- Email: [email protected]
TRISOMY AFTER COLCHICINE THERAPY
1160
they could be. I should be interested if Mr. Matthews and Mr. Matthews could confirm my point of view in another study on transplacental haemorrhage with the technique and instruments used in East Europe. S. M. I. DAMSTRA-WIJMENGA.
as
bone of lead inhaled from car exhaust fumes or ingested with food, a high calcium intake might lessen lead-pyruvate formation
myocardium and consequent impairment of efficiency. two accompanying tables from my report to the North Lindsey Water Board compare mortality-rates in Grimsby and Scunthorpe before and after Scunthorpe’s water-supply
in
The
was
THE WATER STORY SIR,-In your leader (May 17, p. 1012) you cite a suggestion of Anderson et aU that the excess mortality in soft" water areas is attributable to sudden " deaths possibly due to fatal arrhythmias following infarction. Crawford et al.,2 however, found almost as strong a correlation with deaths from bronchitis as with deaths from cardiovascular disease. On a much smaller scale, comparisons between the population of Scunthorpe before and after the introduction of artificial water softening illustrates the same point. The observed increase in mortality from all causes of 200 per 100,000 in middle-aged men was only partly due to the rise of 136 in cardiovascular mortality. Almost a third of the excess mortality which followed the introduction of water softening comprised deaths from non-cardiovascular causes. TABLE I-DEATHS FROM ALL CAUSES AT
AGES
45-64
YEARS)
SUPPLY WAS SOFTENED IN
M.R.
(MORTALITY-RATES
BEFORE AND AFTER
PER
SCUNTHORPE’S
100,000 WATER
1959
= mortality-rate.
Details of deaths in 1964-7 derived from forms S.D. 25 issued by General Register Office. Details of deaths in Grimsby 1950-53 provided by the Registrar General. Details of deaths in Scunthorpe 1950-53 compiled from records of Scunthorpe M.B. health department. Population 1950-53 from 1951 Census, and for 1964-67 from 1966 Sample Census. TABLE
II-DEATHS
RATES PER
FROM
I0O,OOO AT
I
softened in 1959. am
indebted
to
the
Registrar General and
Scunthorpe, for the data Public Health Department, Barton-on-Humber,
M.O.H.
Lincs.
upon
to
which these
Dr. S. were
Childs,
compiled.
J. S. ROBERTSON.
TRISOMY AFTER COLCHICINE THERAPY SIR,-I have read with interest the correspondence 1that followed the report of Miss Ferreira and Dr. Buoniconti.3 Should we not consider the genetic make-up of the gouty individual rather than the colchicine as a factor predisposing to
non-disjunction ? There is good evidence
for the non-random occurrence of chromosomal errors in man and several predisposing factors have been suggested, including viral infections and autoimmune states.45 In plants and in Drosophila, mutant genes have been described which cause or predispose to nondisjunction. s ’ There is less evidence of this in man, but a growing number of reports have documented the concurrence of aneuploidy and the homozygous or heterozygous state for inherited metabolic disorders: galactossemia and trisomy-’ 21 ; phenylketonuria and trisomy-D,9 trisomy-21," and XXY 11; acute intermittent porphyria and XXY 12 13; cystinuria and trisomy-21 14 5; and cystic fibrosis of the pancreas and trisomy-21.16 17 Recently, in describing findings in an individual with trisomy-21 who was also heterozygous for the cystinuria gene, we pointed out that the mother of the propositus would not have been identified as heterozygous for this gene had not her trisomic son participated in a screening programme for hereditary aminoacidurias.15 I realise that these associations may be entirely fortuitous, but it is nevertheless important that, in the future, studies should be done for metabolic disorders in parents of subjects with aneuploidy of unknown cause. Department of Pathology, Dartmouth Medical School, Hanover, New Hampshire, U.S.A. 03755.
DICK HOEFNAGEL.
DISEASES (MORTALITY(DERIVED AS IN TABLE I)
CARDIOVASCULAR
AGES
45-64
YEARS)
SIR,-We consider that the finding 18of increased frequency of aneuploid cells in blood-cultures of patients under colchicine therapy is merely suggestive of a possible increased risk for the offspring of such patients. The scepticism of Dr. Walker (Feb. 1, p. 257) about this is only natural, and item (1) of his sketch for an investigation of the reproductive performance of parents with gout coincides almost exactly with a project we have under way. One difficulty in this approach is that probably our These observations are most readily explained by the hypothesis that myocardia of drinkers of soft water are less able to function when oxygen tensions are low than are myocardia of hard-water drinkers. This would apply whether the low oxygen tension were local and due to impaired coronary circulation, or general and due to poor oxygenation in pulmonary disease or poor oxygen transport in anasmia, and would affect deaths from many causes. In addition to the two possible mechanisms mentioned in your excellent review-i.e., poisoning by metals dissolved from pipes by soft water, and the possible direct effect of calcium--one other possibility should be considered. This is that calcium intake may determine the effect of poison from other sources. For example, by expediting the fixation in 1. 2.
Anderson, T. W., Le Riche, W. H., MacKay, J. S. New Engl. J. Med. 1969, 280, 805. Crawford, M. D., Gardner, M. J., Morris, J. N., Lancet, 1968, i, 827.
1. 2. 3. 4. 5. 6. 7. 8.
9. 10. 11. 12. 13. 14. 15. 16. 17. 1.
Walker, F. A. Lancet, 1969, p. 257. Timson, J. ibid. Feb. 15, 1969, p. 370. Ferreira, N. R., Buoniconti, A. ibid. 1968, ii, 1304. Hecht, F., Bryant, J. S., Gruber, D., Townes, P. L. New Engl. J. Med. 1964, 271, 1081. Penrose, L. S., Smith, G. F. Down’s Anomaly. London, 1966. Beadle, G. W. Z. indukt. Abstamm.-u. VererbLehre, 1932, 63, 195. Lewis, E. B., Gencarella, W. Genetics, 1952, 37, 600. Bahrs, B., Ostertag, W. Genetics Today. Proceedings of the XI International Congress of Genetics, The Hague, 1963 (edited by S. J. Geerts); vol. I, p. 289. Oxford, 1963. Atkins, L., Rosenthal, M. K. New Engl. J. Med. 1961, 265, 314. Fisch, R. O., Horrobin, J. M. Clin. Pediat. 1968, 7, 226. Benirschke, K., Brownhill, L., Efron, M. L., Hoefnagel, D. J. ment. Defic. Res. 1962, 6, 44. Hambert, G., Wetterberg, L. Lancet, 1964, ii, 419. Nielsen, J. ibid. 1966, i, 984. Tanguay, R. B., Galindo, J. Am. J. clin. Path. 1966, 46, 442. Hoefnagel, D., Pomeroy, J., Benz, R. J. ment. Defic. Res. 1968, 12, 317. Milunsky, A. Pediatrics, Springfield, 1968, 42, 502. Vetrella, M., Barthemai, W., Matsuda, H. Klin. Wschr. 1969, 47, 333. Ferreira, N. R., Buoniconti, A. Lancet, 1968, ii, 1304.
1161
sample will not be big enough, since a number of patients were not under colchicine treatment at the time they reproduced. Perhaps the results of parallel surveys of patients and matched controls from several big
towns
will have
to
be added up for
analysis. In contrast with the observation of 2 persons under colchicine among 54 parents of Down’s syndrome (D.S.) patients in our laboratory, Dr. Walker did not find any among the parents of 200 D.S. patients. It could be that the two surveys are not perfectly comparable. For one thing, since in Brazil drug stores are required to label fully the medicines they sell, patients know the name of the drugs they are taking. This is not always so in the United States. The incidence of gout in the locality of the survey, the frequency with which doctors prescribe colchicine for gout, and the age-distribution of the parents of the D.S. patients in the samples studied are other variables which might influence the results. Dr. Timson (Feb. 15, p. 370) suggests that the high frequency found in our laboratory of D.S. patients born to parents under colchicine treatment may be due to the relatively high possibility of the two events coinciding by chance. However, gout patients are estimated as 0-5% of all patients in non-specialised clinics, and even in rheumatological clinics they are only about 4%." Dr. Timson’s hypothesis would requireamongthemiddleaged part of the general population a frequency of 3-7% of gout patients under colchicine therapy at the time they reproduced. However, we agree with Dr. Timson that the standard treatment with colchicine of the cultures of both patients and controls accentuated the in-vivo effect of the drug in the patients. Laboratory of Human Genetics, NOMAIHACI RAMOS FERREIRA University Department of Biology, O. FROTA-PESSOA. São Paulo, Brazil.
therapy
RUBELLA VACCINES SIR,-In your annotation last week (p. 1085) the proposition that high-titre y-globulins will prevent the disease, and that previous failures have been due to using insufficient antibody of low titre, is very misleading. Apart from a difficulty that there is no accepted comparative unit for defining high rubella titres in y-globulin the statement seems based solely on the experiment by Dr. G. M. Schiff in which a single small virus dose was given to 10 susceptible volunteers, 5 of whom, having received a large dose of specially prepared y-globulin 24 hours later, were protected. That rubella virus could be inhibited under these circumstances is not altogether surprising. The experiment seems unrelated, however, to the natural course of Continued exposure of a susceptible person over events. several days to a proven index case in the same household is known to be far more likely to result in rubella than a single chance exposure elsewhere.2O Added to this is the shedding by a patient with rubella of unmeasured amounts of virus during the late incubation period before the appearance of the rash, so that the practicability of routinely giving y-globulin within 24 hours of first exposure is small. On the other hand, the presence of even minimal amounts of circulating antibody at the time of exposure appears sufficient to ward off the disease. This, and the difficulties of preparing adequate amounts of y-globulin with high rubella titres, should still make active immunisation the only reasonable choice. Virus Reference Laboratory, Central Public Health Laboratory, London N.W.9.
A. D. MACRAE.
*** We agree with Dr. Macrs that an accepted unit is needed, but there
can
be
no
doubt that Schiff’s
y-globulin
was
strong.
Nothing we said was intended to indicate that passive immunisation was more than an occasional possibility in exceptional
DISCRIMINANTS AND BREAST CANCER
SiR,—The paper by Dr. Wade and his colleagues (April 26, p. 853) raises a number of interesting points about of androgen and corticosteroid excretion in patients with early breast cancer. We now believe that our original concepts were an oversimplification of a very complicated situation; but the fact remains that we found a significant relationship between the amounts of these steroids excreted and the cancer-recurrence rate after mastectomy.l Subsequent work by Miller and Durant2 (not cited by Wade et al.) indicated that our findings might not apply to the generality of breast-cancer patients, since the proportion of patients with negative discriminants in their series was much lower than in ours. We have now completed a study of a further 300 patients and our results are entirely in agreement measurements
with those of Miller and Durant. It is also becoming clear that the age and menopausal status of the patient and the stage and grade of cancer are important, and that there is a complex relationship between these factors, endocrine function, and subsequent clinical history. We were interested to see the comparison of the steroid excretion of patients with early breast cancer with that of healthy controls and patients with unspecified diseases. We abandoned a similar investigation five or six years ago when we realised that there was already abundant published evidence that sick people tended to excrete smaller quantities of ketosteroids than healthy ones, and that the degree of abnormality was probably related to the nutritional status and the duration of the illness.3 It was obvious that at the end of such a study we should have been comparing the endocrine status of our early-breast-cancer patients with that of patients with a variety of diseases which had unknown effects on endocrine function. Interpretation of the results would therefore have presented great problems. For these reasons it would be extremely difficult to obtain satisfactory controls for breastcancer patients. We have never suggested that " the discriminant is specifically affected in early breast cancer ", since a superficial acquaintance with published reports would have shown this to be highly improbable. If a particular endocrine state, however brought about, is related to the growth and other characteristics of a tumour, then the observation that this state can also be found in patients without breast cancer is irrelevant.
As Wade et al. point out, we did not use a discriminant function (which was designed to predict the response of patients with advanced breast cancer to endocrine ablation) in our forward study in Guernsey.4 We had already had cause to regret using this function for early cancer cases, so it would have been quite inappropriate to use it for the Guernsey patients. We simply applied what was judged to be the best statistical analysis to the data. We cannot understand the comment of Wade and his colleagues that " The ’ distance’ discriminant which was introduced in that [the Guernsey] report was insufficiently defined there for us to be able to calculate our own points for their fig. 2 ", when the text of the paper specifically offered to make the raw data available to other workers in the field. One of the
findings
was
that the group of
women
who
subsequently developed breast cancer tended to excrete subnormal amounts of androgen metabolites. It would be a logical step for Wade et al. to continue their present inquiry by setting up a forward study to see whether women who develop diseases of any sort share this abnormality of steroid excretion with breast-cancer patients. Imperial Cancer Research Fund, Lincoln’s Inn Fields, London W.C.2.
Guy’s Hospital, London S.E.1.
R. D. BULBROOK.
J. L. HAYWARD.
circumstances.-ED. L. 19. Cobra, C. Archs interam. Rheum., Rio de Janeiro, 1964, 7, 144. 20. Report of the Public Health Laboratory Working Party on Rubella. Br. med. J. 1968, iii, 203.
1. Bulbrook, R. D., Hayward, J. L., Thomas, B. S. Lancet, 1964, 2. Miller, H., Durant, J. A. Clin. Biochem. 1968, 1, 286. 3. See Chan, C.-Y., Wang, C.-W. Chin. J. Physiol. 1939, 14, 151. 4. Bulbrook, R. D., Hayward, J. L. Lancet, 1967, i, 519.
i, 945.
they could be. I should be interested if Mr. Matthews and Mr. Matthews could confirm my point of view in another study on transplacental haemorrhage with the technique and instruments used in East Europe. S. M. I. DAMSTRA-WIJMENGA.
as
bone of lead inhaled from car exhaust fumes or ingested with food, a high calcium intake might lessen lead-pyruvate formation
myocardium and consequent impairment of efficiency. two accompanying tables from my report to the North Lindsey Water Board compare mortality-rates in Grimsby and Scunthorpe before and after Scunthorpe’s water-supply
in
The
was
THE WATER STORY SIR,-In your leader (May 17, p. 1012) you cite a suggestion of Anderson et aU that the excess mortality in soft" water areas is attributable to sudden " deaths possibly due to fatal arrhythmias following infarction. Crawford et al.,2 however, found almost as strong a correlation with deaths from bronchitis as with deaths from cardiovascular disease. On a much smaller scale, comparisons between the population of Scunthorpe before and after the introduction of artificial water softening illustrates the same point. The observed increase in mortality from all causes of 200 per 100,000 in middle-aged men was only partly due to the rise of 136 in cardiovascular mortality. Almost a third of the excess mortality which followed the introduction of water softening comprised deaths from non-cardiovascular causes. TABLE I-DEATHS FROM ALL CAUSES AT
AGES
45-64
YEARS)
SUPPLY WAS SOFTENED IN
M.R.
(MORTALITY-RATES
BEFORE AND AFTER
PER
SCUNTHORPE’S
100,000 WATER
1959
= mortality-rate.
Details of deaths in 1964-7 derived from forms S.D. 25 issued by General Register Office. Details of deaths in Grimsby 1950-53 provided by the Registrar General. Details of deaths in Scunthorpe 1950-53 compiled from records of Scunthorpe M.B. health department. Population 1950-53 from 1951 Census, and for 1964-67 from 1966 Sample Census. TABLE
II-DEATHS
RATES PER
FROM
I0O,OOO AT
I
softened in 1959. am
indebted
to
the
Registrar General and
Scunthorpe, for the data Public Health Department, Barton-on-Humber,
M.O.H.
Lincs.
upon
to
which these
Dr. S. were
Childs,
compiled.
J. S. ROBERTSON.
TRISOMY AFTER COLCHICINE THERAPY SIR,-I have read with interest the correspondence 1that followed the report of Miss Ferreira and Dr. Buoniconti.3 Should we not consider the genetic make-up of the gouty individual rather than the colchicine as a factor predisposing to
non-disjunction ? There is good evidence
for the non-random occurrence of chromosomal errors in man and several predisposing factors have been suggested, including viral infections and autoimmune states.45 In plants and in Drosophila, mutant genes have been described which cause or predispose to nondisjunction. s ’ There is less evidence of this in man, but a growing number of reports have documented the concurrence of aneuploidy and the homozygous or heterozygous state for inherited metabolic disorders: galactossemia and trisomy-’ 21 ; phenylketonuria and trisomy-D,9 trisomy-21," and XXY 11; acute intermittent porphyria and XXY 12 13; cystinuria and trisomy-21 14 5; and cystic fibrosis of the pancreas and trisomy-21.16 17 Recently, in describing findings in an individual with trisomy-21 who was also heterozygous for the cystinuria gene, we pointed out that the mother of the propositus would not have been identified as heterozygous for this gene had not her trisomic son participated in a screening programme for hereditary aminoacidurias.15 I realise that these associations may be entirely fortuitous, but it is nevertheless important that, in the future, studies should be done for metabolic disorders in parents of subjects with aneuploidy of unknown cause. Department of Pathology, Dartmouth Medical School, Hanover, New Hampshire, U.S.A. 03755.
DICK HOEFNAGEL.
DISEASES (MORTALITY(DERIVED AS IN TABLE I)
CARDIOVASCULAR
AGES
45-64
YEARS)
SIR,-We consider that the finding 18of increased frequency of aneuploid cells in blood-cultures of patients under colchicine therapy is merely suggestive of a possible increased risk for the offspring of such patients. The scepticism of Dr. Walker (Feb. 1, p. 257) about this is only natural, and item (1) of his sketch for an investigation of the reproductive performance of parents with gout coincides almost exactly with a project we have under way. One difficulty in this approach is that probably our These observations are most readily explained by the hypothesis that myocardia of drinkers of soft water are less able to function when oxygen tensions are low than are myocardia of hard-water drinkers. This would apply whether the low oxygen tension were local and due to impaired coronary circulation, or general and due to poor oxygenation in pulmonary disease or poor oxygen transport in anasmia, and would affect deaths from many causes. In addition to the two possible mechanisms mentioned in your excellent review-i.e., poisoning by metals dissolved from pipes by soft water, and the possible direct effect of calcium--one other possibility should be considered. This is that calcium intake may determine the effect of poison from other sources. For example, by expediting the fixation in 1. 2.
Anderson, T. W., Le Riche, W. H., MacKay, J. S. New Engl. J. Med. 1969, 280, 805. Crawford, M. D., Gardner, M. J., Morris, J. N., Lancet, 1968, i, 827.
1. 2. 3. 4. 5. 6. 7. 8.
9. 10. 11. 12. 13. 14. 15. 16. 17. 1.
Walker, F. A. Lancet, 1969, p. 257. Timson, J. ibid. Feb. 15, 1969, p. 370. Ferreira, N. R., Buoniconti, A. ibid. 1968, ii, 1304. Hecht, F., Bryant, J. S., Gruber, D., Townes, P. L. New Engl. J. Med. 1964, 271, 1081. Penrose, L. S., Smith, G. F. Down’s Anomaly. London, 1966. Beadle, G. W. Z. indukt. Abstamm.-u. VererbLehre, 1932, 63, 195. Lewis, E. B., Gencarella, W. Genetics, 1952, 37, 600. Bahrs, B., Ostertag, W. Genetics Today. Proceedings of the XI International Congress of Genetics, The Hague, 1963 (edited by S. J. Geerts); vol. I, p. 289. Oxford, 1963. Atkins, L., Rosenthal, M. K. New Engl. J. Med. 1961, 265, 314. Fisch, R. O., Horrobin, J. M. Clin. Pediat. 1968, 7, 226. Benirschke, K., Brownhill, L., Efron, M. L., Hoefnagel, D. J. ment. Defic. Res. 1962, 6, 44. Hambert, G., Wetterberg, L. Lancet, 1964, ii, 419. Nielsen, J. ibid. 1966, i, 984. Tanguay, R. B., Galindo, J. Am. J. clin. Path. 1966, 46, 442. Hoefnagel, D., Pomeroy, J., Benz, R. J. ment. Defic. Res. 1968, 12, 317. Milunsky, A. Pediatrics, Springfield, 1968, 42, 502. Vetrella, M., Barthemai, W., Matsuda, H. Klin. Wschr. 1969, 47, 333. Ferreira, N. R., Buoniconti, A. Lancet, 1968, ii, 1304.
1161
sample will not be big enough, since a number of patients were not under colchicine treatment at the time they reproduced. Perhaps the results of parallel surveys of patients and matched controls from several big
towns
will have
to
be added up for
analysis. In contrast with the observation of 2 persons under colchicine among 54 parents of Down’s syndrome (D.S.) patients in our laboratory, Dr. Walker did not find any among the parents of 200 D.S. patients. It could be that the two surveys are not perfectly comparable. For one thing, since in Brazil drug stores are required to label fully the medicines they sell, patients know the name of the drugs they are taking. This is not always so in the United States. The incidence of gout in the locality of the survey, the frequency with which doctors prescribe colchicine for gout, and the age-distribution of the parents of the D.S. patients in the samples studied are other variables which might influence the results. Dr. Timson (Feb. 15, p. 370) suggests that the high frequency found in our laboratory of D.S. patients born to parents under colchicine treatment may be due to the relatively high possibility of the two events coinciding by chance. However, gout patients are estimated as 0-5% of all patients in non-specialised clinics, and even in rheumatological clinics they are only about 4%." Dr. Timson’s hypothesis would requireamongthemiddleaged part of the general population a frequency of 3-7% of gout patients under colchicine therapy at the time they reproduced. However, we agree with Dr. Timson that the standard treatment with colchicine of the cultures of both patients and controls accentuated the in-vivo effect of the drug in the patients. Laboratory of Human Genetics, NOMAIHACI RAMOS FERREIRA University Department of Biology, O. FROTA-PESSOA. São Paulo, Brazil.
therapy
RUBELLA VACCINES SIR,-In your annotation last week (p. 1085) the proposition that high-titre y-globulins will prevent the disease, and that previous failures have been due to using insufficient antibody of low titre, is very misleading. Apart from a difficulty that there is no accepted comparative unit for defining high rubella titres in y-globulin the statement seems based solely on the experiment by Dr. G. M. Schiff in which a single small virus dose was given to 10 susceptible volunteers, 5 of whom, having received a large dose of specially prepared y-globulin 24 hours later, were protected. That rubella virus could be inhibited under these circumstances is not altogether surprising. The experiment seems unrelated, however, to the natural course of Continued exposure of a susceptible person over events. several days to a proven index case in the same household is known to be far more likely to result in rubella than a single chance exposure elsewhere.2O Added to this is the shedding by a patient with rubella of unmeasured amounts of virus during the late incubation period before the appearance of the rash, so that the practicability of routinely giving y-globulin within 24 hours of first exposure is small. On the other hand, the presence of even minimal amounts of circulating antibody at the time of exposure appears sufficient to ward off the disease. This, and the difficulties of preparing adequate amounts of y-globulin with high rubella titres, should still make active immunisation the only reasonable choice. Virus Reference Laboratory, Central Public Health Laboratory, London N.W.9.
A. D. MACRAE.
*** We agree with Dr. Macrs that an accepted unit is needed, but there
can
be
no
doubt that Schiff’s
y-globulin
was
strong.
Nothing we said was intended to indicate that passive immunisation was more than an occasional possibility in exceptional
DISCRIMINANTS AND BREAST CANCER
SiR,—The paper by Dr. Wade and his colleagues (April 26, p. 853) raises a number of interesting points about of androgen and corticosteroid excretion in patients with early breast cancer. We now believe that our original concepts were an oversimplification of a very complicated situation; but the fact remains that we found a significant relationship between the amounts of these steroids excreted and the cancer-recurrence rate after mastectomy.l Subsequent work by Miller and Durant2 (not cited by Wade et al.) indicated that our findings might not apply to the generality of breast-cancer patients, since the proportion of patients with negative discriminants in their series was much lower than in ours. We have now completed a study of a further 300 patients and our results are entirely in agreement measurements
with those of Miller and Durant. It is also becoming clear that the age and menopausal status of the patient and the stage and grade of cancer are important, and that there is a complex relationship between these factors, endocrine function, and subsequent clinical history. We were interested to see the comparison of the steroid excretion of patients with early breast cancer with that of healthy controls and patients with unspecified diseases. We abandoned a similar investigation five or six years ago when we realised that there was already abundant published evidence that sick people tended to excrete smaller quantities of ketosteroids than healthy ones, and that the degree of abnormality was probably related to the nutritional status and the duration of the illness.3 It was obvious that at the end of such a study we should have been comparing the endocrine status of our early-breast-cancer patients with that of patients with a variety of diseases which had unknown effects on endocrine function. Interpretation of the results would therefore have presented great problems. For these reasons it would be extremely difficult to obtain satisfactory controls for breastcancer patients. We have never suggested that " the discriminant is specifically affected in early breast cancer ", since a superficial acquaintance with published reports would have shown this to be highly improbable. If a particular endocrine state, however brought about, is related to the growth and other characteristics of a tumour, then the observation that this state can also be found in patients without breast cancer is irrelevant.
As Wade et al. point out, we did not use a discriminant function (which was designed to predict the response of patients with advanced breast cancer to endocrine ablation) in our forward study in Guernsey.4 We had already had cause to regret using this function for early cancer cases, so it would have been quite inappropriate to use it for the Guernsey patients. We simply applied what was judged to be the best statistical analysis to the data. We cannot understand the comment of Wade and his colleagues that " The ’ distance’ discriminant which was introduced in that [the Guernsey] report was insufficiently defined there for us to be able to calculate our own points for their fig. 2 ", when the text of the paper specifically offered to make the raw data available to other workers in the field. One of the
findings
was
that the group of
women
who
subsequently developed breast cancer tended to excrete subnormal amounts of androgen metabolites. It would be a logical step for Wade et al. to continue their present inquiry by setting up a forward study to see whether women who develop diseases of any sort share this abnormality of steroid excretion with breast-cancer patients. Imperial Cancer Research Fund, Lincoln’s Inn Fields, London W.C.2.
Guy’s Hospital, London S.E.1.
R. D. BULBROOK.
J. L. HAYWARD.
circumstances.-ED. L. 19. Cobra, C. Archs interam. Rheum., Rio de Janeiro, 1964, 7, 144. 20. Report of the Public Health Laboratory Working Party on Rubella. Br. med. J. 1968, iii, 203.
1. Bulbrook, R. D., Hayward, J. L., Thomas, B. S. Lancet, 1964, 2. Miller, H., Durant, J. A. Clin. Biochem. 1968, 1, 286. 3. See Chan, C.-Y., Wang, C.-W. Chin. J. Physiol. 1939, 14, 151. 4. Bulbrook, R. D., Hayward, J. L. Lancet, 1967, i, 519.
i, 945.