961
"acceptably controlled" on the basis of the tabulated data? Patients previously thought to be well controlled on cromoglycate may show no change in symptom frequency when the drug is discontinued or placebo substituted, possibly owing to spontaneous improvement in the disease over a long be deemed
period.3 these problems may be overcome by comparing cromoglywith placebo immediately before the trial or incorporating a double placebo period into the trial, neither of which was done in this study. Insufficient evidence is available to decide whether theophylline is as effective as cromoglycate in the prophylaxis of asthmatic symptoms in true cromoglycate responders. The conclusion that cromoglycate was effective in the management of asthma seems to be unfounded. H. R. GRIBBIN Western Hospital, A. E. TATTERSFIELD Southampton cate
15/17 TRANSLOCATION IN ACUTE PROMYELOCYTIC LEUKÆMIA
SIR,—DR Rowley and her colleagues have described a consistent chromosomal change in patients with acute promyelocytic leukæmia (A.P.L.), showing the karyotype, 46,XX, or XY, ins (15;17) (q22?; q21?).1 We have also seen a case of A.P.L. with abnormalities on chromosomes 15 and 17. A female patient, aged 51, 6 weeks after symptoms first
diagnosed as having A.P.L. appeared. Leuksemic promyelo44% cytes comprised of leucocytes in peripheral blood and 48% was
of nucleated cells in sternal marrow on admission. After 2 months of chemotherapy she died of acute renal failure without overt
hsematological improvement.
Schematic two
partial karyotype, arrows indicating break points in translocating chromosomes.
Pseudodiploidy, 46,XX,Dq+,17q-, was observed in 14 marand in 10 blood-cells by the Giemsa staining method. Q and G banded karyotypes from 15 cells showed two abnormal chromosomes interpreted as resulting from a reciprocal translocation between the long arms of a no. 15 and a no. 17 (see figure). The karyotype was designated as 46,XX,t(15;17) (q22;q21). The break at band 17q21 was considered to have occurred near to the proximal edge, from the fact that a welldefined negative band could not be seen between the pale band l7q12 and a slightly brighter segment corresponding to 15q23—15qter in the abnormal no. 17 chromosome. We do row
not
know whether or
not
any deletion occurred in chromosome
bands involved in the rearrangement. Dr Kaneko and Dr Sakurai (see accompanying letter) put a similar interpretation on another case of A.P.L. with a karyotypic change akin to ours. We thank Dr Masaharu Sakurai for his advice.
Departments of Anatomy and Internal Meicine, Tokyo Women’s Medical College, Tokyo 162, Japan
MICHIKO OKADA TAMOTSU MIYAZAKI KURA KUMOTA
3 Williams,
H., McNicol, K. N. Br. med. J. 1969, iv, 321. 1 Rowley, J U , Golomb, H. M., Dougherty, C. Lancet, 1977, i, 2 Rowley, J. D, Potter, D. Blood, 1976, 47, 705.
549.
SIR,—We have studied the chromosomes of A.P.L.
and
our
a patient with findings were similar to those of Dr Rowley and
her colleagues. A 17-year-old male was admitted to hospital with generalised petechix and gingival bleeding. His haemoglobin was 8.77 g/dl, white blood-cells 9200/µl, with 19% myeloblasts and 20% promyelocytes, and a platelet-count 10 000/µl. The bone-marrow was hypercellular with 35.6% myeloblasts and 45.6% promyelocytes. Activated partial thromboplastin-time was 41 s, prothrombin-time 17 s, fibrinogen 96 mg/dl, fibrin-degradation products 80 µg/ml, factor v 50%, and factor viu 45%. A.P.L. was diagnosed. He was treated with daunomycin, cytarabine, vincristine, and prednisolone, followed by treatment with doxorubicin (’Adriamycin’), cyclocytidine, 6-mercaptopurine, and prednisolone, and he has been in a complete haematological remission for 7 months. Chromosomes were studied on direct preparations of bonemarrow before therapy by Giemsa, quinacrine, and trypsinGiemsa methods. All of the 24 cells in metaphase analysed by Giemsa method showed a diploid number of chromosomes with an abnormally small no.17. Thirteen cells stained by quinacrine and 18 cells by trypsin-Giemsa revealed a slightly larger no. 15 chromosome in addition to the abnormal no.17, abnormalities similar to those Rowley et al. described. Our interpretation, however, was that a reciprocal translocation had occurred between a no. 15 and a no. 17, resulting in a karyotype probably expressed as 46,XY,t(15;17) (q22;q21). We presumed that a reciprocal translocation was involved rather than an insertion, as interpreted by Rowley et al., because the long arm of the abnormal no.15 had a terminal band much brighter than that of the normal no.15 and the terminal band of the long arm of the abnormal no.17 was not as bright as that of the normal no.17. A similar conclusion has been obtained by Dr Okada and colleagues in another patient with A.P.L. (see accompanying letter). We cannot, however, exclude another possibility that a break occurred at 17ql2 instead of 17q21 because very often the band q 12 of the abnormal no.17 did not seem as broad as that of the normal no.17. If this is so we would expect that a very narrow bright band (part of 17ql2) would be recognised within the broad dull band of the abnormal no. 15 by a more sensitive banding technique. At any rate, we all seem to be dealing with the same karyotype whose phenotypic expression is A.P.L. Chromosome Research Laboratory, Saitama Cancer Centre, Ina, Saitama 362, Japan
YASUHIKO KANEKO MASAHARU SAKURAI
BIRMINGHAM ACCIDENT HOSPITAL
SIR Your Birmingham correspondent (March 19, p. 644) claims that the Birmingham Accident Hospital has friends who respect its history, its work, and its policy past, present and future. He is right. I am one of them, as would any responsible services person be who is concerned with the future of B in Britain. The controversy of the specialist accident hospital versus the accident service in a general hospital complex has raged for years, with orthopaedic surgeons like myself supporting-in some instances more by words than deeds-the latter view. However, because some orthopaedic surgeons have failed to grasp, for many reasons, the responsibility for the delivery of a total-care accident service, the Government has been forced to create the new specialty of accident-and-emergency surgeons. However, this will never solve local or national problems in the delivery of expert care for the injured. Continental experience such as that in Germany, Austria, Hungary, and the U.S.S.R., and American experience as at Parklands Hospital in Dallas, Texas, should teach us that we cannot stop the developments of well-organised multidisciplinary services for the care of the injured. A national institute of traumatology in the United Kingdom
accident
962 be put off any longer. The Accident Hospital, given the meagre support it requires, is the unit to fill this role now and in the future. Dispersal of its staff and hence its "spirit" to the corners of an ad-hoc accident service throughout Birmingham will prevent this all-important step towards the emergence of what must come in Britain-namely, leadership, training, research, and development in traumatology in an institute or institutes. Only two units have so far earned the right to be so called-the Radcliffe Infirmary, Oxford, and the Birmingham Accident Hospital. Save the Accident Hospital for the future and let us not be constrained by temporary difficulties which encourage the cry of "necessity" to economise here, close this, distribute that,
cannot
equalise this. the plea for every infringement of human freedom. It is the argument of tyrants, it is the creed of slaves." -WILLIAM PITT (Nov. 18, 1783).
"Necessity Is
Institute of Orthopædics in the University of Birmingham, Robert Jones and Agnes Hunt
Orthopædic Hospital, Oswestry, Shropshire SY10
7AG
BRIAN T. O’CONNOR
COST CONSCIOUSNESS AND PRIVATE PRACTICE
SIR,—Iwas interested to see from your Commentary from Westminster (April 23, p. 917) that the Department of Health is worrying about the way we consultants spend our quarter of a million pounds each, each year. There is one clear way in which the cost of an individual patient’s treatment is brought home to consultants, and that is when patients are admitted to private beds in a National Health Service hospital, especially when they are not covered by insurance. Since I have had a part-time contract I have been very much more aware of the costs of the treatment I give and the investigations I request. If the Government has its way and gets rid of paying patients completely I shall lose any possibility of knowing what the costs are. Retaining the small amount of private practice in the N.H.S. is the cheapest way of keeping consultants aware of the costs of what they are doing. Metchley Park Road, Edghaston, Birmingham, B15 2PQ
25
A. D. BARNES
FLUORIDISED MILK
SIR,-The Borrow Dental Milk Foundation thanks Dr Seale and others (March 19, p. 659) for giving us the opportunity to explain why the trademark ’Dentamilk’ is used to promote its selective method of fluoridising milk to reduce dental caries in children. The Foundation, a non-profit-making charity, does not own the trademark, and cannot give a licence for it to be used until the dairy product is ready for distribution. In the meantime the owner of the trademark has granted the use of the word to the Foundation. If a trademark were not registered it might be acquired (or suppressed) by any commercial organisation for use exclusively in the pursuit of its own interests. Wehope that fluoridised milk will be widely distributed in many countries during 1977. Where a fresh liquid milk supply is unavailable for processing the dairy product, other vehicles to distribute fluoride may be used. The Foundation is, for example, sponsoring a project in Israel where fluoride is being administered to children in the juices of citrus fruits. In six other countries fluoridised milk is being used in pilot schemes. Borrow Dental Milk Foundation, Lister House, 11 and 12 Wimpole Street, London W1M 7AB
MAXWELL BRESLER
Commentary
from Westminster
FROM A CORRESPONDENT
Curbing Expenditure on Drugs reduce the money which the pharmaceutical industry spends on sales promotion is part of an overall strategy to curb the nation’s rising GOVERNMENT action
to
drug bill. After two years of hard negotiating with the industry, officials at the Department of Health and Social Security have now embarked on talks with the medical profession to see what can be achieved. The aim is to reach a voluntary agreement on methods by which savings in prescribing might be made without detriment to patients. It was only on this basis that the B.M.A. accepted the Department’s invitation to the talks. But Ministers are hopeful that the results of the discussions will amount to substantial savings for the N.H.S. Expenditure on drugs in the National Health Service has risen sharply over the past ten years. For drugs prescribed by family doctors the cost has gone up from £ 142 million in 1968 to an estimated £415 million this year, and the level of prescribing is expected to grow by around 5% a year. What worries Ministers is that this budget is one of those not subject to cash limits and on present trends it is expected to be one of the fastest growing sectors in the health and personal social services. Not only has the net ingredient cost per prescription risen considerably (by 25% between 1974 and 1975) but the number of prescriptions has also gone up from 264 million in 1973 to 282 million in 1975. Statistics, of course, are not the whole story. More and better drugs can mean more people staying out of hospital and more people at work, amounting to considerable savings. With this and the delicate issue of clinical freedom in mind, Ministers know this to be an area where they must tread softly. Mr David Ennals, Secretary of State for Social Services, said in a recent speech: "I have no reason to believe that the prescribing standards of doctors in this country are not the equal of those anywhere in the world. The cost of drugs per head of population is lower in this country than elsewhere in the E.E.C. But there may still be scope for further economy without harm to patients". Wastage and accumulation of drugs are two aspects which bother the Government. Mr Ennals has said that some wastage might result when a patient’s condition did not respond to the drug prescribed and treatment had to be changed or when patients failed to follow their doctors’ advice on dosage and length of treatment. These are the areas which D.H.S.S. officials and the B.M.A. will be examining. One informal meeting has already been held and others are being planned. Some ideas are coming from the profession itself, others from the Department. Both sides are anxious to make the public more aware of the cost of drugs. For instance, the profession has suggested an experiment for labelling the more expensive medicines to draw attention to their cost. One suggestion is that the cost could be written on the labels at the time of issue from chemists’ shops. Mr Ennals himself has outlined a number of points for discussion. They include a publicity campaign aimed at pa’
"acceptably controlled" on the basis of the tabulated data? Patients previously thought to be well controlled on cromoglycate may show no change in symptom frequency when the drug is discontinued or placebo substituted, possibly owing to spontaneous improvement in the disease over a long be deemed
period.3 these problems may be overcome by comparing cromoglywith placebo immediately before the trial or incorporating a double placebo period into the trial, neither of which was done in this study. Insufficient evidence is available to decide whether theophylline is as effective as cromoglycate in the prophylaxis of asthmatic symptoms in true cromoglycate responders. The conclusion that cromoglycate was effective in the management of asthma seems to be unfounded. H. R. GRIBBIN Western Hospital, A. E. TATTERSFIELD Southampton cate
15/17 TRANSLOCATION IN ACUTE PROMYELOCYTIC LEUKÆMIA
SIR,—DR Rowley and her colleagues have described a consistent chromosomal change in patients with acute promyelocytic leukæmia (A.P.L.), showing the karyotype, 46,XX, or XY, ins (15;17) (q22?; q21?).1 We have also seen a case of A.P.L. with abnormalities on chromosomes 15 and 17. A female patient, aged 51, 6 weeks after symptoms first
diagnosed as having A.P.L. appeared. Leuksemic promyelo44% cytes comprised of leucocytes in peripheral blood and 48% was
of nucleated cells in sternal marrow on admission. After 2 months of chemotherapy she died of acute renal failure without overt
hsematological improvement.
Schematic two
partial karyotype, arrows indicating break points in translocating chromosomes.
Pseudodiploidy, 46,XX,Dq+,17q-, was observed in 14 marand in 10 blood-cells by the Giemsa staining method. Q and G banded karyotypes from 15 cells showed two abnormal chromosomes interpreted as resulting from a reciprocal translocation between the long arms of a no. 15 and a no. 17 (see figure). The karyotype was designated as 46,XX,t(15;17) (q22;q21). The break at band 17q21 was considered to have occurred near to the proximal edge, from the fact that a welldefined negative band could not be seen between the pale band l7q12 and a slightly brighter segment corresponding to 15q23—15qter in the abnormal no. 17 chromosome. We do row
not
know whether or
not
any deletion occurred in chromosome
bands involved in the rearrangement. Dr Kaneko and Dr Sakurai (see accompanying letter) put a similar interpretation on another case of A.P.L. with a karyotypic change akin to ours. We thank Dr Masaharu Sakurai for his advice.
Departments of Anatomy and Internal Meicine, Tokyo Women’s Medical College, Tokyo 162, Japan
MICHIKO OKADA TAMOTSU MIYAZAKI KURA KUMOTA
3 Williams,
H., McNicol, K. N. Br. med. J. 1969, iv, 321. 1 Rowley, J U , Golomb, H. M., Dougherty, C. Lancet, 1977, i, 2 Rowley, J. D, Potter, D. Blood, 1976, 47, 705.
549.
SIR,—We have studied the chromosomes of A.P.L.
and
our
a patient with findings were similar to those of Dr Rowley and
her colleagues. A 17-year-old male was admitted to hospital with generalised petechix and gingival bleeding. His haemoglobin was 8.77 g/dl, white blood-cells 9200/µl, with 19% myeloblasts and 20% promyelocytes, and a platelet-count 10 000/µl. The bone-marrow was hypercellular with 35.6% myeloblasts and 45.6% promyelocytes. Activated partial thromboplastin-time was 41 s, prothrombin-time 17 s, fibrinogen 96 mg/dl, fibrin-degradation products 80 µg/ml, factor v 50%, and factor viu 45%. A.P.L. was diagnosed. He was treated with daunomycin, cytarabine, vincristine, and prednisolone, followed by treatment with doxorubicin (’Adriamycin’), cyclocytidine, 6-mercaptopurine, and prednisolone, and he has been in a complete haematological remission for 7 months. Chromosomes were studied on direct preparations of bonemarrow before therapy by Giemsa, quinacrine, and trypsinGiemsa methods. All of the 24 cells in metaphase analysed by Giemsa method showed a diploid number of chromosomes with an abnormally small no.17. Thirteen cells stained by quinacrine and 18 cells by trypsin-Giemsa revealed a slightly larger no. 15 chromosome in addition to the abnormal no.17, abnormalities similar to those Rowley et al. described. Our interpretation, however, was that a reciprocal translocation had occurred between a no. 15 and a no. 17, resulting in a karyotype probably expressed as 46,XY,t(15;17) (q22;q21). We presumed that a reciprocal translocation was involved rather than an insertion, as interpreted by Rowley et al., because the long arm of the abnormal no.15 had a terminal band much brighter than that of the normal no.15 and the terminal band of the long arm of the abnormal no.17 was not as bright as that of the normal no.17. A similar conclusion has been obtained by Dr Okada and colleagues in another patient with A.P.L. (see accompanying letter). We cannot, however, exclude another possibility that a break occurred at 17ql2 instead of 17q21 because very often the band q 12 of the abnormal no.17 did not seem as broad as that of the normal no.17. If this is so we would expect that a very narrow bright band (part of 17ql2) would be recognised within the broad dull band of the abnormal no. 15 by a more sensitive banding technique. At any rate, we all seem to be dealing with the same karyotype whose phenotypic expression is A.P.L. Chromosome Research Laboratory, Saitama Cancer Centre, Ina, Saitama 362, Japan
YASUHIKO KANEKO MASAHARU SAKURAI
BIRMINGHAM ACCIDENT HOSPITAL
SIR Your Birmingham correspondent (March 19, p. 644) claims that the Birmingham Accident Hospital has friends who respect its history, its work, and its policy past, present and future. He is right. I am one of them, as would any responsible services person be who is concerned with the future of B in Britain. The controversy of the specialist accident hospital versus the accident service in a general hospital complex has raged for years, with orthopaedic surgeons like myself supporting-in some instances more by words than deeds-the latter view. However, because some orthopaedic surgeons have failed to grasp, for many reasons, the responsibility for the delivery of a total-care accident service, the Government has been forced to create the new specialty of accident-and-emergency surgeons. However, this will never solve local or national problems in the delivery of expert care for the injured. Continental experience such as that in Germany, Austria, Hungary, and the U.S.S.R., and American experience as at Parklands Hospital in Dallas, Texas, should teach us that we cannot stop the developments of well-organised multidisciplinary services for the care of the injured. A national institute of traumatology in the United Kingdom
accident
962 be put off any longer. The Accident Hospital, given the meagre support it requires, is the unit to fill this role now and in the future. Dispersal of its staff and hence its "spirit" to the corners of an ad-hoc accident service throughout Birmingham will prevent this all-important step towards the emergence of what must come in Britain-namely, leadership, training, research, and development in traumatology in an institute or institutes. Only two units have so far earned the right to be so called-the Radcliffe Infirmary, Oxford, and the Birmingham Accident Hospital. Save the Accident Hospital for the future and let us not be constrained by temporary difficulties which encourage the cry of "necessity" to economise here, close this, distribute that,
cannot
equalise this. the plea for every infringement of human freedom. It is the argument of tyrants, it is the creed of slaves." -WILLIAM PITT (Nov. 18, 1783).
"Necessity Is
Institute of Orthopædics in the University of Birmingham, Robert Jones and Agnes Hunt
Orthopædic Hospital, Oswestry, Shropshire SY10
7AG
BRIAN T. O’CONNOR
COST CONSCIOUSNESS AND PRIVATE PRACTICE
SIR,—Iwas interested to see from your Commentary from Westminster (April 23, p. 917) that the Department of Health is worrying about the way we consultants spend our quarter of a million pounds each, each year. There is one clear way in which the cost of an individual patient’s treatment is brought home to consultants, and that is when patients are admitted to private beds in a National Health Service hospital, especially when they are not covered by insurance. Since I have had a part-time contract I have been very much more aware of the costs of the treatment I give and the investigations I request. If the Government has its way and gets rid of paying patients completely I shall lose any possibility of knowing what the costs are. Retaining the small amount of private practice in the N.H.S. is the cheapest way of keeping consultants aware of the costs of what they are doing. Metchley Park Road, Edghaston, Birmingham, B15 2PQ
25
A. D. BARNES
FLUORIDISED MILK
SIR,-The Borrow Dental Milk Foundation thanks Dr Seale and others (March 19, p. 659) for giving us the opportunity to explain why the trademark ’Dentamilk’ is used to promote its selective method of fluoridising milk to reduce dental caries in children. The Foundation, a non-profit-making charity, does not own the trademark, and cannot give a licence for it to be used until the dairy product is ready for distribution. In the meantime the owner of the trademark has granted the use of the word to the Foundation. If a trademark were not registered it might be acquired (or suppressed) by any commercial organisation for use exclusively in the pursuit of its own interests. Wehope that fluoridised milk will be widely distributed in many countries during 1977. Where a fresh liquid milk supply is unavailable for processing the dairy product, other vehicles to distribute fluoride may be used. The Foundation is, for example, sponsoring a project in Israel where fluoride is being administered to children in the juices of citrus fruits. In six other countries fluoridised milk is being used in pilot schemes. Borrow Dental Milk Foundation, Lister House, 11 and 12 Wimpole Street, London W1M 7AB
MAXWELL BRESLER
Commentary
from Westminster
FROM A CORRESPONDENT
Curbing Expenditure on Drugs reduce the money which the pharmaceutical industry spends on sales promotion is part of an overall strategy to curb the nation’s rising GOVERNMENT action
to
drug bill. After two years of hard negotiating with the industry, officials at the Department of Health and Social Security have now embarked on talks with the medical profession to see what can be achieved. The aim is to reach a voluntary agreement on methods by which savings in prescribing might be made without detriment to patients. It was only on this basis that the B.M.A. accepted the Department’s invitation to the talks. But Ministers are hopeful that the results of the discussions will amount to substantial savings for the N.H.S. Expenditure on drugs in the National Health Service has risen sharply over the past ten years. For drugs prescribed by family doctors the cost has gone up from £ 142 million in 1968 to an estimated £415 million this year, and the level of prescribing is expected to grow by around 5% a year. What worries Ministers is that this budget is one of those not subject to cash limits and on present trends it is expected to be one of the fastest growing sectors in the health and personal social services. Not only has the net ingredient cost per prescription risen considerably (by 25% between 1974 and 1975) but the number of prescriptions has also gone up from 264 million in 1973 to 282 million in 1975. Statistics, of course, are not the whole story. More and better drugs can mean more people staying out of hospital and more people at work, amounting to considerable savings. With this and the delicate issue of clinical freedom in mind, Ministers know this to be an area where they must tread softly. Mr David Ennals, Secretary of State for Social Services, said in a recent speech: "I have no reason to believe that the prescribing standards of doctors in this country are not the equal of those anywhere in the world. The cost of drugs per head of population is lower in this country than elsewhere in the E.E.C. But there may still be scope for further economy without harm to patients". Wastage and accumulation of drugs are two aspects which bother the Government. Mr Ennals has said that some wastage might result when a patient’s condition did not respond to the drug prescribed and treatment had to be changed or when patients failed to follow their doctors’ advice on dosage and length of treatment. These are the areas which D.H.S.S. officials and the B.M.A. will be examining. One informal meeting has already been held and others are being planned. Some ideas are coming from the profession itself, others from the Department. Both sides are anxious to make the public more aware of the cost of drugs. For instance, the profession has suggested an experiment for labelling the more expensive medicines to draw attention to their cost. One suggestion is that the cost could be written on the labels at the time of issue from chemists’ shops. Mr Ennals himself has outlined a number of points for discussion. They include a publicity campaign aimed at pa’
