83
chemotherapy in patients without overt metastatic disease.7-9 The early results were all highly encouraging, but follow-up reports now indicate the late appearance of pulmonary and bone metastases.’"These are often single or unilateral, and therefore more amenable to surgery than the more familiar multiple lesions. In 1975 Marcove and colleagues" recorded a 31% 5-year survival-rate from the time of primary amputation, but some of the patients had several thoracotomies in addition to intensive chemotherapy. Giritsky et al. 12 now report their experience with 12 patients in whom metastatic disease arose after primary amputation and chemotherapy. Nineteen thoracotomies were performed, and ten of the patients received radiation to the lungs before or after thoracotomy, some of them also having bromofor radiosensitisation. These workers suggest that a reduction by chemotherapy of the tumour doubling time is an important indicator of the likely success of such aggressive therapy. Patients with tumour doubling times of less than 40 days seem unlikely to benefit. The improved survival-rates have encouraged orthopxdic surgeons to re-examine the need for amputation, and the centres in the U.S.A. which pioneered chemotherapy for osteosarcoma are all now reporting on enbloc resection with either cadaver allograft bone replacement or fitting of individually constructed prostheses.13, 14 It is too soon to evaluate results, but these techniques necessitate scrupulous attention to detail and prevention of infection if they are to be successful. The multidisciplinary approach to management of
deoxyuridine
in small number of specialised centres and the reported series are often highly selected and are being compared with large past series which have been less well monitored. A review from the Mayo clinic" shows that in the years 1969-1974, when the treatment policy was primary surgery and little or no chemotherapy, there was an increase in survival-rates which now stand at 40%. The Mayo workers suggest that improved radiological techniques led to earlier detection of lung metastases and exclusion of cases which would previously have been included. They also suggest that there may be a change in the natural history of the disease related to changes in aaiological and host factors. The present treatment programmes are punishing. In experienced hands they carry a high morbidity and a mortality which is not negligible. The early (and as yet unpublished) results of the M.R.C. treatment trials are similar to those of the American centres, although only moderate doses of chemotherapy are employed.16 Price
osteogenic
sarcoma
has
produced important changes
outlook, but the results do
come
from
a
Sullivan, M. P., Ferbach, D. J. Cancer, 1976, 361, 598. Holland, J. F., Wang, J. J., Sinks, L. F., Blom, J., Senn, H., Bank, A., Glidewell, O. New Engl. J. Med. 1974, 291, 998. 9. Rosen, G., Suwansirikul, S., Kwon, C., Tanc Wu, S. K., Beattie, E. J., Murphy, M. L. Cancer, 1974, 33, 1151. 10. Jaffe, N., Frei, E , Watts, H., Traggis, D. Cancer Chemotherapy Reps. 1978, 62, 259. 11. Marcove, R. C , Martini, N., Rose, N. G. Clin. Orthop. 1975, 111, 65. 12. Giritsky, A. S., Excubanas, E , Mark, J. B. D. J. thorac. cardiovasc. Surg. 7. Sutow, W. W., 8. Cortes, E. P.,
13.
1978, 75, 354 Eilber, F. R., Grant, T., Morton,
D. L. Cancer Treatment
Rep. 1978, 62,
and Geffreel7 pointed out in 1973 that the total number of new cases of osteogenic sarcoma in the U.K. each year would not exceed 150. Maybe the time has come to refer these cases to a few selected centres which can carry out detailed pretreatment evaluation and which can adopt the multidisciplinary approach which now seems essential. Answers might then emerge to the questions now plaguing the American investigators. 18
EYES RIGHT ON RETINITIS PIGMENTOSA THE blinding disease retinitis pigmentosa has been in the news three times in a fortnight. A poorly informed programme on Independent Television was followed by a remarkably knowledgeable debate in the Commons on June 13, and by an international get-together of retinitis-pigmentosa societies on June 24-26 in London. ITV combined an emotional approach to the patient’s wants rather than his needs with a critical line on the scepticism of British ophthalmology toward highly publicised, if uncontrolled, treatments in Russia’ and in Switzerland. The interviewer urged an expert to explain the word "placebo" but took the notion of genetic counselling as common knowledge. We actually witnessed a Liverpool mother-one of a family of 11 patients--dismiss the idea of voluntary birth-control because scientists can be expected to solve the problem in a matter of a few years. The ivt.P.s were in more socially relevant mood. Sometimes the Medical Research Council’s working-party report was acknowledged, sometimes just leaned on. Not for the Commons fancy placental and other implants or, for that matter, any "therapy" not rigorously tested. But matters such as mobility could certainly be looked at, said the Under-Secretary, Mr Alfred Morris, and he would encourage local authorities to pay more attention to this group of sufferers. The various retinitis-pigmentosa societies are remarkable for their realism. The British Retinitis Pigmentosa Society has prudently collected amongst its medical advisers people who actually work in the field. It is consequently immune from unjustified hope and concentrates on social-almost pastoral-aspects. Patients are beginning to realise that they may be facing a problem of
eugenics. The Commons were told that the Medical Research Council is sponsoring two projects, on clinical and genetic aspects, and on the abnormal retinal physiology. Otherwise, what is the state of play in Britain? On the clinical front, there has been a broad advance in understanding of the genetics of the various types of R.P. Their multiple hereditability may point to structural anomalies in dominant inheritance, and enzymatic disorders in autosomal cases. Parallels are to be found in mouse and rat dystrophies, respectively. The X-linked type has received much statistical attention in Britain,2,3 and competent genetic counselling is available in the major centres. Updating of the evidence has strengthened its regional validity. Research is progressing apace on diagnosis by sensory techniques which have supplemented genetic information in other conditions. For in-
213. 14. 15.
Jaffe, N., Watts, H., Fellows, K., Vawter, G. ibid. p. 217. Gilchrist, G. S., Ivins, J. C., Retts, R. E., Pritchard, D. J., Taylor, Edmondson, M J. ibid p. 289.
16. Medical Research Council 17. Price, C. H.G , Jeffree, G.
Working Party on Bone Sarcoma. M. Br. J. Cancer, 1973, 28, 515.
W.
F.,
18. Muggia, F M., Lowe, A. C. Cancer Treatment Rep. 1978, 62, 301. 1. Br. J. Ophth. 1975, 59, 175. 2. Jay, B., Bird, A. Trans. Am. Acad. Ophth. Otol. 1972, 77, 641. 3. Bird, A. C. Br. J. Ophth. 1975, 59, 177. 4. Jay, B. Bull. hellen. Ophth. Soc. 1977, 45/2, 30.
84 stance, quantitative analysis of visual-contrast and other thresholds is expected to yield the type of information obtained from diagnosis of inherited colour defects. Studies with the objective technique of fundus reflectometry,s wherein the patient’s retina is bleached, have revealed correlates with visual defects in retinitis patients,6and have lately been confirmed and extended.7 In the early stages of retinitis pigmentosa, a patient’s ability to see in the dark is determined solely by the amount of rhodopsin that can be bleached. Combined with fundamental work on receptor regeneration and phagocytosis,8 these studies have helped to narrow the number of tasks to which priorities have to be assigned. In the laboratory, acquisition of normal control data continues--e.g., determination of the senile variation of human photoreceptor morphology.9 Work is also progressing in the immunological sphere. Retinal pigment epithelium is now known to be antigenically distinct from photoreceptors.1o In the case of rat dystrophieswhich do not seem to be typical of those of man6-it seems clear that the phagocytosing pigment epithelium has no stomach for photoreceptors.11 Thus the present research efforts cannot be said to be negligible. It is not ideas that are lacking but people to carry them through. Until Government revises its policy on fundamental research, the best hope lies in social adjustment based on genetic considerations.
INTERFERON TREATMENT OF HERPES ZOSTER IT is easy to become sceptical about the use of interferon in human diseases-the idea was put forward so long ago and so little of substance has emerged. Some encouragement is to be had from work just reported by T. C. Merigan and colleagues,’ who conducted three successive trials, each in 30 patients, with two different. batches of human leucocyte interferon of increasing potency and purity. The more highly purified interferon. was given at two dosages-1-7 and 5.1 x 105 uAg/ day-and in general the higher dosages and the purer interferon gave better results. The trial was doubleblind, placebo-controlled, and randomised and the groups were comparable by several criteria. The patients mostly had lymphomas or solid tumours, were under treatment by radiotherapy or chemotherapy, and were first seen about three days, and later about two days, after the onset of herpes zoster. In the 45 interferontreated patients there were fewer complications such as
meningoencephalitis or segmental paresis-1 case against 6 in 45 controls. Only the highest dose reduced progression in the dermatome first affected. In the second two trials, the frequency of postherpetic neuralgia was reduced from 8/29 to 2/29, and the number of patient-days of pain during hospital admission was almost halved. There is therefore no doubt that interferon improved the clinical course of herpes zoster in 5. Weale, R. A. Vision Res. 1962, 1, 354. 6. Highman, V. N., Weale, R. A. Amer. J. Ophth. 1973, 75, 822. 7. Ripps, H., Bnn, K. P., Weale, R. A., Proc XXIII int. ophth. Congr. Kyoto, 1978. 8. Young, R. W. ibid 9. Marshall, J. ibid. 10. Reich-D’Almeida, F., Rahl, A. H. S. Nature, 1974, 252, 307. 11. Reich-D’Almeida, F., Hockley, D. J. Exp. Eye Res. 1975, 21, 347. 1. Merigan, T. C., Rand, K. H., Pollard, R. B., Abdallah, P. S., Jordan, G. W. Fried, R. P. New Engl. J. Med. 1978, 298, 981.
such
patients; and probably
the improvement was cliniuseful. There were no side-effects apart from a cally reduction in reticulocyte-count in all cases and a reduction in circulating granulocytes in patients given the highest dose. There are few rigorously controlled clinical trials to show that human interferon is useful in a herpes-virus infection of man. (In one such trial Jones and others2 found interferon drops effective in ulcerative herpetic keratitis.) Interferon is still scarce and progress will be slow; but the work must continue.
PUNISHING PARENTS PUNISHMENT has been defined haviour that reduces the future
as a
consequence of be-
probability of that
be-
haviour,’ and most parents would argue that the admonitions, deprivations, and blows by which they their children’s behaviour have roughly that aim. But punishment is not necessarily painful4 though it has to be regarded as noxious. According to the definition given above, the application of a stimulus cannot be regarded as a punishment unless it works. This neatly isolates punishment from other noxious parental behaviours ranging from prickliness to gratuitous violence. It serves to separate maintaining discipline from exhibiting bad temper. Aside from whether it works at the time, it is of interest to know whether punishment has long-term effects. Lefkowitz et al.’ have followed a group originally seen as eight-year-olds for over ten years to see whether the punished will punish. Sex differences, intelligence, and sociocultural variables stood between the individuals’ own experience and their proclivity to punish their own (as yet hypothetical) children. The duller boys with more aggressive fathers are likely to be punitive in their turn, and are currently rated more aggressive. Duller girls mimic their mothers’ violent treatment of them. Lefkowitz and co-workers believe that lower intelligence reduces the scope for finding nonpunitive alternatives in child-rearing, but they acknowledge that less intelligent children may incur more punishment by being more frustrating to teach. However, it is very difficult to decide either in prospect or in retrospect, whether a parent’s "punitive" behaviour was provoked or merely gratuitous. Motive is relevant since it might explain why some people argue,6so strenuously, along with Jeremy Bentham, that "all punishment is mischief and that beatings sow the seeds of future child abuse, whereas others feel that the reason behind the decline in classroom behaviour, and increasing vandalism and delinquency, is the abandonment of the precept "chasten thy son while there is hope, and let not thy soul spare for his crying".’ Before we can give really sound advice about the role of punishment in child-rearing, we need to know whether all punishment grows into violence, and indeed whether people who have known punishment have any positive qualities which the others are less likely to achieve.
regulate
B. R., Coster, D. J., Falcon, M. G., Cantell, K. Lancet, 1976, ii, 128. N. H., Holz, W. C. in Operant Behaviour (edited by W. K. Honig) New York, 1966. 4. Johnston, J. M. Am. Psychol. 1972, 27, 1033. 5. Lefkowitz, M. M., Huesmann, L. R., Eron, L. D. Archs gen. Psychiat. 1978,
2. 3.
Jones, Azrin,
35, 186. 6. Maurer, A. Am. Psychol. 7. Proverbs, xviii, 19.
1974, 29, 614.
chemotherapy in patients without overt metastatic disease.7-9 The early results were all highly encouraging, but follow-up reports now indicate the late appearance of pulmonary and bone metastases.’"These are often single or unilateral, and therefore more amenable to surgery than the more familiar multiple lesions. In 1975 Marcove and colleagues" recorded a 31% 5-year survival-rate from the time of primary amputation, but some of the patients had several thoracotomies in addition to intensive chemotherapy. Giritsky et al. 12 now report their experience with 12 patients in whom metastatic disease arose after primary amputation and chemotherapy. Nineteen thoracotomies were performed, and ten of the patients received radiation to the lungs before or after thoracotomy, some of them also having bromofor radiosensitisation. These workers suggest that a reduction by chemotherapy of the tumour doubling time is an important indicator of the likely success of such aggressive therapy. Patients with tumour doubling times of less than 40 days seem unlikely to benefit. The improved survival-rates have encouraged orthopxdic surgeons to re-examine the need for amputation, and the centres in the U.S.A. which pioneered chemotherapy for osteosarcoma are all now reporting on enbloc resection with either cadaver allograft bone replacement or fitting of individually constructed prostheses.13, 14 It is too soon to evaluate results, but these techniques necessitate scrupulous attention to detail and prevention of infection if they are to be successful. The multidisciplinary approach to management of
deoxyuridine
in small number of specialised centres and the reported series are often highly selected and are being compared with large past series which have been less well monitored. A review from the Mayo clinic" shows that in the years 1969-1974, when the treatment policy was primary surgery and little or no chemotherapy, there was an increase in survival-rates which now stand at 40%. The Mayo workers suggest that improved radiological techniques led to earlier detection of lung metastases and exclusion of cases which would previously have been included. They also suggest that there may be a change in the natural history of the disease related to changes in aaiological and host factors. The present treatment programmes are punishing. In experienced hands they carry a high morbidity and a mortality which is not negligible. The early (and as yet unpublished) results of the M.R.C. treatment trials are similar to those of the American centres, although only moderate doses of chemotherapy are employed.16 Price
osteogenic
sarcoma
has
produced important changes
outlook, but the results do
come
from
a
Sullivan, M. P., Ferbach, D. J. Cancer, 1976, 361, 598. Holland, J. F., Wang, J. J., Sinks, L. F., Blom, J., Senn, H., Bank, A., Glidewell, O. New Engl. J. Med. 1974, 291, 998. 9. Rosen, G., Suwansirikul, S., Kwon, C., Tanc Wu, S. K., Beattie, E. J., Murphy, M. L. Cancer, 1974, 33, 1151. 10. Jaffe, N., Frei, E , Watts, H., Traggis, D. Cancer Chemotherapy Reps. 1978, 62, 259. 11. Marcove, R. C , Martini, N., Rose, N. G. Clin. Orthop. 1975, 111, 65. 12. Giritsky, A. S., Excubanas, E , Mark, J. B. D. J. thorac. cardiovasc. Surg. 7. Sutow, W. W., 8. Cortes, E. P.,
13.
1978, 75, 354 Eilber, F. R., Grant, T., Morton,
D. L. Cancer Treatment
Rep. 1978, 62,
and Geffreel7 pointed out in 1973 that the total number of new cases of osteogenic sarcoma in the U.K. each year would not exceed 150. Maybe the time has come to refer these cases to a few selected centres which can carry out detailed pretreatment evaluation and which can adopt the multidisciplinary approach which now seems essential. Answers might then emerge to the questions now plaguing the American investigators. 18
EYES RIGHT ON RETINITIS PIGMENTOSA THE blinding disease retinitis pigmentosa has been in the news three times in a fortnight. A poorly informed programme on Independent Television was followed by a remarkably knowledgeable debate in the Commons on June 13, and by an international get-together of retinitis-pigmentosa societies on June 24-26 in London. ITV combined an emotional approach to the patient’s wants rather than his needs with a critical line on the scepticism of British ophthalmology toward highly publicised, if uncontrolled, treatments in Russia’ and in Switzerland. The interviewer urged an expert to explain the word "placebo" but took the notion of genetic counselling as common knowledge. We actually witnessed a Liverpool mother-one of a family of 11 patients--dismiss the idea of voluntary birth-control because scientists can be expected to solve the problem in a matter of a few years. The ivt.P.s were in more socially relevant mood. Sometimes the Medical Research Council’s working-party report was acknowledged, sometimes just leaned on. Not for the Commons fancy placental and other implants or, for that matter, any "therapy" not rigorously tested. But matters such as mobility could certainly be looked at, said the Under-Secretary, Mr Alfred Morris, and he would encourage local authorities to pay more attention to this group of sufferers. The various retinitis-pigmentosa societies are remarkable for their realism. The British Retinitis Pigmentosa Society has prudently collected amongst its medical advisers people who actually work in the field. It is consequently immune from unjustified hope and concentrates on social-almost pastoral-aspects. Patients are beginning to realise that they may be facing a problem of
eugenics. The Commons were told that the Medical Research Council is sponsoring two projects, on clinical and genetic aspects, and on the abnormal retinal physiology. Otherwise, what is the state of play in Britain? On the clinical front, there has been a broad advance in understanding of the genetics of the various types of R.P. Their multiple hereditability may point to structural anomalies in dominant inheritance, and enzymatic disorders in autosomal cases. Parallels are to be found in mouse and rat dystrophies, respectively. The X-linked type has received much statistical attention in Britain,2,3 and competent genetic counselling is available in the major centres. Updating of the evidence has strengthened its regional validity. Research is progressing apace on diagnosis by sensory techniques which have supplemented genetic information in other conditions. For in-
213. 14. 15.
Jaffe, N., Watts, H., Fellows, K., Vawter, G. ibid. p. 217. Gilchrist, G. S., Ivins, J. C., Retts, R. E., Pritchard, D. J., Taylor, Edmondson, M J. ibid p. 289.
16. Medical Research Council 17. Price, C. H.G , Jeffree, G.
Working Party on Bone Sarcoma. M. Br. J. Cancer, 1973, 28, 515.
W.
F.,
18. Muggia, F M., Lowe, A. C. Cancer Treatment Rep. 1978, 62, 301. 1. Br. J. Ophth. 1975, 59, 175. 2. Jay, B., Bird, A. Trans. Am. Acad. Ophth. Otol. 1972, 77, 641. 3. Bird, A. C. Br. J. Ophth. 1975, 59, 177. 4. Jay, B. Bull. hellen. Ophth. Soc. 1977, 45/2, 30.
84 stance, quantitative analysis of visual-contrast and other thresholds is expected to yield the type of information obtained from diagnosis of inherited colour defects. Studies with the objective technique of fundus reflectometry,s wherein the patient’s retina is bleached, have revealed correlates with visual defects in retinitis patients,6and have lately been confirmed and extended.7 In the early stages of retinitis pigmentosa, a patient’s ability to see in the dark is determined solely by the amount of rhodopsin that can be bleached. Combined with fundamental work on receptor regeneration and phagocytosis,8 these studies have helped to narrow the number of tasks to which priorities have to be assigned. In the laboratory, acquisition of normal control data continues--e.g., determination of the senile variation of human photoreceptor morphology.9 Work is also progressing in the immunological sphere. Retinal pigment epithelium is now known to be antigenically distinct from photoreceptors.1o In the case of rat dystrophieswhich do not seem to be typical of those of man6-it seems clear that the phagocytosing pigment epithelium has no stomach for photoreceptors.11 Thus the present research efforts cannot be said to be negligible. It is not ideas that are lacking but people to carry them through. Until Government revises its policy on fundamental research, the best hope lies in social adjustment based on genetic considerations.
INTERFERON TREATMENT OF HERPES ZOSTER IT is easy to become sceptical about the use of interferon in human diseases-the idea was put forward so long ago and so little of substance has emerged. Some encouragement is to be had from work just reported by T. C. Merigan and colleagues,’ who conducted three successive trials, each in 30 patients, with two different. batches of human leucocyte interferon of increasing potency and purity. The more highly purified interferon. was given at two dosages-1-7 and 5.1 x 105 uAg/ day-and in general the higher dosages and the purer interferon gave better results. The trial was doubleblind, placebo-controlled, and randomised and the groups were comparable by several criteria. The patients mostly had lymphomas or solid tumours, were under treatment by radiotherapy or chemotherapy, and were first seen about three days, and later about two days, after the onset of herpes zoster. In the 45 interferontreated patients there were fewer complications such as
meningoencephalitis or segmental paresis-1 case against 6 in 45 controls. Only the highest dose reduced progression in the dermatome first affected. In the second two trials, the frequency of postherpetic neuralgia was reduced from 8/29 to 2/29, and the number of patient-days of pain during hospital admission was almost halved. There is therefore no doubt that interferon improved the clinical course of herpes zoster in 5. Weale, R. A. Vision Res. 1962, 1, 354. 6. Highman, V. N., Weale, R. A. Amer. J. Ophth. 1973, 75, 822. 7. Ripps, H., Bnn, K. P., Weale, R. A., Proc XXIII int. ophth. Congr. Kyoto, 1978. 8. Young, R. W. ibid 9. Marshall, J. ibid. 10. Reich-D’Almeida, F., Rahl, A. H. S. Nature, 1974, 252, 307. 11. Reich-D’Almeida, F., Hockley, D. J. Exp. Eye Res. 1975, 21, 347. 1. Merigan, T. C., Rand, K. H., Pollard, R. B., Abdallah, P. S., Jordan, G. W. Fried, R. P. New Engl. J. Med. 1978, 298, 981.
such
patients; and probably
the improvement was cliniuseful. There were no side-effects apart from a cally reduction in reticulocyte-count in all cases and a reduction in circulating granulocytes in patients given the highest dose. There are few rigorously controlled clinical trials to show that human interferon is useful in a herpes-virus infection of man. (In one such trial Jones and others2 found interferon drops effective in ulcerative herpetic keratitis.) Interferon is still scarce and progress will be slow; but the work must continue.
PUNISHING PARENTS PUNISHMENT has been defined haviour that reduces the future
as a
consequence of be-
probability of that
be-
haviour,’ and most parents would argue that the admonitions, deprivations, and blows by which they their children’s behaviour have roughly that aim. But punishment is not necessarily painful4 though it has to be regarded as noxious. According to the definition given above, the application of a stimulus cannot be regarded as a punishment unless it works. This neatly isolates punishment from other noxious parental behaviours ranging from prickliness to gratuitous violence. It serves to separate maintaining discipline from exhibiting bad temper. Aside from whether it works at the time, it is of interest to know whether punishment has long-term effects. Lefkowitz et al.’ have followed a group originally seen as eight-year-olds for over ten years to see whether the punished will punish. Sex differences, intelligence, and sociocultural variables stood between the individuals’ own experience and their proclivity to punish their own (as yet hypothetical) children. The duller boys with more aggressive fathers are likely to be punitive in their turn, and are currently rated more aggressive. Duller girls mimic their mothers’ violent treatment of them. Lefkowitz and co-workers believe that lower intelligence reduces the scope for finding nonpunitive alternatives in child-rearing, but they acknowledge that less intelligent children may incur more punishment by being more frustrating to teach. However, it is very difficult to decide either in prospect or in retrospect, whether a parent’s "punitive" behaviour was provoked or merely gratuitous. Motive is relevant since it might explain why some people argue,6so strenuously, along with Jeremy Bentham, that "all punishment is mischief and that beatings sow the seeds of future child abuse, whereas others feel that the reason behind the decline in classroom behaviour, and increasing vandalism and delinquency, is the abandonment of the precept "chasten thy son while there is hope, and let not thy soul spare for his crying".’ Before we can give really sound advice about the role of punishment in child-rearing, we need to know whether all punishment grows into violence, and indeed whether people who have known punishment have any positive qualities which the others are less likely to achieve.
regulate
B. R., Coster, D. J., Falcon, M. G., Cantell, K. Lancet, 1976, ii, 128. N. H., Holz, W. C. in Operant Behaviour (edited by W. K. Honig) New York, 1966. 4. Johnston, J. M. Am. Psychol. 1972, 27, 1033. 5. Lefkowitz, M. M., Huesmann, L. R., Eron, L. D. Archs gen. Psychiat. 1978,
2. 3.
Jones, Azrin,
35, 186. 6. Maurer, A. Am. Psychol. 7. Proverbs, xviii, 19.
1974, 29, 614.
