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lung cancer" and in early breast cancer.3 This kind of analysis isuseful since it helps to generate new trials.

Department of Biostatistics and Epidemiology,and Department of Radiotherapy,

Institut Gustave-Roussy,94805 Villejuif, France

JEAN-PIERRE PIGNONRODRIGO ARRIAGADA

1. Warde P, Payne D. Does thoracic irradiation improve survival and local control inlimited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol 1992;10: 890-95.

2. Pignon JP, Arriagada R, Ihde DC, et al. A meta-analysis of thoracic radiotherapy forsmall-cell lung cancer. N Engl J Med 1992; 327: 1618-24.

3. Early Breast Cancer Trialists’ Collaborative Group. Systemic treatment of early breastcancer by hormonal, cytotoxic, or immune therapy: 133 randomized trials

involving 331 000 recurrences and 244 000 deaths among 75 000 women. Lancet1992; 339: 1-15, 71-85.

4. Pignon JP, Arriagada R. Role of thoracic radiotherapy in limited-stage small-cell lungcancer: Quantitative review based on literature versus meta-analysis based onindividual data. J Clin Oncol 1992; 10: 1819-20.

SiR,—Dr Stewart and Dr Parmar regard MAPs as less biasedand more reliable than MALs. A further benefit of MAPs is the

opportunity to examine explicitly the efficacy of therapy in differentpatients’ subgroups. Too often, with a MAL the desired subgroup-specific analyses are not presented by the original workers. Yet, ofthe 401 meta-analyses of clinical trials or epidemiological studiesidentified from a MEDLINE search for 1982-92, less than 10%used the MAP approach. There are good reasons for this bias.Stewart and Parmar state that MAP "can take considerable timeand resources", since several staff may be needed to co-ordinatedata collation and follow-up, as well as check, clean, and reformatthe various datasets. But there are other practical obstacles to MAP.A limited survey of archiving practices among several

pharmaceutical companies and research funding organisations inEurope and the USA found considerable variation in the availabilityof archived patients’ data from clinical trials. The duration of

archiving after study termination also ranged from 2 to 20 years.This situation is likely to improve with implementation of the goodclinical practice (GCP) guidelines, which require that sponsors ofapplications for the marketing of new drugs, archive their clinicaltrials’ data for at least 15 years after study termination. Secondly,there are no clearcut rules governing access by other scientists toclinical trials’ data. Requests under the Freedom of Information Acthave been used on a few occasions to force investigators of USgovernment funded studies to release data against their will-butmuch uncertainty surrounds the interpretation of the Act to clinicaltrials’ data. In the UK, research funding agencies usually delegatethis responsibility to the study co-ordinators. However,investigators and pharmaceutical companies may be reluctant toshare their data for several reasons, and unless the study is fundedby a US government agency, such as the National Institutes ofHealth, there is nothing to compel them to do so.The notion of routine archiving of clinical trials’ data is still fairly

new. The only existing national archive of clinical trials’ data knownto us is the National Technical Information Service (NTIS) whichhas maintained a computer data file on selected US federally fundedresearch since 1975. The process of MAP would be greatlyfacilitated by standardisation of procedures for archiving data, andrules governing access to the data for legitimate purposes. Astandard format for storage of data (on tape or disc), procedures formaintaining confidentiality, and incentives for individual

investigators to contribute data would also be needed. For thepresent, the conduct of MAPs is likely to be confined to a fewinstitutions with the necessary infrastructure to undertake them.

Chelsea and Westminster Hospital,London SW10 9TH, UK

Clinical Epidemiology Unit,University of Pennsylvania School of Medicine,Philadelphia, USA

PHILIPPA EASTERBROOK

JESSE BERLIN

Passive smokingSIR,—Your editorials are usually well informed, but that of Feb

27 is an exception. You would have done well to take account of theEnvironmental Protection Agency’s report’ on environmentaltobacco smoke (ETS), the subject of your following commentary byClark Heath.

The EPA’s statement that ETS is equivalent to the smoke thatsmokers inhale falls short of objective verification. Less than twodozen ETS components can be measured, with the extremedilutions. EPA concurs that average annual exposures to ETS

particles are less than actively smoking one cigarette and

categorically excludes dose/effect thresholds. Yet, much work inanimals shows thresholds at fairly high doses and classifies tobaccosmoke as a weak carcinogen.2 Active smoking epidemiology alsohints at thresholds.3

In the end, these vanishing ETS exposures produce inconclusiveepidemiological results. As the International Agency for Researchon Cancer (IARC) says, data are "... compatible either with anincrease or with an absence of risk".2 In fact, most results arecompatible with odds ratios below unity, and IARC’s eventualattribution of ETS risk is vague.EPA claims statistical significance by the questionable gambit of

adopting one-tailed statistics and 90% CIs, and on the basis ofdiscordant meta-analysis and arbitrary adjustments. Despitecontrary epidemiological evidence, EPA also decided that severalknown confounders of lung cancer risk were no impediment to itsconclusions. EPA’s estimate of 19 % excess lung cancer comes from11 of 13 US studies available before the release of the report. The

agency decided not to consider any epidemiological studies of ETSin workplaces and two recent and large federally funded ETSstudies, which together invalidate the Agency’s conclusions even byinflated statistical standards.4,5 EPAs evaluation of respiratory risksfor children has analogous methodological shortcomings.

Thus, Clark Heath’s attributions of robust science are

perplexing. It may be a minor point that the risk criteria he describesare not those of the EPA, and that his conjectures on histopathologyare dashed by the lastest epidemiological studies that EPA

ignored.4,5 Contrary to his wishes, however, the OccupationalHealth and Safety Administration may find it difficult to regulateETS because component concentrations are thousands to a millionfold below corresponding levels that the Agency allows in

workplaces.3 And his "strong support for a cause-effect association"derives from Bradford Hill’s criteria, dictated again by a perceivednecessity of interpretation and not by science.

Although the EPA report may yet prove an effective policyinstrument, the Agency’s claim of scientific support seems ill-founded. As the debate on scientific misconduct continues, it isinevitable to ask, can an official report be forgiven on grounds of itsgood intention, that otherwise would guarantee severe censure toany individual scientist or academic institution? Do benevolentintentions to curb cigarette use ever justify the means? These are notrivial partisan questions in defence of tobacco interests. Ultimately,their answers will determine the credibility of science, its continuingpublic support, and whether civic institutions are worthy of thepublic’s trust.Health Policy Center,6704 Barr Road,Bethesda, Maryland 20816, USA GIO BATTA GORI

1. Environmental Protection Agency. Respiratory health effects of passive smoking: lungcancer and other disorders. EPA, Washington, DC, 1992.

2. International Agency for Research on Cancer. Evaluation of the carcinogenic risk ofchemicals to man. Vol 38: Tobacco smoking. IARC, Lyon, 1986: 308.

3. Gori GB, Mantel N. Mainstream and environmental tobacco smoke. Regul ToxicolPharmacol 1991; 14: 88-105.

4. Stockwell HG, Goldman AL, et al. Environmental tobacco smoke and lung cancer nskin nonsmoking women. JNCI 1992; 84: 1417-22.

5. Brownson RC, Alvanja MCR, et al. Passive smoking and lung cancer in nonsmokingwomen. AJPH 1992; 82: 1525-30.

War-stress-induced medical emergencies insouth Croatia

SIR,-Bergovec and colleagues! reported increased frequency ofacute myocardial infarction (AMI) and hospital mortality duringthe time when air-raid alarms were frequent in Zagreb city. Wereport somewhat different data from Split, a coastal town in Croatia.The frequency of AMI and gastrointestinal bleeding amongpatients needing emergency admittance was investigated from Sept16 to Nov 17,1991, when our region was attacked from land and sea,and air-raid alarms sounded frequently. AMI in this period wascompared with the corresponding data for 1990, the last prewar

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FREQUENCY OF AMI, DEATHS DUETO AMI, GASTROINTESTINALBLEEDING, AND BLEEDING DUODENAL ULCERS IN SPLIT

HOSPITAL IN COMPARABLE PERIODS IN 1990, 1991, AND 1992

G!B==gastromtestma! bleed Ing; DUB=duodenal ulcer bleedmg.*Total no of admissions’ 1990=600 ; 1991 =545; 1992-688. Percentages are oftotal no of admissions.

tPercentages are of no of AMI and GIB, respectively.ip < 0.01 vs 1991.

year, and 1992, when the war in Bosnia and Hercegovina began tohave an effect (table).

Contrary to the experience in IsraeF and Zagreb, we noted no risein the frequency of AMI in the study period; not even in Septemberwhen the first sirens were sounded, preventing patients fromreaching hospital. Nor did mortality in AMI patients in hospitalrise, possibly because of our policy of not evacuating the coronarycare unit unless it was clearly endangered. We have only onceevacuated, when shells from battleships were landing within 500 mof the hospital. During the study period a slight unexpecteddecrease in the incidence of gastrointestinal bleeding was noted.However, a substantial increase in bleeding duodenal ulcers wasfound in the following year (1992), possibly indicating the effects ofchronic psychosocial stress in postwar Croatia, and the continuingwar in neighbouring Bosnia and Hercegovina.We suggest that adequate consideration should be given to the

inevitable psychological and physical stress of evacuation and itsnegative affect on survival in AMI patients and that it should beavoided whenever reasonably possible.

Clinical Hospital Split,58 000 Split,Croatia

ZVONKO RUMBOLDTDINKO MIRICIVO BOZIC

LOVEL GIUNIO

STOJAN POLICANTE TONKIC

1. Bergovec M, Mitiatov S, Prpic H, Rogan S, Batarelo V, Sjerobabski V. Acutemyocardial infarction among civilians in Zagreb city area. Lancet 1992; 339: 303.

2. Meisel SR, Kutz I, Dayan KI, et al. Effect of Iraqi missile war on incidence of acutemyocardial infarction and sudden death in Israeli civilians. Lancet 1991; 338:660-61.

Postgraduate district hospital training inZambia

SiR,&mdash;The experience in Zambia that you record (Jan 16, p 168)is typical of many east and central African countries. A majordifficulty is that doctors are trained in hospitals mainly by clinicians,but when posted to the districts they are expected to act asmanagers. They may be called district medical officers, but they areresponsible for planning, budgeting, allocating resources,

supervising staff, monitoring, and evaluating. They have theseresponsibilities against a background of increased decentralisationof districts.

In addition to the Zambian initiative there are two other activities

addressing the issue. The University of Zimbabwe Medical Schoolhas started an innovative programme with support from theRockefeller Foundation and Centers for Disease Control. This

programme, which is aimed at experienced graduate health

workers, combines intensive short courses with supervised fieldwork over two years, resulting in the award of an MPH degree. Thecurriculum is competency-based, with a major emphasis on healthservices management.Another initiative is by Management Sciences for Health, a

Boston-based, non-profit-making health consulting and trainingorganisation. They will be offering an intensive one-month courseon management decentralised health services in Harare, Zimbabwe,in June and July, 1993. The course is aimed at providing themanagement skills needed by clinically trained staff who are inmanagement positions.By recognising the need to improve management skills of district

managers, donors have been able to support the improvement in

efficiency needed to cope with the serious health problemschallenging east and central Africa.

Management Sciences for Health,165 Allandale Road,Boston, Massachusetts 2130, USA R. O. LAING

Department of Community Medicine,University of Zimbabwe Medical School,Harare, Zimbabwe C. H. TODD

Box-plotsSIR,-Dr Campbell (March 20, p 763) comments on my use of

the term 95 % CI in my commentary on box-plots and suggests thatI had confused statistics of estimation and description. I hadintended to suggest that it had become common to give the valuesthat would include the inner 95% of the data, based on the mean

&plusmn; 1.96 x SD. I did not mean the "confidence interval of the mean"which would have to be calculated from the SE. It seems that theterm 95 % CI cannot be used for the inner 95 % range of data, and Ithank Campbell for his correction.

Department of Clinical Microbiology,University College Hospital,London WC1E 6AU, UK A. P. R. WILSON

Anaphylactoid reaction after injection ofalteplase

SIR,-Because alteplase (recombinant tissue plasminogenactivator [rt-PA], Boehringer Ingelheim) is structurally identical toendogenous t-PA, its administration should not cause anaphylacticreactions. We report a 69-year-old beekeeper who had an acutemyocardial infarction. He received glyceryl trinitrate 500 J..lg,nifedipine 10 mg, and aspirin 150 mg orally. A 200 J direct-currentshock corrected ventricular fibrillation outside hospital and wasfollowed by intravenous lignocaine before an intravenous bolus ofalteplase 50 mg. 25 min later, the patient had gross facial, tongue,and neck oedema. He was unable to speak. Urticaria occurred on thechest and arms. Chlorpheniramine 10 mg and hydrocortisone 200mg were administered intravenously with resolution of signs overthe next hour.

Investigations revealed normal functional and quantitative Clesterase inhibitor, and total haemolytic and C3 and C4 componentsof complement. Circulating immune complexes were absent.Serum IgG, IgA, and IgM were normal but IgE was 1133 kU/L(normal < 120). His history included atopy. Radio-

allergoimmunosorbent test (RAST) to honey-bee venom wasstrongly positive. Plasma samples were taken on days 10 and 90 fort-PA antibody measurement by competitive enzyme-linkedimmunosorbent assay, by radioimmunoprecipitation, and by adot-blot method with radiolabelled t-PA. All three methods yieldedno detectable antibody while, where appropriate, a positive controlrabbit t-PA antibody could be detected at a dilution of 107.

Oral aspirin and glyceryl trinitrate were reintroduced while dilutesolutions of the contents of a nifedipine capsule, a vial of alteplase(which also contains L-arginine, phosphoric acid, and polysorbate80), and 0-5 ml lignocaine 2% provoked no allergic response wheninoculated intradermally. The patient was discharged on

terfenadine 60 mg three times a day and has subsequently reported adecrease in urticarial symptoms.

Because testing proved negative, we believe this anaphylactoidreaction was not due to an anribody-anrigen or direct chemicalreaction to any of the administered preparations. There is anothercase report of this reaction in an atopic individual with a history ofurticarial rashes, positive RAST to elm-bark pollen, and elevatedserum IgE who was infused with rt-PA. This individual also testedt-PA antibody negative with normal Cl esterase inhibitor.!

Plasmin is formed in quantity after the administration of rt-PAand activates complement cascade, especially C3a and C5a, whichrelease histamine and other inflammatory mediators. Plasmin alsoactivates the kinin system. In most patients, these effects areclinically insignificant, but our atopic patient had significantactivation. Serial measurements of Clr and Cls consumption, andC3a and C5a production during the reaction and measurement ofurinary histamine production would have been helpful.