk of cervical cancer to the risk in all women tested. The PPV of severe dyskaryosis/?invasive and ?glandular neoplasia cytology (equivalent to squamous cell carcinoma and adenocarcinoma/adenocarcinoma in situ, respectively, in the Bethesda System) were 34% and 12%, respectively; the PPV of severe dyskaryosis (HSIL: severe dysplasia) was 4%. The NNS was lowest when the incidence of cervical cancer was highest, at ages 25-39 years, but the proportion of those with abnormal cytology who have cancer was also lowest in younger women. CONCLUSIONS: The PPV of at least severe dyskaryosis (HSIL: severe dysplasia) for cancer was 4-10% of women aged 25-64 years, justifying a 2-week referral to colposcopy and demonstrating the importance of failsafe monitoring for such patients. The sensitivity of cytology for cervical cancer was excellent across all age groups.

Trends in the lifetime risk of developing cancer in Great Britain: comparison of risk for those born from 1930 to 1960.

BACKGROUND: Typically, lifetime risk is calculated by the period method using current risks at different ages. Here, we estimate the probability of being diagnosed with cancer for individuals born in a given year, by estimating future risks as the cohort ages. METHODS: We estimated the lifetime risk of cancer in Britain separately for men and women born in each year from 1930 to 1960. We projected rates of all cancers (excluding non-melanoma skin cancer) and of all cancer deaths forwards using a flexible age-period-cohort model and backwards using age-specific extrapolation. The sensitivity of the estimated lifetime risk to the method of projection was explored. RESULTS: The lifetime risk of cancer increased from 38.5% for men born in 1930 to 53.5% for men born in 1960. For women it increased from 36.7 to 47.5%. Results are robust to different models for projections of cancer rates. CONCLUSIONS: The lifetime risk of cancer for people born since 1960 is >50%. Over half of people who are currently adults under the age of 65 years will be diagnosed with cancer at some point in their lifetime.

What is the lifetime risk of developing cancer?: the effect of adjusting for multiple primaries.

BACKGROUND: The 'lifetime risk' of cancer is generally estimated by combining current incidence rates with current all-cause mortality ('current probability' method) rather than by describing the experience of a birth cohort. As individuals may get more than one type of cancer, what is generally estimated is the average (mean) number of cancers over a lifetime. This is not the same as the probability of getting cancer. METHODS: We describe a method for estimating lifetime risk that corrects for the inclusion of multiple primary cancers in the incidence rates routinely published by cancer registries. The new method applies cancer incidence rates to the estimated probability of being alive without a previous cancer. The new method is illustrated using data from the Scottish Cancer Registry and is compared with 'gold-standard' estimates that use (unpublished) data on first primaries. RESULTS: The effect of this correction is to make the estimated 'lifetime risk' smaller. The new estimates are extremely similar to those obtained using incidence based on first primaries. The usual 'current probability' method considerably overestimates the lifetime risk of all cancers combined, although the correction for any single cancer site is minimal. CONCLUSION: Estimation of the lifetime risk of cancer should either be based on first primaries or should use the new method.

Supersites within superfolds. Binding site similarity in the absence of homology.

A method is presented to assess the significance of binding site similarities within superimposed protein three-dimensional (3D) structures and applied to all similar structures in the Protein Data Bank. For similarities between 3D structures lacking significant sequence similarity, the important distinction was made between remote homology (an ancient common ancestor) and analogy (likely convergence to a folding motif) according to the structural classification of proteins (SCOP) database. Supersites were defined as structural locations on groups of analogous proteins (i.e. superfolds) showing a statistically significant tendency to bind substrates despite little evidence of a common ancestor for the proteins considered. We identify three potentially new superfolds containing supersites: ferredoxin-like folds, four-helical bundles and double-stranded beta helices. In addition, the method quantifies binding site similarities within homologous proteins and previously identified supersites such as that found in the beta/alpha (TIM) barrels. For the nine superfolds, the accuracy of predictions of binding site locations is assessed. Implications for protein evolution, and the prediction of protein function either through fold recognition or tertiary structure comparison, are discussed.

Human papillomavirus screening and cervical cancer prevention.

Infection with one of several types of human papillomavirus (HPV) appears to be a necessary first step in the development of invasive cervical cancer. We cannot currently treat HPV infections; thus, the role of HPV testing is to identify women with precancerous lesions that can be removed and, in so doing, prevent progression to invasive carcinoma. Although HPV testing may help to identify women at risk of cervical cancer who might be missed by other screening tests, it is inherently nonspecific at identifying those who would otherwise develop cervical cancer. In order to avoid overtreatment of women with minor lesions with little potential for progression, HPV testing needs to be repeated or combined with Pap smears. Protocols for HPV screening have yet to be properly evaluated. Here we consider several possible applications of HPV testing in the prevention of cervical cancer. The most immediate role is as a secondary test in women with minor cytological abnormalities. Appropriate use of HPV testing as a primary screening tool depends on the setting. In a developed country without an organized screening program, HPV testing might be used in addition to Pap smears in women age 35 and over to increase sensitivity. Within an organized screening program, HPV testing might be used in combination with Pap testing, but with extended screening intervals so as to obtain the maximum advantage to women without unduly increasing costs. Where resources are strictly limited, an attractive option would be to perform visual inspection of the cervix after application of dilute acetic acid using a low threshold for referral, and to test for HPV only on those with abnormal looking lesions.

Efficiently weighted estimating equations with application to proportional excess hazards.

A general approach to estimation, that can lead to efficient estimation in two stages, is presented. The method will not always be available, but sufficient conditions for efficiency are provided together with four examples of its use: (1) estimation of the odds ratio in 1:M matched case-control studies with a dichotomous exposure variable; (2) estimation of the relative hazard in a two-sample survival setting; (3) estimation of the regression parameters in the proportional excess hazards model; and (4) estimation in a partly linear parametric additive hazards model. The method depends upon finding a family of weighted estimating equations, which includes a simple initial equation yielding a consistent estimate and also an equation that yields an efficient estimate, provided the optional weights are used.

From genotypes to genes: doubling the sample size.

This paper considers the analysis of genetic case-control data. One approach considers the allele frequency in cases and controls. Because each individual has two alleles at any autosomal locus, there will be twice as many alleles as people. Another approach considers the risk of the disease in those who do not have the allele of interest (A), those who have a single copy (heterozygous), and those who are homozygous for A. A third approach does not differentiate between individuals with one or two copies of A. This was common when alleles were determined serologically and one could not distinguish between homozygotes and those with one copy of A and one of an unknown allele. All three approaches have been used in the literature, but this is the first systematic comparison of them. The different interpretations of the odds ratios from such analyses are explored and conditions are given under which the first two approaches are asymptotically equivalent. The chi-squared statistics from the three approaches are discussed. Both the odds ratio and the chi-squared statistic from the analysis that treats alleles rather than genotypes as individual entities are appropriate only when the Hardy-Weinberg equilibrium holds. When the equilibrium holds, the allele-based test statistic is asymptotically equivalent to the test for trend using the genotype data. Thus, analyses that treat alleles rather than people as observations should not be used. Instead, we recommend that such data should be analyzed by genotype.

Standardized lifetime risk.

The authors propose the use of two new standardized measures of risk, the standardized lifetime risk and the standardized number of years of life lost. These measures maintain the advantages of standardized rates but are more readily understood without special training. In this paper, standardizing weights based on 1992 data from England and Wales are provided, and the new measures are illustrated with a variety of examples. The new standardized rates are useful for examining trends over time; for comparing the impact of various diseases on public health; and for comparing rates of a given disease in several different countries. The authors think it is far more informative to say that 41 out of every 1,000 women die of breast cancer than to say that the standardized mortality rate is 51 per 100,000 women per year.

Risks of second primary malignancy in patients with cutaneous and ocular melanoma in Denmark, 1943-1989.

Risks of 2nd primary cancer were assessed in all patients with cutaneous melanoma (12,460) and all patients with ocular melanoma (2,018) incident in Denmark from 1943 to 1989 and followed for totals of 88,667 person-years and 16,045 person-years, respectively. After cutaneous melanoma, 972 2nd cancers occurred. The risk of non-melanoma skin cancer was significantly raised in each sex. Risk of all non-skin cancers was not raised for all ages but was significantly increased for patients with the primary melanoma incident at ages under 50 years (standardised incidence ratio [SIR], i.e., ratio of observed to expected cancer incidence, multiplied by 100 = 117; 95% confidence interval [CI] 101-134). There were significantly increased risks of chronic lymphocytic leukaemia in males and both sexes combined, brain and nervous system cancers in females and both sexes combined and oropharyngeal cancer in both sexes combined. Risk of pancreatic cancer was not raised, suggesting that cutaneous melanoma patients generally do not share the diathesis for this malignancy which has been observed in certain families with atypical naevi and melanoma. There was no relation of 2nd primary cancer risks to duration since the first primary and no indication of any appreciable treatment-related risk. After ocular melanoma, 216 2nd cancers occurred. There was a significantly increased risk of 2nd cancer overall in males but not females and a significantly increased risk of liver cancer in each sex. Risk of non-melanoma skin cancer (NMSC) was not raised, which suggests that the aetiology of ocular melanoma is not mainly dependent on UV exposure, at least of the type causing NMSC.

Estimating the efficacy of screening by auditing smear histories of women with and without cervical cancer. The National Co-ordinating Network for Cervical Screening Working Group.

The screening histories of all 348 women with invasive cervical cancer diagnosed in 1992 in 24 self-selected district health authorities and health boards in England, Wales and Scotland were compared with those of 677 age- and residency-matched controls. The controls were randomly selected from the family health services authority (FHSA) register. Screening histories, comprising the dates and results of all smears taken before the date of diagnosis of the patient's cancer, were determined from the FHSA computer and laboratory records. We estimate that the number of cases of cervical cancer in participating districts in 1992 would have been 57% (95% confidence interval 28-86%) greater if there had been no previous screening. In women under the age of 70 it would have been approximately 75% (31-115%) greater. Extrapolation of the results from this pilot suggests that screening prevented between 1100 and 3900 cases of invasive cervical cancer in the UK in 1992. Women with stage 1B cancer or worse were more likely to have no record of previous screening than controls: 47% of these women under the age of 70 had been adequately screened according to current (5 yearly screening) guidelines, compared with 75% of matched controls. Thirteen per cent of all patients under age 70 had screening histories indicative of inadequate follow-up of smears requiring colposcopy. The proportion of microinvasive cases with screening predating diagnosis was similar to the proportion of controls. There was a strong correlation between stage and age: 56% of cancers in women under 35 were microinvasive compared with just 9% in women 65 years or over. The 'relative protection' following a negative smear was greatest in the first 12 months and fell off towards the end of the fifth year. These data suggest that full adherence to current guidelines could perhaps have prevented another 1250 cases, but additional steps would have been required to prevent some of the 2300 remaining cases in women under the age of 70.

Avoidance of premature death: a new definition for the proportion cured.

For many cancers, five-year survival is used as a synonym for cure. For some sites, such as breast, this is inappropriate since there is still considerable excess mortality 5-15 years following diagnosis. We propose using the probability of not dying prematurely as a surrogate for the probability of being cured. This is estimated without the need for information on the cause of death by comparing all-cause-mortality rates in patients with cancer to those in the general population. We also consider the probability of 'cure' in those who have survived a certain number of years since diagnosis. These quantities are estimated for various cancer sites using SEER data. The proportion not dying prematurely varies considerably for common cancers from 12% for lung cancer to 84% for prostate cancer. In women, the percentage 'cured' for colon and breast cancer are very similar at 56% and 58% respectively, but in those who survive 5 years, they are quite different--91% and 78% respectively. The proposed statistic is useful. For diseases in which excess mortality is primarily within five years of diagnosis, it agrees well with 5-year relative survival. Interpretation of differences between countries or over time is complicated and requires consideration of incidence and mortality data.

Antibodies to heat-shock protein 27 are associated with improved survival in patients with breast cancer.

The overexpression of the heat-shock proteins hsp90, hsp70 and hsp27 in human mammary carcinomas has previously been shown to correlate with reduced overall survival. Moreover, antibodies to hsp90 were detectable in the serum of a large proportion of breast cancer patients but they were not found in normal controls. High antibody levels also correlated with reduced survival. Here, we show that antibodies to hsp27 were also detectable in the sera from breast cancer patients but not from normal controls, whereas antibodies to hsp70 were detectable in approximately one-third of both groups. The presence of antibodies to hsp27 was correlated with an improved rather than a reduced survival, particularly beyond the first 5 years. Hence, the overexpression of hsps in breast cancer cells does not provoke a generalized immune response to all the hsps. Moreover, the presence of antibodies to different hsps has distinct associations with survival. These effects are discussed in terms of the mechanisms that provoke an immune response to the hsps and the protective/non-protective effects of such a response.