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PRENATAL RADIATION EXPOSURE AND CHILDHOOD CANCER
751 shift is strikingly similar to the differences reported here between the white and blue areas of the aortic intima of young pigs. It therefore seems possible that before morphological changes appear in the intima, and even before lipid accumulation is detectable, areas of the intima are the development of atherosclerotic lesions. show enhanced permeability, lower levels of phospholipids, and higher levels of cholesterol. The fact that the changes we observed in 6-month-old pigs were more pronounced than those seen by Schwartz in 2-month-old animals suggests the existence of a time effect in dephospholipidation and cholesterol-ester accumulation. Are these changes in lipid composition and aortic permeability the first biological steps in atherogenesis ?
predisposed These
to
areas
Atherosclerosis Research Unit of the Organisation for Health Research TNO, Gaubius Institute of the
University of Leiden, Leiden, Netherlands.
SIR,-In May, 1969, we started using general anaesthesia for bone-marrow aspiration and other manoeuvres in a leukaemia clinic. Eight to ten of the children attending the clinic each week need a bone-marrow biopsy, lumbar puncture, or both. For all these children the tests need to be repeated at regular intervals; and we started using general anxsthesia because of the difficulties of sedating outpatients. Since changing to general anaesthesia we have been impressed by the rapidity, coupled with safety, with which the clinic can be conducted. Our outpatient department is situated in the middle of Manchester, six miles away from the hospital, and so the clinic is conducted on the ward where all the cases are usually admitted. Staff nurses have been specially appointed for helping in the clinic. The ward is a large Nightingale ward of 28 beds. The children come to the hospital having had no breakfast. In a side-ward, anaesthesia is induced by an aneesthetist with intravenous methohexitone, given through a 27 gauge Brunswick needle into an anterior wrist vein. It is necessary to give a larger dose, weight for weight, than is used in adults, and the usual dose given is 2-2-5 mg. per kg. Aspiration of bone-marrow, lumbar puncture, intravenous injection, and so on is rapidly completed, with all the advantages of having the patient unconscious. For the longer manoeuvres it is necessary to supplement anaesthesia with nitrous oxide, oxygen, and halothane. When the test is completed, the patient is wheeled out on the trolley into the open ward, where he recovers consciousness within a few minutes under the supervision of a staff nurse. Minutes later he is eating breakfast or lunch. So far we have managed treatment in this way on 911 occasions. Our patients are most commonly aged between two and five years. The children much prefer it: so do their parents. Because the patient is still, the hxmatologist can insert the needle easily and aspirate a good sample of marrow, with corresponding improvement in the quality of the films. Eight to ten bone-marrows, &c., are completed in an hour. We have had no complications. We would like to express our gratitude to Sister B. Jenkinson for her able cooperation. D. 1. K. E. acknowledges grants from the Medical Research Council and Leukxmia Research Fund. P. M. J. is supported by a grant from the Wigan and District Cancer Research Committee.
Manchester M27 1HA.
SIR,-Dr. Berkeley’s letter (Jan. 30, p. 241) is misleading about B.C.G. policy in Glasgow. Contact vaccination was started in Glasgow in 1950 and infant vaccination in 1952, when some 10% of infants were vaccinated. This coverage gradually increased to around 50% in 1960 and 70% in the past 3 years. Vaccination of 13-year-olds commenced in 1953, and the proportion of this age vaccinated has been higher than of infants. Parental consent is as high as 97% and, after tuberculin testing, some 11,000 schoolchildren are vaccinated each year. Health Department, Glasgow. JOHN CLARK.
C. PRIES F. B. KLYNSTRA.
OUTPATIENT ANÆSTHESIA FOR A CHILDREN’S LEUKÆMIA CLINIC
Royal Manchester Children’s Hospital, Pendlebury,
B.C.G. VACCINATION AND LEUKÆMIA MORTALITY
D. I. K. EVANS P. MORRIS JONES P. MORRIS E. A. SHAW.
PRENATAL RADIATION EXPOSURE AND CHILDHOOD CANCER
SIR,-Obstetric X-rays are ordered by doctors who have no say in how many films will be taken, and are taken by technicians who follow procedures originally recommended by a consortium of radiologists but sufficiently flexible to allow certain types of hospital to be slightly more lavish in their use of films than others (see accompanying table). It is therefore difficult to take seriously Professor Burch’s suggestion (Jan. 2, p. 43) that differences in film numbers are connected with differences in predispositions to bear a child who subsequently dies from a malignant disease. The Oxford Survey of Childhood Cancers, which made it possible to relate types of hospital and numbers of films, has been cited by Professor Burch in support of his ideas about the origins of juvenile cancers.1 So I should like to explain why theories of disease causation which are based solely on age-specific incidence-curves are apt to be misleading. Professor Burch’s theory belongs to this category, and offers us an elaborate explanation of why the risk of developing malignant diseases decreases with age during childhood and adolescence, and subsequently increases with the fifth or sixth power of age.Since, however, this sequence of events is typical of all causes of death, all that needs to be said is that, irrespective of their cause and nature, all pathological processes prove most harmful towards the end of the lifespan and least harmful during the prime of life (see accompanying figure). Professor Burch has not made the mistake of assuming that the so-called power-law relationship between age and incidence is unique to cancers.But, instead of regarding the non-specificity as a sign that age has a more powerful effect on the consequences of disease processes than on their causes, he offers it as proof that the process whereby normal cells are converted into malignant cells (cancer initiation) is steeply age-dependent, and totally ignores the possibility that the age-dependence is reflecting not numbers of initiations but proportions of successful initiations, or cancer promotions-i.e., the means whereby sufficient numbers of malignant cells collect to form tumours.
This interpretation of age-specific incidence-rates and mortality-rates is the reverse of what one would expect if the power-law relationships are a sign that the limited lifespan of human beings is guaranteed, not by making contacts with noxious influences increasingly probable as age advances, but by making tissues increasingly vulnerable to their effects. Presumably Professor Burch would not 1. 2. 3.
have drawn the
same
conclusions if he had had the
Burch, P. R. J. Lancet, 1970, ii, 1189. Burch, P. R. J. Proc. R. Soc. B, 1965, 162, 223. Burch, P. R. J. in Radiation and Ageing (edited by P. J. Lindop and G. A. Sacher); p. 117. London, 1966.
752 NUMBERS OF FILMS USED IN VARIOUS OBSTETRIC X-RAY EXAMINATIONS IN DIFFERENT TYPES OF HOSPITAL FROM OXFORD SURVEY OF CHILDHOOD CANCERS)
(DATA
*
Including G.P. hospitals and local-authority clinics.
t Pyelograms, barium meals, and cholecystograms.
opportunity to study abortive cancer initiations, because, judging by the frequency of minor infections and trivial injuries, abortive cancer initiations could be commoner in the middle of the lifespan than at either extreme. In short, the Burch theory not only runs counter to one of the most important laws of natural selection, but it also rests on the dubious assumption that there are funda-
Age-specific death-rates from stated causes in England and Wales, 1968 (rates on logarithmic scale).
(1) (2) (3) (4) (5) (6)
All
causes (per 100,000). Neoplasms (I.C.D. 140-239) (per 1,000,000). Pneumonia (r.C.D. 480-486) (per 1,000,000). Digestive diseases (I.C.D. 520-577) (per 1,000,000). Cardiovascular (r.C.D. 390 458) (per 1,000,000). Neurological (r.C.D. 320-389) (per 1,000,000).
mental differences between cancers and other diseases. Needless to say, there are differences, but most of them are traceable to our ignorance of the precise nature of cancer initiators and initiations (though we suspect mutagens and viruses of causing somatic mutations), to our inability to recognise abortive initiations (though we are beginning to suspect that cancers in situ do not have the same sinister significance as clinically recognisable tumours), and to difficulty in distinguishing between tissues which are premalignant in the sense that they are making it probable that promotion will follow initiation (e.g., suffering from’ senile or presenile changes) and ones which are premalignant in the sense that they are actually harbouring a successful growth (though data from the Oxford Survey suggest that intervals between initiation and the onset of symptoms are less variable than is often supposed 4). Meanwhile we have only to rid ourselves of the idea that neoplastic processes are fundamentally different from other pathological processes to realise that we already know enough about the epidemiology of cancers in general and juvenile cancers in particular to regard the following suggestions as reasonable working hypotheses. First, that in order to be recognised as a carcinogen in human beings a tissue poison must have had an opportunity to inflict lasting damage on (i) a particular set of tissues and (ii) a sufficiently large population for doctors to recognise that there has been a selective increase in cancer promotion as well as cancer initiation risks. Secondly, that, in their role as carcinogens, tissue poisons not only have dosedependent, tissue-dependent, and age-dependent effects, but also effects which reflect relationships between the affected tissue and the environment; for example, indigenous infections would be expected to affect the frequency and manifestations of hamiopoietic neoplasms more than other tumours. Thirdly, that the exceptionally early origins of juvenile cancers4 may be a sign that, towards the end of their relatively short lifespans, embryonic tissues offer the same favourable opportunities for mutant cells to multiply as adult tissues offer towards the end of their relatively long lifespans-i.e., that it is the age of a tissue, not the age of an individual, which determines cancer liability. Department of Social Medicine, Oxford University. 4.
ALICE STEWART.
Stewart, A. M., Kneale, G. W. Lancet, 1970, ii, 4.
predisposed These
to
areas
Atherosclerosis Research Unit of the Organisation for Health Research TNO, Gaubius Institute of the
University of Leiden, Leiden, Netherlands.
SIR,-In May, 1969, we started using general anaesthesia for bone-marrow aspiration and other manoeuvres in a leukaemia clinic. Eight to ten of the children attending the clinic each week need a bone-marrow biopsy, lumbar puncture, or both. For all these children the tests need to be repeated at regular intervals; and we started using general anxsthesia because of the difficulties of sedating outpatients. Since changing to general anaesthesia we have been impressed by the rapidity, coupled with safety, with which the clinic can be conducted. Our outpatient department is situated in the middle of Manchester, six miles away from the hospital, and so the clinic is conducted on the ward where all the cases are usually admitted. Staff nurses have been specially appointed for helping in the clinic. The ward is a large Nightingale ward of 28 beds. The children come to the hospital having had no breakfast. In a side-ward, anaesthesia is induced by an aneesthetist with intravenous methohexitone, given through a 27 gauge Brunswick needle into an anterior wrist vein. It is necessary to give a larger dose, weight for weight, than is used in adults, and the usual dose given is 2-2-5 mg. per kg. Aspiration of bone-marrow, lumbar puncture, intravenous injection, and so on is rapidly completed, with all the advantages of having the patient unconscious. For the longer manoeuvres it is necessary to supplement anaesthesia with nitrous oxide, oxygen, and halothane. When the test is completed, the patient is wheeled out on the trolley into the open ward, where he recovers consciousness within a few minutes under the supervision of a staff nurse. Minutes later he is eating breakfast or lunch. So far we have managed treatment in this way on 911 occasions. Our patients are most commonly aged between two and five years. The children much prefer it: so do their parents. Because the patient is still, the hxmatologist can insert the needle easily and aspirate a good sample of marrow, with corresponding improvement in the quality of the films. Eight to ten bone-marrows, &c., are completed in an hour. We have had no complications. We would like to express our gratitude to Sister B. Jenkinson for her able cooperation. D. 1. K. E. acknowledges grants from the Medical Research Council and Leukxmia Research Fund. P. M. J. is supported by a grant from the Wigan and District Cancer Research Committee.
Manchester M27 1HA.
SIR,-Dr. Berkeley’s letter (Jan. 30, p. 241) is misleading about B.C.G. policy in Glasgow. Contact vaccination was started in Glasgow in 1950 and infant vaccination in 1952, when some 10% of infants were vaccinated. This coverage gradually increased to around 50% in 1960 and 70% in the past 3 years. Vaccination of 13-year-olds commenced in 1953, and the proportion of this age vaccinated has been higher than of infants. Parental consent is as high as 97% and, after tuberculin testing, some 11,000 schoolchildren are vaccinated each year. Health Department, Glasgow. JOHN CLARK.
C. PRIES F. B. KLYNSTRA.
OUTPATIENT ANÆSTHESIA FOR A CHILDREN’S LEUKÆMIA CLINIC
Royal Manchester Children’s Hospital, Pendlebury,
B.C.G. VACCINATION AND LEUKÆMIA MORTALITY
D. I. K. EVANS P. MORRIS JONES P. MORRIS E. A. SHAW.
PRENATAL RADIATION EXPOSURE AND CHILDHOOD CANCER
SIR,-Obstetric X-rays are ordered by doctors who have no say in how many films will be taken, and are taken by technicians who follow procedures originally recommended by a consortium of radiologists but sufficiently flexible to allow certain types of hospital to be slightly more lavish in their use of films than others (see accompanying table). It is therefore difficult to take seriously Professor Burch’s suggestion (Jan. 2, p. 43) that differences in film numbers are connected with differences in predispositions to bear a child who subsequently dies from a malignant disease. The Oxford Survey of Childhood Cancers, which made it possible to relate types of hospital and numbers of films, has been cited by Professor Burch in support of his ideas about the origins of juvenile cancers.1 So I should like to explain why theories of disease causation which are based solely on age-specific incidence-curves are apt to be misleading. Professor Burch’s theory belongs to this category, and offers us an elaborate explanation of why the risk of developing malignant diseases decreases with age during childhood and adolescence, and subsequently increases with the fifth or sixth power of age.Since, however, this sequence of events is typical of all causes of death, all that needs to be said is that, irrespective of their cause and nature, all pathological processes prove most harmful towards the end of the lifespan and least harmful during the prime of life (see accompanying figure). Professor Burch has not made the mistake of assuming that the so-called power-law relationship between age and incidence is unique to cancers.But, instead of regarding the non-specificity as a sign that age has a more powerful effect on the consequences of disease processes than on their causes, he offers it as proof that the process whereby normal cells are converted into malignant cells (cancer initiation) is steeply age-dependent, and totally ignores the possibility that the age-dependence is reflecting not numbers of initiations but proportions of successful initiations, or cancer promotions-i.e., the means whereby sufficient numbers of malignant cells collect to form tumours.
This interpretation of age-specific incidence-rates and mortality-rates is the reverse of what one would expect if the power-law relationships are a sign that the limited lifespan of human beings is guaranteed, not by making contacts with noxious influences increasingly probable as age advances, but by making tissues increasingly vulnerable to their effects. Presumably Professor Burch would not 1. 2. 3.
have drawn the
same
conclusions if he had had the
Burch, P. R. J. Lancet, 1970, ii, 1189. Burch, P. R. J. Proc. R. Soc. B, 1965, 162, 223. Burch, P. R. J. in Radiation and Ageing (edited by P. J. Lindop and G. A. Sacher); p. 117. London, 1966.
752 NUMBERS OF FILMS USED IN VARIOUS OBSTETRIC X-RAY EXAMINATIONS IN DIFFERENT TYPES OF HOSPITAL FROM OXFORD SURVEY OF CHILDHOOD CANCERS)
(DATA
*
Including G.P. hospitals and local-authority clinics.
t Pyelograms, barium meals, and cholecystograms.
opportunity to study abortive cancer initiations, because, judging by the frequency of minor infections and trivial injuries, abortive cancer initiations could be commoner in the middle of the lifespan than at either extreme. In short, the Burch theory not only runs counter to one of the most important laws of natural selection, but it also rests on the dubious assumption that there are funda-
Age-specific death-rates from stated causes in England and Wales, 1968 (rates on logarithmic scale).
(1) (2) (3) (4) (5) (6)
All
causes (per 100,000). Neoplasms (I.C.D. 140-239) (per 1,000,000). Pneumonia (r.C.D. 480-486) (per 1,000,000). Digestive diseases (I.C.D. 520-577) (per 1,000,000). Cardiovascular (r.C.D. 390 458) (per 1,000,000). Neurological (r.C.D. 320-389) (per 1,000,000).
mental differences between cancers and other diseases. Needless to say, there are differences, but most of them are traceable to our ignorance of the precise nature of cancer initiators and initiations (though we suspect mutagens and viruses of causing somatic mutations), to our inability to recognise abortive initiations (though we are beginning to suspect that cancers in situ do not have the same sinister significance as clinically recognisable tumours), and to difficulty in distinguishing between tissues which are premalignant in the sense that they are making it probable that promotion will follow initiation (e.g., suffering from’ senile or presenile changes) and ones which are premalignant in the sense that they are actually harbouring a successful growth (though data from the Oxford Survey suggest that intervals between initiation and the onset of symptoms are less variable than is often supposed 4). Meanwhile we have only to rid ourselves of the idea that neoplastic processes are fundamentally different from other pathological processes to realise that we already know enough about the epidemiology of cancers in general and juvenile cancers in particular to regard the following suggestions as reasonable working hypotheses. First, that in order to be recognised as a carcinogen in human beings a tissue poison must have had an opportunity to inflict lasting damage on (i) a particular set of tissues and (ii) a sufficiently large population for doctors to recognise that there has been a selective increase in cancer promotion as well as cancer initiation risks. Secondly, that, in their role as carcinogens, tissue poisons not only have dosedependent, tissue-dependent, and age-dependent effects, but also effects which reflect relationships between the affected tissue and the environment; for example, indigenous infections would be expected to affect the frequency and manifestations of hamiopoietic neoplasms more than other tumours. Thirdly, that the exceptionally early origins of juvenile cancers4 may be a sign that, towards the end of their relatively short lifespans, embryonic tissues offer the same favourable opportunities for mutant cells to multiply as adult tissues offer towards the end of their relatively long lifespans-i.e., that it is the age of a tissue, not the age of an individual, which determines cancer liability. Department of Social Medicine, Oxford University. 4.
ALICE STEWART.
Stewart, A. M., Kneale, G. W. Lancet, 1970, ii, 4.