1138 BIPHASIC TUMOUR-ENHANCING AND TUMOUR-INHIBITING EFFECTS OF NONSPECIFIC IMMUNOTHERAPY
SIR,-Non-specific immunotherapy of cancer by a variety of agents, such as B.c.G., has often resulted in dramatic regression of a variety of tumours.l However, an number of reports has indicated that this mode of treatment may result in enhancement rather than inhibition of tumour growth.l Conditions under which non-specific immunotherapy result in enhancement or inhibition of identical tumours were studied as follows.
increasing
The immune system of mice was stimulated by intraperitoneal injection of rat ascites-tumour (Novikoff hepatoma) cells at various periods before intraperitoneal inoculation of the mice with L1210 leukaemia. Previously untreated mice died within
1-3 weeks after inoculation with lethal doses of L1210 cells. Survival of mice for at least 3 months after L1210 injection was used as an index ot inhibition of leukaemia growth. ,
9 of 11 AKR/J and 19 of 20 SW mice injected with 5 x 106 rat hepatoma alone survived. Only 3 of 24 SW mice and 0 of 29 AKR/J mice survived injection with 1.7 to 3-5 x 106 L1210 cells alone. In contrast, 26 of 28 AKR/J mice survived injection of lethal numbers of L1210 cells at 7, 19, and 44 days after injection of rat hepatoma. 7 of 8 SW mice survived injection of the L1210 cells 27 days after injection of rat hepatoma. The survival of BDFl mice was not prolonged by stimulation with Novikoff hepatoma 12, 14, and 28 days before L1210 inoculation. 18 of 25 AKR/J and SW mice survived injection of a sublethal dose (2 x 105) of L1210 cells alone. In contrast, 0 of 23 of the mice survived when injected with 2 x 105 L1210 cells 1-6 days after stimulation with rat hepatoma. Thus, our results indicate that non-specific immunotherapy may enhance leukaemia growth at relatively short periods after initiation of therapy, and inhibit leukaemia growth at larger periods after initiation of the therapy. A major hazard of non-specific immunotherapy is the possibility that initial tumour-enhancing effects may irreversibly disseminate the tumour cells. Further research is urgently required to define and reduce possible tumourenhancing effects of this mode of treatment. R. A. Cooke Institute of Allergy, Roosevelt Hospital and ISRAEL SIEGEL College of Physicians and Surgeons, MICHAEL H. GRIECO Columbia University, New York, N.Y. 10019, U.S.A. JANET V. RICE.
MUCOSAL ULCERS AND ANAEROBIC ORGANISMS SIR,-We were interested in the report by Dr Ursing and Dr Kamme (April 5, p. 775) that metronidazole is of benefit to patients with Crohn’s disease. However, we feel that their hypothesis that anaerobic organisms are directly involved in the pathogenesis of this disease is open to question. It seems to us that a more likely explanation is that anaerobic organisms present in the normal bowel may become pathogenic when this is damaged by Crohn’s disease and may thereby produce further tissue damage which is reversible if they are eradicated by appropriate antibiotics. We have used
clindamycin, an equally effective agent against anaerobes, in a similar situation in our leukoemic patients. Damage to the oral mucosa after cytotoxic therapy is sometimes followed by inflammation and necrosis of adjacent tissue. As well as being hazardous in the presence of neutropenia, this complication is distressing and often requires strong analgesia. 8 adults with acute myeloid leukaemia (2 were terminal) 1.
Bast, R. C., Zbar, B., Borsos, T., Rapp, H. J. New Engl. J. Med. 1974, 290, 1413.
developed this complication, and were started on clindamycin (1200 mg. per day). Most of these lesions had failed to respond to local and systemic treatment with other antibacterial and antifungal agents without anaerobic specificity. Pain relief was rapid and usually occurred within 24 hours. This was accompanied by a rapid reduction in local tissue swelling with the necrotic tissue taking longer to heal. More recently, because of its specificity against anaerobic organisms, and the absence of serious side-effects in its short-term use, we have also used metronidazole with partial success for another patient. Bacteriological examination showed no evidence of Vincent’s organisms in any of these cases. At that time it was not routine practice to culture mouth swabs anaerobically, but the response to these agents has prompted us to consider anaerobic infection in these circumstances, and to make greater efforts to isolate these organisms. Leukæmia Unit, Royal Postgraduate Medical School, Hammersmith Hospital, London W12 0HS. Leukæmia Unit, Royal Marsden Hospital, Downs Road, Sutton, Surrey.
R. A. STORRING.
M. E. GERKEN.
TEACHING OF ANATOMY
SIR,-As medical students, we were very heartened to read Professor Sinclair’s paper on the teaching of anatomy (April 19, p. 875), in which he deplores the decline of regional topography for professional purposes, and we should like to say that we concur with his conclusions, but not with his proposed method of remedying them. The Oxford course has been designed with an eye to producing " research-workers ", not doctors ", with a consequent lack in the preclinical years of clinicallyoriented work. When qualified, we shall be what Professor Sinclair refers to as " scientifically educated doctors ", and we shall have had just one year of anatomy, a course of 22 weeks, during which time we have rushed through the whole body with barely enough time to complete one area before moving on to the next. Since we firmly believe that a thorough knowledge of anatomy is essential to any doctor, we feel that this amount of time is insufficient, and that an extra term would be useful. Unfortunately, however, this is impracticable because of the necessity to move on to more esoteric subjects. Admittedly we do, at least, get the chance to do a whole-body dissection, which is more than some medical students get. However, we lose out owing to the paucity of clinically oriented tuition, which may be correlated to the lack of medically qualified staff actually in the department. Normally we have a single one-hour lecture a week, but more often than not the consultant surgeon who gives the lecture is called away and his place taken by one of his registrars, some of whom have little idea of what is required for a clinical lecture to preclinical students. Lectures in clinical anatomy are the reward for much painstaking learning: they make it seem worth while after all. As there has been a change in the anatomy taught, so there has been a change in the way of finding out how much students have learnt; now the emphasis is on written assessment, rather than vivas. Indeed at Oxford we have a system of fortnightly true-false tests, marked by a computer. Tests of this sort induce the guessing-game attitude, so the department has now programmed the computer to take marks off for wrong answers, with the result that most "
leave quite a few questions out, as it is all too by filling in those questions of which one is not 100% certain. We appreciate that computer-marked
people
now
easy to fail
1139 assessments
are more
efficient in utilisation of the staff’s
time, which is all the more important because of the staff shortage. Obviously the ideal method of assessment is a viva-voce examination, except that it is subject too much to the individual variation in the examiners, and therefore may be unfair, which was why it was dropped at Oxford. Next best, we feel, would be to have short-note examinations at longer intervals than the true-false tests: this would give us a chance to show that at least we understood the general features and principles, even if This method would, of not the details for a question. course, require more from the staff. As to the question of when anatomy should be taught, we feel that it should all be taught in the preclinical years, since it would lead to a more confident approach to the clinical course. Another interesting possibility is to do a degree in physiological sciences and then a bridging course in anatomy in the long vacation before starting the clinical course, although we believe this has been suggested before and rejected. As it is, we already get the opportunity to study pharmacology, biochemistry, immunology, and other subjects, which Professor Sinclair suggests be moved into the preclinical years-it’s all part of becoming " a scientifically educated doctor "! Finally let us say that we are not writing because we are dissatisfied, but because we want to ensure that a subject that we consider vitally important retains its status in the medical curriculum. G. P. SPICKETT I. R. PARKER Pembroke College, M. S. STEAD. Oxford OX1 1DW.
by
THE OPEN UNIVERSITY AND THE DISTRIBUTION OF DOCTORS
SIR; Professor Acheson’s proposals (April 26,
p.
965)
in themselves admirable. I like them also because they could provide a late chance of reducing the uneven geographical distribution of doctors, particularly of British graduates. The D.H.S.S. seems to have no sensible ideas, and its Minister, it seems, is to aggravate this intractable problem by paying a Londonweighting allowance which will stop some doctors from going where they are more needed. I therefore hope that the profession will support Professor Acheson’s initiative and not be, discouraged by Dr Fry’s forecast of " medical unemployment within 10-15 years " (May 3, p. 1029). His evidence for this forecast, when available, will need to indicate whether the unemployment will be localised or generalised. And will it be among G.P.s or hospital specialists ? Or among community physicians and medical administrators ? (surely not ?); among overseas doctors or British ones ? Even the term "unemployment " has become imprecise: it can mean no more than being unable to get the job you want in the place you prefer, even though there are vacancies for other posts elsewhere. I believe simply that the relatively inexpensive conversion of suitable north-country district general hospitals to teaching hospitals for the clinical part of an Open University course would be more likely to provide both general practitioners and specialists for those under-doctored areas than increasing the numbers of students in all those medical schools in the south of England, particularly in those of the London-weighting belt. But the authorities will, of course, need no reminding that even this expense could be eliminated altogether by continuing to employ overseas doctors.
are
Medical School, 43 Woodstock Road,
Oxford.
JOHN POTTER.
ASTHMA MORTALITY ASSOCIATED WITH PNEUMOTHORAX AND INTERMITTENT POSITIVE-PRESSURE BREATHING
SIR,—I read with considerable interest the article by Karetzky (April 12, p. 828) reporting the death of two
Dr
patients with asthma following the administration of a bronchodilator aerosol by intermittent positive-pressure breathing (I.P.P.B.). I have employed this technique for many years in the treatment of both adults and children with severe asthma (using salbutamol in preference to isoprenaline) and have yet to see a single instance of spontaneous pneumothorax for which this procedure might have been responsible. Indeed, my colleagues and I regard it as a major advance in the treatment of severe
asthma, and since it became available the number of patients requiring tracheal intubation and artificial pulmonary ventilation in this
unit has fallen
to
almost
negligible proportions. In view of this experience, which is shared by most respiratory physicians in the United Kingdom, we should examine very critically the evidence on which Dr Karetzky bases his conclusion that this form of treatment is dangerous and was indeed responsible for the death of his two patients. I am surprised by the statement that pneumothorax is not generally regarded as a potentially lethal complication of severe asthma. This is certainly not the attitude adopted by respiratory physicians here, who are so concerned about the danger of an unrecognised pneumothorax in patients with severe asthma that they X-ray the chest as soon as the patient is admitted to hospital, and repeat the examination if there is any unexpected deterioration. Patients with very severe asthma on treatment with intermittent positive-pressure ventilation via an endotracheal tube may develop a pneumothorax, unilateral or bilateral, often associated with mediastinal and subcutaneous emphysema. My colleagues and I have observed this complication in a number of cases, but only when the inflationary pressure has had to be increased to very high levels (in the region of 50-60 cm. water) to achieve adequate pulmonary ventilation in the presence of an extreme degree of airways obstruction. It seems hardly conceivable that I.P.P.B. administered via a face mask at an inflationary pressure of only 10-15 cm. water can produce an increase in intra-alveolar pressure of sufficient magnitude to cause rupture of the alveolar walls, particularly since the actual inflationary pressure transmitted to the bronchi, and thus to the alveoli, must be limited to some extent by the resistance to airflow offered by the larynx. A number of statements in the first case-report throw considerable doubt on the diagnosis of bilateral pneumothorax. It is stated that " auscultation of the chest revealed barely audible wheezes or breath sounds " and that " physical examination [there is no mention of an As all exX-ray] indicated bilateral pneumothorax". " perienced physicians know, a silent chest is a common feature of very severe asthma, even in the absence of pneumothorax, and it is quite impossible to diagnose bilateral pneumothorax in these circumstances from signs alone. Even what Dr Karetzky describes as physical " chest tube placement " cannot be accepted as confirmation of the diagnosis, since the insertion of an intercostal tube into a grossly overdistended lung can release large quantities of air into a water-seal drainage system, and thus simulate the presence of a pneumothorax. It would appear that full resuscitative measures, including tracheal intubation and artificial pulmonary ventilation, were not instituted when the Paco2 rose to 79 mm. Hg (a potentially lethal level in bronchial asthma) since, according to the table, the Paco, increased to 84 mm. Hg an hour later, presumably before the patient was " intubated " 15 minutes before her death. In this context the asthma
SIR,-Non-specific immunotherapy of cancer by a variety of agents, such as B.c.G., has often resulted in dramatic regression of a variety of tumours.l However, an number of reports has indicated that this mode of treatment may result in enhancement rather than inhibition of tumour growth.l Conditions under which non-specific immunotherapy result in enhancement or inhibition of identical tumours were studied as follows.
increasing
The immune system of mice was stimulated by intraperitoneal injection of rat ascites-tumour (Novikoff hepatoma) cells at various periods before intraperitoneal inoculation of the mice with L1210 leukaemia. Previously untreated mice died within
1-3 weeks after inoculation with lethal doses of L1210 cells. Survival of mice for at least 3 months after L1210 injection was used as an index ot inhibition of leukaemia growth. ,
9 of 11 AKR/J and 19 of 20 SW mice injected with 5 x 106 rat hepatoma alone survived. Only 3 of 24 SW mice and 0 of 29 AKR/J mice survived injection with 1.7 to 3-5 x 106 L1210 cells alone. In contrast, 26 of 28 AKR/J mice survived injection of lethal numbers of L1210 cells at 7, 19, and 44 days after injection of rat hepatoma. 7 of 8 SW mice survived injection of the L1210 cells 27 days after injection of rat hepatoma. The survival of BDFl mice was not prolonged by stimulation with Novikoff hepatoma 12, 14, and 28 days before L1210 inoculation. 18 of 25 AKR/J and SW mice survived injection of a sublethal dose (2 x 105) of L1210 cells alone. In contrast, 0 of 23 of the mice survived when injected with 2 x 105 L1210 cells 1-6 days after stimulation with rat hepatoma. Thus, our results indicate that non-specific immunotherapy may enhance leukaemia growth at relatively short periods after initiation of therapy, and inhibit leukaemia growth at larger periods after initiation of the therapy. A major hazard of non-specific immunotherapy is the possibility that initial tumour-enhancing effects may irreversibly disseminate the tumour cells. Further research is urgently required to define and reduce possible tumourenhancing effects of this mode of treatment. R. A. Cooke Institute of Allergy, Roosevelt Hospital and ISRAEL SIEGEL College of Physicians and Surgeons, MICHAEL H. GRIECO Columbia University, New York, N.Y. 10019, U.S.A. JANET V. RICE.
MUCOSAL ULCERS AND ANAEROBIC ORGANISMS SIR,-We were interested in the report by Dr Ursing and Dr Kamme (April 5, p. 775) that metronidazole is of benefit to patients with Crohn’s disease. However, we feel that their hypothesis that anaerobic organisms are directly involved in the pathogenesis of this disease is open to question. It seems to us that a more likely explanation is that anaerobic organisms present in the normal bowel may become pathogenic when this is damaged by Crohn’s disease and may thereby produce further tissue damage which is reversible if they are eradicated by appropriate antibiotics. We have used
clindamycin, an equally effective agent against anaerobes, in a similar situation in our leukoemic patients. Damage to the oral mucosa after cytotoxic therapy is sometimes followed by inflammation and necrosis of adjacent tissue. As well as being hazardous in the presence of neutropenia, this complication is distressing and often requires strong analgesia. 8 adults with acute myeloid leukaemia (2 were terminal) 1.
Bast, R. C., Zbar, B., Borsos, T., Rapp, H. J. New Engl. J. Med. 1974, 290, 1413.
developed this complication, and were started on clindamycin (1200 mg. per day). Most of these lesions had failed to respond to local and systemic treatment with other antibacterial and antifungal agents without anaerobic specificity. Pain relief was rapid and usually occurred within 24 hours. This was accompanied by a rapid reduction in local tissue swelling with the necrotic tissue taking longer to heal. More recently, because of its specificity against anaerobic organisms, and the absence of serious side-effects in its short-term use, we have also used metronidazole with partial success for another patient. Bacteriological examination showed no evidence of Vincent’s organisms in any of these cases. At that time it was not routine practice to culture mouth swabs anaerobically, but the response to these agents has prompted us to consider anaerobic infection in these circumstances, and to make greater efforts to isolate these organisms. Leukæmia Unit, Royal Postgraduate Medical School, Hammersmith Hospital, London W12 0HS. Leukæmia Unit, Royal Marsden Hospital, Downs Road, Sutton, Surrey.
R. A. STORRING.
M. E. GERKEN.
TEACHING OF ANATOMY
SIR,-As medical students, we were very heartened to read Professor Sinclair’s paper on the teaching of anatomy (April 19, p. 875), in which he deplores the decline of regional topography for professional purposes, and we should like to say that we concur with his conclusions, but not with his proposed method of remedying them. The Oxford course has been designed with an eye to producing " research-workers ", not doctors ", with a consequent lack in the preclinical years of clinicallyoriented work. When qualified, we shall be what Professor Sinclair refers to as " scientifically educated doctors ", and we shall have had just one year of anatomy, a course of 22 weeks, during which time we have rushed through the whole body with barely enough time to complete one area before moving on to the next. Since we firmly believe that a thorough knowledge of anatomy is essential to any doctor, we feel that this amount of time is insufficient, and that an extra term would be useful. Unfortunately, however, this is impracticable because of the necessity to move on to more esoteric subjects. Admittedly we do, at least, get the chance to do a whole-body dissection, which is more than some medical students get. However, we lose out owing to the paucity of clinically oriented tuition, which may be correlated to the lack of medically qualified staff actually in the department. Normally we have a single one-hour lecture a week, but more often than not the consultant surgeon who gives the lecture is called away and his place taken by one of his registrars, some of whom have little idea of what is required for a clinical lecture to preclinical students. Lectures in clinical anatomy are the reward for much painstaking learning: they make it seem worth while after all. As there has been a change in the anatomy taught, so there has been a change in the way of finding out how much students have learnt; now the emphasis is on written assessment, rather than vivas. Indeed at Oxford we have a system of fortnightly true-false tests, marked by a computer. Tests of this sort induce the guessing-game attitude, so the department has now programmed the computer to take marks off for wrong answers, with the result that most "
leave quite a few questions out, as it is all too by filling in those questions of which one is not 100% certain. We appreciate that computer-marked
people
now
easy to fail
1139 assessments
are more
efficient in utilisation of the staff’s
time, which is all the more important because of the staff shortage. Obviously the ideal method of assessment is a viva-voce examination, except that it is subject too much to the individual variation in the examiners, and therefore may be unfair, which was why it was dropped at Oxford. Next best, we feel, would be to have short-note examinations at longer intervals than the true-false tests: this would give us a chance to show that at least we understood the general features and principles, even if This method would, of not the details for a question. course, require more from the staff. As to the question of when anatomy should be taught, we feel that it should all be taught in the preclinical years, since it would lead to a more confident approach to the clinical course. Another interesting possibility is to do a degree in physiological sciences and then a bridging course in anatomy in the long vacation before starting the clinical course, although we believe this has been suggested before and rejected. As it is, we already get the opportunity to study pharmacology, biochemistry, immunology, and other subjects, which Professor Sinclair suggests be moved into the preclinical years-it’s all part of becoming " a scientifically educated doctor "! Finally let us say that we are not writing because we are dissatisfied, but because we want to ensure that a subject that we consider vitally important retains its status in the medical curriculum. G. P. SPICKETT I. R. PARKER Pembroke College, M. S. STEAD. Oxford OX1 1DW.
by
THE OPEN UNIVERSITY AND THE DISTRIBUTION OF DOCTORS
SIR; Professor Acheson’s proposals (April 26,
p.
965)
in themselves admirable. I like them also because they could provide a late chance of reducing the uneven geographical distribution of doctors, particularly of British graduates. The D.H.S.S. seems to have no sensible ideas, and its Minister, it seems, is to aggravate this intractable problem by paying a Londonweighting allowance which will stop some doctors from going where they are more needed. I therefore hope that the profession will support Professor Acheson’s initiative and not be, discouraged by Dr Fry’s forecast of " medical unemployment within 10-15 years " (May 3, p. 1029). His evidence for this forecast, when available, will need to indicate whether the unemployment will be localised or generalised. And will it be among G.P.s or hospital specialists ? Or among community physicians and medical administrators ? (surely not ?); among overseas doctors or British ones ? Even the term "unemployment " has become imprecise: it can mean no more than being unable to get the job you want in the place you prefer, even though there are vacancies for other posts elsewhere. I believe simply that the relatively inexpensive conversion of suitable north-country district general hospitals to teaching hospitals for the clinical part of an Open University course would be more likely to provide both general practitioners and specialists for those under-doctored areas than increasing the numbers of students in all those medical schools in the south of England, particularly in those of the London-weighting belt. But the authorities will, of course, need no reminding that even this expense could be eliminated altogether by continuing to employ overseas doctors.
are
Medical School, 43 Woodstock Road,
Oxford.
JOHN POTTER.
ASTHMA MORTALITY ASSOCIATED WITH PNEUMOTHORAX AND INTERMITTENT POSITIVE-PRESSURE BREATHING
SIR,—I read with considerable interest the article by Karetzky (April 12, p. 828) reporting the death of two
Dr
patients with asthma following the administration of a bronchodilator aerosol by intermittent positive-pressure breathing (I.P.P.B.). I have employed this technique for many years in the treatment of both adults and children with severe asthma (using salbutamol in preference to isoprenaline) and have yet to see a single instance of spontaneous pneumothorax for which this procedure might have been responsible. Indeed, my colleagues and I regard it as a major advance in the treatment of severe
asthma, and since it became available the number of patients requiring tracheal intubation and artificial pulmonary ventilation in this
unit has fallen
to
almost
negligible proportions. In view of this experience, which is shared by most respiratory physicians in the United Kingdom, we should examine very critically the evidence on which Dr Karetzky bases his conclusion that this form of treatment is dangerous and was indeed responsible for the death of his two patients. I am surprised by the statement that pneumothorax is not generally regarded as a potentially lethal complication of severe asthma. This is certainly not the attitude adopted by respiratory physicians here, who are so concerned about the danger of an unrecognised pneumothorax in patients with severe asthma that they X-ray the chest as soon as the patient is admitted to hospital, and repeat the examination if there is any unexpected deterioration. Patients with very severe asthma on treatment with intermittent positive-pressure ventilation via an endotracheal tube may develop a pneumothorax, unilateral or bilateral, often associated with mediastinal and subcutaneous emphysema. My colleagues and I have observed this complication in a number of cases, but only when the inflationary pressure has had to be increased to very high levels (in the region of 50-60 cm. water) to achieve adequate pulmonary ventilation in the presence of an extreme degree of airways obstruction. It seems hardly conceivable that I.P.P.B. administered via a face mask at an inflationary pressure of only 10-15 cm. water can produce an increase in intra-alveolar pressure of sufficient magnitude to cause rupture of the alveolar walls, particularly since the actual inflationary pressure transmitted to the bronchi, and thus to the alveoli, must be limited to some extent by the resistance to airflow offered by the larynx. A number of statements in the first case-report throw considerable doubt on the diagnosis of bilateral pneumothorax. It is stated that " auscultation of the chest revealed barely audible wheezes or breath sounds " and that " physical examination [there is no mention of an As all exX-ray] indicated bilateral pneumothorax". " perienced physicians know, a silent chest is a common feature of very severe asthma, even in the absence of pneumothorax, and it is quite impossible to diagnose bilateral pneumothorax in these circumstances from signs alone. Even what Dr Karetzky describes as physical " chest tube placement " cannot be accepted as confirmation of the diagnosis, since the insertion of an intercostal tube into a grossly overdistended lung can release large quantities of air into a water-seal drainage system, and thus simulate the presence of a pneumothorax. It would appear that full resuscitative measures, including tracheal intubation and artificial pulmonary ventilation, were not instituted when the Paco2 rose to 79 mm. Hg (a potentially lethal level in bronchial asthma) since, according to the table, the Paco, increased to 84 mm. Hg an hour later, presumably before the patient was " intubated " 15 minutes before her death. In this context the asthma
