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A BLOOD-LYMPHOCYTE TEST FOR CANCER?
327
culture, but it is nevertheless of low reactivity and in either even it should be used with children or adults,26, 27 although caution in pregnancy.2dThe attenuated virus does not seem to be transmitted to the contacts of vaccinated persons and the vaccine has been used widely in the U.S.A. since 1968. There are a few contraindications minor side-effects
are
uncommon
injection-such as hypersensitivity to egg protein and neomycin, and conditions liable to impair the immunological response-but, in short, the vaccine has largely fulfilled its early promise.20-31 However, mumps is usually a mild, if unpleasant, disease of childhood and as many as 30", of cases are subclinical 32; its prevention by vaccination can be justified only if the illness carries a substantial risk of important complications or if the vaccine is completely to
its
safe. The
common
complications
are
orchitis
and
aseptic meningitis, and data on their frequency have been gained in a survey by the research unit of the Royal College of General Practitioners (unpublished). Orchitis, which is usually unilateral, complicated 9%, of cases in males over 14 years of age. Orchitis is painful, but is usually relieved by corticosteroids and, although some testicular atrophy often
about
results, sterility is very rare.33 Aseptic meningitis (often referred to as mumps encephalitis) developed in 2-4% of cases, but uneventful recovery is usual in this condition. Deafness is sometimes a sequel to mumps, but its incidence is undoubtedly low, and other more serious complications, such as pancreatitis, myocarditis, and severe encephalitis with coma, are very rare. Neither the frequency nor the severity of complications therefore provides strong justification for recommending mumps vaccination for all children. The dangers of live mumps vaccine are theoretical rather than real. Thus, it cannot be certain that live vaccines are completely free from contaminating viruses, but this possibility is small with the use of leucosis-free chickens as a source of the embryo tissue in which the virus is grown, and with the stringent safety precautions nowadays required.34 Perhaps a greater danger is that vaccine-induced immunity may wane in time, leaving susceptible adults in whom mumps is likely to be more serious than in childhood. If infection does develop after vaccination, conceivably it may occasionally follow a severe, atypical pattern, as has been observed after killed and live measles vaccine 35-37 and killed respiratory-syncytialvirus vaccine. 38 There is no evidence to suggest that such fears about mumps vaccine have any basis in fact, but they cannot be disregarded. 26. 27. 28. 29.
30. 31. 32. 33.
34. 35. 36. 37. 38.
Nickey, L.N., Huchton, P., McGee, W. G. Sth. med.J. 1970, 63, 306. Davidson, W. L., Buynak, E. B., Leagus, M. B., Whitman, J. E., Hilleman, M. R. J. Am. med. Ass. 1967, 201, 995. Yamauchi, T., Wilson, C., St. Geme, J. W. New Engl. J. Med. 1974, 290, 710. British Medical Journal, 1967, i, 779. Lancet, 1968, ii, 1022. ibid. 1969, i, 1302. Mumps Surveillance Report No. 2. U.S. Department of Health, Education and Welfare, September, 1972. Christie, A. B. Infectious Diseases: Epidemiology and Clinical Practice; p. 435. Edinburgh, 1969. Perkins, F. T. Br. med. Bull. 1969, 25, 208. Fulginiti, V. A., Kempe, C. H. Lancet, 1967, ii, 468. Brodsky, A. L. J. Am. med. Ass. 1972, 222, 1415. Cherry, J. D., Feigin, R. D., Lobes, A., Shackelford, P. G. Pediatrics, 1972, 50, 712. Lancet, 1969, ii, 311.
There are a number of ways in which mumps vaccine might be used. It could be offered to all children to try to control or eliminate the disease. It has been used in this way with some success both in the U.S.S.R.,39 where the first mumps vaccines were prepared as early as 1954, and in the State of Massachusetts.4o° Should preparations suitable for administration by mouth 39 or nose 41 become available, such widespread vaccination might become more generally acceptable. Alternatively, the recommendations of the U.S. Department of Health may be followed-it suggests that, whilst vaccine may be used at any age over 1 year and is of particular value in older children and adults who have not had mumps, vaccination " should not be allowed to take priority over more essential ongoing community health activities 11.122 The vaccine might be considered for selective vaccination in individuals or groups thought to be at special risk. Thus in Finland and in India killed mumps vaccine was effective in protecting Army recruits for up to a year.43, 44Live vaccine has also been used to control outbreaks, and when given to an exposed population has prevented further cases from about four weeks after administration.39, 45 In the United Kingdom there is not much demand for mumps vaccination and there seems little reason to contemplate its general use until there is clear evidence on long-term safety, which should be forthcoming as experience is gained in countries where the vaccine is widely used-mainly the U.S.S.R. and the U.S.A. Until then, vaccination will probably be limited to the prevention of mumps in individuals or groups at special risk. It might be justified, for example, in military groups where many cases of orchitis could seriously impair efficiency-about 20° of young men may be expected to have escaped clinical or subclinical infection and therefore be susceptible to infection.33 Protection of children due for admission to hospital for important major surgery may sometimes be advisable, and, if used promptly, vaccination might be of use on occasion to control outbreaks in residential institutions.
A BLOOD-LYMPHOCYTE TEST FOR CANCER? ABOUT one in four human-beings has overt neoplasia some time in life. In addition, many take undiagnosed microscopic or latent neoplastic or preneoplastic foci to their graves. The ultimate in tests would be one that identified individuals with a single neoplastic or preneoplastic focus anywhere in the body; but 39. Smorodintsev, A. A., Nasibov, M. N. in Proceedings of a Conference on the Application of Vaccines against Viral, Rickettsial, and Bacterial Diseases of Man; p. 220. Pan American Health Organisation Scientific Publication No. 226. Washington, D.C., 1971. 40. Fiumara, N. J. ibid. p. 225. 41. Yamanishi, K., Takahashi, M., Kurimura, T., Ueda, S., Suzuki, N., Baba, K., Okuno, Y. Biken’s J. 1971, 14, 259. 42. U.S. Public Health Service Advisory Committee on Immunisation Practice Recommendations, Mumps Vaccine; p. 13. Morbidity and Mortality, 21, No. 25, September, 1972. 43. Penttinen, K., Cantell, K., Somer, P., Poikolainen, A. Am. J. Epidem. 1968, 88, 234. 44. Sood, Y. P. Indian J. med. Res. 1968, 56, 234. 45. Maynard, J. E., Shramek, G., Noble, G. R., Deinhardt, T., Clark, P. Am. J. Epidem. 1970, 92, 301.
328 such a test would have little practical value unless two lilies, each with the other. The difference in better methods of locating small lesions were devised. response of lymphocytes, in terms of s.c.M. either In the case of some latent cancers and preneoplastic to P.H.A. alone or to C.B.P. alone, seems almost foci, the information most needed concerns whether enough to distinguish between persons with and to be latent and and when they will cease without overt cancer. Cercek et al. included only 2 begin to the end of the At other cases of premalignant conditions in their investigation sensitivity spectrum grow. would come tests that distinguish individuals who - one case of polyposis coli and one of hyperkeratosis advanced have disease of the skin. Both responded to C.B.P. with a decrease relatively already malignant from those who are ill for some other reason. A reliable in s.c.M. in the same way as patients with established test of this kind would have diagnostic value in certain The polyposis case responded with an cancers. circumstances. L. Cercek, B. Cercek, and C. 1. V. increase in s.c.M. to P.H.A. and the hyperkeratosis case Franklin 1,2have now described the so-called S.C.M. responded with decreased s.c.M. to P.H.A, i.e., which fall into this in the same way as a normal individual. Obviously, test, may category. more information is needed about the response of s.c.M. is short for " structuredness of cytoplasmic patients with precancerous or early cancerous lesions matrix ", and changes in s.c.M. are measured by before one can form a clear idea of the practical value fluorescence polarisation after excitation of fluorescein of the s.c.M. test. Also one would like to know whether molecules liberated in the cytoplasm from a nonthe response pattern of lymphocytes reverts to normal fluorescent substrate by enzymatic hydrolysis.Cercek when cancer is completely eradicated. et al. found that lymphocytes from normal subjects and from patients with chronic lymphatic leukaemia show differences in s.c.M. when exposed to the mitoThey genic agent, phytohsemagglutinin (P.H.A.). CONCERN FOR QUALITY wondered whether other forms of malignant disease are associated with the presence of lymphocytes which IN April the Commonwealth Medical Association develop abnormal S.C.M. in response to P.H.A. And urged its members to take all necessary steps to remove they wondered, too, whether exposure to antigens preventable causes of medical migration from developsuch as the " cancer basic protein " (C.B.P.) and the ing to developed countries.’1 Similar commitments and had been entered into at previous C.M.A. meetings, " encephalitogenic agent" (E.F.) described by Field Caspary,4 instead of to P.H.A., would lead to S.C.M. yet the lopsided brain drain goes on. Dependence on medical immigration is just as great in the United changes in lymphocytes from normal subjects or States2 as it is in Britain and some other European patients with cancers or other diseases. Lymphocytes derived from 70 out of 71 supposedly healthy donors countries.3 Some critics see this as a form of piracy, and from all of 17 patients with non-neoplastic and certainly when the cost of medical education is diseases responded to P.H.A., as expected, by an taken into account the importation of foreign-trained immediate decrease in s.c.M. to 79% of the control doctors goes a long way towards offsetting the medical 41 whereas from none of and other aid which countries such as Britain and the value, lymphocytes patients known to have neoplastic disease (of breast, bladder, United States provide. However, most foreign medical oral bone, brain, ovary, uterus, larynx, cavity, lung, graduates come to a country with a more fully developed in and so showed decrease s.c.M. in resskin, on) any system of health care and research to acquire postto In 1 of P.H.A. case pharyngeal carcinoma, ponse graduate experience; they like what they find, and showed increased s.c.M. then the wandering scholar becomes the emigre. That blood-lymphocytes actually on exposure to P.H.A. By contrast, lymphocytes from dependence is untenable is now widely recognised by 41 and from of 1 out of none only healthy subjects, many richer nations, but their own targets of self17 patients with non-neoplastic diseases, showed sufficiency are proving very elusive, and so long as decreased S.C.M. in response to C.B.P., whereas this is so the medical staffing problems of the developwith from all of 41 derived lymphocytes patients ing world can only be helped by imposing harsh restrictions at one or both ends of the brain drain. neoplastic disease showed decreased s.c.M. in response to this " antigen ". Similarly, decrease in s.c.M. was One factor that could pressure Governments into seen in response to E.F. in all of 6 cancer patients tested tackling the goal of self-sufficiency more energetically but in none of 6 healthy subjects. is a concern about the quality of the foreign medical On the face of it these findings seem to provide the graduate-not just his clinical or academic competence but also his language ability and his understanding of basis of tests that will permit accurate and clearcut how different health-care systems work. Mutterings distinction between patients with overt malignant about the quality of foreign medical graduates have diseases and patients with non-neoplastic diseases or for some time been heard on both sides of the Atlantic, no disease at all. Cercek and his colleagues suggest but now, in a burst of exposure, the issue is out in the that a test for cancer could be based on the ratio of the responses of lymphocytes to C.B.P. and to open. In America a group from Harvard warns of a return to pre-Flexner standards 4,5; and in Britain a could this be said to be P.H.A., although gilding Cercek, L., Cercek, B., Garrett, J. V. in Lymphocytic Recognition and Effector Mechanisms (edited by K. Lindahl-Kiessling and K. Osoba); p. 553. New York, 1974. 2. Cercek, L., Cercek, B., Franklin, C. I. V. Br. J. Cancer, 1974, 29, 1.
1. Br. med. J. 1974, ii, suppl. p. 70. 2. Foreign Medical Graduates in America.
3. 4.
345. 3. 4.
Cercek, L., Cercek, B., Ockey, C. H. Biophysik, 1973, 10, 187. Field, E. J., Caspary, E. A. Lancet, 1970, ii, 1337.
5.
By PATRICIO R. MARMOT. Springfield, Illinois: Charles C. Thomas, 1974. Pp. 181. $8.50. Lancet, 1973, ii, 1367. Weiss, R. J., Kleinman, J. C., Brandt, U. C., Fledman, J. J., McGuiness, A. C. New Engl.J. Med. 1974, 290, 1408. Weiss, R. J., Kleinman, J. C., Brandt, U. C., Felsenthal, D. S. ibid. 1974, 290, 1453.
culture, but it is nevertheless of low reactivity and in either even it should be used with children or adults,26, 27 although caution in pregnancy.2dThe attenuated virus does not seem to be transmitted to the contacts of vaccinated persons and the vaccine has been used widely in the U.S.A. since 1968. There are a few contraindications minor side-effects
are
uncommon
injection-such as hypersensitivity to egg protein and neomycin, and conditions liable to impair the immunological response-but, in short, the vaccine has largely fulfilled its early promise.20-31 However, mumps is usually a mild, if unpleasant, disease of childhood and as many as 30", of cases are subclinical 32; its prevention by vaccination can be justified only if the illness carries a substantial risk of important complications or if the vaccine is completely to
its
safe. The
common
complications
are
orchitis
and
aseptic meningitis, and data on their frequency have been gained in a survey by the research unit of the Royal College of General Practitioners (unpublished). Orchitis, which is usually unilateral, complicated 9%, of cases in males over 14 years of age. Orchitis is painful, but is usually relieved by corticosteroids and, although some testicular atrophy often
about
results, sterility is very rare.33 Aseptic meningitis (often referred to as mumps encephalitis) developed in 2-4% of cases, but uneventful recovery is usual in this condition. Deafness is sometimes a sequel to mumps, but its incidence is undoubtedly low, and other more serious complications, such as pancreatitis, myocarditis, and severe encephalitis with coma, are very rare. Neither the frequency nor the severity of complications therefore provides strong justification for recommending mumps vaccination for all children. The dangers of live mumps vaccine are theoretical rather than real. Thus, it cannot be certain that live vaccines are completely free from contaminating viruses, but this possibility is small with the use of leucosis-free chickens as a source of the embryo tissue in which the virus is grown, and with the stringent safety precautions nowadays required.34 Perhaps a greater danger is that vaccine-induced immunity may wane in time, leaving susceptible adults in whom mumps is likely to be more serious than in childhood. If infection does develop after vaccination, conceivably it may occasionally follow a severe, atypical pattern, as has been observed after killed and live measles vaccine 35-37 and killed respiratory-syncytialvirus vaccine. 38 There is no evidence to suggest that such fears about mumps vaccine have any basis in fact, but they cannot be disregarded. 26. 27. 28. 29.
30. 31. 32. 33.
34. 35. 36. 37. 38.
Nickey, L.N., Huchton, P., McGee, W. G. Sth. med.J. 1970, 63, 306. Davidson, W. L., Buynak, E. B., Leagus, M. B., Whitman, J. E., Hilleman, M. R. J. Am. med. Ass. 1967, 201, 995. Yamauchi, T., Wilson, C., St. Geme, J. W. New Engl. J. Med. 1974, 290, 710. British Medical Journal, 1967, i, 779. Lancet, 1968, ii, 1022. ibid. 1969, i, 1302. Mumps Surveillance Report No. 2. U.S. Department of Health, Education and Welfare, September, 1972. Christie, A. B. Infectious Diseases: Epidemiology and Clinical Practice; p. 435. Edinburgh, 1969. Perkins, F. T. Br. med. Bull. 1969, 25, 208. Fulginiti, V. A., Kempe, C. H. Lancet, 1967, ii, 468. Brodsky, A. L. J. Am. med. Ass. 1972, 222, 1415. Cherry, J. D., Feigin, R. D., Lobes, A., Shackelford, P. G. Pediatrics, 1972, 50, 712. Lancet, 1969, ii, 311.
There are a number of ways in which mumps vaccine might be used. It could be offered to all children to try to control or eliminate the disease. It has been used in this way with some success both in the U.S.S.R.,39 where the first mumps vaccines were prepared as early as 1954, and in the State of Massachusetts.4o° Should preparations suitable for administration by mouth 39 or nose 41 become available, such widespread vaccination might become more generally acceptable. Alternatively, the recommendations of the U.S. Department of Health may be followed-it suggests that, whilst vaccine may be used at any age over 1 year and is of particular value in older children and adults who have not had mumps, vaccination " should not be allowed to take priority over more essential ongoing community health activities 11.122 The vaccine might be considered for selective vaccination in individuals or groups thought to be at special risk. Thus in Finland and in India killed mumps vaccine was effective in protecting Army recruits for up to a year.43, 44Live vaccine has also been used to control outbreaks, and when given to an exposed population has prevented further cases from about four weeks after administration.39, 45 In the United Kingdom there is not much demand for mumps vaccination and there seems little reason to contemplate its general use until there is clear evidence on long-term safety, which should be forthcoming as experience is gained in countries where the vaccine is widely used-mainly the U.S.S.R. and the U.S.A. Until then, vaccination will probably be limited to the prevention of mumps in individuals or groups at special risk. It might be justified, for example, in military groups where many cases of orchitis could seriously impair efficiency-about 20° of young men may be expected to have escaped clinical or subclinical infection and therefore be susceptible to infection.33 Protection of children due for admission to hospital for important major surgery may sometimes be advisable, and, if used promptly, vaccination might be of use on occasion to control outbreaks in residential institutions.
A BLOOD-LYMPHOCYTE TEST FOR CANCER? ABOUT one in four human-beings has overt neoplasia some time in life. In addition, many take undiagnosed microscopic or latent neoplastic or preneoplastic foci to their graves. The ultimate in tests would be one that identified individuals with a single neoplastic or preneoplastic focus anywhere in the body; but 39. Smorodintsev, A. A., Nasibov, M. N. in Proceedings of a Conference on the Application of Vaccines against Viral, Rickettsial, and Bacterial Diseases of Man; p. 220. Pan American Health Organisation Scientific Publication No. 226. Washington, D.C., 1971. 40. Fiumara, N. J. ibid. p. 225. 41. Yamanishi, K., Takahashi, M., Kurimura, T., Ueda, S., Suzuki, N., Baba, K., Okuno, Y. Biken’s J. 1971, 14, 259. 42. U.S. Public Health Service Advisory Committee on Immunisation Practice Recommendations, Mumps Vaccine; p. 13. Morbidity and Mortality, 21, No. 25, September, 1972. 43. Penttinen, K., Cantell, K., Somer, P., Poikolainen, A. Am. J. Epidem. 1968, 88, 234. 44. Sood, Y. P. Indian J. med. Res. 1968, 56, 234. 45. Maynard, J. E., Shramek, G., Noble, G. R., Deinhardt, T., Clark, P. Am. J. Epidem. 1970, 92, 301.
328 such a test would have little practical value unless two lilies, each with the other. The difference in better methods of locating small lesions were devised. response of lymphocytes, in terms of s.c.M. either In the case of some latent cancers and preneoplastic to P.H.A. alone or to C.B.P. alone, seems almost foci, the information most needed concerns whether enough to distinguish between persons with and to be latent and and when they will cease without overt cancer. Cercek et al. included only 2 begin to the end of the At other cases of premalignant conditions in their investigation sensitivity spectrum grow. would come tests that distinguish individuals who - one case of polyposis coli and one of hyperkeratosis advanced have disease of the skin. Both responded to C.B.P. with a decrease relatively already malignant from those who are ill for some other reason. A reliable in s.c.M. in the same way as patients with established test of this kind would have diagnostic value in certain The polyposis case responded with an cancers. circumstances. L. Cercek, B. Cercek, and C. 1. V. increase in s.c.M. to P.H.A. and the hyperkeratosis case Franklin 1,2have now described the so-called S.C.M. responded with decreased s.c.M. to P.H.A, i.e., which fall into this in the same way as a normal individual. Obviously, test, may category. more information is needed about the response of s.c.M. is short for " structuredness of cytoplasmic patients with precancerous or early cancerous lesions matrix ", and changes in s.c.M. are measured by before one can form a clear idea of the practical value fluorescence polarisation after excitation of fluorescein of the s.c.M. test. Also one would like to know whether molecules liberated in the cytoplasm from a nonthe response pattern of lymphocytes reverts to normal fluorescent substrate by enzymatic hydrolysis.Cercek when cancer is completely eradicated. et al. found that lymphocytes from normal subjects and from patients with chronic lymphatic leukaemia show differences in s.c.M. when exposed to the mitoThey genic agent, phytohsemagglutinin (P.H.A.). CONCERN FOR QUALITY wondered whether other forms of malignant disease are associated with the presence of lymphocytes which IN April the Commonwealth Medical Association develop abnormal S.C.M. in response to P.H.A. And urged its members to take all necessary steps to remove they wondered, too, whether exposure to antigens preventable causes of medical migration from developsuch as the " cancer basic protein " (C.B.P.) and the ing to developed countries.’1 Similar commitments and had been entered into at previous C.M.A. meetings, " encephalitogenic agent" (E.F.) described by Field Caspary,4 instead of to P.H.A., would lead to S.C.M. yet the lopsided brain drain goes on. Dependence on medical immigration is just as great in the United changes in lymphocytes from normal subjects or States2 as it is in Britain and some other European patients with cancers or other diseases. Lymphocytes derived from 70 out of 71 supposedly healthy donors countries.3 Some critics see this as a form of piracy, and from all of 17 patients with non-neoplastic and certainly when the cost of medical education is diseases responded to P.H.A., as expected, by an taken into account the importation of foreign-trained immediate decrease in s.c.M. to 79% of the control doctors goes a long way towards offsetting the medical 41 whereas from none of and other aid which countries such as Britain and the value, lymphocytes patients known to have neoplastic disease (of breast, bladder, United States provide. However, most foreign medical oral bone, brain, ovary, uterus, larynx, cavity, lung, graduates come to a country with a more fully developed in and so showed decrease s.c.M. in resskin, on) any system of health care and research to acquire postto In 1 of P.H.A. case pharyngeal carcinoma, ponse graduate experience; they like what they find, and showed increased s.c.M. then the wandering scholar becomes the emigre. That blood-lymphocytes actually on exposure to P.H.A. By contrast, lymphocytes from dependence is untenable is now widely recognised by 41 and from of 1 out of none only healthy subjects, many richer nations, but their own targets of self17 patients with non-neoplastic diseases, showed sufficiency are proving very elusive, and so long as decreased S.C.M. in response to C.B.P., whereas this is so the medical staffing problems of the developwith from all of 41 derived lymphocytes patients ing world can only be helped by imposing harsh restrictions at one or both ends of the brain drain. neoplastic disease showed decreased s.c.M. in response to this " antigen ". Similarly, decrease in s.c.M. was One factor that could pressure Governments into seen in response to E.F. in all of 6 cancer patients tested tackling the goal of self-sufficiency more energetically but in none of 6 healthy subjects. is a concern about the quality of the foreign medical On the face of it these findings seem to provide the graduate-not just his clinical or academic competence but also his language ability and his understanding of basis of tests that will permit accurate and clearcut how different health-care systems work. Mutterings distinction between patients with overt malignant about the quality of foreign medical graduates have diseases and patients with non-neoplastic diseases or for some time been heard on both sides of the Atlantic, no disease at all. Cercek and his colleagues suggest but now, in a burst of exposure, the issue is out in the that a test for cancer could be based on the ratio of the responses of lymphocytes to C.B.P. and to open. In America a group from Harvard warns of a return to pre-Flexner standards 4,5; and in Britain a could this be said to be P.H.A., although gilding Cercek, L., Cercek, B., Garrett, J. V. in Lymphocytic Recognition and Effector Mechanisms (edited by K. Lindahl-Kiessling and K. Osoba); p. 553. New York, 1974. 2. Cercek, L., Cercek, B., Franklin, C. I. V. Br. J. Cancer, 1974, 29, 1.
1. Br. med. J. 1974, ii, suppl. p. 70. 2. Foreign Medical Graduates in America.
3. 4.
345. 3. 4.
Cercek, L., Cercek, B., Ockey, C. H. Biophysik, 1973, 10, 187. Field, E. J., Caspary, E. A. Lancet, 1970, ii, 1337.
5.
By PATRICIO R. MARMOT. Springfield, Illinois: Charles C. Thomas, 1974. Pp. 181. $8.50. Lancet, 1973, ii, 1367. Weiss, R. J., Kleinman, J. C., Brandt, U. C., Fledman, J. J., McGuiness, A. C. New Engl.J. Med. 1974, 290, 1408. Weiss, R. J., Kleinman, J. C., Brandt, U. C., Felsenthal, D. S. ibid. 1974, 290, 1453.