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SOMATIC-CELL MUTATION AND CANCER
849
TRANSVENOUS BIOPSY OF THE HEART PREVENTION, or early recognition, of acute rejection has been one of the big problems in heart transplantation. When rejection starts, early effective In animals and in man clues treatment is essential. the from be obtained can electrocardiogram, but serial shown that histological changes in have dogs biopsies precede electrocardiographic changes by as much as 48 hours. Therefore the technique described by the Stanford group on p. 821 this week is a substantial advance. Using a new instrument, Mr Caves and his colleagues obtained serial specimens in patients with transplanted hearts and were able to diagnose and treat rejection episodes very early; also they were able to cut down the immunosuppressive therapy as soon as the histological appearances returned to normal. The results are promising: 35 out of 37 rejection episodes were successfully reversed; and 11 of 12 patients were alive forty days to thirteen months ’after
transplantation. Heart transplantation is not the only situation where myocardial biopsy may be valuable clinically. In the past, samples have been obtained by needle biopsy 12 (which does not secure endocardial tissue) or at elective thoracotomy 3,4; but now the bioptome,5 in its several forms, has greatly simplified the investigation.
At
greater risk than that of cardiac cathefresh terisation, endomyocardial tissue can be obtained. The bioptome is introduced through the usual cardiac catheterisation routes. Its exact position is ascertained no
by fluoroscopy and intracardiac electrocardiography 6; with its jaws open it is pressed against the ventricular wall; and a piece of endomyocardial tissue about 3 mm. in diameter is excised. Two or three samples are usually taken, to ensure that representative areas have been obtained. The bioptome has been most extensively used by Japanese workers, who have investigated over 500 patients. Histological and ultrastructural examination in 150 of these has permitted detailed description of various conditions affecting the heart and a classification of primary myocardial disease.7 Material obtained with a modified bioptomehas been analysed at the National Heart Hospital, London.99 Specimens from 67 patients, 49 of whom were suspected of having primary myocardial disease, were analysed and in two-thirds it was possible to confirm or exclude the diagnosis. The bioptome thus allows not only for description and classification, but also for accurate diagnosis obtainable in no other way (during life). The instrument has other possibilities, because the easy accessibility of fresh myocardial tissue will facilitate analysis of enzyme systems and viral investigations - approaches which should be particularly rewarding 1.
2. 3. 4.
5. 6. 7.
Sutton,
D. C., Sutton, G. C., Kent, G. Q. Bull. Northwest Univ. med. Sch. 1956, 30, 213. Sutton, D. C., Sutton, G. C. Am. Heart J. 1960, 60, 364. Weinberg, M., Raffensberger, J., Driscoll, J. F., Sutton, G. C., Tobin, J. R. Circulation, 1963, 28, 823. Sutton, G. C., Driscoll, J. F., Gunnar, R. M., Tobin, J. R. Prog. cardiovasc. Dis. 1964, 7, 83. Sakakibara, S., Konno, S. Jap. Heart J. 1962, 3, 537. Richardson, P. J. in Cardiac Biopsy in Cardiomyopathy. London (in the press). Sekiguchi, M., Konno, S., Hasegawa, F., Hirosawa, K. Bull. Heart Inst. Japan, 1972/73, 14, 30.
8. Richardson, P. J. Lancet, April 13, 1974, p. 660. 9. Olsen, E. G. J. ibid. p. 658.
primary myocardial disease. The complications of endomyocardial biopsy 10 have included right-sided pneumothorax immediately after the procedure, isolated premature ventricular contraction, donor atrial flutter, atrial fibrillation, nodal rhythm, and supraventricular tachycardia. In most cases, the material comes from the ventricle and the samples are necessarily small; therefore it may be asked whether they are representative of the underlying condition. In those patients who have died (not as the result of the investigation) the correlation between biopsy diagnosis and necropsy diagnosis has been close. At necropsy, incidentally, it is usually hard to see where the biopsy specimens came from. The bioptome, used with discretion, should yield information which may lead to understanding of many myocardial diseases.
in
SOMATIC-CELL MUTATION AND CANCER IN so far as the somatic-cell-mutation theory of carcinogenesis has been around for over 50 years, the hypothesis may be thought to have withstood the test of time. But that no-one has disproved it in all those years may mean no more than that it was not a very useful hypothesis in the first place. The fact that Sir Macfarlane Burnet’s attractive immunologicalsurveillance hypothesis is based on the assumption that the theory is true makes it both the more difficult to
question the importance of somatic mutation and
Much current the more dangerous not to do so. research into the causation, diagnosis, and treatment of cancer assumes the essential truth of both the and somatic-mutation immunological-surveillance theories. How confident can we be that this research is well founded ?
Cells which constitute neoplasms can usually be shown to differ in appearance and behaviour from the tissue cells from which they are thought to have been derived in one or more various ways-for example, degree of differentiation; polarity; adhesiveness; variability in size, shape, staining, and chromosome number; secretory activity; and enzymic activity. According to Finckh,11 the apparent rarity of spontaneous regressions of established neoplasms has been taken by most observers to support the view that the abnormal cells belong to a clone or to clones of cells that have been permanently genetically changed as a result of mutation(s). Finckh’s first attack on this bastion of belief stems from his experience as a histopathologist. The distinctive features of cells of which cancers are composed are often quantitative rather than qualitative, and histopathologists often find it difficult or impossible to distinguish between cells from cancers and cells from non-cancers. This attack will not impress those who regard histopathology as a descriptive discipline and histopathological diagnosis, by itself, as an insensitive investigative method. On the other hand, Finckh certainly hits his target when he points out that in most malignant tumours the cells vary considerably in appearance and that the presence of between-cell variation is, in 10. 11.
Konno, S., Sekiguchi, M., Sakakibara, S. Radiol. Clins N. Am. 1971, 9, 491. Finckh, E. S. Med. J. Aust. 1974, i, 438.
850
fact,
a useful diagnostic criterion. The morphological appearances of many malignant tumours, he says, do not support the view that the cells of which they are composed belong to a single clone of genetically altered cells. Although at this point in his paper he suggests that many of the features of cancer-cell morphology and behaviour may be epiphenomena, he passes over the possibility that a mutation which interfered with the process of cell division might result both in between-cell variation and in cancer.12 In his next attack Finckh’s aim is less accurate. His suggestion that the pattern of carcinogenesis is usually consistent for any one tissue and any one carcinogenic agent is seriously open to dispute in the case of chemical carcinogens. Theoretically the entry into cells of a specific block of genetic information in the form of viral nucleic acids is likely to bring about a similar mutation-like change in all the cells infected, whereas random or semi-random damage to the inherited genetic complement of cells by ionising radiations or reactive chemical agents is much less likely to result in the same genetic defect in all of them. In practice, there are greater morphological and antigenic similarities between tumours induced by a specific oncogenic virus than between tumours arising in response to a specific chemical carcinogen. 13-19 The support that this fact gives to the somatic-cell mutation theory is acknowledged obliquely by Finckh, but this does not deter him from coming down more in favour of a theory based on abnormal differentiation. He asks, " Must heritable changes in cells be genetic ? " The process of increasing specialisation seen in successive generations of cells during embryogenesis seems to be unidirectional, and alterations are passed
on to cellular offspring in heritable fashion. Nuclear fusion experiments 20, 211 have shown that these heritable changes are not the result of mutations, since the nuclei of the differentiated cells retain intact the total complement of genetic information Could then the present in the fertilised ovum. apparently heritable changes seen in cancer " cells be the result of abnormal differentiation in the embryological sense, rather than of mutation ? Phases of cellular multiplication and migration occur normally during embryogenesis. Their inappropriate occurrence later in life might theoretically be manifested as cancer. The idea is not a new one,22 and Finckh cites no new evidence for this being an important mechanism in relation to the more commonly occurring kinds of neoplastic disease in man. A feature of the phases of cellular multiplication and migration that occur during embryogenesis is that they are indeed phases which eventually cease. The same is true of regenera"
12. 13. 14. 15. 16. 17.
Roe, F. J. C. in The Biology of Cancer (edited by E. J. Ambrose and F. J. C. Roe); p. 1. London, 1966. Klein, G., Klein, E. J. natn. Cancer Inst. 1964, 32, 547. Huebner, R. J., Rowe, W. P., Turner, H. C., Lane, W. T. Proc. natn. Acad. Sci. U.S.A. 1963, 50, 379. Koch, M. A., Sabin, A. B. Proc. Soc. exp. Biol. Med. 1963, 113, 4. Prehn, R. T., Main, J. M. J. natn. Cancer Inst. 1957, 18, 769. Klein, G., Klein, E. Cold Spring Harb. Symp. quant. Biol. 1962, 27, 463.
Pasternak, G., Horn, K. H., Graft, A. Acta biol. med. Germ. 1962, 9, 302. 19. Globerson, A., Feldman, M. J. natn. Cancer Inst. 1964, 32, 1229. 20. Gurdon, J. B. J. Embryol. exp. Morphol. 1962, 10, 622. 21. Harris, H. J. Cell Sci. 1967, 2, 23. 22. Monod, J., Jacob, F. Cold Spring Harb. Symp. quant. Biol. 1961 26, 383. 18.
tive processes after wounding. The fact that the cells of certain odd-ball cancers, such as neuroblastomas, stop dividing and migrating and differentiate instead provides little ground for believing that the same could happen or could be induced to happen by appropriate therapeutic measures in the case of the run of more commonly occurring cancers. Finckh has done well to remind us that the somaticcell mutation of carcinogenesis is only a theory and On balance, however, it is not an established fact. difficult to believe that increased knowledge of mechanisms involved in embryogenesis will lead to the wholesale rejection of the somatic-cell-mutation theory of carcinogenesis.
general
SHOULDER-HAND SYNDROME PAINFUL restriction of shoulder movements was recognised in the last century as a sequel to anginal attacks. Osler, true to form, was the first to describe the association.1 Fifty years later various " reflex " neurovascular disorders of the shoulder, arm, and hand were brought together under the title of "
shoulder-hand syndrome 1"2a potentially serious and disabling disorder usually found after myocardial infarction, cerebrovascular accident, trauma, or other insult, but occasionally arising without an obvious trigger. Pain, stiffness, and tenderness of the shoulder with limited movement, indistinguishable from a capsulitis, are the usual first symptoms, and these sometimes progress to swelling, pain, stiffness, and discoloration of hand and fingers. Occasionally the arm and hand alone are affected. At worst the endresult is flexion deformity of the fingers with contractures, atrophy of interosseous muscles, and trophic changes in the skin. Understanding of the pathogenesis of the syndrome and assessment of measures for its prevention and treatment are complicated by the sometimes long interval between the presumed trigger and the syndrome itself. After myocardial infarction, for example, the syndrome may start up to 18 weeks later and be unrelated to the site, severity, or duration of the cardiac pain.33 Unlike most newly delineated syndromes, it seems to have become steadily less common —indeed, many physicians now rarely see it. Although early mobilisation and active physiotherapy have been credited with the falling incidence, prophylactic physiotherapy to the shoulder is now the exception rather than the rule, and it is far from clear how early mobilisation prevents the onset of the syndrome weeks later. The mysteries of pathogenesis may never be solved, but the continuing challenge to early diagnosis of this now perhaps rare syndrome must never be forgotten. A host of treatments has been used successfully, but the one factor common to them all is a better outcome if treatment starts early. If physical therapy is not quickly effective, the simplest and most predictably effective treatment may be prednisolone in as small a dose as 10 mg. daily.5 1. 2. 3. 4. 5.
Osler, W. Lectures on Angina Pectoris and Allied States. New York, 1897. Steinbrocker, O. Am. J. Med. 1947, 3, 402. Woodhouse, S. P. N.Z. med. J. 1968, 68, 387. Russek, H. I. Med. Clins N. Am. 1958, 42, 1555. Mowat, A. G. Ann. rheum. Dis. 1974, 33, 120.
TRANSVENOUS BIOPSY OF THE HEART PREVENTION, or early recognition, of acute rejection has been one of the big problems in heart transplantation. When rejection starts, early effective In animals and in man clues treatment is essential. the from be obtained can electrocardiogram, but serial shown that histological changes in have dogs biopsies precede electrocardiographic changes by as much as 48 hours. Therefore the technique described by the Stanford group on p. 821 this week is a substantial advance. Using a new instrument, Mr Caves and his colleagues obtained serial specimens in patients with transplanted hearts and were able to diagnose and treat rejection episodes very early; also they were able to cut down the immunosuppressive therapy as soon as the histological appearances returned to normal. The results are promising: 35 out of 37 rejection episodes were successfully reversed; and 11 of 12 patients were alive forty days to thirteen months ’after
transplantation. Heart transplantation is not the only situation where myocardial biopsy may be valuable clinically. In the past, samples have been obtained by needle biopsy 12 (which does not secure endocardial tissue) or at elective thoracotomy 3,4; but now the bioptome,5 in its several forms, has greatly simplified the investigation.
At
greater risk than that of cardiac cathefresh terisation, endomyocardial tissue can be obtained. The bioptome is introduced through the usual cardiac catheterisation routes. Its exact position is ascertained no
by fluoroscopy and intracardiac electrocardiography 6; with its jaws open it is pressed against the ventricular wall; and a piece of endomyocardial tissue about 3 mm. in diameter is excised. Two or three samples are usually taken, to ensure that representative areas have been obtained. The bioptome has been most extensively used by Japanese workers, who have investigated over 500 patients. Histological and ultrastructural examination in 150 of these has permitted detailed description of various conditions affecting the heart and a classification of primary myocardial disease.7 Material obtained with a modified bioptomehas been analysed at the National Heart Hospital, London.99 Specimens from 67 patients, 49 of whom were suspected of having primary myocardial disease, were analysed and in two-thirds it was possible to confirm or exclude the diagnosis. The bioptome thus allows not only for description and classification, but also for accurate diagnosis obtainable in no other way (during life). The instrument has other possibilities, because the easy accessibility of fresh myocardial tissue will facilitate analysis of enzyme systems and viral investigations - approaches which should be particularly rewarding 1.
2. 3. 4.
5. 6. 7.
Sutton,
D. C., Sutton, G. C., Kent, G. Q. Bull. Northwest Univ. med. Sch. 1956, 30, 213. Sutton, D. C., Sutton, G. C. Am. Heart J. 1960, 60, 364. Weinberg, M., Raffensberger, J., Driscoll, J. F., Sutton, G. C., Tobin, J. R. Circulation, 1963, 28, 823. Sutton, G. C., Driscoll, J. F., Gunnar, R. M., Tobin, J. R. Prog. cardiovasc. Dis. 1964, 7, 83. Sakakibara, S., Konno, S. Jap. Heart J. 1962, 3, 537. Richardson, P. J. in Cardiac Biopsy in Cardiomyopathy. London (in the press). Sekiguchi, M., Konno, S., Hasegawa, F., Hirosawa, K. Bull. Heart Inst. Japan, 1972/73, 14, 30.
8. Richardson, P. J. Lancet, April 13, 1974, p. 660. 9. Olsen, E. G. J. ibid. p. 658.
primary myocardial disease. The complications of endomyocardial biopsy 10 have included right-sided pneumothorax immediately after the procedure, isolated premature ventricular contraction, donor atrial flutter, atrial fibrillation, nodal rhythm, and supraventricular tachycardia. In most cases, the material comes from the ventricle and the samples are necessarily small; therefore it may be asked whether they are representative of the underlying condition. In those patients who have died (not as the result of the investigation) the correlation between biopsy diagnosis and necropsy diagnosis has been close. At necropsy, incidentally, it is usually hard to see where the biopsy specimens came from. The bioptome, used with discretion, should yield information which may lead to understanding of many myocardial diseases.
in
SOMATIC-CELL MUTATION AND CANCER IN so far as the somatic-cell-mutation theory of carcinogenesis has been around for over 50 years, the hypothesis may be thought to have withstood the test of time. But that no-one has disproved it in all those years may mean no more than that it was not a very useful hypothesis in the first place. The fact that Sir Macfarlane Burnet’s attractive immunologicalsurveillance hypothesis is based on the assumption that the theory is true makes it both the more difficult to
question the importance of somatic mutation and
Much current the more dangerous not to do so. research into the causation, diagnosis, and treatment of cancer assumes the essential truth of both the and somatic-mutation immunological-surveillance theories. How confident can we be that this research is well founded ?
Cells which constitute neoplasms can usually be shown to differ in appearance and behaviour from the tissue cells from which they are thought to have been derived in one or more various ways-for example, degree of differentiation; polarity; adhesiveness; variability in size, shape, staining, and chromosome number; secretory activity; and enzymic activity. According to Finckh,11 the apparent rarity of spontaneous regressions of established neoplasms has been taken by most observers to support the view that the abnormal cells belong to a clone or to clones of cells that have been permanently genetically changed as a result of mutation(s). Finckh’s first attack on this bastion of belief stems from his experience as a histopathologist. The distinctive features of cells of which cancers are composed are often quantitative rather than qualitative, and histopathologists often find it difficult or impossible to distinguish between cells from cancers and cells from non-cancers. This attack will not impress those who regard histopathology as a descriptive discipline and histopathological diagnosis, by itself, as an insensitive investigative method. On the other hand, Finckh certainly hits his target when he points out that in most malignant tumours the cells vary considerably in appearance and that the presence of between-cell variation is, in 10. 11.
Konno, S., Sekiguchi, M., Sakakibara, S. Radiol. Clins N. Am. 1971, 9, 491. Finckh, E. S. Med. J. Aust. 1974, i, 438.
850
fact,
a useful diagnostic criterion. The morphological appearances of many malignant tumours, he says, do not support the view that the cells of which they are composed belong to a single clone of genetically altered cells. Although at this point in his paper he suggests that many of the features of cancer-cell morphology and behaviour may be epiphenomena, he passes over the possibility that a mutation which interfered with the process of cell division might result both in between-cell variation and in cancer.12 In his next attack Finckh’s aim is less accurate. His suggestion that the pattern of carcinogenesis is usually consistent for any one tissue and any one carcinogenic agent is seriously open to dispute in the case of chemical carcinogens. Theoretically the entry into cells of a specific block of genetic information in the form of viral nucleic acids is likely to bring about a similar mutation-like change in all the cells infected, whereas random or semi-random damage to the inherited genetic complement of cells by ionising radiations or reactive chemical agents is much less likely to result in the same genetic defect in all of them. In practice, there are greater morphological and antigenic similarities between tumours induced by a specific oncogenic virus than between tumours arising in response to a specific chemical carcinogen. 13-19 The support that this fact gives to the somatic-cell mutation theory is acknowledged obliquely by Finckh, but this does not deter him from coming down more in favour of a theory based on abnormal differentiation. He asks, " Must heritable changes in cells be genetic ? " The process of increasing specialisation seen in successive generations of cells during embryogenesis seems to be unidirectional, and alterations are passed
on to cellular offspring in heritable fashion. Nuclear fusion experiments 20, 211 have shown that these heritable changes are not the result of mutations, since the nuclei of the differentiated cells retain intact the total complement of genetic information Could then the present in the fertilised ovum. apparently heritable changes seen in cancer " cells be the result of abnormal differentiation in the embryological sense, rather than of mutation ? Phases of cellular multiplication and migration occur normally during embryogenesis. Their inappropriate occurrence later in life might theoretically be manifested as cancer. The idea is not a new one,22 and Finckh cites no new evidence for this being an important mechanism in relation to the more commonly occurring kinds of neoplastic disease in man. A feature of the phases of cellular multiplication and migration that occur during embryogenesis is that they are indeed phases which eventually cease. The same is true of regenera"
12. 13. 14. 15. 16. 17.
Roe, F. J. C. in The Biology of Cancer (edited by E. J. Ambrose and F. J. C. Roe); p. 1. London, 1966. Klein, G., Klein, E. J. natn. Cancer Inst. 1964, 32, 547. Huebner, R. J., Rowe, W. P., Turner, H. C., Lane, W. T. Proc. natn. Acad. Sci. U.S.A. 1963, 50, 379. Koch, M. A., Sabin, A. B. Proc. Soc. exp. Biol. Med. 1963, 113, 4. Prehn, R. T., Main, J. M. J. natn. Cancer Inst. 1957, 18, 769. Klein, G., Klein, E. Cold Spring Harb. Symp. quant. Biol. 1962, 27, 463.
Pasternak, G., Horn, K. H., Graft, A. Acta biol. med. Germ. 1962, 9, 302. 19. Globerson, A., Feldman, M. J. natn. Cancer Inst. 1964, 32, 1229. 20. Gurdon, J. B. J. Embryol. exp. Morphol. 1962, 10, 622. 21. Harris, H. J. Cell Sci. 1967, 2, 23. 22. Monod, J., Jacob, F. Cold Spring Harb. Symp. quant. Biol. 1961 26, 383. 18.
tive processes after wounding. The fact that the cells of certain odd-ball cancers, such as neuroblastomas, stop dividing and migrating and differentiate instead provides little ground for believing that the same could happen or could be induced to happen by appropriate therapeutic measures in the case of the run of more commonly occurring cancers. Finckh has done well to remind us that the somaticcell mutation of carcinogenesis is only a theory and On balance, however, it is not an established fact. difficult to believe that increased knowledge of mechanisms involved in embryogenesis will lead to the wholesale rejection of the somatic-cell-mutation theory of carcinogenesis.
general
SHOULDER-HAND SYNDROME PAINFUL restriction of shoulder movements was recognised in the last century as a sequel to anginal attacks. Osler, true to form, was the first to describe the association.1 Fifty years later various " reflex " neurovascular disorders of the shoulder, arm, and hand were brought together under the title of "
shoulder-hand syndrome 1"2a potentially serious and disabling disorder usually found after myocardial infarction, cerebrovascular accident, trauma, or other insult, but occasionally arising without an obvious trigger. Pain, stiffness, and tenderness of the shoulder with limited movement, indistinguishable from a capsulitis, are the usual first symptoms, and these sometimes progress to swelling, pain, stiffness, and discoloration of hand and fingers. Occasionally the arm and hand alone are affected. At worst the endresult is flexion deformity of the fingers with contractures, atrophy of interosseous muscles, and trophic changes in the skin. Understanding of the pathogenesis of the syndrome and assessment of measures for its prevention and treatment are complicated by the sometimes long interval between the presumed trigger and the syndrome itself. After myocardial infarction, for example, the syndrome may start up to 18 weeks later and be unrelated to the site, severity, or duration of the cardiac pain.33 Unlike most newly delineated syndromes, it seems to have become steadily less common —indeed, many physicians now rarely see it. Although early mobilisation and active physiotherapy have been credited with the falling incidence, prophylactic physiotherapy to the shoulder is now the exception rather than the rule, and it is far from clear how early mobilisation prevents the onset of the syndrome weeks later. The mysteries of pathogenesis may never be solved, but the continuing challenge to early diagnosis of this now perhaps rare syndrome must never be forgotten. A host of treatments has been used successfully, but the one factor common to them all is a better outcome if treatment starts early. If physical therapy is not quickly effective, the simplest and most predictably effective treatment may be prednisolone in as small a dose as 10 mg. daily.5 1. 2. 3. 4. 5.
Osler, W. Lectures on Angina Pectoris and Allied States. New York, 1897. Steinbrocker, O. Am. J. Med. 1947, 3, 402. Woodhouse, S. P. N.Z. med. J. 1968, 68, 387. Russek, H. I. Med. Clins N. Am. 1958, 42, 1555. Mowat, A. G. Ann. rheum. Dis. 1974, 33, 120.