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and protein expression might be to use a combination of in-situRNA hybridisation with exon-specific probes and immuno-histochemistry with a panel of CD44-variant antibodies.

We thank Prof P Herrlich for providing VFF9.

Stephen B Fox, Kevin C GatterNuffield Department of Pathology, John Radcliffe Hospital, Oxford OX3 9DU, UK

David G Jackson, Gavin R Screaton, Martin V Bell, John I BellNuffield Department of Clinical Medicine, John Radcliffe Hospital

Adrian L Harris, David Simmons, Jonathan FawcettICRF Molecular Oncology Laboratory and Cell Adhesion Laboratory, Institute ofMolecular Medicine, John Radcliffe Hospital

1 Heider KH, Hofmann M, Hors E, et al. A human homologue of the ratmetastasis-associated variant of CD44 is expressed in colorectalcarcinomas and adenomatous polyps. J Cell Biol 1993; 120: 227-33.

2 Screaton GR, Bell MV, Jackson DG, Cornelis FB, Gerth U, Bell JI.Genomic structure of DNA encoding the lymphocyte homing receptorCD44 reveals at least 12 alternatively spliced exons. Proc Natl Acad SciUSA 1992; 89: 12160-64.

3 Matsumura Y, Tarin D. Significance of CD44 gene products forcancer diagnosis and disease evaluation. Lancet 1992; 340: 1053-58.

4 Tanabe K, Ellis L, Saya H. Expression of CD44R1 adhesion moleculein colon carcinomas and metastases. Lancet 1993; 341: 725-26.

5 Jackson DG, Screaton GR, Bell MV, Bell JI. CD44 and cancer. Lancet1993; 341: 252-53.

6 Koopman G, Heider K-H, Horst E, et al. Activated humanlymphocytes and aggressive non-Hodgkin’s lymphomas express ahomologue of the rat metastasis-associated variant of CD44. J ExpMed 1993; 177: 897-904.

Vitamin A and childhood mortalitySIR-The Ghana vitamin A supplementation trial (July 3, p 7)supports the findings of several studies in Asia that have shownsimilar reductions in child mortality associated with vitamin Asupplementation. By contrast, almost all studies of vitamin Asupplementation on morbidity have shown no differences inprevalence of diarrhoea and respiratory infections (the majorcauses of childhood deaths in developing countries) betweenchildren receiving vitamin A or placebo. Measles is the one

cause of childhood morbidity in which it has been clearly shownthat vitamin A supplements reduce the severity of illness andcase-fatality rates.1,2 Could it be that in the Ghana study, andperhaps also the Asian studies, the reductions in mortality rateswere due mainly to a reduction in death from measles?This question cannot be definitively answered because the

cause of death was not accurately established. In the Ghana andother trials, the cause of death was established by "verbalautopsy" (a wonderful oxymoron): a field worker, usuallymonths after the child died, questioned parents and othersabout events preceding the child’s death, including symptoms.This information was then reviewed by 3 physicians whoassigned the cause of death to 1 of 11 categories. I think these"causes of death" are suspect, and suggest deaths recorded asdue to "malaria" or "gastroenteritis" (23% and 26% of deaths,respectively) were probably deaths in which pyrexia anddiarrhoea were the presenting symptoms. Since malaria cannotbe definitively diagnosed without identifying plasmodia in

blood, could some of these deaths preceded by fever anddiarrhoea have been due to measles before the rash? Measlesoften presents with high temperature and diarrhoea, and isdifficult even for a physician to diagnose in the days before therash.

In the Ghana study there was a difference of 98 deathsbetween those receiving vitamin A supplements and theplacebo group: 56 due to "acute gastroenteritis" and "chronicdiarrhoea or malnutrition", 9 "malaria", 12 "measles", and 17"cause not known". So 94 of the 98 deaths are in these 5

categories. My hypothesis is that the difference between the

groups may have been due almost entirely to a reduction indeaths from measles. There is clear evidence that providingvitamin A supplements to children with measles dramaticallyreduces fatality rates. Such data do not exist for gastrointestinalor respiratory infections. If this is so, there are important policyimplications. Vitamin A supplements every 4 to 6 months areagain being proposed as a "magic bullet" and a highlycost-effective way of reducing child mortality, a strategy I

consider inappropriate and unsustainable.3 There are also

strong moves to include vitamin A dosing as part of immunis-ation programmes. Surely a much higher priority should beplaced on efforts to assure a widespread coverage of measlesimmunisation. In the Ghana study, the 20% of deaths due tomeasles could have been prevented by immunisation withoutvitamin A supplements. I suggest also that most of the otherdeaths claimed to be prevented by vitamin A could also havebeen prevented by immunisation.

Michael C LathamDivision of Nutritional Sciences, Cornell University, Savage Hall, Ithaca,New York 14853, USA

1 Barclay AJG, Foster A, Sommer A. Vitamin A supplements andmortality related to measles: a randomised clinical trial. BMJ 1987;294: 294-96.

2 Hussey GD, Klein M. A randomized controlled trial of vitamin A inchildren with severe measles. N Engl J Med 1990; 323: 160-64.

3 Latham MC, Habicht J-P. Vitamin A and childhood mortality. N EnglJ Med 1991; 324: 10-11.

Screening mammography

SIR—Nyström and colleagues’ (April 17, p 973) overview offive Swedish studies of breast cancer mortality after screeningmammography raised concerns (June 12, p 1531) about thediscrepancy between its data and previously published studiesfrom four of the centres, which had shown a slight excess ofbreast cancer mortality in women initially screened before age501,2 or 55.3 Further, Skrabanek (June 12, p 1531) questionedwhether there was excess overall mortality in women screenedat all ages. The reply from Nystrom and Larsson lends weightto both these concerns.

Nystrom and Larsson provide more detailed information- own numbers of deaths from breast cancer in women screenedat ages 40-49 in the invited and control groups in eachcentre-to supplement their published aggregate data. Forthree centresu2 modest differences between previously pub-lished data and those used by Nystrom and colleagues can beaccounted for by small differences in methodology (Malmö)but for one of them the numbers of deaths in the earlier

publication and in Nystrom’s study were strikingly different.In 1988, Andersson et aP reported 28 deaths from breast

cancer in the invited group and 22 in the controls at the end ofthe Malmö trial in 1986, for women aged less than 55 on entryinto the trial. From the same study, Nystrom and Larssonreport 8 deaths from breast cancer in the invited group and 16in the control group for women aged 40-49 at time of entry. Isthis difference explained mainly by the inclusion of womenaged 50-54 in the earlier report? If so, there would have been 20deaths in the invited group and 6 in the controls aged 50-54 atthe time of entry-a striking excess risk of breast cancer for thescreened women aged 50-54 in Maimo. Is there another

explanation?Nystrom and Larsson responded to Skrabanek by showing

that the observed number of deaths from all causes in the

mammographically screened women was similar to an expectednumber calculated from population rates. A more precise andapt comparison is that between the mortality rates in theexposed and control groups. That comparison, based on the

550

total number of deaths given in Skrabanek’s letter and the

aggregate person-years given in the original article by Nystromand colleagues, yields a rate ratio of 1-05 (5% excess deaths inthe screened group). Nystrom and colleagues could make thiscomparison even more precise and help determine whetherthere was a true excess overall mortality in the screened groupby comparing them directly with the control group in a detailedanalysis stratified by age and centre.There is also an apparent discrepancy between the number of

person-years of follow-up in the control group aged 40-49 intable III of the April 17 paper (350 000) and that shown in thetable of their June 12 letter (394 000).

Michael SwiftDivision of Human Molecular Genetics, New York Medical College, Hawthorne,New York 10532, USA

1 Tabar L, Fagerberg G, Duffy SW, Day NE, Gad A, Grontoft O.Update of the Swedish two-county programme of mammographicscreening for breast cancer. Radiol Clin N Am 1992; 30: 187-210.

2 Frisell J, Eklund G, Hellstrom L, Lidbrink E, Rutqvist L-E,Somell A. Randomized study of mammography screening: preliminaryreport on mortality in the Stockholm trial. Breast Cancer Res Treat1991; 18: 49-56.

3 Andersson I, Aspergren K, Janzon L, et al. Mammographic screeningand mortality from breast cancer: the Malmo mammographicscreening trial. BMJ 1988; 297: 943-48.

Authors’reply

SIR—We have now done a further analysis applying the sameage groupings as the Malmö team used in their follow-up to1986. In the age group 45-54 there were 35 deaths with breastcancer as the underlying cause of death in the invited group andin the controls, resulting in an odds ratio of 0-95 (95% CI0-72-2-28). This implies that in the age group 50-54 there were27 deaths in the invited group and 19 in the controls (odds ratio1 28, 95% CI 0-72-228). The 95% CI is wide and we do notagree that this represents "a striking excess risk".Nor do we agree that "A more precise and apt comparison is

that between the mortality rates ...". We prefer (see ourresponse to Skrabanek) standardised relative risks to cruderelative risks. We apologise for the error in our letter: theperson-years of follow-up in controls should have been 350 000.

Lennarth Nyström, Lars-Gunnar LarssonDepartment of Epidemiology and Public Health and Oncology, Umeå University,S-90185 Umeå, Sweden

SIR—Frankel’s note (Aug 14, p 425) on the National HealthService Breast Screening Programme in the UK raises impor-tant issues. The reported detection rate of 6 2 cancers per 1000women screened suggests that the sensitivity is fairly high, butthe fact that only 20% of cancers were under 1 cm is

disappointing. Although Tabar et all have set a goal of 50% ofinvasive cancers under 1-5 cm, it is likely that, if mortality is tobe reduced, a larger percentage of invasive cancers must befound that are less than 1 cm.2 A goal of screening should be thedetection of 40% or more of invasive cancers when they are1 cm or smaller.For some, the most important figure is the positive predic-

tive value (PPV), but it is the distribution of size and stage ofthe cancers that provides the most important measure of thesuccess of a screening programme. Certainly efforts should bemade to avoid biopsies for benign reasons whenever possible,but with mammography this can only come at the expense ofdelayed diagnosis.3 PPVs for clinically instigated biopsy haverarely been questioned despite the fact that they are only15-30%-yet similar levels are deemed unacceptable for

mammography, this is illogical since mammographicallydetected cancers are more likely to be smaller and at an earlier

stage.4 Efforts to raise the PPV should be made for clinicallydetected lesions first. High PPVs can be achieved for screening,but this comes at the expense of early detection.s To maximisethe percentage of tumours 1 cm or smaller will probably requiremore aggressive intervention and result in a lower PPV.

Daniel B KopansDepartment of Radiology, Massachusetts General Hospital,Boston, Massachusetts 02114, USA

1 Tabar L, Fagerberg G, Duffy SW, Day NE, Gad A, Grontoft O.Update of the Swedish two-county program of mammographicscreening for breast cancer. Radiol Clin N Am 1992; 30: 187-210.

2 Rosen PP, Groshen S, Saigo PE, Kinne DW, Hellman S. A long-termfollow-up study of survival in stage I (T1 N0 M0) and stage II (T1 N1M0) breast carcinoma. J Clin Oncol 1989; 7: 355-66.

3 D’Orsi CJ. To follow or not to follow, that is the question. Radiology1992; 184: 306.

4 Bassett LW, Liu TH, Giuliano AE, Gold RH. The prevalence ofcarcinoma in palpable vs impalpable mammographically detectedlesions. Am J Roentgenol 1991; 157: 21-24.

5 Kopans DB. The positive predictive value of mammography. Am JRoentgenol 1992; 158: 521-26.

School performance in very preterm children

SIR—Increasing numbers of preterm infants survive without(major) handicaps but with more subtle long-term morbidities,such as learning difficulties and lower school-grades, and theneed for special education occurs more frequently than in thegeneral population. However, long-term follow-up is rare,

mainly hospital-based, and covers only small numbers. In theNetherlands a virtually complete year-cohort of very-preterm(less than 32 weeks) and/or very-low-birthweight (less than1500 g) infants born alive in 1983 (94% of the total Dutchpopulation meeting these entry criteria) were enrolled in afollow-up study. At age 5 years, 28% of these children hadeither a handicap or a disability.1 At that age 12% werereceiving special education compared with 1.1 % in the generalpopulation of 5-year-olds. These children are now 9 years old,an age by which most children needing special education haveusually been identified. We report the school results of 813children (88% of survivors) as given by the parents in a postalquestionnaire. Non-response was significantly associated withhandicaps and disabilities at age 5 years and with lowsocioeconomic status and therefore may have led to someunderestimation of the learning problems.At 9 years of age, 155 children (19%) were in special

education, compared with 6-5% of the 9-year-olds in the totalDutch population. Whereas most of the children already inspecial education at 5 years of age had neurodevelopmental orsensory handicaps, the children who entered special educationbetween the age of 5 and 9 years predominantly had moderatecognitive impairments and moderate behavioural and learningdifficulties. More than half the study children who enteredspecial education between these ages were judged not disabledat 5 years of age, although most had some neurodevelopmentalimpairment that might have predicted learning problems. Asmany as 32% of the preterm infants in mainstream educationwere below the level for their age, compared with 10% of the9-year-old children in the general population. Remedial

teaching or other forms of special assistance were given to 27%of the children at the appropriate age-level and to 60% ofchildren below age-level.Thus, only 40% of all assessed children and 49% of the

children without handicap or disability at 5 years of age were inmainstream education at an age-appropriate level without extrahelp. A standardised examination of all study children is

needed to establish the extent of learning difficulties, especiallyaimed at counselling of parents about the present educational