1172
feron which was used in the experiment in Britain which showed that intranasal interferon would prevent rhinovirus colds.5 But he also supplied STRANDER in Stockholm with interferon. STRANDER and his colleagues have now used interferon in a series of patients with osteogenic sarcoma, doses of 3 x 106 units being given usually three times a week on an outpatient basis. The treatment was added to standard initial surgical or radiation treatment. Interferon had virtually no adverse effects and the latest analyses, reported in New York, show that up to 5 years the treated patients have fewer metastases and survive longer than controls given standard treatment either in the past (historical controls) or in parallel with the study group (concurrent controls). About half are still alive at the end of that time. These important observations have now been extended in several ways. Firstly, STRANDER has treated small numbers of patients with other diseases and after some initial encouragement6 his group reported 4 patients with myelomatosis, 2 of whom showed quite dramatic remission.7 He reported at New York that they have now studied 16 patients of whom 2 had complete and 5 had partial remissions, and he has initiated a controlled trial of this treatment. GUTTERMAN has confirmed these findings, including the fact that patients in a late or advanced stage of the disease do not respond. Furthermore, quite clear objective remission has been seen in 3 patients at Stanford University who were treated with interferon for lymphocytic non-Hodgkin’s lymphoma, though 3 patients with histiocytic disease did not respond.8 GUTTERMAN9 also described the regression of metastatic subcutaneous breast-cancer nodules in patients given intramuscular interferon. Interferon can be made from human fibroblasts as well as from leucocytes, and this material is antigenically different, is less stable, and has some differences in biological activity from leucocyte interferon; yet it also has anti-tumour effects in man-for instance, when given locally it induced regression of breasttumour metastases.
All this has stimulated
feron for
more
trials, and
a
long period of development, interferon is now being produced from the Namalva strain of lymphoblastoid cells. The advantage is that the cells are not subject to the vagaries of supply of human leucocytes, and that they can be grown in suspended culture fermenter tanks, unlike fibro-
after
a
blasts which need to be grown on surfaces. The cultures still need large supplies of serum and are subject to bacterial contamination; also the cells contain Epstein-Barr virus genome, so there is a hypothetical risk that the gene or its product might be present in the final product, despite the substantial purification built into the process-which makes the product some ten times more potent per milligram of protein than CANTELL’S purified interferon. However, the product should be acceptable for use in serious diseases. This production process could be scaled up to yield substantial amounts of interferon for clinical use, but before this happens some important scientific questions must be answered. Although this product seems to be a mixture of leucocyte-type interferon with traces of fibroblast-type interferon, we do not know what will be the biological effects of the interferons and the accompanying impurities. Thus, to establish its clinical usefulness and safety, trials are needed and a committee has been formed, under the auspices of the Medical Research Council, to coordinate and speed these up. The Imperial Cancer Research Fund played an important role in supporting the earlier stages of this work and their staff along with other oncologists and virologists will be conducting trials to establish the effects of lymphoblastoid interferon, probably first in myelomatosis. If successful these will need to be followed by exploratory short-term studies in other tumours and long-term full-scale trials to establish the best dosage schedules and the clinical usefulness of interferon either alone or along with surgery or chemotherapy. Prediction in medical science is a foolish exercise but it seems likely that interferon is going to prove useful in the management of malignant disease, though much more work is needed to find out how demand for more interand when it should be used.
new
pilot plants
are now
turning leucocyte and fibroblast interferon in various parts of the world. It was announced in New York that the American Cancer Society has allocated at least two million dollars for the purchase of interferons for this purpose. In Britain, out
5.
Merigan,
T.
C., Reed, S. E., Hall, T. S., Tyrrell, D. A. J. Lancet, 1973, i
563.
Ideström, K., Cantell, K., Killander, D., Nilsson, K., Strander, H., Willems J. Acta med. scand. 1979, 205, 149. 7. Mellstedt, H., Ahre, A., Björkholm, M., Holm, G., Johansson, B., Strander H. Lancet, 1979, i, 245. 8. Merigan, T. C., Sikora, K., Breeden, J. H., Levy, R., Rosenberg, S. A. New Engl J.Med. 1979,299,1449. 9. Gutterman, J. ibid. (in the press).
6.
in Acute-on-chronic Respiratory Failure
Oxygen
FROM time to time inthe course of chronic obstructive lung disease an acute exacerbation demands intensive hospital treatment. These incidents, generally related to increased bronchial infection, are often marked by severe respiratory failure, with arterial blood-gas tensions well outside normal limits of Pao2 60 mm Hg, 7.98 kPa; Paco,
1173
49 mm Hg, 6.52 kPa, Usually hypoxia ’s severe, but the degree of hypercapnia ’/aries widely between patients. In simple terms; hypoxia arises
mainly from venti13tion/perf1.u:ion mismatching, exacerbated by retained ?e’"retions m previously useful lung; hypercapnia. indicating alveolar hypoventilation, is due to impaired .-e7,piratory irive, with acute or chronic insensitivity of the respiratory centre to C02. No patient breathing atmospheric air will sustain a PgC.o-, above 90 mm Hg (11.97 kPa) for long, not only because CO., narcosis reduces his capably to (:0ngh and to breathe, but also because the alveolar-air equation dictates that his Pao2will have come dose to the fatal limit of around 20 mm Hg (2 66 k?a), Proper treatment of an acute exacerbation ?an be rewarding, while poor management can be disastrous. Neglect of simple aspects such as keeping the patient awake to cough, can lead to rapid deterioration. Too high an inspired oxygen with insumcient monitoring can precipitate spiralling hypercapnia, narcosis, and the need for artificial ventilation. In 1965 CAMPBELL clearly laid the guidelines on which modern treatment of acute-on-chronic respiratory failure is based. His advice on controlled oxygen is widely accepted, yet there remain 1_iic:s who opt for a high percentage of inspired oxygen during the initial phase of management. In considering controlled oxygen treatment, it is useful to bear in mind the clinical effects of different degrees of hypoxia. Roughly speaking, a Pao2 of less than 20 mm Hg (2.66 kPa) is fatal; when Pa02 drops below 40 mm Hg (3-32 kPa) there is probably some tissue damage, although the rightward shift of the oxygen dissociation curve caused by coexisting acidosis provides some protection; lesser degrees of hypoxia have important effects on respiration, bone-marrow, and circulation, but these are essentially adaptive, long-term changes. The sharply elbowed curve relating hypoxia to clinical effect has been compared to a climber’s gentle descent towards an abyss, or, in more mundane terms, to a car about to run out of petrol. There are few signs of impending catastrophe in either case. In treatment, one priority must be to raise P a02 to a safe level; but, as in the mountaineering and motoring analogies, the increase need only be a small one to maintain life. 1n praçtical terms, an initial increase in inspired oxygen fraction of a few percent, by 24% ’Ventimask’, is sufficient. This is unlikely to precipitate spiralling hypercapnia, provided that the patient is kept awake and that he expectorates retained secretions. If he makes satisfactory clinical progress during the first critical hour or two, it is usually safe to increase the inspired oxygen fraction to 28% by ven
feron which was used in the experiment in Britain which showed that intranasal interferon would prevent rhinovirus colds.5 But he also supplied STRANDER in Stockholm with interferon. STRANDER and his colleagues have now used interferon in a series of patients with osteogenic sarcoma, doses of 3 x 106 units being given usually three times a week on an outpatient basis. The treatment was added to standard initial surgical or radiation treatment. Interferon had virtually no adverse effects and the latest analyses, reported in New York, show that up to 5 years the treated patients have fewer metastases and survive longer than controls given standard treatment either in the past (historical controls) or in parallel with the study group (concurrent controls). About half are still alive at the end of that time. These important observations have now been extended in several ways. Firstly, STRANDER has treated small numbers of patients with other diseases and after some initial encouragement6 his group reported 4 patients with myelomatosis, 2 of whom showed quite dramatic remission.7 He reported at New York that they have now studied 16 patients of whom 2 had complete and 5 had partial remissions, and he has initiated a controlled trial of this treatment. GUTTERMAN has confirmed these findings, including the fact that patients in a late or advanced stage of the disease do not respond. Furthermore, quite clear objective remission has been seen in 3 patients at Stanford University who were treated with interferon for lymphocytic non-Hodgkin’s lymphoma, though 3 patients with histiocytic disease did not respond.8 GUTTERMAN9 also described the regression of metastatic subcutaneous breast-cancer nodules in patients given intramuscular interferon. Interferon can be made from human fibroblasts as well as from leucocytes, and this material is antigenically different, is less stable, and has some differences in biological activity from leucocyte interferon; yet it also has anti-tumour effects in man-for instance, when given locally it induced regression of breasttumour metastases.
All this has stimulated
feron for
more
trials, and
a
long period of development, interferon is now being produced from the Namalva strain of lymphoblastoid cells. The advantage is that the cells are not subject to the vagaries of supply of human leucocytes, and that they can be grown in suspended culture fermenter tanks, unlike fibro-
after
a
blasts which need to be grown on surfaces. The cultures still need large supplies of serum and are subject to bacterial contamination; also the cells contain Epstein-Barr virus genome, so there is a hypothetical risk that the gene or its product might be present in the final product, despite the substantial purification built into the process-which makes the product some ten times more potent per milligram of protein than CANTELL’S purified interferon. However, the product should be acceptable for use in serious diseases. This production process could be scaled up to yield substantial amounts of interferon for clinical use, but before this happens some important scientific questions must be answered. Although this product seems to be a mixture of leucocyte-type interferon with traces of fibroblast-type interferon, we do not know what will be the biological effects of the interferons and the accompanying impurities. Thus, to establish its clinical usefulness and safety, trials are needed and a committee has been formed, under the auspices of the Medical Research Council, to coordinate and speed these up. The Imperial Cancer Research Fund played an important role in supporting the earlier stages of this work and their staff along with other oncologists and virologists will be conducting trials to establish the effects of lymphoblastoid interferon, probably first in myelomatosis. If successful these will need to be followed by exploratory short-term studies in other tumours and long-term full-scale trials to establish the best dosage schedules and the clinical usefulness of interferon either alone or along with surgery or chemotherapy. Prediction in medical science is a foolish exercise but it seems likely that interferon is going to prove useful in the management of malignant disease, though much more work is needed to find out how demand for more interand when it should be used.
new
pilot plants
are now
turning leucocyte and fibroblast interferon in various parts of the world. It was announced in New York that the American Cancer Society has allocated at least two million dollars for the purchase of interferons for this purpose. In Britain, out
5.
Merigan,
T.
C., Reed, S. E., Hall, T. S., Tyrrell, D. A. J. Lancet, 1973, i
563.
Ideström, K., Cantell, K., Killander, D., Nilsson, K., Strander, H., Willems J. Acta med. scand. 1979, 205, 149. 7. Mellstedt, H., Ahre, A., Björkholm, M., Holm, G., Johansson, B., Strander H. Lancet, 1979, i, 245. 8. Merigan, T. C., Sikora, K., Breeden, J. H., Levy, R., Rosenberg, S. A. New Engl J.Med. 1979,299,1449. 9. Gutterman, J. ibid. (in the press).
6.
in Acute-on-chronic Respiratory Failure
Oxygen
FROM time to time inthe course of chronic obstructive lung disease an acute exacerbation demands intensive hospital treatment. These incidents, generally related to increased bronchial infection, are often marked by severe respiratory failure, with arterial blood-gas tensions well outside normal limits of Pao2 60 mm Hg, 7.98 kPa; Paco,
1173
49 mm Hg, 6.52 kPa, Usually hypoxia ’s severe, but the degree of hypercapnia ’/aries widely between patients. In simple terms; hypoxia arises
mainly from venti13tion/perf1.u:ion mismatching, exacerbated by retained ?e’"retions m previously useful lung; hypercapnia. indicating alveolar hypoventilation, is due to impaired .-e7,piratory irive, with acute or chronic insensitivity of the respiratory centre to C02. No patient breathing atmospheric air will sustain a PgC.o-, above 90 mm Hg (11.97 kPa) for long, not only because CO., narcosis reduces his capably to (:0ngh and to breathe, but also because the alveolar-air equation dictates that his Pao2will have come dose to the fatal limit of around 20 mm Hg (2 66 k?a), Proper treatment of an acute exacerbation ?an be rewarding, while poor management can be disastrous. Neglect of simple aspects such as keeping the patient awake to cough, can lead to rapid deterioration. Too high an inspired oxygen with insumcient monitoring can precipitate spiralling hypercapnia, narcosis, and the need for artificial ventilation. In 1965 CAMPBELL clearly laid the guidelines on which modern treatment of acute-on-chronic respiratory failure is based. His advice on controlled oxygen is widely accepted, yet there remain 1_iic:s who opt for a high percentage of inspired oxygen during the initial phase of management. In considering controlled oxygen treatment, it is useful to bear in mind the clinical effects of different degrees of hypoxia. Roughly speaking, a Pao2 of less than 20 mm Hg (2.66 kPa) is fatal; when Pa02 drops below 40 mm Hg (3-32 kPa) there is probably some tissue damage, although the rightward shift of the oxygen dissociation curve caused by coexisting acidosis provides some protection; lesser degrees of hypoxia have important effects on respiration, bone-marrow, and circulation, but these are essentially adaptive, long-term changes. The sharply elbowed curve relating hypoxia to clinical effect has been compared to a climber’s gentle descent towards an abyss, or, in more mundane terms, to a car about to run out of petrol. There are few signs of impending catastrophe in either case. In treatment, one priority must be to raise P a02 to a safe level; but, as in the mountaineering and motoring analogies, the increase need only be a small one to maintain life. 1n praçtical terms, an initial increase in inspired oxygen fraction of a few percent, by 24% ’Ventimask’, is sufficient. This is unlikely to precipitate spiralling hypercapnia, provided that the patient is kept awake and that he expectorates retained secretions. If he makes satisfactory clinical progress during the first critical hour or two, it is usually safe to increase the inspired oxygen fraction to 28% by ven
