752
shift to one of the other modes of definition, as in the transition from myxoedema to hypothyroidism, or from Down's syndrome to trisomy 21. Unfortunately, many doctors remain blissfully unaware of this logical structure and continue to be influenced by outmoded realist assumptions. One still hears eminent physicians say, "X isn't a disease, it's only a syndrome"; psychiatrists still say, "I'm sure he's a schizophrenic even though he doesn't yet show any of the typical symptoms"; and chest physicians still argue whether a patient has chronic bronchitis (a clinical syndrome) or emphysema (a structural abnormality). As an empirical cflscipline medicine has always been suspicious of anything that smacks of philosophy, but this attitude may be a luxury we cannot afford where our own most fundamental concept is concerned. If for no other reason, Moran Campbell and Scadding's study is welcome as evidence that sociologists are no longer the only people with an interest in the meaning of the term disease. 1 2
3 4 5
Scadding, J G, Lancet, 1967, 2, 877. Kendell, R E, British Journal of Psychiatry, 1975, 127, 305. Linder, R, Perceptual and Motor Skills, 1965, 20, suppl p 1081. Sedgwick, P, Hastings Center Studies, 1973, 3, 19. Engelhardt, H T, in Evaluation and Explanation in the Biomedical Sciences, ed H T Engelhardt and S F Spicker, p 137. Dordrecht, Reidel, 1975.
Bed bugs, insects, and hepatitis B Hepatitis B virus may be transmitted in two main ways. The first is by blood and some plasma derivatives, and by any procedure in which the skin or mucosa is penetrated by inadequately sterilised contaminated needles and instruments. Known modes of transmission of hepatitis B include tattooing, acupuncture, piercing of the ear and nose, scarification, ritual operations, and blood letting. The second main method of spread occurs non-parenterally, by intimate contact and by the sexual route. Both of these latter possibilities have been recognised more recently, but we now know that this list does not exhaust the epidemiological propensities of this infection: is, for instance, hepatitis B spread by mosquitoes and other blood-sucking arthropods, particularly in hot climates ? This possibility has been studied for several years, but the results have been conflicting.' Hepatitis B surface antigen, a marker of the virus,2 has been detected in several species of mosquitoes trapped in the wild or fed artificially on infected blood. Even so, no convincing evidence has been obtained of either replication of the virus or persistence of the antigen in the insect. Bed bugs, on the other hand, live more intimately with man than mosquitoes, feed on blood, and could transfer blood and hepatitis B virus from one occupant of a bed to another. Indeed, hepatitis B surface antigen was detected in one of 18 pools of engorged bed bugs (species Cimex hemipterus) collected from brothels in the Ivory Coast.3 In a laboratory study two species of bed bugs-the common bed bug, C lectularius, and Rhodinus prolixus from South America-were fed artificially on blood from a patient with acute hepatitis B.4 The surface antigen remained detectable in the bugs for over four weeks, and juvenile bugs fed on the antigen when in the fourth or fifth instar stage still retained it after moulting-the time when bugs usually start to search for a host and to refeed. In another study,5 bed bugs of the species C hemipterus were
BRITISH MEDICAL JOURNAL
29 SEPTEMBER 1979
collected on several separate occasions from bedding in village huts in Senegal. Hepatitis B surface antigen was detected in engorged and unengorged nymph and adult bed bugs, as well as in bugs kept alive without a blood meal for 30 days. Moreover, e antigen (a marker of infectivity of hepatitis B virus2) was found in one engorged and one unengorged bed bug. Hence we might reasonably deduce that bed bugs feeding on the occupants of the same bed could increase the risk of hepatitis B infection. Blood-sucking bed bugs can regurgitate virus, and it might be present in their saliva; while two other modes of transmission of the virus might be by killing the insect during feeding, and by faecal extrusion of the unaltered virus by the bug after a meal of blood. By themselves these observations are insufficient evidence for accepting the bed bug as a vector of hepatitis B virus, but Jupp and McElligott6 have now taken the story a step further. A colony of C lectularius was fed on blood containing hepatitis B surface antigen. Again, there was no evidence that the virus replicated in the bugs: the antigen persisted after one moult only (transstadial transmission) and it was not transmitted transovarially. Nevertheless, antigen was transmitted by adult bugs through a membrane into three out of 35 cannisters of antigen-negative blood and, as judged by the acquisition of hepatitis B surface antibody, to a rabbit by adult bugs and to two out of 10 guinea-pigs on which antigen-positive fourth and fifth nymphal instars had fed. These findings indicate that bed bugs can transmit hepatitis B mechanically to non-permissive hosts, and it is reasonable to assume that transmission rates to susceptible primates might be high. Hence the question of transmission of hepatitis B by blood-sucking insects merits further investigation, especially since we could at least control this type of spread of this important infection. 1 2
3 4 5
6
Viral Hepatitis, World Health Organisation Technical Report Series, No 570. Geneva, World Health Organisation, 1975. Zuckerman, A J, British Medical 1979, 2, 84. Brotman, B, Prince, A M, and Godfrey, H R, Lancet, 1973, 1, 1305. Newkirk, M M, Downe, A E R, and Simon, J B, Gastroenterology, 1975, 69, 982. Wills, W, et al, Lancet, 1977, 2, 217. Jupp, P G, and McElligott, S E, South African Medical-Journal, 1979, 2, 54.
Journal,
Treatment of advanced prostatic carcinoma Carcinoma of the prostate commonly spreads to bone and lymphatics. If metastases are sought diligently they will sometimes be found in men whose local disease is apparently at an early stage, and almost always in those in whom it is advanced.1 2 The treatment of the latter is therefore frequently palliative. In the patient with advanced disease obstruction to the urinary outflow by the primary tumour is easily dealt with by transurethral resection and pain from localised bone metastases is often effectively controlled by radiotherapy. Thereafter we have few guidelines in planning long-term treatment of metastases, partly because of the generally slow progression of untreated disease and partly because probably as many men die with prostatic cancer as from it. Nevertheless, 80-90% of all patients with prostatic carcinoma will respond, at least temporarily, to treatment aimed at limiting the production of androgens or at stopping
BRITISH MEDICAL JOURNAL
29 SEPTEMBER 1979
their effects.3 Initially the choice lies between oestrogens and orchidectomy. The trials of the Veterans Administration Urological Research Group have helped in showing both the value of a co-operative controlled trial conducted on a large number of patients and how hormone treatment should be used.4 5 These studies indicated that in patients with advanced local or metastatic disease such treatment was more effective than a placebo in giving symptomatic relief. Moreover, the risk of morbidity and death from cardiovascular complications of oestrogen treatment were shown to depend on the dose and they could be minimised by reducing the amount of diethylstilboestrol given from 5 to 1 mg daily. Nevertheless, no significant effect on overall survival could be detected with oestrogen, orchidectomy, or both combined, though the group made a case for prompt treatment since this was found to delay the onset of symptoms and objective evidence of progression. There is much to be said for a policy of starting oestrogens from the time metastases are diagnosed, even in patients without symptoms. The dose of diethylstilboestrol should be more than 0-2 mg and less than 5 mg daily. The Veterans group found that 1 mg a day was effective and produced minimal side effects, even impotence being not invariable. Even so, we still do not know whether, compared with higher oestrogen dosage or orchidectomy, in the long term this dose will reduce cancer mortality, and hence improve overall survival. Such an improvement is likely to be only marginal, and undoubtedly patients with cardiovascular disease, a history of thromboembolism, or oestrogen intolerance are best treated by subcapsular or total orchidectomy. Unfortunately, the histological heterogeneity of most prostatic tumours6 and their metastases is reflected in their ultimate escape from control by oestrogens. Patients who develop symptoms from their metastases while they are being treated with oestrogens-or who have never responded to them-present one of the great unsolved problems of urological management. There seems little point in giving other forms of oestrogen, though stilboestrol diphosphate and chlortrianasene have been used. Many urologists also feel that large intravenous doses of stilboestrol may still be helpful when the smaller oral dose has become ineffective, though this impression has never been confirmed by clinical trial. In the hope that the tumour may respond to suppression of other forms of androgen, hypophysectomy7 or adrenalectomy8 is sometimes performed. In particular, the former may have a dramatic effect on pain from bony metastases, though neither method gives more than a few months of added survival. Similar manipulations of endocrine function with agents such as corticosteroids, danazol, and aminoglutethimide9 probably offer little more than short-term benefit. Another group of drugs theoretically act by inhibiting the binding of the active form of testosterone to its receptor protein. Cyproterone and flutamide10 have been used in this ingenious approach to the problem, but unfortunately neither seems to be more effective than oestrogens in controlling advanced disease. Finally, and inexplicably, testosterone itself has produced some benefit in the occasional patient and, in most patients, it does not promote progression of the disease.'1 Non-hormonal treatment of advanced cancer of the prostate has yet to be fully evaluated. Though it is unlikely that carcinoma of the prostate would be susceptible to immunotherapy, non-specific immune stimulation has been attempted with BCG, though any benefit achieved was offset by severe side effects (generalised granulomatous disease and gastro-
753
intestinal haemorrhage).'2 The results of chemotherapy of advanced disease have also been disappointing, though the variety of agents used and the assessment of their action have not been so rigorously thorough as in other tumours. The latest of three trials by the National Prostatic Cancer Project in the United States concluded that cyclophosphamide and imidazole-carboxamide have definite activity in advanced disease, and are more effective than 5-fluouracil and procarbazine.13 Unfortunately, only subjective responses were evaluated and no comparison was made with the effects of placebos. Furthermore, the evidence that the drugs had any activity at all was derived almost entirely from patients whose disease was maintained stable rather than showed definite regression. Survival was little improved and unpleasant side effects were common. The same criticism may also be applied to the optimistic conclusions from several studies on the use of estramustine14 15 -a drug combining the cytotoxic effect of an alkylating agent with an oestrogen, whose action is presumably to promote preferential uptake by prostatic tissue. The difficulties of assessment are well brought out by Chisholm et al16 in a thoughtful analysis of their own data. Once again they showed that a patient's report of his own subjective response is always open to question and that his doctor's subjective interpretation of an objective response is equally unreliable. Any search for an appropriate chemotherapeutic regimen should now include drug combinations and perhaps platinum diamminodichloride, an agent which may be very effective in other forms of urological cancer. Nevertheless, to justify the expense of long-term chemotherapy"7 and the inevitably unpleasant side effects it should become obvious early that treatment can give a long period of sustained remission. Only then will the patient and his doctor be in full agreement on the value of the newly introduced regimen. 1 Flocks, R H, et al,
Urology Clinics of North America, 1975, 2, 163. Prout, G R, Cancer, 1973, 32, 1096. 3Resnick, M I, and Grayhack, J T, Urology Clinics of North America, 1975, 2, 141. 4Bailar, J C, and Byar, D P, Cancer, 1970, 26, 257. 5 Jordan, W P, Blackard, C E, and Byar, D P, Southern Medical Journal, 1977, 70, 1411. 6 Holland, J M, and Grayhack, J T, in Scientific Foundations of Urology, vol 2, ed G D Chisholm and D I Innes-Williams, p 338. London, Heinemann, 1977. 7Smith, E J R, Gurling, K J, and Baron, D N, British Journal of Urology, 1959, 31, 181. Mahoney, E M, and Harrison, J H, Journal of Urology, 1972, 108, 936. 9 Shearer, R J, et al, British Journal of Urology, 1973, 45, 668. 10 Neri, R, et al, Endocrinology, 1972, 91, 427. 11 Prout, G R, and Brewer, W R, Cancer, 1967, 20, 1871. 12 Robinson, M R G, et al, British Journal of Urology, 1977, 49, 221. 13 Schmidt, J D, et al,3ournal of Urology, 1979, 121, 185. 14 Mittleman, A, Shukla, S K, and Murphy, G P, Journal of Urology, 1976, 115, 409. 15 Nagal, R, and Kolln, C-P, British Journal of Urology, 1977, 49, 73. 16 Chisholm, G D, O'Donoghue, E P N, and Kennedy, C L, British3Journal of Urology, 1977, 49, 717. 17 Bagshawe, K D, Annals of the Royal College of Surgeons of England, 1978, 60, 36. 2
Abnormal smears in pregnancy We have no evidence that cancer in situ occurs more frequently in pregnancy than at other times. The reported rates vary widely, mainly because authors have not stated whether the women in their studies have had cervical smear tests before pregnancy. A recent study gave a cancer in situ rate of 2-6 per
shift to one of the other modes of definition, as in the transition from myxoedema to hypothyroidism, or from Down's syndrome to trisomy 21. Unfortunately, many doctors remain blissfully unaware of this logical structure and continue to be influenced by outmoded realist assumptions. One still hears eminent physicians say, "X isn't a disease, it's only a syndrome"; psychiatrists still say, "I'm sure he's a schizophrenic even though he doesn't yet show any of the typical symptoms"; and chest physicians still argue whether a patient has chronic bronchitis (a clinical syndrome) or emphysema (a structural abnormality). As an empirical cflscipline medicine has always been suspicious of anything that smacks of philosophy, but this attitude may be a luxury we cannot afford where our own most fundamental concept is concerned. If for no other reason, Moran Campbell and Scadding's study is welcome as evidence that sociologists are no longer the only people with an interest in the meaning of the term disease. 1 2
3 4 5
Scadding, J G, Lancet, 1967, 2, 877. Kendell, R E, British Journal of Psychiatry, 1975, 127, 305. Linder, R, Perceptual and Motor Skills, 1965, 20, suppl p 1081. Sedgwick, P, Hastings Center Studies, 1973, 3, 19. Engelhardt, H T, in Evaluation and Explanation in the Biomedical Sciences, ed H T Engelhardt and S F Spicker, p 137. Dordrecht, Reidel, 1975.
Bed bugs, insects, and hepatitis B Hepatitis B virus may be transmitted in two main ways. The first is by blood and some plasma derivatives, and by any procedure in which the skin or mucosa is penetrated by inadequately sterilised contaminated needles and instruments. Known modes of transmission of hepatitis B include tattooing, acupuncture, piercing of the ear and nose, scarification, ritual operations, and blood letting. The second main method of spread occurs non-parenterally, by intimate contact and by the sexual route. Both of these latter possibilities have been recognised more recently, but we now know that this list does not exhaust the epidemiological propensities of this infection: is, for instance, hepatitis B spread by mosquitoes and other blood-sucking arthropods, particularly in hot climates ? This possibility has been studied for several years, but the results have been conflicting.' Hepatitis B surface antigen, a marker of the virus,2 has been detected in several species of mosquitoes trapped in the wild or fed artificially on infected blood. Even so, no convincing evidence has been obtained of either replication of the virus or persistence of the antigen in the insect. Bed bugs, on the other hand, live more intimately with man than mosquitoes, feed on blood, and could transfer blood and hepatitis B virus from one occupant of a bed to another. Indeed, hepatitis B surface antigen was detected in one of 18 pools of engorged bed bugs (species Cimex hemipterus) collected from brothels in the Ivory Coast.3 In a laboratory study two species of bed bugs-the common bed bug, C lectularius, and Rhodinus prolixus from South America-were fed artificially on blood from a patient with acute hepatitis B.4 The surface antigen remained detectable in the bugs for over four weeks, and juvenile bugs fed on the antigen when in the fourth or fifth instar stage still retained it after moulting-the time when bugs usually start to search for a host and to refeed. In another study,5 bed bugs of the species C hemipterus were
BRITISH MEDICAL JOURNAL
29 SEPTEMBER 1979
collected on several separate occasions from bedding in village huts in Senegal. Hepatitis B surface antigen was detected in engorged and unengorged nymph and adult bed bugs, as well as in bugs kept alive without a blood meal for 30 days. Moreover, e antigen (a marker of infectivity of hepatitis B virus2) was found in one engorged and one unengorged bed bug. Hence we might reasonably deduce that bed bugs feeding on the occupants of the same bed could increase the risk of hepatitis B infection. Blood-sucking bed bugs can regurgitate virus, and it might be present in their saliva; while two other modes of transmission of the virus might be by killing the insect during feeding, and by faecal extrusion of the unaltered virus by the bug after a meal of blood. By themselves these observations are insufficient evidence for accepting the bed bug as a vector of hepatitis B virus, but Jupp and McElligott6 have now taken the story a step further. A colony of C lectularius was fed on blood containing hepatitis B surface antigen. Again, there was no evidence that the virus replicated in the bugs: the antigen persisted after one moult only (transstadial transmission) and it was not transmitted transovarially. Nevertheless, antigen was transmitted by adult bugs through a membrane into three out of 35 cannisters of antigen-negative blood and, as judged by the acquisition of hepatitis B surface antibody, to a rabbit by adult bugs and to two out of 10 guinea-pigs on which antigen-positive fourth and fifth nymphal instars had fed. These findings indicate that bed bugs can transmit hepatitis B mechanically to non-permissive hosts, and it is reasonable to assume that transmission rates to susceptible primates might be high. Hence the question of transmission of hepatitis B by blood-sucking insects merits further investigation, especially since we could at least control this type of spread of this important infection. 1 2
3 4 5
6
Viral Hepatitis, World Health Organisation Technical Report Series, No 570. Geneva, World Health Organisation, 1975. Zuckerman, A J, British Medical 1979, 2, 84. Brotman, B, Prince, A M, and Godfrey, H R, Lancet, 1973, 1, 1305. Newkirk, M M, Downe, A E R, and Simon, J B, Gastroenterology, 1975, 69, 982. Wills, W, et al, Lancet, 1977, 2, 217. Jupp, P G, and McElligott, S E, South African Medical-Journal, 1979, 2, 54.
Journal,
Treatment of advanced prostatic carcinoma Carcinoma of the prostate commonly spreads to bone and lymphatics. If metastases are sought diligently they will sometimes be found in men whose local disease is apparently at an early stage, and almost always in those in whom it is advanced.1 2 The treatment of the latter is therefore frequently palliative. In the patient with advanced disease obstruction to the urinary outflow by the primary tumour is easily dealt with by transurethral resection and pain from localised bone metastases is often effectively controlled by radiotherapy. Thereafter we have few guidelines in planning long-term treatment of metastases, partly because of the generally slow progression of untreated disease and partly because probably as many men die with prostatic cancer as from it. Nevertheless, 80-90% of all patients with prostatic carcinoma will respond, at least temporarily, to treatment aimed at limiting the production of androgens or at stopping
BRITISH MEDICAL JOURNAL
29 SEPTEMBER 1979
their effects.3 Initially the choice lies between oestrogens and orchidectomy. The trials of the Veterans Administration Urological Research Group have helped in showing both the value of a co-operative controlled trial conducted on a large number of patients and how hormone treatment should be used.4 5 These studies indicated that in patients with advanced local or metastatic disease such treatment was more effective than a placebo in giving symptomatic relief. Moreover, the risk of morbidity and death from cardiovascular complications of oestrogen treatment were shown to depend on the dose and they could be minimised by reducing the amount of diethylstilboestrol given from 5 to 1 mg daily. Nevertheless, no significant effect on overall survival could be detected with oestrogen, orchidectomy, or both combined, though the group made a case for prompt treatment since this was found to delay the onset of symptoms and objective evidence of progression. There is much to be said for a policy of starting oestrogens from the time metastases are diagnosed, even in patients without symptoms. The dose of diethylstilboestrol should be more than 0-2 mg and less than 5 mg daily. The Veterans group found that 1 mg a day was effective and produced minimal side effects, even impotence being not invariable. Even so, we still do not know whether, compared with higher oestrogen dosage or orchidectomy, in the long term this dose will reduce cancer mortality, and hence improve overall survival. Such an improvement is likely to be only marginal, and undoubtedly patients with cardiovascular disease, a history of thromboembolism, or oestrogen intolerance are best treated by subcapsular or total orchidectomy. Unfortunately, the histological heterogeneity of most prostatic tumours6 and their metastases is reflected in their ultimate escape from control by oestrogens. Patients who develop symptoms from their metastases while they are being treated with oestrogens-or who have never responded to them-present one of the great unsolved problems of urological management. There seems little point in giving other forms of oestrogen, though stilboestrol diphosphate and chlortrianasene have been used. Many urologists also feel that large intravenous doses of stilboestrol may still be helpful when the smaller oral dose has become ineffective, though this impression has never been confirmed by clinical trial. In the hope that the tumour may respond to suppression of other forms of androgen, hypophysectomy7 or adrenalectomy8 is sometimes performed. In particular, the former may have a dramatic effect on pain from bony metastases, though neither method gives more than a few months of added survival. Similar manipulations of endocrine function with agents such as corticosteroids, danazol, and aminoglutethimide9 probably offer little more than short-term benefit. Another group of drugs theoretically act by inhibiting the binding of the active form of testosterone to its receptor protein. Cyproterone and flutamide10 have been used in this ingenious approach to the problem, but unfortunately neither seems to be more effective than oestrogens in controlling advanced disease. Finally, and inexplicably, testosterone itself has produced some benefit in the occasional patient and, in most patients, it does not promote progression of the disease.'1 Non-hormonal treatment of advanced cancer of the prostate has yet to be fully evaluated. Though it is unlikely that carcinoma of the prostate would be susceptible to immunotherapy, non-specific immune stimulation has been attempted with BCG, though any benefit achieved was offset by severe side effects (generalised granulomatous disease and gastro-
753
intestinal haemorrhage).'2 The results of chemotherapy of advanced disease have also been disappointing, though the variety of agents used and the assessment of their action have not been so rigorously thorough as in other tumours. The latest of three trials by the National Prostatic Cancer Project in the United States concluded that cyclophosphamide and imidazole-carboxamide have definite activity in advanced disease, and are more effective than 5-fluouracil and procarbazine.13 Unfortunately, only subjective responses were evaluated and no comparison was made with the effects of placebos. Furthermore, the evidence that the drugs had any activity at all was derived almost entirely from patients whose disease was maintained stable rather than showed definite regression. Survival was little improved and unpleasant side effects were common. The same criticism may also be applied to the optimistic conclusions from several studies on the use of estramustine14 15 -a drug combining the cytotoxic effect of an alkylating agent with an oestrogen, whose action is presumably to promote preferential uptake by prostatic tissue. The difficulties of assessment are well brought out by Chisholm et al16 in a thoughtful analysis of their own data. Once again they showed that a patient's report of his own subjective response is always open to question and that his doctor's subjective interpretation of an objective response is equally unreliable. Any search for an appropriate chemotherapeutic regimen should now include drug combinations and perhaps platinum diamminodichloride, an agent which may be very effective in other forms of urological cancer. Nevertheless, to justify the expense of long-term chemotherapy"7 and the inevitably unpleasant side effects it should become obvious early that treatment can give a long period of sustained remission. Only then will the patient and his doctor be in full agreement on the value of the newly introduced regimen. 1 Flocks, R H, et al,
Urology Clinics of North America, 1975, 2, 163. Prout, G R, Cancer, 1973, 32, 1096. 3Resnick, M I, and Grayhack, J T, Urology Clinics of North America, 1975, 2, 141. 4Bailar, J C, and Byar, D P, Cancer, 1970, 26, 257. 5 Jordan, W P, Blackard, C E, and Byar, D P, Southern Medical Journal, 1977, 70, 1411. 6 Holland, J M, and Grayhack, J T, in Scientific Foundations of Urology, vol 2, ed G D Chisholm and D I Innes-Williams, p 338. London, Heinemann, 1977. 7Smith, E J R, Gurling, K J, and Baron, D N, British Journal of Urology, 1959, 31, 181. Mahoney, E M, and Harrison, J H, Journal of Urology, 1972, 108, 936. 9 Shearer, R J, et al, British Journal of Urology, 1973, 45, 668. 10 Neri, R, et al, Endocrinology, 1972, 91, 427. 11 Prout, G R, and Brewer, W R, Cancer, 1967, 20, 1871. 12 Robinson, M R G, et al, British Journal of Urology, 1977, 49, 221. 13 Schmidt, J D, et al,3ournal of Urology, 1979, 121, 185. 14 Mittleman, A, Shukla, S K, and Murphy, G P, Journal of Urology, 1976, 115, 409. 15 Nagal, R, and Kolln, C-P, British Journal of Urology, 1977, 49, 73. 16 Chisholm, G D, O'Donoghue, E P N, and Kennedy, C L, British3Journal of Urology, 1977, 49, 717. 17 Bagshawe, K D, Annals of the Royal College of Surgeons of England, 1978, 60, 36. 2
Abnormal smears in pregnancy We have no evidence that cancer in situ occurs more frequently in pregnancy than at other times. The reported rates vary widely, mainly because authors have not stated whether the women in their studies have had cervical smear tests before pregnancy. A recent study gave a cancer in situ rate of 2-6 per
