- Email: [email protected]
DANGERS AND LIMITATIONS OF THE IMMUNOLOGICAL TREATMENT OF CANCER
654
looked. The whole project is an exercise in human relations. In his essay Sir Bruce Fraser1 went on to say: "
Just as you cannot make people good by Act of Parliament, you cannot make people cooperative by Ministry circular. The Ministry can exhort, advise, facilitate: it cannot compel cooperation, which is more an attitude of mind than an administrative procedure. If the parties concerned don’t like each other’s faces, don’t believe in what they’re doing or don’t believe that the other parties believe in what they’re doing; if, above all, they are not being spurred on by the forces of national and local public opinion, then cooperation may be grudging and efficiency may be patchy." so
We are particularly grateful to the members of the medical planning liaison committee who have continued to support and encourage us, but neither they nor the bodies they represent are in any way committed to our views. We should like to thank our colleagues Dr. J. A. D. Anderson, Dr. P. Draper, Mr. M. Wadsworth, and many others who have helped to formulate our views in both formal and informal discussion and have read and criticised many drafts of this paper; Mr. Martin Hackett of the planning department of the G.L.C. and his colleagues and predecessors for their patience and cooperation; Mr. Brian Brookes for the diagrams; and Miss Helen Blackburn our indefatigable secretary. Finally, we must acknowledge our indebtedness to the Nuffield Foundation for a generous grant. Requests for reprints should be addressed to R. S.
immunological paralysis instead of resistance. The possibility of inducing non-reactivity in immunologically mature organisms also depends on the strength (or phylogenetic closeness) of the antigen used. In general, weaker or phylogenetically closer antigens can more easily induce such non-reactivity.15 Tumour-specific antigens are very weak and the danger of inducing non-reactivity is extremely high. On the other hand, very small doses of such antigens can provoke a sufficient degree of resistance. Non-specific stimulation can again help in this situation, but inhibition of the immune system of the host by, for example, antimitotic substances can have a deleterious the progress of the disease.16s Increased Immunoresistance Neither the antigenicity of a tumour nor the sensitivity of its cells to immunodestruction remain constant. Some workers have shown that, although a tumour-specific antigen may persist during repeated transplantation in syngeneic hosts, 17 18 there is a quantitative reduction in antigenicity. If tumours are forced to grow against the resistance of an immunised host then not only is there a more pronounced reduction of antigenicity 19 but the
influence
tumour
DANGERS AND LIMITATIONS OF THE IMMUNOLOGICAL TREATMENT OF CANCER P. KOLDOVSKY M.D. Prague OF THE INSTITUTE OF EXPERIMENTAL BIOLOGY AND
CZECHOSLOVAK ACADEMY OF
GENETICS, SCIENCES, PRAGUE, 6*
SOME experimentally induced tumours have antigens which are specific for the tumours and are not present in the host; and such tumours can be destroyed by immunological mechanisms comparable with an autoimmune reaction.12 These findings have reawakened interest in the possibility of treating cancer by immunological methods, and there are several reports of clinical observations and theoretical speculations on immunological treatment (reviewed by Southam 13). Nevertheless, there is substantial experimental evidence for the dangers and limitations of such treatment, and it is important that these should be stressed at this time. DANGERS AND LIMITATIONS
Weak Response by the Host The vigour and speed of the immunological response of the host to a grafted tumour is dependent upon the strength of the antigenic stimulation. Some mouse tumours can also overcome strong immune barriers based on the H-2 locus-controlled interstrain differences.12 But even the strongest tumour-specific antigen is extremely weak in comparison with H-2 locus antigens. Thus, any host response will be feeble, slow, and possibly insufficient to
destroy
a
rapidly growing
tumour.
However,
some
results show that the use of specific or non-specific stimulation can accelerate and increase the immune
against tumour antigens.14 Induction of Immunological Paralysis
response
even
There must be very close contact between the host’s immunologically competent cells and the tumour antigen lest the large dose used for immunisation should induce * Present
appointment: research fellow, Division of Experimental Biology
and Virology, Imperial Cancer Research Fund, London, N.W.7. 12. Hellstrom, K. E., Moller, G. Progr. Allergy, 1965, 9, 158. 13. Southam, C. M. Cancer Res. 1960, 20, 271. 14. Old, L. J., Benacerraf, B., Clarke, D. A., Carswell, E. A., Stockert, E. ibid. 1961, 21, 1281.
on
itself may become
more
immunoresistant.20
Possibly, then, even a slowly growing antigenic tumour might eventually become more virulent and fatal because of the progressive selection of less immunogenic and more immunoresistant clones of malignant cells. Increased Growth of Tumour As early as 1907, Flexner and Jobling 21 showed that prior immunisation may facilitate the growth of an allogeneic tumour. Later, it was shown that this response can be provoked by either allogeneic or heterogeneic antiserum .22 The generally accepted explanation of this paradoxical immunological enhancement is that serumantibodies coat the tumour cells in such way as to reduce both their immunogenicity and immunosensitivity. Changes in the host may play a role 23 and enhancement against a weak tumour antigen is also possible. 24 The dangers of enhancing the growth of tumours in man by unsuitable treatment have been discussed by Batchelor and Tuffrey.25
Limitations of Immunisation Immunisation in a heterologous relationship was first considered by Hericourt and Richet.26 The use of immune " serum is dangerous and very ineffective but, on the other hand, immune cells play the dominant role in transplantation immunity, so that attention was later attracted to the use of heterologous immune cells. But the present knowledge of immunity mechanisms does not confirm that this will be useful. Even in such a close heterologous relationship as rat and mouse, the rat cannot distinguish individual differences in transplantation antigens between various strains of mice. This means that the allogeneic reaction has a greater potential for antigenic discrimination than the heterologous relationship. If a heterologous organism cannot distinguish and react specifically against strong transplantation antigens, then it "
15. 16. 17.
Hasek, M., Lengerova, A., Hraba, T. Adv. Immun. 1961, 1, 1. Southam, C. M. Cancer Res. 1961, 21, 1302. Globerson, A., Feldman, M. J. natn. Cancer Inst. 1964, 32, 1229. 18. Harris, R. J. C. Symposium of the International Union against Cancer. Munksgaard, 1966. 19. Sjogren, H. O. J. natn. Cancer Inst. 1964, 32, 661. 20. Koldovsky, P., Svoboda, J. Folia biol. 1962, 8, 144. 21. Flexner, S., Jobling, W. Proc. Soc. exp. Biol. Med. 1907, 5, 16. 22. Kaliss, N. Cancer Res. 1958, 18, 992. 23. Moller, G. Transplantation, 1964, 2, 405. 24. Bubenik, J., Koldovsky, P. Folia biol. 1964, 10, 427. 25. Batchelor, J. R., Tuffrey, M. A. Lancet, 1964, i, 613. 26. Hericourt, J., Richet, C. C. r. Acad. Sci., Paris, 1895, 21, 373.
655
is difficult to hope for specific recognition and reaction against extremely weak tumour antigens, without, at the same time, endangering normal tissue. The possibility of using heterologous cells from pre-
immunised animals is excluded for
_
a further reason. The of so-called in the recipient natural antibodies presence will tend to inhibit the function of the injected organism cells and in a few heterologous days specific cytotoxic and antibodies will cytolytic appear which will eliminate the cells. Some effect foreign might be expected from antibound to the bodies heterologous cells but these will alsc soon be eliminated by a specific host-reaction. Lately, some work has been done on the use of heterologous immunisation." 18 The idea is based on the discovery of immunological tolerance, for it was expected that an animal tolerant to normal antigens will still read
against tumour-specific antigens. Theoretically, a monospecific reaction would be expected. But it is not easy tc have animals fully tolerant to all transplantation antigens in heterologous relationship. No-one has yet succeeded in using such a heterologous relationship as man and animal. In practice it would be necessary to have animals tolerant to all the major human transplantation antigens and this seems to be impossible. Also, tolerance in heterologous relationship cannot be fully individual-specific,15 and sc the ability of the animal to distinguish small antigenic differences may just be the same as that of the normal animal, CONCLUSIONS
The immunological treatment of cancer is of great theoretical interest but there seems, as yet, little possibility of a practical application. The most hopeful procedure would seem to be to immunise the patient with a very small amount of tumour antigen (but not the living cells of his own tumour) after the bulk of the malignant growth has been removed by surgery. Two clinical observations support the possibility that the immune apparatus had been rendered ineffective by the large mass of primary tumour. After the removal of a choriocarcinoma 29 and the Grawitz tumour of kidney, 30 lung metastases disappeared in both cases. Whole-body irradiation and cytotoxic drugs, which will reduce the patients’ own reactivity, must be used with great care. Similarly, passive immunisation with an antiserum or active immunisation with large amounts of tumour antigen, with the attendant dangers of enhancement or immunological paralysis, should not be used. It has been shown for bacterial antigens,31 transplantation antigens,32 and tumour-specific antigens,33 that immune cells can be sensitised in vitro and can then react From these observations arises a new specifically. possibility-that of sensitising specifically the patient’s own immune cells in vitro against his cancer and injecting these cells directly against tumour and metastases after as much tumour tissue as possible has been removed at
operations. Procedures which stimulate the reticuloendothelial system generally-e.g., B.C.G., non-specific protein, and vitamin B12-may be used to promote the immunological response. 27. 28. 29. 30. 31. 32. 33.
Levi, E., Schechtman, A. M., Sherins, R. S., Tobias, S. Nature, Lond. 1959, 184, 563. Zilber, L. A., Krjukova, I. N., Narcissov, N. V., Birjulina, T. I. Probl. Oncol. 1958, 4, 285. Bardawill, W. A., Toy, B. L. Ann. N. Y. Acad. Sci. 1959, 80, 197. Arcomano, J. P., Barnett, J. C., Bottone, J. J. Am. J. Surg. 1958, 96, 703. Harris, S., Harris, T. N. J. Immun. 1955, 74, 318. Ginsburg, H., Sachs, L. J. cell. comp. Physiol. 1965, 66, 199. Koldovsky, P. Symposium of the International Union against Cancer. Munksgaard, 1966.
Probably, many tumours will eventually respond to immunological treatment, but overenthusiastic clinical experimentation now may result in failures and thus hinder the fundamental research, which, given time, will provide satisfactory answers. I thank Dr. D. M. V. Parrott and Dr. R. J. C. Harris for helpful discussions. Requests for reprints should be addressed to P. K. at the Division of Experimental Biology and Virology, Imperial Cancer Research Fund, Burtonhole Lane, London, N.W.7.
Parliament Teaching Hospital and Medical School for Wessex Region? ON March 8 Mr. DAVID PRICE pointed out that the Wessex region was unique in not having its own teaching hospital and medical school. He contended that the hospital board’s plan to build two new large hospitals in Southampton would be admirably suited to meet the needs of a teaching hospital, and that the University of Southampton already possessed the academic infrastructure for a medical school, since it was capable of providing most preclinical courses and was already undertaking a considerable amount of postgraduate work. Sir JOHN FLETCHER-COOKE recalled that the Wessex region already provided general and specialist courses for doctors who had been practising for many years and who wanted to keep abreast of recent developments. It also provided 9 postgraduate training centres, which had already received capital grants totalling E120,000. The only thing missing was the undergraduate stage. Mr. KENNETH ROBINSON, the Minister of Health, said that unless and until a decision was made to establish a medical school in the region, the need for a teaching hospital as such did not arise. He drew attention to the close academic association which had developed between the Wessex region and the University of London and the medical schools of St. Thomas’s, Westminster, and St. George’s Hospitals. A comprehensive service to patients was available at district hospitals, and specialised regional services had been developed which, in the old days, would perhaps have been provided only at a teaching hospital. However, he promised that the arguments put forward in favour of a new medical school and teaching hospital would not be overlooked. So far, apart from the Nottingham scheme, no decision had been taken to set up an additional school either at Hull or anywhere else.
Royal Assent On March 10 the Royal Assent was given to the National Insurance Act, 1966, and the National Health Service Act, 1966.
QUESTION
TIME
Royal Commission on Medical Education Mr. A. P. DEAN asked the Prime Minister when the Royal Commission on Medical Education would complete its work.The PRIME MINISTER replied: I hope within about 2 years. From
April
1
Preclinical Salaries salaries for university teachers will
preclinical
range as follows: Lecturers.-f,1470 to maxima ranging from C2630 to f,3415. Senior lecturers and readers.-Salaries within the new maxima for preclinical lecturers.
Patients and Doctors The estimated average number of patients on the lists of doctors providing full general medical services in England and wnli-q
at
The
()r1" 1 W’’’’’
possible
fc%lln-,Vq-
figures will be slightly smaller since it is not eliminate all duplicate entries from doctors’ lists.
true to
ac
looked. The whole project is an exercise in human relations. In his essay Sir Bruce Fraser1 went on to say: "
Just as you cannot make people good by Act of Parliament, you cannot make people cooperative by Ministry circular. The Ministry can exhort, advise, facilitate: it cannot compel cooperation, which is more an attitude of mind than an administrative procedure. If the parties concerned don’t like each other’s faces, don’t believe in what they’re doing or don’t believe that the other parties believe in what they’re doing; if, above all, they are not being spurred on by the forces of national and local public opinion, then cooperation may be grudging and efficiency may be patchy." so
We are particularly grateful to the members of the medical planning liaison committee who have continued to support and encourage us, but neither they nor the bodies they represent are in any way committed to our views. We should like to thank our colleagues Dr. J. A. D. Anderson, Dr. P. Draper, Mr. M. Wadsworth, and many others who have helped to formulate our views in both formal and informal discussion and have read and criticised many drafts of this paper; Mr. Martin Hackett of the planning department of the G.L.C. and his colleagues and predecessors for their patience and cooperation; Mr. Brian Brookes for the diagrams; and Miss Helen Blackburn our indefatigable secretary. Finally, we must acknowledge our indebtedness to the Nuffield Foundation for a generous grant. Requests for reprints should be addressed to R. S.
immunological paralysis instead of resistance. The possibility of inducing non-reactivity in immunologically mature organisms also depends on the strength (or phylogenetic closeness) of the antigen used. In general, weaker or phylogenetically closer antigens can more easily induce such non-reactivity.15 Tumour-specific antigens are very weak and the danger of inducing non-reactivity is extremely high. On the other hand, very small doses of such antigens can provoke a sufficient degree of resistance. Non-specific stimulation can again help in this situation, but inhibition of the immune system of the host by, for example, antimitotic substances can have a deleterious the progress of the disease.16s Increased Immunoresistance Neither the antigenicity of a tumour nor the sensitivity of its cells to immunodestruction remain constant. Some workers have shown that, although a tumour-specific antigen may persist during repeated transplantation in syngeneic hosts, 17 18 there is a quantitative reduction in antigenicity. If tumours are forced to grow against the resistance of an immunised host then not only is there a more pronounced reduction of antigenicity 19 but the
influence
tumour
DANGERS AND LIMITATIONS OF THE IMMUNOLOGICAL TREATMENT OF CANCER P. KOLDOVSKY M.D. Prague OF THE INSTITUTE OF EXPERIMENTAL BIOLOGY AND
CZECHOSLOVAK ACADEMY OF
GENETICS, SCIENCES, PRAGUE, 6*
SOME experimentally induced tumours have antigens which are specific for the tumours and are not present in the host; and such tumours can be destroyed by immunological mechanisms comparable with an autoimmune reaction.12 These findings have reawakened interest in the possibility of treating cancer by immunological methods, and there are several reports of clinical observations and theoretical speculations on immunological treatment (reviewed by Southam 13). Nevertheless, there is substantial experimental evidence for the dangers and limitations of such treatment, and it is important that these should be stressed at this time. DANGERS AND LIMITATIONS
Weak Response by the Host The vigour and speed of the immunological response of the host to a grafted tumour is dependent upon the strength of the antigenic stimulation. Some mouse tumours can also overcome strong immune barriers based on the H-2 locus-controlled interstrain differences.12 But even the strongest tumour-specific antigen is extremely weak in comparison with H-2 locus antigens. Thus, any host response will be feeble, slow, and possibly insufficient to
destroy
a
rapidly growing
tumour.
However,
some
results show that the use of specific or non-specific stimulation can accelerate and increase the immune
against tumour antigens.14 Induction of Immunological Paralysis
response
even
There must be very close contact between the host’s immunologically competent cells and the tumour antigen lest the large dose used for immunisation should induce * Present
appointment: research fellow, Division of Experimental Biology
and Virology, Imperial Cancer Research Fund, London, N.W.7. 12. Hellstrom, K. E., Moller, G. Progr. Allergy, 1965, 9, 158. 13. Southam, C. M. Cancer Res. 1960, 20, 271. 14. Old, L. J., Benacerraf, B., Clarke, D. A., Carswell, E. A., Stockert, E. ibid. 1961, 21, 1281.
on
itself may become
more
immunoresistant.20
Possibly, then, even a slowly growing antigenic tumour might eventually become more virulent and fatal because of the progressive selection of less immunogenic and more immunoresistant clones of malignant cells. Increased Growth of Tumour As early as 1907, Flexner and Jobling 21 showed that prior immunisation may facilitate the growth of an allogeneic tumour. Later, it was shown that this response can be provoked by either allogeneic or heterogeneic antiserum .22 The generally accepted explanation of this paradoxical immunological enhancement is that serumantibodies coat the tumour cells in such way as to reduce both their immunogenicity and immunosensitivity. Changes in the host may play a role 23 and enhancement against a weak tumour antigen is also possible. 24 The dangers of enhancing the growth of tumours in man by unsuitable treatment have been discussed by Batchelor and Tuffrey.25
Limitations of Immunisation Immunisation in a heterologous relationship was first considered by Hericourt and Richet.26 The use of immune " serum is dangerous and very ineffective but, on the other hand, immune cells play the dominant role in transplantation immunity, so that attention was later attracted to the use of heterologous immune cells. But the present knowledge of immunity mechanisms does not confirm that this will be useful. Even in such a close heterologous relationship as rat and mouse, the rat cannot distinguish individual differences in transplantation antigens between various strains of mice. This means that the allogeneic reaction has a greater potential for antigenic discrimination than the heterologous relationship. If a heterologous organism cannot distinguish and react specifically against strong transplantation antigens, then it "
15. 16. 17.
Hasek, M., Lengerova, A., Hraba, T. Adv. Immun. 1961, 1, 1. Southam, C. M. Cancer Res. 1961, 21, 1302. Globerson, A., Feldman, M. J. natn. Cancer Inst. 1964, 32, 1229. 18. Harris, R. J. C. Symposium of the International Union against Cancer. Munksgaard, 1966. 19. Sjogren, H. O. J. natn. Cancer Inst. 1964, 32, 661. 20. Koldovsky, P., Svoboda, J. Folia biol. 1962, 8, 144. 21. Flexner, S., Jobling, W. Proc. Soc. exp. Biol. Med. 1907, 5, 16. 22. Kaliss, N. Cancer Res. 1958, 18, 992. 23. Moller, G. Transplantation, 1964, 2, 405. 24. Bubenik, J., Koldovsky, P. Folia biol. 1964, 10, 427. 25. Batchelor, J. R., Tuffrey, M. A. Lancet, 1964, i, 613. 26. Hericourt, J., Richet, C. C. r. Acad. Sci., Paris, 1895, 21, 373.
655
is difficult to hope for specific recognition and reaction against extremely weak tumour antigens, without, at the same time, endangering normal tissue. The possibility of using heterologous cells from pre-
immunised animals is excluded for
_
a further reason. The of so-called in the recipient natural antibodies presence will tend to inhibit the function of the injected organism cells and in a few heterologous days specific cytotoxic and antibodies will cytolytic appear which will eliminate the cells. Some effect foreign might be expected from antibound to the bodies heterologous cells but these will alsc soon be eliminated by a specific host-reaction. Lately, some work has been done on the use of heterologous immunisation." 18 The idea is based on the discovery of immunological tolerance, for it was expected that an animal tolerant to normal antigens will still read
against tumour-specific antigens. Theoretically, a monospecific reaction would be expected. But it is not easy tc have animals fully tolerant to all transplantation antigens in heterologous relationship. No-one has yet succeeded in using such a heterologous relationship as man and animal. In practice it would be necessary to have animals tolerant to all the major human transplantation antigens and this seems to be impossible. Also, tolerance in heterologous relationship cannot be fully individual-specific,15 and sc the ability of the animal to distinguish small antigenic differences may just be the same as that of the normal animal, CONCLUSIONS
The immunological treatment of cancer is of great theoretical interest but there seems, as yet, little possibility of a practical application. The most hopeful procedure would seem to be to immunise the patient with a very small amount of tumour antigen (but not the living cells of his own tumour) after the bulk of the malignant growth has been removed by surgery. Two clinical observations support the possibility that the immune apparatus had been rendered ineffective by the large mass of primary tumour. After the removal of a choriocarcinoma 29 and the Grawitz tumour of kidney, 30 lung metastases disappeared in both cases. Whole-body irradiation and cytotoxic drugs, which will reduce the patients’ own reactivity, must be used with great care. Similarly, passive immunisation with an antiserum or active immunisation with large amounts of tumour antigen, with the attendant dangers of enhancement or immunological paralysis, should not be used. It has been shown for bacterial antigens,31 transplantation antigens,32 and tumour-specific antigens,33 that immune cells can be sensitised in vitro and can then react From these observations arises a new specifically. possibility-that of sensitising specifically the patient’s own immune cells in vitro against his cancer and injecting these cells directly against tumour and metastases after as much tumour tissue as possible has been removed at
operations. Procedures which stimulate the reticuloendothelial system generally-e.g., B.C.G., non-specific protein, and vitamin B12-may be used to promote the immunological response. 27. 28. 29. 30. 31. 32. 33.
Levi, E., Schechtman, A. M., Sherins, R. S., Tobias, S. Nature, Lond. 1959, 184, 563. Zilber, L. A., Krjukova, I. N., Narcissov, N. V., Birjulina, T. I. Probl. Oncol. 1958, 4, 285. Bardawill, W. A., Toy, B. L. Ann. N. Y. Acad. Sci. 1959, 80, 197. Arcomano, J. P., Barnett, J. C., Bottone, J. J. Am. J. Surg. 1958, 96, 703. Harris, S., Harris, T. N. J. Immun. 1955, 74, 318. Ginsburg, H., Sachs, L. J. cell. comp. Physiol. 1965, 66, 199. Koldovsky, P. Symposium of the International Union against Cancer. Munksgaard, 1966.
Probably, many tumours will eventually respond to immunological treatment, but overenthusiastic clinical experimentation now may result in failures and thus hinder the fundamental research, which, given time, will provide satisfactory answers. I thank Dr. D. M. V. Parrott and Dr. R. J. C. Harris for helpful discussions. Requests for reprints should be addressed to P. K. at the Division of Experimental Biology and Virology, Imperial Cancer Research Fund, Burtonhole Lane, London, N.W.7.
Parliament Teaching Hospital and Medical School for Wessex Region? ON March 8 Mr. DAVID PRICE pointed out that the Wessex region was unique in not having its own teaching hospital and medical school. He contended that the hospital board’s plan to build two new large hospitals in Southampton would be admirably suited to meet the needs of a teaching hospital, and that the University of Southampton already possessed the academic infrastructure for a medical school, since it was capable of providing most preclinical courses and was already undertaking a considerable amount of postgraduate work. Sir JOHN FLETCHER-COOKE recalled that the Wessex region already provided general and specialist courses for doctors who had been practising for many years and who wanted to keep abreast of recent developments. It also provided 9 postgraduate training centres, which had already received capital grants totalling E120,000. The only thing missing was the undergraduate stage. Mr. KENNETH ROBINSON, the Minister of Health, said that unless and until a decision was made to establish a medical school in the region, the need for a teaching hospital as such did not arise. He drew attention to the close academic association which had developed between the Wessex region and the University of London and the medical schools of St. Thomas’s, Westminster, and St. George’s Hospitals. A comprehensive service to patients was available at district hospitals, and specialised regional services had been developed which, in the old days, would perhaps have been provided only at a teaching hospital. However, he promised that the arguments put forward in favour of a new medical school and teaching hospital would not be overlooked. So far, apart from the Nottingham scheme, no decision had been taken to set up an additional school either at Hull or anywhere else.
Royal Assent On March 10 the Royal Assent was given to the National Insurance Act, 1966, and the National Health Service Act, 1966.
QUESTION
TIME
Royal Commission on Medical Education Mr. A. P. DEAN asked the Prime Minister when the Royal Commission on Medical Education would complete its work.The PRIME MINISTER replied: I hope within about 2 years. From
April
1
Preclinical Salaries salaries for university teachers will
preclinical
range as follows: Lecturers.-f,1470 to maxima ranging from C2630 to f,3415. Senior lecturers and readers.-Salaries within the new maxima for preclinical lecturers.
Patients and Doctors The estimated average number of patients on the lists of doctors providing full general medical services in England and wnli-q
at
The
()r1" 1 W’’’’’
possible
fc%lln-,Vq-
figures will be slightly smaller since it is not eliminate all duplicate entries from doctors’ lists.
true to
ac