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MATERNAL DIAGNOSTIC X-IRRADIATION BEFORE CONCEPTION AND THE FREQUENCY OF MONGOLISM IN CHILDREN SUBSEQUENTLY BORN
1335
high-fat milk (1610 F), which ml., did not stress the fatmechanism sufficiently. The findings absorbing that the hypocalcæmic action of cow’s milk suggest be avoided by the addition of calcium, although might in a milk of high mineral content. would result this
possible
that the
contained 2-9 g. per 100
We thank Glaxo Laboratories Ltd. for their support and for the
experimental milk formulx. Mrs. E. Bates measured the calcium and phosphorus concentrations. Miss M. Driscoll, Miss C. Copland, and Miss F. Hickson assisted in obtaining specimens and with the statistical analyses. We thank the medical and nursing staff of the obstetric unit for their collaboration. D. B. is
a
Wellcome senior research fellow in clinical science.
Requests for reprints should be addressed
to
T. E. O.
REFERENCES 1. 2. 3. 4. 5.
6. 7. 8. 9. 10.
11. 12.
T. E.,
Oppé, Lancet, 1968, i, 1045. Widdowson, Physns, 1969, 3, 285. Willis, J. B. Spectrochim. Acta, 1960, 16, 259. Delsal, J. L., Manhouri, H. Bull. Soc. Chim. biol. 1958, 40, 1623. Sobel, A. E., Rockenmacher, M., Kramer, B. J. biol. Chem. 1945 159, 159. McClure, F. J., McCann, H. G. Archs oral. Biol. 1960, 2, 151. Clark, I. Am. J. Physiol. 1969, 217, 865. Smith, D. A., Nordin, B. E. C. Clin. Sci. 1964, 26, 479. Widdowson, E. M., McCance, R. A., Harrison, G. E., Sutton, A. Lancet, 1963, ii, 1250. Copp, D. H., Kuczerpa, A. V. in Calcitonin: Proceedings of the Symposium on Thyrocalcitonin and the C Cells (edited by S. Taylor); p. 18. London, 1968. Gruden, N., Rabadija, L., Kostial, K. Arch. Hig. Rada, 1968, 19, 25. McCance, R. A., Widdowson, E. M. Spec. Rep. Ser. med. Res. Coun. Redstone, D. R. E. M. Jl R. Coll.
1967, no. 297.
MATERNAL DIAGNOSTIC X-IRRADIATION BEFORE CONCEPTION AND THE
FREQUENCY OF MONGOLISM IN SUBSEQUENTLY BORN
CHILDREN
ALAN C. STEVENSON RITA MASON
KATHLEEN D. EDWARDS
Population Genetics Unit, Oxford
Medical Research Council
Follow-up of 1052 children born to mothers who had X-ray investigations involving doses to ovaries before conception showed that 3 children had Down’s syndrome. It is estimated that this number is not significantly different from that which would be expected when the high proportion of older mothers in the study is taken into account. This study does not seem to support a hypothesis that X-ray diagnostic procedures before conception increase the frequency of mongolism in children subsequently Sum ary
born. Introduction
FROM time to time it has been suggested that relasmall X-ray exposures of the gonads of women cause an increase in the frequency of mongolism in offspring subsequently conceived. Uchida and Curtis1 compared the results of questioning three groups of mothers, matched for maternal age, about previous X-ray exposures of abdomen and pelvis before conception. The first group of mothers had had children with Down’s syndrome, the second with cleft palate and/or hare-lip, and the third were neighbours of the first group. A significantly higher proportion of the mothers with mongol children appeared to have had
tively
four or more X-ray exposures or fluoroscopy of the abdomen and pelvis. Lunn had not found any such association in the study of 117 mothers of mongol children and matched controls; Schull and Neel3 pointed out that there was no suggestion of such an effect in mothers previously exposed to ionising radiation in Hiroshima and Nagasaki; and Carter et al.could find no evidence from questioning 50 mothers of mongols and controls that the former had had more X-ray exposure. The findings of Stevenson and Matousek5 from questioning 197 mothers of mongols and controls similarly failed to reveal any differences in previous X-ray exposure. However, Sigler et al.in comparing the preconception radiation history of 216 mothers of mongols and controls, matched for maternal age, interpreted their findings as showing that although there was no difference in the X-ray radiographic history in the two groups of mothers, mothers of mongols had had a significantly increased exposure to both fluoroscopic and therapeutic irradiation. However, the numbers were small, so perhaps the data are not
altogether convincing.
Uchida et al. tried to minimise the difficulty of maternal recollections of X-ray by identifying women who had had X-ray exposures of the abdomen and pelvis in a large hospital in Winnipeg between 1956 and 1959. Starting in 1964, they attempted to follow these women to collect information about subsequent births and further X-ray exposures. For controls matched for maternal age they used children born to these women before abdominal irradiation, but because they found themselves short of control mothers of high maternal age they had to derive some further subjects from the X-ray registers for the years 1960 to 1964. Instead of using as controls all the children conceived before X-ray exposure of the mothers, they attempted to match each mother of a mongol from available controls by maternal age at the time of birth of a child. In so doing, however, they excluded a number of mongols. It must have been difficult to be objective because, as the authors say, they already knew virtually all the mongol children in the area. They finally identified 524 mothers who had had in all 972 children conceived after irradiation (table i). Of these 972 children 8 were mongols. In addition, 2 were trisomic for chromosome 18, and 1 had a structural chromosome abnormality, but in the present context these 3 will be ignored since it is not stated how many children with abnormalities other than clinical mongolism had their chromosomes tested in the exposed and control groups Only 1 mongol (and 1 XXY child) were born to the control mothers. The mother of the mongol child in the control series was in the 35-39 age-group. Uchida and her colleagues give tentative gonadal doses in millirads for the various procedures. The mothers who had post-conception mongols were estimated to have had between 650 and 12,600 mrads, with a mean of 3250 mrads, compared with a mean of about 1400 mrads for all mothers. These results, showing a frequency in children of irradiated mothers eight times that in controls, are very striking and possibly unexpected in view of what is known of
1336
dose/effect relationships in the induction of aneuploidy in Drosophila and of the induction of sex-chromosome monosomy by irradiation of late germ-cell stages in female mice. Further, there is no evidence that trisomy has ever been induced in mammals by irradiation of mothers. In view of the findings of Uchida took a comparable study in Oxford.
et
al.7
we
TABLE II-DISTRIBUTION OF NUMBERS OF PRECONCEPTION
PROCEDURES AND ESTIMATED DOSES
under-
Ascertainment who had had salpingograms for the investiof infertility and women aged 15-40 whose names gation appeared on the X-ray registers as having had specified examinations were investigated. Of 3267 women ascertained, 1284 could not be traced, and 436 were not interviewed because they were widowed, divorced, or mentally ill, or because they had been sterilised. The remaining 1547 were questioned (1519 by personal interview, 28 by letter) about their children and X-ray exposure, the latter being checked by search of hospital records or postal inquiries to hospitals. Only 645 mothers yielded information about children conceived after irradiation (902 had not conceived since X-ray examination). However, this compares favourable with the Winnipeg study, in which 524 of 6062 mothers were interviewed. The Oxford X-ray records did not give addresses of patients or indicate whether or not they were married, and in only a minority was the hospital number recorded. As a result, the tracing of clinical records was very difficult. On average, each year of the X-ray registers yielded fewer than 5 children born to mothers aged 40 or over, and of 595 mothers (who had had 968 children) only 42 had had children at the age of 40 or over. Accordingly we identified all mothers in this age-group whose children had been born in the United Oxford Hospitals in the years 1967-69. In this way we found 35 mothers who had not already been identified and visited. They had in all 84 post-irradiation children, including 35 born when they were aged 40 or over. All
women
Findings The Oxford data on births after preconception maternal irradiation are shown in table I. 3 children had Down’s syndrome (all trisomy 21). The comparable data reported from Winnipeg are included in the table. 2 children in the Oxford series had recessive gene traits (1 fibrocystic disease, 1 tyrosinosis), 1 had TABLE I-NUMBERS OF BIRTHS, wIONGOL BIRTHS, AND AGES OF MOTHERS WHO HAD CHILDREN BORN AFTER PRECONCEPTION X-RAY EXPOSURE
D-group trisomy, and
16 had common congenital abnormalities known not to be determined at a single locus or by a detectable chromosomal aberration. There were 14 stillbirths among 1052 births. Table II shows the numbers and types of X-ray procedures experienced by women in the Oxford study before conception and also estimated dosages in millirads for each procedure. These estimates are taken from the Report on Radiological Hazards to Patients9 (the Adrian report). The dosage includes that from all films taken. The estimates used by Uchida and her colleagues are also given in table 11. We did not follow up women who had gallbladder X-rays or barium meals without follow-through, since it was felt that the shielding used in these procedures would permit only minute scatter to the ovaries. Also there were various procedures such as placentograms and myelograms used in Winnipeg which were not encountered in the Oxford X-ray records. The mothers of the 3 children with Down’s syndrome all had a single excretion-urography investigation and no other X-ray examinations before conception. Discussion
"
Expectation " based on data quoted by Penrose and Smithfor frequency of mongols born to mothers of different ages. Figures seem to be applicable all over the world. These frequencies are: 0
Maternal age
20-} 25-
1/1600
3035-
40+
1/880 1/290 1/95
Although this study was similar to that in Winnipeg there are difficulties in comparing the findings. Fewer subjects originally ascertained were untraced in Oxford, but the proportion traced is still rather low. The problems of estimating the energy absorbed by ovaries from abdominal and pelvic X-ray exposures are well known. The estimates for various procedures in Winnipeg are higher than those estimated in the Adrian report, and procedures in Oxford probably result in smaller gonadal doses than those quoted from that report. The Oxford data are rather loaded by salpingograms because of ease of ascertainment of these investigations. Some procedures encountered in Toronto
were not used in Oxford, and some procedures scored as giving gonadal exposure in Toronto were ignored in Oxford.
1337 the mean gonadal dosage before conthe children recorded in Toronto appears of ception to have been about 1400 mrads, whereas in Oxford it The mean interval between was about 900 mrads. X-ray exposure and conception in Oxford was 40 months ±35 months. However, the mean interval between the last exposure and conception was about The interval between irradiation and 31 months. conception in Winnipeg can be estimated from the data as about 25 months, but it is not clear whether this is the time from the last exposure or the mean interval between all exposures and conception. It is difficult to compare the two sets of data. At face value the Winnipeg figure suggests that 1 or 2 rads increase the frequency of mongolism in offspring conceived thereafter by a factor of between four and eight. Such a suggestion is not supported by the Oxford data. Neither in this type of study nor in retrospective studies can the possibility of serious biases be excluded. When such a high proportion of women ascertained are not interviewed the possibility of some undetected bias is worrying. In retrospective studies there is the possibility that mothers with abnormal children remember their X-ray history better than mothers who had normal children. However, even in the present type of study, which Uchida terms " prospective ", the mother’s memory has to be assumed to be correct except for the exposures by which she was ascertained. These difficulties, together with the usual ones of the significances of differences between small proportions where the total number of characterised individuals (i.e., mongols in this study) is small, make it impossible to be dogmatic. All that can be said is that this study does not support a hypothesis that small doses of preconceptional irradiation increase the probability that mothers would have children with mongolism. It seems likely that such an effect, if there is one, will only be detected by long-term studies, perhaps those made possible by recordAs
assessed,
linkage techniques. We are indebted to Dr. G. M. Ardran, who stimulated us to undertake this study, and Dr. F. H. Kemp, both of the department of radiology, United Oxford Hospitals, who made all their records available to us. It would have been impossible to carry out this study without continued help from Mr. J. Davies, Mrs. N. Knott, and their colleagues in the records department of the United Oxford Hospitals. We never failed to have full cooperation from the many general practitioners in the Oxford district whose permission we sought to visit their patients. Dr. J. A. Baldwin, of the Oxford Record Linkage Unit, was good enough to identify for us the mothers over 40 who had children in 1967-69. Finally, we are most grateful to Mr. D. Golding, of the statistical unit of the Oxford Regional Hospital Board, for arranging the card-punching and tabulations of the data. Requests for reprints should be addressed to A. C. S., M.R.C. Population Genetics Research Unit, Old Road, Headington, Oxford OX3 7LE. REFERENCES 1. 2. 3. 4. 5.
Uchida, I. A., Curtis, E. J. Lancet, 1961, ii, 848. Lunn, J. E. Scott. med. J. 1959, 4, 368. Schull, W. J., Neel, J. V. Lancet, 1962, i, 537. Carter, C. O., Evans, K. A., Stewart, A. M. ibid. 1962, ii, 1042. Stevenson, A. C., Matousek, V. U.N. Document A/A8/82/6/L.700,
6.
Sigler,
1965. A. T., Lilienfeld, A. M., Cohen, B. H., Westlake, J. E. Bull. Johns Hopkins Hosp. 1965, 117, 374. 7. Uchida, I. A., Holunga, R., Lawler, C. Lancet, 1968, ii, 1045. 8. Penrose, L. S., Smith, G. F. Down’s Anomaly. London, 1966. 9. Radiological Hazards to Patients. 2nd Report 1960. Ministry of Health, Department of Health for Scotland. H.M. Stationery Office, London.
Preliminary
Communications
LYMPHOCYTE SENSITISATION: AN IN-VITRO TEST FOR CANCER ? E. T. FIELD
E. A. CASPARY
Medical Research Council Demyelinating Diseases Unit, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE
Blood-lymphocytes of patients with a malignant neoplasm (even in its earliest stages) are sensitised to basic proteins derived from both the central and peripheral nervous system. This sensitisation is independent of the nature of the malignant tumour but does not occur with benign neoplasms. The sensitisation is independent of clinical signs of (non-metastatic) involvement of the nervous system and persists for many years after successful surgical treatment of the neoplasm. If certain clearly defined limitations are observed, this lymphocyte sensitisation could be employed as a diagnostic or screening procedure. The significance of the sensitisation is Summary
not
clear. INTRODUCTION
BLOOD-LYMPHOCYTES become sensitised to central and peripheral nervous-system protein in a variety of neurological diseases where there is destruction of
parenchyma.1 The proteins to which such sensitivity occurs encephalitogenic factor (E.F.)-a basic protein
nervous
are
of histone-like nature derived from human brain 2-and a basic protein derived from human sciatic nerve (S.N.B.P.). When injected together with Freund’s adjuvant into guineapigs the E.F. readily produces allergic encephalitis, and the s.N.B.P. allergic neuritis. Using these antigens a study was undertaken of patients with carcinomatous neuropathy or signs of cerebellar degeneration. Whilst sensitisation was anticipated in these cases, its occurrence in all patients
harbouring a malignant neoplasm was quite unexpected. We present here our preliminary observations and offer some tentative interpretation. MATERIAL AND METHODS
patients were examined, of whom 53 had known malignant neoplasms-3 carcinoma of stomach (1 with neuropathy); 15 carcinoma of bronchus (1 with neuropathy) ; 6 carcinoma of breast; 2 carcinoma of oesophagus; 1 mesothelioma of lung; 2 carcinoma of kidney; 5 carcinoma of bladder; 1 carcinoma of pancreas; 1 carcinoma of rectum; 3 rodent ulcers of face; 7 carcinoma of cervix (5 in situ); 1 carcinoma of thyroid; 1 neuroblastoma; 1 sarcoma botryoides of vulva; 3 anterior exenteration and 1 total exenteration (4, 5, 9, and 21 years ago respectively but now well). The remaining 3 patients were suspected of harbouring a carcinoma. 4 patients had neuropathy-2 with definite carcinoma (1 of bronchus, 1 of stomach, and 2 with suspected carcinoma). 3 had cerebellar degeneration: 1 had had a carcinoma of cervix removed 3 years previously; the other 2 were suspected carcinoma cases (table I). As controls, 38 normal subjects were studied (table III) and 12 with simple (benign) tumours (table II). Of the 56
high-fat milk (1610 F), which ml., did not stress the fatmechanism sufficiently. The findings absorbing that the hypocalcæmic action of cow’s milk suggest be avoided by the addition of calcium, although might in a milk of high mineral content. would result this
possible
that the
contained 2-9 g. per 100
We thank Glaxo Laboratories Ltd. for their support and for the
experimental milk formulx. Mrs. E. Bates measured the calcium and phosphorus concentrations. Miss M. Driscoll, Miss C. Copland, and Miss F. Hickson assisted in obtaining specimens and with the statistical analyses. We thank the medical and nursing staff of the obstetric unit for their collaboration. D. B. is
a
Wellcome senior research fellow in clinical science.
Requests for reprints should be addressed
to
T. E. O.
REFERENCES 1. 2. 3. 4. 5.
6. 7. 8. 9. 10.
11. 12.
T. E.,
Oppé, Lancet, 1968, i, 1045. Widdowson, Physns, 1969, 3, 285. Willis, J. B. Spectrochim. Acta, 1960, 16, 259. Delsal, J. L., Manhouri, H. Bull. Soc. Chim. biol. 1958, 40, 1623. Sobel, A. E., Rockenmacher, M., Kramer, B. J. biol. Chem. 1945 159, 159. McClure, F. J., McCann, H. G. Archs oral. Biol. 1960, 2, 151. Clark, I. Am. J. Physiol. 1969, 217, 865. Smith, D. A., Nordin, B. E. C. Clin. Sci. 1964, 26, 479. Widdowson, E. M., McCance, R. A., Harrison, G. E., Sutton, A. Lancet, 1963, ii, 1250. Copp, D. H., Kuczerpa, A. V. in Calcitonin: Proceedings of the Symposium on Thyrocalcitonin and the C Cells (edited by S. Taylor); p. 18. London, 1968. Gruden, N., Rabadija, L., Kostial, K. Arch. Hig. Rada, 1968, 19, 25. McCance, R. A., Widdowson, E. M. Spec. Rep. Ser. med. Res. Coun. Redstone, D. R. E. M. Jl R. Coll.
1967, no. 297.
MATERNAL DIAGNOSTIC X-IRRADIATION BEFORE CONCEPTION AND THE
FREQUENCY OF MONGOLISM IN SUBSEQUENTLY BORN
CHILDREN
ALAN C. STEVENSON RITA MASON
KATHLEEN D. EDWARDS
Population Genetics Unit, Oxford
Medical Research Council
Follow-up of 1052 children born to mothers who had X-ray investigations involving doses to ovaries before conception showed that 3 children had Down’s syndrome. It is estimated that this number is not significantly different from that which would be expected when the high proportion of older mothers in the study is taken into account. This study does not seem to support a hypothesis that X-ray diagnostic procedures before conception increase the frequency of mongolism in children subsequently Sum ary
born. Introduction
FROM time to time it has been suggested that relasmall X-ray exposures of the gonads of women cause an increase in the frequency of mongolism in offspring subsequently conceived. Uchida and Curtis1 compared the results of questioning three groups of mothers, matched for maternal age, about previous X-ray exposures of abdomen and pelvis before conception. The first group of mothers had had children with Down’s syndrome, the second with cleft palate and/or hare-lip, and the third were neighbours of the first group. A significantly higher proportion of the mothers with mongol children appeared to have had
tively
four or more X-ray exposures or fluoroscopy of the abdomen and pelvis. Lunn had not found any such association in the study of 117 mothers of mongol children and matched controls; Schull and Neel3 pointed out that there was no suggestion of such an effect in mothers previously exposed to ionising radiation in Hiroshima and Nagasaki; and Carter et al.could find no evidence from questioning 50 mothers of mongols and controls that the former had had more X-ray exposure. The findings of Stevenson and Matousek5 from questioning 197 mothers of mongols and controls similarly failed to reveal any differences in previous X-ray exposure. However, Sigler et al.in comparing the preconception radiation history of 216 mothers of mongols and controls, matched for maternal age, interpreted their findings as showing that although there was no difference in the X-ray radiographic history in the two groups of mothers, mothers of mongols had had a significantly increased exposure to both fluoroscopic and therapeutic irradiation. However, the numbers were small, so perhaps the data are not
altogether convincing.
Uchida et al. tried to minimise the difficulty of maternal recollections of X-ray by identifying women who had had X-ray exposures of the abdomen and pelvis in a large hospital in Winnipeg between 1956 and 1959. Starting in 1964, they attempted to follow these women to collect information about subsequent births and further X-ray exposures. For controls matched for maternal age they used children born to these women before abdominal irradiation, but because they found themselves short of control mothers of high maternal age they had to derive some further subjects from the X-ray registers for the years 1960 to 1964. Instead of using as controls all the children conceived before X-ray exposure of the mothers, they attempted to match each mother of a mongol from available controls by maternal age at the time of birth of a child. In so doing, however, they excluded a number of mongols. It must have been difficult to be objective because, as the authors say, they already knew virtually all the mongol children in the area. They finally identified 524 mothers who had had in all 972 children conceived after irradiation (table i). Of these 972 children 8 were mongols. In addition, 2 were trisomic for chromosome 18, and 1 had a structural chromosome abnormality, but in the present context these 3 will be ignored since it is not stated how many children with abnormalities other than clinical mongolism had their chromosomes tested in the exposed and control groups Only 1 mongol (and 1 XXY child) were born to the control mothers. The mother of the mongol child in the control series was in the 35-39 age-group. Uchida and her colleagues give tentative gonadal doses in millirads for the various procedures. The mothers who had post-conception mongols were estimated to have had between 650 and 12,600 mrads, with a mean of 3250 mrads, compared with a mean of about 1400 mrads for all mothers. These results, showing a frequency in children of irradiated mothers eight times that in controls, are very striking and possibly unexpected in view of what is known of
1336
dose/effect relationships in the induction of aneuploidy in Drosophila and of the induction of sex-chromosome monosomy by irradiation of late germ-cell stages in female mice. Further, there is no evidence that trisomy has ever been induced in mammals by irradiation of mothers. In view of the findings of Uchida took a comparable study in Oxford.
et
al.7
we
TABLE II-DISTRIBUTION OF NUMBERS OF PRECONCEPTION
PROCEDURES AND ESTIMATED DOSES
under-
Ascertainment who had had salpingograms for the investiof infertility and women aged 15-40 whose names gation appeared on the X-ray registers as having had specified examinations were investigated. Of 3267 women ascertained, 1284 could not be traced, and 436 were not interviewed because they were widowed, divorced, or mentally ill, or because they had been sterilised. The remaining 1547 were questioned (1519 by personal interview, 28 by letter) about their children and X-ray exposure, the latter being checked by search of hospital records or postal inquiries to hospitals. Only 645 mothers yielded information about children conceived after irradiation (902 had not conceived since X-ray examination). However, this compares favourable with the Winnipeg study, in which 524 of 6062 mothers were interviewed. The Oxford X-ray records did not give addresses of patients or indicate whether or not they were married, and in only a minority was the hospital number recorded. As a result, the tracing of clinical records was very difficult. On average, each year of the X-ray registers yielded fewer than 5 children born to mothers aged 40 or over, and of 595 mothers (who had had 968 children) only 42 had had children at the age of 40 or over. Accordingly we identified all mothers in this age-group whose children had been born in the United Oxford Hospitals in the years 1967-69. In this way we found 35 mothers who had not already been identified and visited. They had in all 84 post-irradiation children, including 35 born when they were aged 40 or over. All
women
Findings The Oxford data on births after preconception maternal irradiation are shown in table I. 3 children had Down’s syndrome (all trisomy 21). The comparable data reported from Winnipeg are included in the table. 2 children in the Oxford series had recessive gene traits (1 fibrocystic disease, 1 tyrosinosis), 1 had TABLE I-NUMBERS OF BIRTHS, wIONGOL BIRTHS, AND AGES OF MOTHERS WHO HAD CHILDREN BORN AFTER PRECONCEPTION X-RAY EXPOSURE
D-group trisomy, and
16 had common congenital abnormalities known not to be determined at a single locus or by a detectable chromosomal aberration. There were 14 stillbirths among 1052 births. Table II shows the numbers and types of X-ray procedures experienced by women in the Oxford study before conception and also estimated dosages in millirads for each procedure. These estimates are taken from the Report on Radiological Hazards to Patients9 (the Adrian report). The dosage includes that from all films taken. The estimates used by Uchida and her colleagues are also given in table 11. We did not follow up women who had gallbladder X-rays or barium meals without follow-through, since it was felt that the shielding used in these procedures would permit only minute scatter to the ovaries. Also there were various procedures such as placentograms and myelograms used in Winnipeg which were not encountered in the Oxford X-ray records. The mothers of the 3 children with Down’s syndrome all had a single excretion-urography investigation and no other X-ray examinations before conception. Discussion
"
Expectation " based on data quoted by Penrose and Smithfor frequency of mongols born to mothers of different ages. Figures seem to be applicable all over the world. These frequencies are: 0
Maternal age
20-} 25-
1/1600
3035-
40+
1/880 1/290 1/95
Although this study was similar to that in Winnipeg there are difficulties in comparing the findings. Fewer subjects originally ascertained were untraced in Oxford, but the proportion traced is still rather low. The problems of estimating the energy absorbed by ovaries from abdominal and pelvic X-ray exposures are well known. The estimates for various procedures in Winnipeg are higher than those estimated in the Adrian report, and procedures in Oxford probably result in smaller gonadal doses than those quoted from that report. The Oxford data are rather loaded by salpingograms because of ease of ascertainment of these investigations. Some procedures encountered in Toronto
were not used in Oxford, and some procedures scored as giving gonadal exposure in Toronto were ignored in Oxford.
1337 the mean gonadal dosage before conthe children recorded in Toronto appears of ception to have been about 1400 mrads, whereas in Oxford it The mean interval between was about 900 mrads. X-ray exposure and conception in Oxford was 40 months ±35 months. However, the mean interval between the last exposure and conception was about The interval between irradiation and 31 months. conception in Winnipeg can be estimated from the data as about 25 months, but it is not clear whether this is the time from the last exposure or the mean interval between all exposures and conception. It is difficult to compare the two sets of data. At face value the Winnipeg figure suggests that 1 or 2 rads increase the frequency of mongolism in offspring conceived thereafter by a factor of between four and eight. Such a suggestion is not supported by the Oxford data. Neither in this type of study nor in retrospective studies can the possibility of serious biases be excluded. When such a high proportion of women ascertained are not interviewed the possibility of some undetected bias is worrying. In retrospective studies there is the possibility that mothers with abnormal children remember their X-ray history better than mothers who had normal children. However, even in the present type of study, which Uchida terms " prospective ", the mother’s memory has to be assumed to be correct except for the exposures by which she was ascertained. These difficulties, together with the usual ones of the significances of differences between small proportions where the total number of characterised individuals (i.e., mongols in this study) is small, make it impossible to be dogmatic. All that can be said is that this study does not support a hypothesis that small doses of preconceptional irradiation increase the probability that mothers would have children with mongolism. It seems likely that such an effect, if there is one, will only be detected by long-term studies, perhaps those made possible by recordAs
assessed,
linkage techniques. We are indebted to Dr. G. M. Ardran, who stimulated us to undertake this study, and Dr. F. H. Kemp, both of the department of radiology, United Oxford Hospitals, who made all their records available to us. It would have been impossible to carry out this study without continued help from Mr. J. Davies, Mrs. N. Knott, and their colleagues in the records department of the United Oxford Hospitals. We never failed to have full cooperation from the many general practitioners in the Oxford district whose permission we sought to visit their patients. Dr. J. A. Baldwin, of the Oxford Record Linkage Unit, was good enough to identify for us the mothers over 40 who had children in 1967-69. Finally, we are most grateful to Mr. D. Golding, of the statistical unit of the Oxford Regional Hospital Board, for arranging the card-punching and tabulations of the data. Requests for reprints should be addressed to A. C. S., M.R.C. Population Genetics Research Unit, Old Road, Headington, Oxford OX3 7LE. REFERENCES 1. 2. 3. 4. 5.
Uchida, I. A., Curtis, E. J. Lancet, 1961, ii, 848. Lunn, J. E. Scott. med. J. 1959, 4, 368. Schull, W. J., Neel, J. V. Lancet, 1962, i, 537. Carter, C. O., Evans, K. A., Stewart, A. M. ibid. 1962, ii, 1042. Stevenson, A. C., Matousek, V. U.N. Document A/A8/82/6/L.700,
6.
Sigler,
1965. A. T., Lilienfeld, A. M., Cohen, B. H., Westlake, J. E. Bull. Johns Hopkins Hosp. 1965, 117, 374. 7. Uchida, I. A., Holunga, R., Lawler, C. Lancet, 1968, ii, 1045. 8. Penrose, L. S., Smith, G. F. Down’s Anomaly. London, 1966. 9. Radiological Hazards to Patients. 2nd Report 1960. Ministry of Health, Department of Health for Scotland. H.M. Stationery Office, London.
Preliminary
Communications
LYMPHOCYTE SENSITISATION: AN IN-VITRO TEST FOR CANCER ? E. T. FIELD
E. A. CASPARY
Medical Research Council Demyelinating Diseases Unit, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE
Blood-lymphocytes of patients with a malignant neoplasm (even in its earliest stages) are sensitised to basic proteins derived from both the central and peripheral nervous system. This sensitisation is independent of the nature of the malignant tumour but does not occur with benign neoplasms. The sensitisation is independent of clinical signs of (non-metastatic) involvement of the nervous system and persists for many years after successful surgical treatment of the neoplasm. If certain clearly defined limitations are observed, this lymphocyte sensitisation could be employed as a diagnostic or screening procedure. The significance of the sensitisation is Summary
not
clear. INTRODUCTION
BLOOD-LYMPHOCYTES become sensitised to central and peripheral nervous-system protein in a variety of neurological diseases where there is destruction of
parenchyma.1 The proteins to which such sensitivity occurs encephalitogenic factor (E.F.)-a basic protein
nervous
are
of histone-like nature derived from human brain 2-and a basic protein derived from human sciatic nerve (S.N.B.P.). When injected together with Freund’s adjuvant into guineapigs the E.F. readily produces allergic encephalitis, and the s.N.B.P. allergic neuritis. Using these antigens a study was undertaken of patients with carcinomatous neuropathy or signs of cerebellar degeneration. Whilst sensitisation was anticipated in these cases, its occurrence in all patients
harbouring a malignant neoplasm was quite unexpected. We present here our preliminary observations and offer some tentative interpretation. MATERIAL AND METHODS
patients were examined, of whom 53 had known malignant neoplasms-3 carcinoma of stomach (1 with neuropathy); 15 carcinoma of bronchus (1 with neuropathy) ; 6 carcinoma of breast; 2 carcinoma of oesophagus; 1 mesothelioma of lung; 2 carcinoma of kidney; 5 carcinoma of bladder; 1 carcinoma of pancreas; 1 carcinoma of rectum; 3 rodent ulcers of face; 7 carcinoma of cervix (5 in situ); 1 carcinoma of thyroid; 1 neuroblastoma; 1 sarcoma botryoides of vulva; 3 anterior exenteration and 1 total exenteration (4, 5, 9, and 21 years ago respectively but now well). The remaining 3 patients were suspected of harbouring a carcinoma. 4 patients had neuropathy-2 with definite carcinoma (1 of bronchus, 1 of stomach, and 2 with suspected carcinoma). 3 had cerebellar degeneration: 1 had had a carcinoma of cervix removed 3 years previously; the other 2 were suspected carcinoma cases (table I). As controls, 38 normal subjects were studied (table III) and 12 with simple (benign) tumours (table II). Of the 56