- Email: [email protected]
Colposcopy Today
486
energy to induce radioactivity irrespective of the radiation dose absorbed. Electron beam machines used in food irradiation should have a maximum energy level of 10 Mev, below which radioactivity will not be induced. The interaction of gamma rays or electrons causes chemical change in food by direct action on food molecules and, principally, by indirect action on the water in moist foods. Typically, free radicals are produced which are highly reactive and short-lived. These radicals react with key organic molecules in the cells of bacteria, causing cell death. Food molecules are also likely to be affected, with loss of vitamins and changes in flavour, and some food packaging materials may be altered.7 Some vitamins, including B,, C, and E, are affected but have been found to be more stable in food systems than when observed in solution. The World Health Organisation has proposed that food irradiation provides two main benefits for the health and wellbeing of man: the destruction of certain food-borne pathogens, thus making food safer, and the prolongation of the shelf-life of food by killing pests and delaying the deterioration process, thereby
increasing food supply.
Salmonella organisms, a major contributor to food-borne disease, are fairly sensitive to irradiation. Deaths and illness occur every year in Britain from salmonella food poisoning caused by consumption of contaminated chicken. Treating chicken after slaughter with a dose of approximately 3 kGy would eliminate most salmonella species and thus contribute to a reduction in the incidence of outbreaks of food poisoning. This process has been proposed by the Food Research Association at Leatherhead. They argue that vitamin losses resulting from the process are of a similar order to those occurring with, for example, the heat pasteurisation of milk. At the same time irradiated chicken would possess the normal characteristics of raw chicken. The food could be treated in either the chilled or frozen state, although a somewhat higher dose is required for frozen products. Clearly, the elimination of salmonellae from massproduced chicken would make a substantial contribution to public health. Irradiation facilities would have to be licensed and inspected frequently. Adequate regulations will be needed to govern the importation of irradiated foods, whether or not irradiation is permitted in the UK. There is no adequate test to determine whether food has been irradiated and this, of itself, can be taken to indicate the subtle nature of chemical changes that occur in irradiated food. Webb and Lang have produced a readable book for the layman. They take a particular stance in relation to proposals to make irradiation legal. Those who propose permissive legislation for this process will now have to respond in terms which can readily be understood by the non-scientist legislator and consumer. 7. Leatherhead Food Research Association Food irradiation—a technical brief Technical notes no 40. Leatherhead Leatherhead Food Research Association, 1986.
Colposcopy Today THE colposcope was pioneered in the United States by Static It was widely used in Europe in the 1970s but rejected at that time in Britain because, although a more accurate biopsy specimen could be taken, the treatment of cervical intra-epithelial neoplasia (CIN)—cone biopsy-was the same whether or not colposcopy had been carried out. Whilst cone biopsy with complete excision of abnormal tissue confers a low risk of subsequent malignant disease,2 disadvantages are the need for hospital admission and the increased risk of prematurity and low birth weight’ associated with the technique. By 1982 a Royal College of Obstetricians and Gynaecologists’ study group4had concluded that "ideally no patient with cervical intra-epithelial neoplasia should be treated unless there has been prior colposcopic assessment", and as such colposcopy is now established as part of the routine evaluation to which all women with an abnormal smear should have access. Directed punch biopsy can provide accurate localisation and histological diagnosis of premalignant lesions, most of which can be destroyed by cryotherapy, diathermy, or laser evaporation.sFor the remainder, preoperative colposcopic assessment will allow the gynaecologist to plan cone biopsy, tailoring the procedure to the extent of the lesion and, in the case of vaginal involvement, to take a "cuff ’ of tissue or use local destructive techniques for the vaginal component followed by cone
biopsy or simple hysterectomy.
The incidence of carcinoma-in-situ increased by 117% between 1973 and 1979 with only an 11% increase in the number of women screenedj6 the greatest increase was in young nulliparous women in whom cone biopsy can compromise fertility. However only two-thirds of women with an abnormal smear in the UK are able to avail themselves of a colposcopic diagnostic service.The wisdom of increasing reliance on cytology alone rather than its combination with colposcopy to detect residual and early recurrent disease has yet to be evaluated, but the results of Walker and colleagues in Dundee8give cause for concern. The Dundee workers found that there was poor correlation between mildly atypical cervical cytology and histology and urged that reliance on cytology alone for surveillance of women who have A, Wilkinson EJ, Mattingly RF. Laser treatment of cervical and vaginal neoplasia. Am J Obstet Gynecol 1977; 128: 128-36. 2 Bevan JR, Attwood ME, Jordan JA, Lucas A, Newton JR. Treatment of preinvasive disease of the cervix by cone biopsy. Br J Obstet Gynaecol 1981; 88: 1140-44 3. Jones JM, Sweetman P, Hibbard BM. The outcome of pregnancy after cone bisposy of the cervix a case controlled study. Br J Obstet Gynaecol 1979, 86: 913-16 4. Jordan JA, Sharp F, Singer A, eds. Preclinical neoplasia of the cervix. Proceedings of the Study Group London: Royal College of Obstetricians and Gynaecologists, 1. Stafl
1982: 299. 5. 6
Singer A, Walker P. What is the optimum treatment of cervical premaligancy? Br Med J 1982; 89: 335-36 Roberts A. Cervical cytology in England and Wales, 1965-80. Health Trends 1982; 14: 41-43
Sharp F, Jordan JA. How many colposcopy centres do we need m the UK? In: Preclinical neoplasia of the cervix. Proceedings of the Study Group London: Royal College of Obstetricians and Gynaecologists, 1982: 229. 8. Walker EM, Dodgson J, Duncan ID. Does mild atypia on a cervical smear warrant further investigation? Lancet 1986; ii: 672-73. 7.
487
already had an abnormal smear should be discouraged. It is now fair to say that any hospital with two or more consultant gynaecologists should be offering its own colposcopy service. Although it is generally accepted that a two-tier system of referral is undesirable and largely unnecessary some techniques, such as contact microcolpohysteroscopy and perhaps laser ablation ofvulvovaginal lesions, are possibly best carried out at specialist centres. Local destructive techniques are not suitable for all premalignant cervical lesions. Singer and Walkers found that the upper and lower limits of CIN III lesions could be demonstrated in over 75 % of "young women", whereas Toplis and colleagues9 observed satisfactory technical colposcopic criteria for local ablation in only 53% of women approaching the menopause and only 18 % of postmenopausal women were deemed suitable for laser ablation. Complete visualisation of the transformation zone and exclusion of malignancy cytologically, colposcopically and, by taking of an accurate biopsy, histologically are the standard conditions that an experienced colposcopist needs to satisfy before applying local destructive techniques. The decision of the RCOG study groupl0 to concentrate training by provision of regular basic courses in colposcopic technique rather than, or in addition to, a system of accreditation does not absolve the responsible trainee from closely monitoring his
colposcopic/histological
correlations and treatment results. Publicity about "high technology" as can be applied to cervical precancer has led many women to expect outpatient ablation for their CIN lesions. Whilst laser conisation of the unanaesthetised patient is now practised, less experienced colposcopists would do well to remember that most cases of invasive cancer after ablative techniques are associated with inadequate primary colposcopic assessment or with inappropriate treatment of a lesion more extensive than eIN .11,13 Patients with persistent inflammatory changes on cervical cytology despite treatment with antibiotics or oestrogens warrant colposcopy in view of the risk of precancer in this group. Two reports9,14 have highlighted the persistent failure of cytological examination, probably because of poor cellular exfoliation, to detect all grades of CIN, and even invasive cancer, in older age groups. Concern has also been expressed that the mortality from cervical cancer in older women is not falling, 15 but it has been .
9 Toplis PJ, Casemore V, Hallam N, Charnock M. Evaluation of colposcopy m the postmenopausal woman. Br J Obstet Gynaecol 1986; 93: 843-51. 10 Jordan JA, Sharp F, Singer A, eds. Preclinical neoplasia of the cervix. Proceedings of the Study Group. London: Royal College of Obstetricians and Gynaecologists, 1982: 287.
11 Sevin B, Ford JH, Girtaener RW, et al. Invasive cancer of the cervix after cryosurgery Obstet Gynecol 1979, 45: 456.
12 Sharp F, Jordan J, eds. Gynaecological laser surgery. Proceedings of
the Study Group. London Royal College of Obstetricians and Gynaecologists, 1985: 137. 13 Tounsend DE, Richart RM, Marks E, Neilsen J. Invasive cancer following outpatient evaluation and therapy for cervical disease. Obstet Gynecol 1981; 57: 145-49. 14 Roberts A, Denholm R, Cordner JW. Cervical intra-epithelial neoplasia in postmenopausal women with negative cervical cytology Br Med J 1985, 290: 281.
assumed that those with mild cytological abnormality progress to invasion slowly, if at all. But, of course,
they will not be detected if surveillance is discontinued at age sixty years as suggested by a Canadian task force. 16 Also worrying is the realisation that two consecutive negative smears, the usual criterion for diagnosis of disease regression,, does not necessarily preclude CIN, 17 although in one study18 nearly 25 % of patients with positive cytology were found to have no evidence of colposcopic or histological abnormality. Of course, cytology and colposcopy together can greatly improve the diagnosis of cervical abnormality. 19 Whilst the malignant potential of CIN III is established, with approximately 50% of cases progressing to cancer, 20 the natural history of minor epithelial atypia, widely believed to be a benign transient condition with a high spontaneous regression rate, remains controversial. The three-fold rise in cervical cancer mortality in young women under thirty-five years, the substantial increase in abnormal cervical smears in young women together with the attendant threat of a further rise in cervical cancer mortality /1 and reports8,22.23 describing histological CIN III or invasive cancer following the detection of mildly atypical cells on a smear have made it essential to establish the progressive potential of early preinvasive disease. The importance of the colposcope in, screening is indicated by the finding that 26 % of young women with cytologically mild
dyskaryosis are subsequently diagnosed as having histologically severe dysplasia on directed biopsy -17 in the same study, 26% of those with mild dyskaryosis progressed to histologically proven CIN III within two years whereas only 7% regressed to normal. Perhaps more worrying is the observation that "of the women whose disease progressed to CIN III, 15% had two consecutive false negative cervical smears and thus might have been discharged from close cytological observation". Although the criteria for selection, regression, progression and length of follow-up have varied greatly between studies, it is clear that there is an inflated spontaneous regression rate (as high as 83 %)24 and a low risk of progression associated with CIN I 15. Husain OAN. Bntain’s failure to prevent deaths from cervical cancer. Br Med J 1984; 289: 50. 16. Canadian Task Force. Cervical cancer screening programs. Summary of 1982 report. Can Med Assoc J 1982; 127: 581. 17. Campion MJ, McCance DJ, Cuzick J, Singer A. Progressive potential of mild cervical atypia: prospective cytological, colposcopic, and virological study. Lancet 1986; ii: 237-40. 18. Singer A, Walker P, Tay SK, Dyson J. Impact of introduction of colposcopy to a district general hospital Br Med J 1984; 289: 1049-51. 19. Coppleson M, Reid B. Preclinical carcinoma of the cervix uteri its origin, nature and management. 1st ed. Oxford: Pergamon, 1967 180. 20. McIndoe WA, McLean MR, Jones RN, Mullins PR. The invasive potential of carcinoma-in-situ of the cervix Obstet Gynecol 1984; 64: 451. 21 Beral V, Booth M. Predicuons of cervical cancer incidence and mortality in England and Wales. Lancet 1986; i: 495 22. Soutter WP, Wisdom S, Broughs AK, Monaghan JM. Should patients with mild atypia in a cervical smear be referred for colposcopy? Br J Obstet Gynaecol 1986; 93: 70-74. 23. Cotton RG, Ellwood JM, Jones GM. Results of delayed follow-up of abnormal cervical smears. Br Med J 1986, 292: 799-800.
488
when the diagnostic procedure includes biopsy. It may be that such a biopsy favourably alters the immune response and natural history of CIN I. Conversely, prospective studies of cervical atypia based only on initial cytology have shown progression rates as high as 60%.25 It is, therefore, sensible to recommend that -women who present with cytologically mild dyskaryosis should be referred for definitive diagnosis by histological examination of a colposcopically directed biopsy.8 Until it is established (perhaps with routine screening by DNA filter hybridisation of cervical cytological specimens) which women with mild changes are at high risk of progression, most researchers believe that even minor lesions should be promptly treated. Patients with histologically proven human papillomavirus (HPV) infection alone are also probably best treated in view of the progressive potential and risk of infectious sexually transmitted disease.26
Report with Confidence
be supported even though the taller CIs will dominate figures more than bars representing one standard error of the mean. Bulpitt also joins other analysts2 in calling for the use of the term ’confidence interval’ rather than confidence limits. This policy has the dual purpose of preventing the citation of one limit and not the other (which can give a highly misleading impression) and of avoiding the connotation of limits as things that cannot be exceeded. When we look at a confidence interval we must also think about the source of the data. What selection factors were operating in the patients being considered? Were the data and the CIs derived only
from a subgroup? In the coming years we hope to see contributors reporting with confidence.
more
Lancet
THE KNOWN AND THE UNKNOWN ABOUT DENGUE FEVER DENGUE fever has been recognised as a clinical entity for least two centuries, as accounts of epidemics in Java in 17793 and in Queensland in 18974 make clear. Mosquito transmission was suspected early this century,5 and was established in experiments with human volunteers which showed that, as with yellow fever,6the principal vector was Aedes aegypti.7-9 The viral aetiology and mosquito transmission of these two important diseases were established long before either virus was cultivated in the at
MANY readers will be pleased to see the decline of the bald statements "not significant p>0-05" and "statistically significant p < 0-05". Medical research is as much concerned with estimation as with hypothesis testing. Estimation is of great importance to those who review the evidence that a drug is efficacious or otherwise. For example, the Drug and Therapeutics Bulletin, reviewing the antispasmodic drug alverine,l stated, "In a double-blind crossover comparison in 37 patients alverine appeared as effective as mebeverine. However, confidence intervals for the difference were not given and therapeutic equivalence cannot be assumed from this small study". The confidence interval gives a range of values that is likely to cover the true but unknown value, and this estimation tells us what we really want to know: how confident are we that alverine is as effective as mebeverine? Similarly, if alverine had been more effective than mebeverine, the confidence interval (CI) would have given us an estimate of the range of benefits to be expected. In his article on p 494 Dr Bulpitt discusses the use of confidence intervals in detail and makes some firm recommendations. Firstly, he advocates standardisation on the 95% confidence interval. In the absence of such standardisation, there will be a temptation to report 90 % CIswhen one wishes to give an impression of precision and conversely to report 99% CIs when one wishes to emphasise variability. Secondly, he proposes that graphical representations of data should include bars representing the 95 % CI, rather than one standard deviation or one standard error of the mean. This call for standardisation must AJ, Knoblich RA Clinicopathologic study of 56 cases showing atypical epithelial changes of the cervix uteri Am J Obstet Gynecol 1957; 73: 120-26. 25. Fox CH. Biological behaviour of cervical dysplasia and carcinoma in situ. Am J Obstet 24 Rawson
Gynecol 1967; 99: 960-74. 26. Singer A. The abnormal cervical smear Br Med J 1986; 293: 1551-56 1. Some antispasmodic drugs for the irritable bowel syndrome. Drug Therap Bull 1986; 24: 93-95
laboratory. 10,11 Dengue and yellow
fever viruses share more than a both are now placed in the Flaviviridae family,12 named after the type species, yellow fever virus. Yellow fever virus strains are closely related to each other, although they can be distinguished by monoclonal antibodies.13 Natural infection is followed by solid immunity against reinfection with any other strain of yellow fever virus. Dengue viruses are more heterogeneous: there are four distinct serotypes, with strain differences within each serotype. Infection with one serotype is followed by solid homotypic immunity," but the individual remains susceptible to infection with dengue viruses of a different serotype. Classical dengue fever is an acute febrile illness with a rash and associated headache, retro-orbital pain, and pains in the common vector:
2. Gardner MJ, Altman DG. Statistics in medicine: confidence intervals rather than p values: estimation rather than hypothesis testing. Br Med J 1986, 292: 746-50 3. Pepper OHP. A note on David Bylon and dengue. Ann Med Hist 1941; 3: 363-68 4. Hare FE. The 1897 epidemic of dengue in north Queensland. Aust Med Gaz 1898, 17: 98-107. 5 Bancroft TL. On the etiology of dengue fever. Aust Med Gaz 1906, 25: 17-18 6. Reed W. Recent research concerning etiology, propagation and prevention of yellow fever by the United States Army Commission. J Hyg 1902; 2: 101-09 7. Cleland JB, Bradley B, McDonald W. On the transmission of Australian dengue by the mosquito Stegomyia fasciata. Med J Aust 1916; ii: 179-84. 8. Cleland JB, Bradley B, McDonald W. Further experiments in the etiology of dengue fever. J Hyg 1919, 18: 217-54. 9. Siler JF, Hall MW, Hitchens AP. Dengue its history, epidemiology, mechanism of transmission, etiology, clinical manifestations, immunity and prevention Philipp J Sci 1926; 29: 1-304 10. Stokes A, Bauer JH, Hudson NP. Experimental transmission of yellow fever to laboratory animals. Am J Trop Med 1928; 8: 103-64. 11 Sabm AB. The dengue group of viruses and its family relationships. Bacteriol Rev 1950; 14: 225-32 12 Westaway EG, Bnnton MA, Gaidamovich SYa, et al. Flaviviridae Intervirol 1985; 24: 183-92. 13. Gould EA, Buckley A, Cammack N, et al. Examination of the immunological relationships between flaviviruses using yellow fever monoclonal antibodies J Gen Virol 1965; 66: 1369-82.
energy to induce radioactivity irrespective of the radiation dose absorbed. Electron beam machines used in food irradiation should have a maximum energy level of 10 Mev, below which radioactivity will not be induced. The interaction of gamma rays or electrons causes chemical change in food by direct action on food molecules and, principally, by indirect action on the water in moist foods. Typically, free radicals are produced which are highly reactive and short-lived. These radicals react with key organic molecules in the cells of bacteria, causing cell death. Food molecules are also likely to be affected, with loss of vitamins and changes in flavour, and some food packaging materials may be altered.7 Some vitamins, including B,, C, and E, are affected but have been found to be more stable in food systems than when observed in solution. The World Health Organisation has proposed that food irradiation provides two main benefits for the health and wellbeing of man: the destruction of certain food-borne pathogens, thus making food safer, and the prolongation of the shelf-life of food by killing pests and delaying the deterioration process, thereby
increasing food supply.
Salmonella organisms, a major contributor to food-borne disease, are fairly sensitive to irradiation. Deaths and illness occur every year in Britain from salmonella food poisoning caused by consumption of contaminated chicken. Treating chicken after slaughter with a dose of approximately 3 kGy would eliminate most salmonella species and thus contribute to a reduction in the incidence of outbreaks of food poisoning. This process has been proposed by the Food Research Association at Leatherhead. They argue that vitamin losses resulting from the process are of a similar order to those occurring with, for example, the heat pasteurisation of milk. At the same time irradiated chicken would possess the normal characteristics of raw chicken. The food could be treated in either the chilled or frozen state, although a somewhat higher dose is required for frozen products. Clearly, the elimination of salmonellae from massproduced chicken would make a substantial contribution to public health. Irradiation facilities would have to be licensed and inspected frequently. Adequate regulations will be needed to govern the importation of irradiated foods, whether or not irradiation is permitted in the UK. There is no adequate test to determine whether food has been irradiated and this, of itself, can be taken to indicate the subtle nature of chemical changes that occur in irradiated food. Webb and Lang have produced a readable book for the layman. They take a particular stance in relation to proposals to make irradiation legal. Those who propose permissive legislation for this process will now have to respond in terms which can readily be understood by the non-scientist legislator and consumer. 7. Leatherhead Food Research Association Food irradiation—a technical brief Technical notes no 40. Leatherhead Leatherhead Food Research Association, 1986.
Colposcopy Today THE colposcope was pioneered in the United States by Static It was widely used in Europe in the 1970s but rejected at that time in Britain because, although a more accurate biopsy specimen could be taken, the treatment of cervical intra-epithelial neoplasia (CIN)—cone biopsy-was the same whether or not colposcopy had been carried out. Whilst cone biopsy with complete excision of abnormal tissue confers a low risk of subsequent malignant disease,2 disadvantages are the need for hospital admission and the increased risk of prematurity and low birth weight’ associated with the technique. By 1982 a Royal College of Obstetricians and Gynaecologists’ study group4had concluded that "ideally no patient with cervical intra-epithelial neoplasia should be treated unless there has been prior colposcopic assessment", and as such colposcopy is now established as part of the routine evaluation to which all women with an abnormal smear should have access. Directed punch biopsy can provide accurate localisation and histological diagnosis of premalignant lesions, most of which can be destroyed by cryotherapy, diathermy, or laser evaporation.sFor the remainder, preoperative colposcopic assessment will allow the gynaecologist to plan cone biopsy, tailoring the procedure to the extent of the lesion and, in the case of vaginal involvement, to take a "cuff ’ of tissue or use local destructive techniques for the vaginal component followed by cone
biopsy or simple hysterectomy.
The incidence of carcinoma-in-situ increased by 117% between 1973 and 1979 with only an 11% increase in the number of women screenedj6 the greatest increase was in young nulliparous women in whom cone biopsy can compromise fertility. However only two-thirds of women with an abnormal smear in the UK are able to avail themselves of a colposcopic diagnostic service.The wisdom of increasing reliance on cytology alone rather than its combination with colposcopy to detect residual and early recurrent disease has yet to be evaluated, but the results of Walker and colleagues in Dundee8give cause for concern. The Dundee workers found that there was poor correlation between mildly atypical cervical cytology and histology and urged that reliance on cytology alone for surveillance of women who have A, Wilkinson EJ, Mattingly RF. Laser treatment of cervical and vaginal neoplasia. Am J Obstet Gynecol 1977; 128: 128-36. 2 Bevan JR, Attwood ME, Jordan JA, Lucas A, Newton JR. Treatment of preinvasive disease of the cervix by cone biopsy. Br J Obstet Gynaecol 1981; 88: 1140-44 3. Jones JM, Sweetman P, Hibbard BM. The outcome of pregnancy after cone bisposy of the cervix a case controlled study. Br J Obstet Gynaecol 1979, 86: 913-16 4. Jordan JA, Sharp F, Singer A, eds. Preclinical neoplasia of the cervix. Proceedings of the Study Group London: Royal College of Obstetricians and Gynaecologists, 1. Stafl
1982: 299. 5. 6
Singer A, Walker P. What is the optimum treatment of cervical premaligancy? Br Med J 1982; 89: 335-36 Roberts A. Cervical cytology in England and Wales, 1965-80. Health Trends 1982; 14: 41-43
Sharp F, Jordan JA. How many colposcopy centres do we need m the UK? In: Preclinical neoplasia of the cervix. Proceedings of the Study Group London: Royal College of Obstetricians and Gynaecologists, 1982: 229. 8. Walker EM, Dodgson J, Duncan ID. Does mild atypia on a cervical smear warrant further investigation? Lancet 1986; ii: 672-73. 7.
487
already had an abnormal smear should be discouraged. It is now fair to say that any hospital with two or more consultant gynaecologists should be offering its own colposcopy service. Although it is generally accepted that a two-tier system of referral is undesirable and largely unnecessary some techniques, such as contact microcolpohysteroscopy and perhaps laser ablation ofvulvovaginal lesions, are possibly best carried out at specialist centres. Local destructive techniques are not suitable for all premalignant cervical lesions. Singer and Walkers found that the upper and lower limits of CIN III lesions could be demonstrated in over 75 % of "young women", whereas Toplis and colleagues9 observed satisfactory technical colposcopic criteria for local ablation in only 53% of women approaching the menopause and only 18 % of postmenopausal women were deemed suitable for laser ablation. Complete visualisation of the transformation zone and exclusion of malignancy cytologically, colposcopically and, by taking of an accurate biopsy, histologically are the standard conditions that an experienced colposcopist needs to satisfy before applying local destructive techniques. The decision of the RCOG study groupl0 to concentrate training by provision of regular basic courses in colposcopic technique rather than, or in addition to, a system of accreditation does not absolve the responsible trainee from closely monitoring his
colposcopic/histological
correlations and treatment results. Publicity about "high technology" as can be applied to cervical precancer has led many women to expect outpatient ablation for their CIN lesions. Whilst laser conisation of the unanaesthetised patient is now practised, less experienced colposcopists would do well to remember that most cases of invasive cancer after ablative techniques are associated with inadequate primary colposcopic assessment or with inappropriate treatment of a lesion more extensive than eIN .11,13 Patients with persistent inflammatory changes on cervical cytology despite treatment with antibiotics or oestrogens warrant colposcopy in view of the risk of precancer in this group. Two reports9,14 have highlighted the persistent failure of cytological examination, probably because of poor cellular exfoliation, to detect all grades of CIN, and even invasive cancer, in older age groups. Concern has also been expressed that the mortality from cervical cancer in older women is not falling, 15 but it has been .
9 Toplis PJ, Casemore V, Hallam N, Charnock M. Evaluation of colposcopy m the postmenopausal woman. Br J Obstet Gynaecol 1986; 93: 843-51. 10 Jordan JA, Sharp F, Singer A, eds. Preclinical neoplasia of the cervix. Proceedings of the Study Group. London: Royal College of Obstetricians and Gynaecologists, 1982: 287.
11 Sevin B, Ford JH, Girtaener RW, et al. Invasive cancer of the cervix after cryosurgery Obstet Gynecol 1979, 45: 456.
12 Sharp F, Jordan J, eds. Gynaecological laser surgery. Proceedings of
the Study Group. London Royal College of Obstetricians and Gynaecologists, 1985: 137. 13 Tounsend DE, Richart RM, Marks E, Neilsen J. Invasive cancer following outpatient evaluation and therapy for cervical disease. Obstet Gynecol 1981; 57: 145-49. 14 Roberts A, Denholm R, Cordner JW. Cervical intra-epithelial neoplasia in postmenopausal women with negative cervical cytology Br Med J 1985, 290: 281.
assumed that those with mild cytological abnormality progress to invasion slowly, if at all. But, of course,
they will not be detected if surveillance is discontinued at age sixty years as suggested by a Canadian task force. 16 Also worrying is the realisation that two consecutive negative smears, the usual criterion for diagnosis of disease regression,, does not necessarily preclude CIN, 17 although in one study18 nearly 25 % of patients with positive cytology were found to have no evidence of colposcopic or histological abnormality. Of course, cytology and colposcopy together can greatly improve the diagnosis of cervical abnormality. 19 Whilst the malignant potential of CIN III is established, with approximately 50% of cases progressing to cancer, 20 the natural history of minor epithelial atypia, widely believed to be a benign transient condition with a high spontaneous regression rate, remains controversial. The three-fold rise in cervical cancer mortality in young women under thirty-five years, the substantial increase in abnormal cervical smears in young women together with the attendant threat of a further rise in cervical cancer mortality /1 and reports8,22.23 describing histological CIN III or invasive cancer following the detection of mildly atypical cells on a smear have made it essential to establish the progressive potential of early preinvasive disease. The importance of the colposcope in, screening is indicated by the finding that 26 % of young women with cytologically mild
dyskaryosis are subsequently diagnosed as having histologically severe dysplasia on directed biopsy -17 in the same study, 26% of those with mild dyskaryosis progressed to histologically proven CIN III within two years whereas only 7% regressed to normal. Perhaps more worrying is the observation that "of the women whose disease progressed to CIN III, 15% had two consecutive false negative cervical smears and thus might have been discharged from close cytological observation". Although the criteria for selection, regression, progression and length of follow-up have varied greatly between studies, it is clear that there is an inflated spontaneous regression rate (as high as 83 %)24 and a low risk of progression associated with CIN I 15. Husain OAN. Bntain’s failure to prevent deaths from cervical cancer. Br Med J 1984; 289: 50. 16. Canadian Task Force. Cervical cancer screening programs. Summary of 1982 report. Can Med Assoc J 1982; 127: 581. 17. Campion MJ, McCance DJ, Cuzick J, Singer A. Progressive potential of mild cervical atypia: prospective cytological, colposcopic, and virological study. Lancet 1986; ii: 237-40. 18. Singer A, Walker P, Tay SK, Dyson J. Impact of introduction of colposcopy to a district general hospital Br Med J 1984; 289: 1049-51. 19. Coppleson M, Reid B. Preclinical carcinoma of the cervix uteri its origin, nature and management. 1st ed. Oxford: Pergamon, 1967 180. 20. McIndoe WA, McLean MR, Jones RN, Mullins PR. The invasive potential of carcinoma-in-situ of the cervix Obstet Gynecol 1984; 64: 451. 21 Beral V, Booth M. Predicuons of cervical cancer incidence and mortality in England and Wales. Lancet 1986; i: 495 22. Soutter WP, Wisdom S, Broughs AK, Monaghan JM. Should patients with mild atypia in a cervical smear be referred for colposcopy? Br J Obstet Gynaecol 1986; 93: 70-74. 23. Cotton RG, Ellwood JM, Jones GM. Results of delayed follow-up of abnormal cervical smears. Br Med J 1986, 292: 799-800.
488
when the diagnostic procedure includes biopsy. It may be that such a biopsy favourably alters the immune response and natural history of CIN I. Conversely, prospective studies of cervical atypia based only on initial cytology have shown progression rates as high as 60%.25 It is, therefore, sensible to recommend that -women who present with cytologically mild dyskaryosis should be referred for definitive diagnosis by histological examination of a colposcopically directed biopsy.8 Until it is established (perhaps with routine screening by DNA filter hybridisation of cervical cytological specimens) which women with mild changes are at high risk of progression, most researchers believe that even minor lesions should be promptly treated. Patients with histologically proven human papillomavirus (HPV) infection alone are also probably best treated in view of the progressive potential and risk of infectious sexually transmitted disease.26
Report with Confidence
be supported even though the taller CIs will dominate figures more than bars representing one standard error of the mean. Bulpitt also joins other analysts2 in calling for the use of the term ’confidence interval’ rather than confidence limits. This policy has the dual purpose of preventing the citation of one limit and not the other (which can give a highly misleading impression) and of avoiding the connotation of limits as things that cannot be exceeded. When we look at a confidence interval we must also think about the source of the data. What selection factors were operating in the patients being considered? Were the data and the CIs derived only
from a subgroup? In the coming years we hope to see contributors reporting with confidence.
more
Lancet
THE KNOWN AND THE UNKNOWN ABOUT DENGUE FEVER DENGUE fever has been recognised as a clinical entity for least two centuries, as accounts of epidemics in Java in 17793 and in Queensland in 18974 make clear. Mosquito transmission was suspected early this century,5 and was established in experiments with human volunteers which showed that, as with yellow fever,6the principal vector was Aedes aegypti.7-9 The viral aetiology and mosquito transmission of these two important diseases were established long before either virus was cultivated in the at
MANY readers will be pleased to see the decline of the bald statements "not significant p>0-05" and "statistically significant p < 0-05". Medical research is as much concerned with estimation as with hypothesis testing. Estimation is of great importance to those who review the evidence that a drug is efficacious or otherwise. For example, the Drug and Therapeutics Bulletin, reviewing the antispasmodic drug alverine,l stated, "In a double-blind crossover comparison in 37 patients alverine appeared as effective as mebeverine. However, confidence intervals for the difference were not given and therapeutic equivalence cannot be assumed from this small study". The confidence interval gives a range of values that is likely to cover the true but unknown value, and this estimation tells us what we really want to know: how confident are we that alverine is as effective as mebeverine? Similarly, if alverine had been more effective than mebeverine, the confidence interval (CI) would have given us an estimate of the range of benefits to be expected. In his article on p 494 Dr Bulpitt discusses the use of confidence intervals in detail and makes some firm recommendations. Firstly, he advocates standardisation on the 95% confidence interval. In the absence of such standardisation, there will be a temptation to report 90 % CIswhen one wishes to give an impression of precision and conversely to report 99% CIs when one wishes to emphasise variability. Secondly, he proposes that graphical representations of data should include bars representing the 95 % CI, rather than one standard deviation or one standard error of the mean. This call for standardisation must AJ, Knoblich RA Clinicopathologic study of 56 cases showing atypical epithelial changes of the cervix uteri Am J Obstet Gynecol 1957; 73: 120-26. 25. Fox CH. Biological behaviour of cervical dysplasia and carcinoma in situ. Am J Obstet 24 Rawson
Gynecol 1967; 99: 960-74. 26. Singer A. The abnormal cervical smear Br Med J 1986; 293: 1551-56 1. Some antispasmodic drugs for the irritable bowel syndrome. Drug Therap Bull 1986; 24: 93-95
laboratory. 10,11 Dengue and yellow
fever viruses share more than a both are now placed in the Flaviviridae family,12 named after the type species, yellow fever virus. Yellow fever virus strains are closely related to each other, although they can be distinguished by monoclonal antibodies.13 Natural infection is followed by solid immunity against reinfection with any other strain of yellow fever virus. Dengue viruses are more heterogeneous: there are four distinct serotypes, with strain differences within each serotype. Infection with one serotype is followed by solid homotypic immunity," but the individual remains susceptible to infection with dengue viruses of a different serotype. Classical dengue fever is an acute febrile illness with a rash and associated headache, retro-orbital pain, and pains in the common vector:
2. Gardner MJ, Altman DG. Statistics in medicine: confidence intervals rather than p values: estimation rather than hypothesis testing. Br Med J 1986, 292: 746-50 3. Pepper OHP. A note on David Bylon and dengue. Ann Med Hist 1941; 3: 363-68 4. Hare FE. The 1897 epidemic of dengue in north Queensland. Aust Med Gaz 1898, 17: 98-107. 5 Bancroft TL. On the etiology of dengue fever. Aust Med Gaz 1906, 25: 17-18 6. Reed W. Recent research concerning etiology, propagation and prevention of yellow fever by the United States Army Commission. J Hyg 1902; 2: 101-09 7. Cleland JB, Bradley B, McDonald W. On the transmission of Australian dengue by the mosquito Stegomyia fasciata. Med J Aust 1916; ii: 179-84. 8. Cleland JB, Bradley B, McDonald W. Further experiments in the etiology of dengue fever. J Hyg 1919, 18: 217-54. 9. Siler JF, Hall MW, Hitchens AP. Dengue its history, epidemiology, mechanism of transmission, etiology, clinical manifestations, immunity and prevention Philipp J Sci 1926; 29: 1-304 10. Stokes A, Bauer JH, Hudson NP. Experimental transmission of yellow fever to laboratory animals. Am J Trop Med 1928; 8: 103-64. 11 Sabm AB. The dengue group of viruses and its family relationships. Bacteriol Rev 1950; 14: 225-32 12 Westaway EG, Bnnton MA, Gaidamovich SYa, et al. Flaviviridae Intervirol 1985; 24: 183-92. 13. Gould EA, Buckley A, Cammack N, et al. Examination of the immunological relationships between flaviviruses using yellow fever monoclonal antibodies J Gen Virol 1965; 66: 1369-82.