1003 INTRAPLEURAL B.C.G. IMMUNOSTIMULATION IN LUNG CANCER letter is made necessary by a serof the following :*Reprinting ious printing mistake relating to the dose of B.c.G. in the first paragraph of the letter as published in our March 12 issue. We apologise to Dr McKneally and his colleagues.-ED.L. SiR,—This letter is written to follow through on our preliminary communication published one year ago in the Feb. 21, 1976, issue of The Lancet.’ In that report we recorded our experience with the first 60 patients to enter a randomised prospective study of the influence of intrapleural B.G.G. immunostimulation after surgery for lung cancer. We reported then that treatment with intrapleural B.c.G. (107 colony-forming units of the Tice strain) followed by oral isoniazid appeared to improve the survival fraction in stage-i patients when compared with control patients treated with isoniazid alone. At the present time we have entered 101 patients into the study. The median duration of observation is 640 days and the longest observation is 1400 days. The results continue to support the view that intrapleural B.c.G. therapy is effective in stage t lung cancer but ineffective in more advanced disease. The following table is a current listing of the number of patients free of cancer/the number of patients studied.

The survival curve of the isoniazid treated control patient group is similar to that of a historical control population at our own hospital and to the survival of a larger population of 330

surgically resected stage-i2 lung-cancer patients treated at the M.D. Anderson Hospital. We have had no serious complications from this treatment when administered in the manner described in our original reports.’3 We know of 3 patients, treated at other institutions with extraordinarily large doses ofB.c.G. who have become seriously ill from this treatment. All of these patients received 50 x 107 colony forming units (the entire contents of an ampoule and, therefore, fifty times the recommended dose) of intrapleural B.c.G. 1 patient developed miliary B.C.G. infection with splenomegaly, positive bone-marrow cultures, and numerous draining sinuses and granulomas, and 1 developed a transient but severe miliary infection with B.c.G. Both of these patients were controlled by intensive antituberculous therapy. 1 patient died from mycobacterial empyema. We emphasise that this treatment is effective in the proper dose range and dangerous when larger doses are given. Excessive doses of B.C.G. seem to increase the growth of transplanted tumours in laboratory animals.

Supported in part by N.I.H. grants RO1-CA-17346, M01-RR00749 N01-CB-53940, and by the New York State Kidney Disease Insti-

and

tute.

Division of Cardio-Thoracic Surgery,

Albany Medical College of Union University, Albany, N.Y. 12208, U.S.A.

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MARTIN F. McKNEALLY CAROLE M. MAVER HARVEY W. KAUSEL

INCIDENCE OF HEREDITARY DISEASE IN MAN

SIR,-The Occasional Survey (April 16, p. 849) presents data, inferences, and conclusions which should not go unchal-

dominant predisposing to arterial disease were substantiated. From the practical point of view the major contribution of our genetic load to serious symptomatic disease from subchromosomal and genic units is from the autosomal recessives : yet these are virtually dismissed in the discussion. The estimate of 2 5%1000 is consistent with several estimates in Anglo-Saxons, and may be regarded as an upper limit of the incidence of these disorders which are due to mutation unassisted by heterozygote advantage. However, this does not mean, as the authors seem to assume, that recurrent mutations are maintaining established recessive disorders by largely restricting their action to that small proportion of loci at which crippled alleles have been defined. A more conventional explanation of the relationship of mutation to recessive disease, which is consistent with the wealth of the genetic material and the complexity of metabolism, is to suppose that most mutants blush unseen, a minority leading to one or more victims of some disorder many generations later. Even then most of these disorders will be new and their metabolic dissection is unlikely to be initiated until several cases have been observed, and may not be completed until many dozen have been born. However clever our descendants may be, and however large a proportion of their medical resources they are prepared to devote to the screening of the unmarried and the unborn, it is difficult to see how they will be able to define and eliminate a recessive disorder before it has been catalogued, or devise heterozygote detection programmes of adequate precision for the screening of carriers of rare disorders. Even if compulsory prenatal diagnosis should invariably allow the death of homozygotes to precede birth this would not affect the gene frequency in the next generation. Serious consequences may result from the acquisition, conveyance, or processing of any form of fuel. Nuclear fuel, although relatively safe to our contemporaries, has the disturbing property of imposing a cumulative contribution to our1 genetic load, a hazard dismissed in the Flowers report notwithstanding its lucid introduction on biological effects, which includes the statement "a recessive mutation will only appear in a later generation, and then only if it is paired with a similarly mutated gene. Thus the absence of genetic abnormalities in the first generation is no guarantee that they will not occur subsequently". This contribution may indeed be so small that we are justified in bequeathing it to our descendants. However, an attempt must be made to quantify this debt before passing it on. It is difficult to see how the consequences of most recessive disorders will be any less tragic if they are exported to the future. It would be equally inappropriate if an article on the incidence of mining accidents were to condone inaction on the grounds that advances in surgery were imminent and the accident-rate in the general population difficult to define. The opinion that the autosomal recessive disorders are a major hazard of radiation and other mutagens is hardly a novel view, even though the expectations to which it leads cannot be observed directly in man for several generations, and these consequences of exposure will not be observed either by those exposed or by those now advising on the hazards of exposure. a common

Infant

Development Unit, Queen Elizabeth Medical Centre, Edgbaston, Birmingham B15 2TG

J. H. EDWARDS

lenged.

While the data on chromosomal aberrations of the livmg (those on the dead are misprinted or mistyped) are a useful summary of the many consistent studies now available, some statements on what is termed "monogenic disorders" lack both credibility and references. The value of 7/1000 for dominant disease is very high if this refers to symptomatic disease, even if the claim that there is

1 McKneally, M. F., Maver, C. M., Kausel, H. W. Lancet, 1976, i, 377. 2 Mountain, C. F., and others. Unpublished. 3 McKneally, M. F., Maver, C., Kausel, H. W., Alley, R. D. J. thor. cardiovas. Surg. 1976, 72, 333.

***This letter

was

shown

to

Dr Ash and her

colleagues

whose

reply follows.-ED.L. SIR The errors noted by Professor Edwards in the data presented on chromosome aberrations in stillbirths and

we

neonatal deaths have been corrected.2 1.

Royal Commission

on

Environmental Pollution. Sixth

Stationery Office, 1976. 2. Lancet, April 30, 1977, p. 964. Cmnd. 6618. H.M.

Report; pp. 23,200.

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Intrapleural B.C.G. immunostimulation in lung cancer.

1003 INTRAPLEURAL B.C.G. IMMUNOSTIMULATION IN LUNG CANCER letter is made necessary by a serof the following :*Reprinting ious printing mistake relatin...
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