The Effect of the Age of Mice on the Incidence of Skin Cancer

The plausibilities of two hypotheses explaining the increased cancer incidence rate in old age caused by a constant dose of carcinogen were compared using a mouse skin painting experiment in which two groups of mice started treatment at different ages. It was shown that the hypothesis of the increased rate being caused simply by increased vulnerability of old animals was not as plausible as the alternative hypothesis of the carcinogen acting to some extent cumulatively

Initiation and promotion at different ages and doses in 2200 mice. III. Linear extrapolation from high doses may underestimate low-dose tumour risks.

The dose-response relationships from the data described in Paper I were analysed. Among unpromoted animals, only doses sufficient to cause ulceration with subsequent promotion due to wound healing caused a rapid crop of tumours, so the dose-response curve exhibited strong upward curvature. Among promoted animals, the response of the skin to initiation appeared to have been nearly saturated by all DMBA doses tested, so that a 30-fold decrease in dose produced only a 3-fold decrease in effect. The dose-response relationship thus exhibited strong downward curvature. Among promoted animals, estimation of the risks associated with very low doses of carcinogen by linear extrapolation through the origin from the effects of larger doses (which is often assumed to be conservative) would under-estimate the true risks by 10-fold or more. Our results emphasize that whereas linear interpolation from the results of high doses may be reasonable for data on the effects of continuous treatment with non-toxic dose levels of carcinogen, it may be misleading when extrapolating, as here, from the effects of single large doses

Initiation and promotion at different ages and doses in 2200 mice. I. Methods, and the apparent persistence of initiated cells.

Delay between initiation and promotion on mouse skin was in 1949 reported by Berenblum and Shubik not to affect tumour yields, and this led to the important concept of the irreversibility of initiation and stimulated the development of multistage models. Subsequent reports have, however, suggested that delay does decrease tumour yields, and this is confirmed by the present study of 2200 mice initiated at 8, 48, or 68 weeks with 10, 30, 100, or 300 microgram of DMBA and promoted by a standard dose of TPA for 15 weeks, after various delays. However, our data suggest that the decrease in tumour yields is chiefly or wholly due to a reduction, among ageing mice, of the ability to respond to promoters, and not to any substantial loss of initiated cells, for late initiation with immediate promotion also yielded a less rapid response than early initiation with immediate promotion. Interpretation of all such studies is complicated by the few weeks that the skin needs to repair ulceration and other damage induced by the higher doses of DMBA, for if promotion with TPA begins before such repair is complete the tumour yield may be misleadingly increased

Role of advanced technology in the detection of sight-threatening eye disease in a UK community setting.

Background/aims: To determine the performance of combinations of structural and functional screening tests in detecting sight-threatening eye disease in a cohort of elderly subjects recruited from primary care. Methods: 505 subjects aged ≥60 years underwent frequency doubling technology (FDT) perimetry, iVue optical coherence tomography (iWellness and peripapillary retinal nerve fibre layer (RNFL) scans) and intraocular pressure with the Ocular Response Analyzer, all performed by an ophthalmic technician. The reference standard was a full ophthalmic examination by an experienced clinician who was masked to the index test results. Subjects were classified as presence or absence of sight-threatening eye disease (clinically significant cataract, primary open-angle glaucoma, intermediate or advanced age-related macular degeneration and significant diabetic retinopathy). Univariate and multivariate logistic regression analyses were used to determine the association between abnormal screening test results and the presence of sight-threatening eye disease. Results: 171 subjects (33.8%) had one or more sight-threatening eye diseases. The multivariate analysis found significant associations with any of the target conditions for visual acuity of <6/12, an abnormal FDT and peripapillary RNFL thickness outside the 99% normal limit. The sensitivity of this optimised screening panel was 61.3% (95% CI 53.5 to 68.7), with a specificity of 78.8% (95% CI 74.0 to 83.1), a positive predictive value of 59.5% (95% CI 53.7 to 65.2) and an overall diagnostic accuracy of 72.9% (95% CI 68.8 to 76.8). Conclusions: A subset of screening tests may provide an accurate and efficient means of population screening for significant eye disease in the elderly. This study provides useful preliminary data to inform the development of further larger, multicentre screening studies to validate this screening panel

Statistical Analysis of the Bio-assay of Continuous Carcinogens

In an experiment consisting of the continuous constant application of various carcinogenic regimens to a pure strain of experimental animals for a long period, the cancer incidence rates so caused may be studied and compared by the fit of an appropriate class of statistical distributions. In this paper we show that a Weibull distribution in which the age-specific cancer incidence rate rises as a power of time since first risk is more appropriate than a lognormal distribution. If the Weibull family of distributions is used, more information can be extracted from the data, and differences of toxicity between various regimens will not bias the comparison of their carcinogenic forces

Electrocardiographic safety evaluation of dihydroartemisinin piperaquine in the treatment of uncomplicated falciparum malaria.

Dihydroartemisinin-piperaquine (DP) could become a leading fixed combination malaria treatment worldwide. Although there is accumulating evidence of efficacy and safety from clinical trials, data on cardiotoxicity are limited. In two randomized controlled trials in Thailand, 56 patients had ECGs performed before treatment, 4 hours after the first dose, and 4 hours after the last dose. The mean (95% CI) changes in QTc interval (Bazett's correction) were 2 (-6 to 9) ms and 14 (7 to 21) ms, respectively. These small changes on the third day of treatment are similar to those observed elsewhere in the convalescent phase following antimalarial treatment with drugs known to have no cardiac effects and are therefore likely to result from recovery from acute malaria and not the treatment given. At therapeutic doses, DP does not have clinically significant effects on the electrocardiogram

Design and analysis of randomized clinical trials requiring prolonged observation of each patient. I. Introduction and design.

The Medical Research Council has for some years encouraged collaborative clinical trials in leukaemia and other cancers, reporting the results in the medical literature. One unreported result which deserves such publication is the development of the expertise to design and analyse such trials. This report was prepared by a group of British and American statisticians, but it is intended for people without any statistical expertise. Part I, which appears in this issue, discusses the design of such trials; Part II, which will appear separately in the January 1977 issue of the Journal, gives full instructions for the statistical analysis of such trials by means of life tables and the logrank test, including a worked example, and discusses the interpretation of trial results, including brief reports of 2 particular trials. Both parts of this report are relevant to all clinical trials which study time to death, and wound be equally relevant to clinical trials which study time to other particular classes of untoward event: first stroke, perhaps, or first relapse, metastasis, disease recurrence, thrombosis, transplant rejection, or death from a particular cause. Part I, in this issue, collects together ideas that have mostly already appeared in the medical literature, but Part II, next month, is the first simple account yet published for non-statistical physicians of how to analyse efficiently data from clinical trials of survival duration. Such trials include the majority of all clinical trials of cancer therapy; in cancer trials,however, it may be preferable to use these statistical methods to study time to local recurrence of tumour, or to study time to detectable metastatic spread, in addition to studying total survival. Solid tumours can be staged at diagnosis; if this, or any other available information in some other disease is an important determinant of outcome, it can be used to make the overall logrank test for the whole heterogeneous trial population more sensitive, and more intuitively satisfactory, for it will then only be necessary to compare like with like, and not, by chance, Stage I with Stage III

Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. analysis and examples.

Part I of this report appeared in the previous issue (Br. J. Cancer (1976) 34,585), and discussed the design of randomized clinical trials. Part II now describes efficient methods of analysis of randomized clinical trials in which we wish to compare the duration of survival (or the time until some other untoward event first occurs) among different groups of patients. It is intended to enable physicians without statistical training either to analyse such data themselves using life tables, the logrank test and retrospective stratification, or, when such analyses are presented, to appreciate them more critically, but the discussion may also be of interest to statisticians who have not yet specialized in clinical trial analyses

Cancer and ageing in mice and men.

In an experiment involving 950 mice with a normal lifespan of 2-3 years, in laboratory conditions, regular benzpyrene application to the skin was started at 10, 25, 40 or 55 weeks of age. The incidence rate of malignant epithelial tumours among the survivors in each group increased steeply with time. This increase was associated directly with duration of exposure but, given duration, was independent of age at the start of exposure, as were the growth rates of already established tumours. In our experiment, although age per se was irrelevant, the cancer incidence rate increased approximately as a power of the duration of exposure to benzpyrene. This shows that the observed approximate power-law increase of most human adult cancer incidence rates with age could exist merely because age equals duration of exposure to background and spontaneous carcinogenic stimuli. Thus, no intrinsic effects of ageing (such as failing immunological surveillance or age related hormonal changes) whatever need to postulated to explain the vast increases in old age of the incidence rates of such human cancers. This result can greatly simplify speculation about mechanisms of carcinogenesis

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