- Email: [email protected]
C.E.A. ANTISERA IN CANCER DETECTION AND THERAPY
461
low-up of 935 English alcoholics’
over 10-15 years
revealed an observed/expected mortality for respiratory diseases of 2.59 and 7.21 in the two sexes. Possible contributory factors include impairment of immunological defences and of bronchial clearance mechanisms, high prevalence of smoking, and inadequate diet. Pulmonary tuberculosis figures prominently amongst the diseases of chronic alcoholics. A survey8 of 227 patients who were admitted to the T.B. ward of the Bethnal Green Hospital between October, 1973, and December, 1976, classed 96 (42%) as alcoholics. 77 (80%) of them were homeless compared with 22 (17%) of the 131 nonalcoholic patients. The hospital is situated in the East End of London in an area which has always attracted a large proportion of London’s down-and-outs to its common lodging houses, the church and Salvation Army hostels, and many derelict houses and bomb-sites. They show all the features of London’s skid-row population-predominantly of celtic or northern origin, male, single, aged 40-50, homeless, socially isolated, manifesting long-standing drink and personality disorders. In addition to their social and personal problems they have a high prevalence of gastrointestinal and pulmonary disease. Their life-style makes them particularly difficult patients for any long-term management of tuberculosis. A quarter of them, for instance, suddenly disappeared or discharged themselves from the ward in the middle of treatment. Although half of the alcoholics eventually returned after one or more drinking episodes, others remained untraced. Other problems came near the time of hospital discharge. Most had nowhere to go. Hostels for alcoholics would not accept them because of their recent infection; hostels for the tuberculous refused them because of their drinking history. Patients were expected to follow a regular regimen of antituberculous drug treatment for 12 months after discharge. Most of them were not registered with a family doctor to supervise it. One patient, when receiving on discharge several bottles containing the first month’s supply of antituberculous drugs, remarked "Doctor, where do you expect me to keep these pills?" In response to the long-felt need and concern of the consultant chest physician, help came from the Methodist East End Mission. A small 10-bedded hostel, managed on a shoestring of voluntary contributions, was opened in October, 1973. Selected homeless tuberculous patients were discharged directly from ward to hostel. A warden kept in close touch with the chest clinic and supervised their drugs. In general there were no differences in the extent of the disease, drug resistance, and clinical or radiographic improvement between the alcoholic and non-alcoholic patient groups, except that 35 (36%) of the alcoholics showed multiple old rib fractures on X-ray. This association of healed rib fractures with extensive mottling of lungs is practically diagnostic of skid-row tuberculosis. The alcoholics also showed a higher prevalence of chronic bronchitis (81%), peptic ulcer (11.4%), and partial gastrectomy (17%). Cirrhosis was notable for its absence-only 1 case in the 96 T.B. alcoholics. Pollak9 suggests that the skid-row alcoholic’s 7. 8.
Edwards, G., and others. ibid. 1974, 35, 841. Caplin, M., Rehahan, M. Topics in Therapeutics, 4; Wells, 1978
9.
Pollak, B. Proc. R. Soc. Med. 1975, 68, 13.
p. 136.
Tunbridge
pattern differs from that of other alcoholics in that he drinks intermittently owing to recurrent spells in prison, and these allow the liver parenchyma to recover between drinking bouts. The homeless alcoholic represents a substantial pool of tuberculous infection. Mass X-ray screening at reception centres, soup kitchens, and other places visited by the homeless would lead to earlier diagnosis of pulmonary tuberculosis in this vulnerable group. Such efforts will be wasted unless they can be backed up by treatment which includes some social rehabilitation or sheltered care.
drinking
C.E.A. ANTISERA IN CANCER DETECTION AND THERAPY
MORE than two decades have passed since Pressman’s that radiolabelled antibodies might facilitate localisation of tumours.l Success has been elusive, although several groups have reported specific uptake of labelled antibodies by experimental tumours and by human tumours growing in immune-deprived animals.2-4 In the past few months, encouraging accounts of this approach have been recorded in patients with diverse epithelial neoplasms.56 Not all workers, however, have been successful. Many factors bear on the success or failure of this approach.5 7 Of prime importance are the properties of the antibodies employedtheir specificity and titre, and their direction against a surface component of the tumour cells. In the absence of a known human-tumour-specific property or "antigen", attention has once more turned to the cell-surface glycoprotein, carcinoembryonic antigen (C.E.A.).8 -This antigen is not specific for malignant disease, but it is found in association with many epithelial-derived tumours and tests for c.E.A. have proved useful in some patients.9 C.E.A. has been extensively purified. High-quality antisera are readily prepared which can in turn be
suggestion
selectively purified by affinity chromatography. The report by Goldenburg and his colleagues6 of the successful localisation of metastatic carcinomas through the use of heterologous immunopurified iodine-labelled anti-c.E.A. immunoglobulin is both encouraging and thought-provoking. Why should these workers have succeeded where others failed? The answer may lie in the quality of their reagents and in the elaborate computer program which helped them distinguish specific radioantibody binding from background activity. The uptake by the tumour was in fact quite small and not seen until many hours after administration of the labelled immunoglobulin. Moreover, raised plasma-c.E.A. levels did not seem to disturb uptake of the antibody by tumour. 1. 2.
Pressman, D. Ann. N. Y. Acad. Sci. 1957, 69, 644. Izzo, M. J., Buchsbaum, D. J., Bale, W. F. Proc. Soc. exp. Biol. Med. 1972, 139, 1185. 3. Primus, F. J., Wang, R. H., Goldenberg, D. M., Hausen, H. J. Cancer Res. 1973, 33, 2977. 4. Mach, J. P., Carrel, S., Merenda, C., Sordat, B., Cerottini, J.-C. Nature, 1974, 248, 704. 5. Belitsky, P., Ghose, T., Aquino, J., Tai, J., Macdonald, A. S. Radiology, 1978, 126, 515. 6. Goldenberg, D. M., DeLand, F., Kim, E., Bennett, S., Primus, F. J., van Nagell, J. R., Estes, N., DeSimone, P., Rayburn, P. New Engl. J. Med. 1978, 298, 1384. 7 Reif, A. E., Curtis, L. E., Duffield, R., Shauffer, I. A.J. surg. Oncol. 1974, 6, 133. 8 Gold, P., Freedman, S. O.J. exp. Med. 1965, 122, 467. 9. Neville, A. M., Cooper, E. H. Ann. clin. Biochem. 1976, 13, 283.
462 In four
patients, the radiolabelled-antiserum technique
identified metastatic foci which had escaped other physical and clinical diagnostic methods. Although prelim-
inary immunochemical evidence and the absence of binding to a non-c.E.A.-containing tumour are highly suggestive that the uptake was specific, proof of this is still lacking. It will be interesting to see, from autoradiography, which cells in the tumour are responsible for the binding or uptake. This may be important for manipulation of the technique to improve results. Is tumour localisation the best clinico-oncological application for such antisera? Physical methods, as opposed to biochemical methods, are unlikely to help greatly in the earlier detection of primary or metastatic lesions. Might not anti-tumour immunoglobulins be more fruitfully employed as carriers of chemotherapeutic agents.10-12 This has already been done experimentally and is feasible in man with anti-c.E.A. antisera. The Fab dimer of heterologous IgG might be advantageous. Detection of the Fc portion would make it less immunogenic and perhaps encourage uptake by neoplastic cells as opposed to stromal cells (many stromal cells have F receptors). The mouse myeloma hybrid system for the preparation of monoclonal antibodies 13 may yield antisera specific to organs, cell-types, or even tumours.14 If this technique can be adapted to produce human immunoglobulins then many of the disadvantages and dangers of heterologous antisera in patients may be overcome.
THE RETRACTED EPHAPSE THE formation of
ephapses after injury, which allow between sympathetic nerve fibres and somatic afferent nerve fibres, has been proposed by Doupe et a1.1 and Nathan2as the mechanism of causalgia. This concept of an electrical synapse has found wide acceptance despite lack of solid experimental support. Now we must revise our ideas. That the sympathetic nervous system plays a central role is demonstrated by the regular alleviation of causalgia by sympathetic-ganglion block or sympathectomy. That some change occurs in the region of the body affected by causalgia which makes it respond abnormally to sympathetic activity is shown by the fact that this type of burning pain is encountered after stimulation of the appropriate ganglia of the sympathetic nervous system during thoracotomy only in causalgic arms whereas normal limbs are unaffected.3 Sympathetic-ganglion block or sympathectomy could conceivably interrupt afferent sympathetic nerve fibres (if they exist) and only lately have we been in a position to be sure that causalgia and other dystrophic
short-circuiting
10. Davies, D. A. L., O’Neill, G. J. Br. J. Cancer, 1973, 28, suppl. I, p. 285. 11. Ghose. T., Nigam, S. P. Cancer, 1972, 29, 1398. 12. Hurwitz, E., Maron, R., Arnon, R., Sela, M. Cancer Biochem. Biophys.
by sympathetic efferpossible by regional sympathetic blockade-secured by saturation of the affected limb with guanethidine injected intravenously during temporary occlusion of the circulation with a tourniquet. 4Guanethidine has great and prolonged affinity for noradrenaline storage sites in the sympathetic nerve endings and the result is profound sympathetic blockade lasting several days. Guanethidine blocks are most effective in controlling pain in causalgia and other dystrophic states in the limbs, and we must pain ent
in the limbs are caused activity. This has been made states
conclude that it is the effect of noradrenaline on sensitised or damaged sensory nerves that causes the pain. If it is noradrenaline that triggers the pain in these conditions we might expect guanethidine to exacerbate the pain at first, because the initial effect of guanethidine is to discharge noradrenaline from its storage sites before occupying them itself. This is in fact what happens: Hannington-Kiff6 found that pain in the hyperpathic region is momentarily increased before it is relieved in dystrophic limbs. It is not simply the overproduction of noradrenaline which explains the pain, because in many peripheral pain states there is no evidence of sympathetic overactivity (such as excessive sweating, pilo-erection, or colour changes) yet relief is achieved with sympathetic blockade. This key-role of noradrenaline in certain types of pain, especially those associated with hyperæsthesia and hyperpathia, has been supported lately by Loh and Nathan.’ The only clue we have to the nature of the target lesion for the noradrenaline is the finding by Wall and Gutnick8 that tiny axon-sprouts in rat neuromas are strongly stimulated by noradrenaline. This effect was stopped by the alpha-blocker phentolamine. It has been found clinically that thymoxamine, another selective alpha-blocker, will also relieve pain and hyperpathia for a matter of hours and without an initial exacerbation.9 The fact that a guanethidine block will relieve causalgia in the arm associated with a partial lesion of the brachial plexus, though this is above the level of the tourniquet and therefore unaffected by the guanethidine, shows that ephapses at the site of injury are not the explanation. The noradrenaline-sensitive defects must be more peripheral in the sensory nerves. Could there be an alteration in the distance relationships of sympathetic nerve endings and somatic afferent nerve endings as suggested by Hannington-Kifl?6 For the time being the nature of the target-lesion must remain an enigma. The spread of causalgic pain within the affected limb and sometimes beyond to involve a whole quadrant of the body requires that we pay attention also to the related build-up of neural activity in the laminse of the dorsal horn of the spinal cord. From the clinical point of view we should regard causalgia and other peripheral pain states with hyperpathia and hyperaesthesia as indications for an early sympathetic block before an apparently simple trigger produces widespread central overactivity and imprinting.
1976, 1, 197. 13. Köhler, G., Milstein, C. Nature, 1975, 256, 495 14. Williams, A. F., Galfrè, G., Milstein, C. Cell, 1977, 12, 663. 1. Doupe, J., Cullen, C. R., Chance, G. Q. J. Neurol, Neurosurg,
1944, 7, 33. 2. Nathan, P. W. Brain, 1947, 70, 145. 3. Walker, A. E., Nulson, F. Archs Neurol. Psychiat.
1948, 58, 559.
Psychiat.
4. 5. 6. 7. 8. 9.
Hannington-Kiff, J. G. Lancet, 1974, i,1019. Hannington-Kiff, J. G. Pain Relief; p. 68. London, 1974. Hannington-Kiff, J. G. Lancet, 1977, i, 1132. Loh, L., Nathan, P. W.J. Neurol. Neurosurg. Psychiat. 1978, 41, 664. Wall, P. D., Gutnick, M. Exp. Neurol. 1974, 43, 580. Hannington-Kiff, J. G. Pain Relief; p. 69. London, 1974.
low-up of 935 English alcoholics’
over 10-15 years
revealed an observed/expected mortality for respiratory diseases of 2.59 and 7.21 in the two sexes. Possible contributory factors include impairment of immunological defences and of bronchial clearance mechanisms, high prevalence of smoking, and inadequate diet. Pulmonary tuberculosis figures prominently amongst the diseases of chronic alcoholics. A survey8 of 227 patients who were admitted to the T.B. ward of the Bethnal Green Hospital between October, 1973, and December, 1976, classed 96 (42%) as alcoholics. 77 (80%) of them were homeless compared with 22 (17%) of the 131 nonalcoholic patients. The hospital is situated in the East End of London in an area which has always attracted a large proportion of London’s down-and-outs to its common lodging houses, the church and Salvation Army hostels, and many derelict houses and bomb-sites. They show all the features of London’s skid-row population-predominantly of celtic or northern origin, male, single, aged 40-50, homeless, socially isolated, manifesting long-standing drink and personality disorders. In addition to their social and personal problems they have a high prevalence of gastrointestinal and pulmonary disease. Their life-style makes them particularly difficult patients for any long-term management of tuberculosis. A quarter of them, for instance, suddenly disappeared or discharged themselves from the ward in the middle of treatment. Although half of the alcoholics eventually returned after one or more drinking episodes, others remained untraced. Other problems came near the time of hospital discharge. Most had nowhere to go. Hostels for alcoholics would not accept them because of their recent infection; hostels for the tuberculous refused them because of their drinking history. Patients were expected to follow a regular regimen of antituberculous drug treatment for 12 months after discharge. Most of them were not registered with a family doctor to supervise it. One patient, when receiving on discharge several bottles containing the first month’s supply of antituberculous drugs, remarked "Doctor, where do you expect me to keep these pills?" In response to the long-felt need and concern of the consultant chest physician, help came from the Methodist East End Mission. A small 10-bedded hostel, managed on a shoestring of voluntary contributions, was opened in October, 1973. Selected homeless tuberculous patients were discharged directly from ward to hostel. A warden kept in close touch with the chest clinic and supervised their drugs. In general there were no differences in the extent of the disease, drug resistance, and clinical or radiographic improvement between the alcoholic and non-alcoholic patient groups, except that 35 (36%) of the alcoholics showed multiple old rib fractures on X-ray. This association of healed rib fractures with extensive mottling of lungs is practically diagnostic of skid-row tuberculosis. The alcoholics also showed a higher prevalence of chronic bronchitis (81%), peptic ulcer (11.4%), and partial gastrectomy (17%). Cirrhosis was notable for its absence-only 1 case in the 96 T.B. alcoholics. Pollak9 suggests that the skid-row alcoholic’s 7. 8.
Edwards, G., and others. ibid. 1974, 35, 841. Caplin, M., Rehahan, M. Topics in Therapeutics, 4; Wells, 1978
9.
Pollak, B. Proc. R. Soc. Med. 1975, 68, 13.
p. 136.
Tunbridge
pattern differs from that of other alcoholics in that he drinks intermittently owing to recurrent spells in prison, and these allow the liver parenchyma to recover between drinking bouts. The homeless alcoholic represents a substantial pool of tuberculous infection. Mass X-ray screening at reception centres, soup kitchens, and other places visited by the homeless would lead to earlier diagnosis of pulmonary tuberculosis in this vulnerable group. Such efforts will be wasted unless they can be backed up by treatment which includes some social rehabilitation or sheltered care.
drinking
C.E.A. ANTISERA IN CANCER DETECTION AND THERAPY
MORE than two decades have passed since Pressman’s that radiolabelled antibodies might facilitate localisation of tumours.l Success has been elusive, although several groups have reported specific uptake of labelled antibodies by experimental tumours and by human tumours growing in immune-deprived animals.2-4 In the past few months, encouraging accounts of this approach have been recorded in patients with diverse epithelial neoplasms.56 Not all workers, however, have been successful. Many factors bear on the success or failure of this approach.5 7 Of prime importance are the properties of the antibodies employedtheir specificity and titre, and their direction against a surface component of the tumour cells. In the absence of a known human-tumour-specific property or "antigen", attention has once more turned to the cell-surface glycoprotein, carcinoembryonic antigen (C.E.A.).8 -This antigen is not specific for malignant disease, but it is found in association with many epithelial-derived tumours and tests for c.E.A. have proved useful in some patients.9 C.E.A. has been extensively purified. High-quality antisera are readily prepared which can in turn be
suggestion
selectively purified by affinity chromatography. The report by Goldenburg and his colleagues6 of the successful localisation of metastatic carcinomas through the use of heterologous immunopurified iodine-labelled anti-c.E.A. immunoglobulin is both encouraging and thought-provoking. Why should these workers have succeeded where others failed? The answer may lie in the quality of their reagents and in the elaborate computer program which helped them distinguish specific radioantibody binding from background activity. The uptake by the tumour was in fact quite small and not seen until many hours after administration of the labelled immunoglobulin. Moreover, raised plasma-c.E.A. levels did not seem to disturb uptake of the antibody by tumour. 1. 2.
Pressman, D. Ann. N. Y. Acad. Sci. 1957, 69, 644. Izzo, M. J., Buchsbaum, D. J., Bale, W. F. Proc. Soc. exp. Biol. Med. 1972, 139, 1185. 3. Primus, F. J., Wang, R. H., Goldenberg, D. M., Hausen, H. J. Cancer Res. 1973, 33, 2977. 4. Mach, J. P., Carrel, S., Merenda, C., Sordat, B., Cerottini, J.-C. Nature, 1974, 248, 704. 5. Belitsky, P., Ghose, T., Aquino, J., Tai, J., Macdonald, A. S. Radiology, 1978, 126, 515. 6. Goldenberg, D. M., DeLand, F., Kim, E., Bennett, S., Primus, F. J., van Nagell, J. R., Estes, N., DeSimone, P., Rayburn, P. New Engl. J. Med. 1978, 298, 1384. 7 Reif, A. E., Curtis, L. E., Duffield, R., Shauffer, I. A.J. surg. Oncol. 1974, 6, 133. 8 Gold, P., Freedman, S. O.J. exp. Med. 1965, 122, 467. 9. Neville, A. M., Cooper, E. H. Ann. clin. Biochem. 1976, 13, 283.
462 In four
patients, the radiolabelled-antiserum technique
identified metastatic foci which had escaped other physical and clinical diagnostic methods. Although prelim-
inary immunochemical evidence and the absence of binding to a non-c.E.A.-containing tumour are highly suggestive that the uptake was specific, proof of this is still lacking. It will be interesting to see, from autoradiography, which cells in the tumour are responsible for the binding or uptake. This may be important for manipulation of the technique to improve results. Is tumour localisation the best clinico-oncological application for such antisera? Physical methods, as opposed to biochemical methods, are unlikely to help greatly in the earlier detection of primary or metastatic lesions. Might not anti-tumour immunoglobulins be more fruitfully employed as carriers of chemotherapeutic agents.10-12 This has already been done experimentally and is feasible in man with anti-c.E.A. antisera. The Fab dimer of heterologous IgG might be advantageous. Detection of the Fc portion would make it less immunogenic and perhaps encourage uptake by neoplastic cells as opposed to stromal cells (many stromal cells have F receptors). The mouse myeloma hybrid system for the preparation of monoclonal antibodies 13 may yield antisera specific to organs, cell-types, or even tumours.14 If this technique can be adapted to produce human immunoglobulins then many of the disadvantages and dangers of heterologous antisera in patients may be overcome.
THE RETRACTED EPHAPSE THE formation of
ephapses after injury, which allow between sympathetic nerve fibres and somatic afferent nerve fibres, has been proposed by Doupe et a1.1 and Nathan2as the mechanism of causalgia. This concept of an electrical synapse has found wide acceptance despite lack of solid experimental support. Now we must revise our ideas. That the sympathetic nervous system plays a central role is demonstrated by the regular alleviation of causalgia by sympathetic-ganglion block or sympathectomy. That some change occurs in the region of the body affected by causalgia which makes it respond abnormally to sympathetic activity is shown by the fact that this type of burning pain is encountered after stimulation of the appropriate ganglia of the sympathetic nervous system during thoracotomy only in causalgic arms whereas normal limbs are unaffected.3 Sympathetic-ganglion block or sympathectomy could conceivably interrupt afferent sympathetic nerve fibres (if they exist) and only lately have we been in a position to be sure that causalgia and other dystrophic
short-circuiting
10. Davies, D. A. L., O’Neill, G. J. Br. J. Cancer, 1973, 28, suppl. I, p. 285. 11. Ghose. T., Nigam, S. P. Cancer, 1972, 29, 1398. 12. Hurwitz, E., Maron, R., Arnon, R., Sela, M. Cancer Biochem. Biophys.
by sympathetic efferpossible by regional sympathetic blockade-secured by saturation of the affected limb with guanethidine injected intravenously during temporary occlusion of the circulation with a tourniquet. 4Guanethidine has great and prolonged affinity for noradrenaline storage sites in the sympathetic nerve endings and the result is profound sympathetic blockade lasting several days. Guanethidine blocks are most effective in controlling pain in causalgia and other dystrophic states in the limbs, and we must pain ent
in the limbs are caused activity. This has been made states
conclude that it is the effect of noradrenaline on sensitised or damaged sensory nerves that causes the pain. If it is noradrenaline that triggers the pain in these conditions we might expect guanethidine to exacerbate the pain at first, because the initial effect of guanethidine is to discharge noradrenaline from its storage sites before occupying them itself. This is in fact what happens: Hannington-Kiff6 found that pain in the hyperpathic region is momentarily increased before it is relieved in dystrophic limbs. It is not simply the overproduction of noradrenaline which explains the pain, because in many peripheral pain states there is no evidence of sympathetic overactivity (such as excessive sweating, pilo-erection, or colour changes) yet relief is achieved with sympathetic blockade. This key-role of noradrenaline in certain types of pain, especially those associated with hyperæsthesia and hyperpathia, has been supported lately by Loh and Nathan.’ The only clue we have to the nature of the target lesion for the noradrenaline is the finding by Wall and Gutnick8 that tiny axon-sprouts in rat neuromas are strongly stimulated by noradrenaline. This effect was stopped by the alpha-blocker phentolamine. It has been found clinically that thymoxamine, another selective alpha-blocker, will also relieve pain and hyperpathia for a matter of hours and without an initial exacerbation.9 The fact that a guanethidine block will relieve causalgia in the arm associated with a partial lesion of the brachial plexus, though this is above the level of the tourniquet and therefore unaffected by the guanethidine, shows that ephapses at the site of injury are not the explanation. The noradrenaline-sensitive defects must be more peripheral in the sensory nerves. Could there be an alteration in the distance relationships of sympathetic nerve endings and somatic afferent nerve endings as suggested by Hannington-Kifl?6 For the time being the nature of the target-lesion must remain an enigma. The spread of causalgic pain within the affected limb and sometimes beyond to involve a whole quadrant of the body requires that we pay attention also to the related build-up of neural activity in the laminse of the dorsal horn of the spinal cord. From the clinical point of view we should regard causalgia and other peripheral pain states with hyperpathia and hyperaesthesia as indications for an early sympathetic block before an apparently simple trigger produces widespread central overactivity and imprinting.
1976, 1, 197. 13. Köhler, G., Milstein, C. Nature, 1975, 256, 495 14. Williams, A. F., Galfrè, G., Milstein, C. Cell, 1977, 12, 663. 1. Doupe, J., Cullen, C. R., Chance, G. Q. J. Neurol, Neurosurg,
1944, 7, 33. 2. Nathan, P. W. Brain, 1947, 70, 145. 3. Walker, A. E., Nulson, F. Archs Neurol. Psychiat.
1948, 58, 559.
Psychiat.
4. 5. 6. 7. 8. 9.
Hannington-Kiff, J. G. Lancet, 1974, i,1019. Hannington-Kiff, J. G. Pain Relief; p. 68. London, 1974. Hannington-Kiff, J. G. Lancet, 1977, i, 1132. Loh, L., Nathan, P. W.J. Neurol. Neurosurg. Psychiat. 1978, 41, 664. Wall, P. D., Gutnick, M. Exp. Neurol. 1974, 43, 580. Hannington-Kiff, J. G. Pain Relief; p. 69. London, 1974.