- Email: [email protected]
MANAGEMENT OF INTRACRANIAL ANEURYSMS
692
SIR,-We agree with the hypothesis of Dr G. J. Miller and Dr N. E. Miller (Jan. 4, p. 16) about a possible antiatherogenic role of plasma - high - density - lipoproteins (H.D.L.). Both Glueck1 and ourselves2 have lately recognised a familial hyperlipoproteinmmia in which most of the cholesterol is carried as H.D.L. (oc) cholesterol. In members of these families no signs of cardiovascular involvement have been found. Moreover, in our series, few patients with familial type-IIA hyperlipoproteinarmia have xanthomata, unlike such patients from other countries. Also, the frequency of ischaemic heart-disease among the families in our series is rather low. Other authors have supported the view that essential hypercholesterolaemia is a " relatively benign trait 11.3 In this respect, it is interesting that, in our patients with type-II hyperlipoproteinsemia, values of H.D.L.cholesterol are higher than those quoted by previous authors.
A reciprocal behaviour of low-density-lipoprotein (L.D.L.)cholesterol and H.D.L.-cholesterol is not supported by our
findings, as we have recorded a positive correlation (r= +0-31) between the two parameters. A positive correlation has been previously quoted in Eskimos4 and in one American group. The complex process of lipid influx and efflux in the arterial wall is shown best by the ratio of plasma-levels of L.D.L.H.D.L. cholesterol.
The trend of the ratio from the highest values in type the lowest value in normal people seems to correlate better with the expected frequencies of cardiovascular disease in hyperlipoproteinamlia states. IIA to
Regional Hospital, Unit for Atherosclerosis and
Hyperlipæmias, Venice, Italy.
P. AVOGARO G. CAZZOLATO M. PAIS.
TREATMENT OF SMALL-CELL CARCINOMA OF BRONCHUS SIR,-A randomised study evaluating the results of treatment with radiotherapy versus chemotherapy in small-cell carcinoma of the bronchus is a timely and laudable effort (Jan. 18, p. 129). It is unfortunate, however, that Dr Laing and his co-workers selected as their chemotherapy a treatment that includes the more toxic but probably less effective alkylating agent nitrogen mustard,8 and a drug (prednisolone) that may have deleterious effects on the survival of patients with lung cancer, as reported in a randomised study by the Veterans Administration
Lung Cancer Study Group.’7
Cyclophosphamide seems to be the most effective single agent in the treatment of small-cell anaplastic carcinoma, 1. 2. 3.
4. 5.
6. 7.
Glueck, C. J. Clin. Res. (in the press). Avogaro, P., Cazzolato, G. Atherosclerosis (in the press). Harlan, W. R., Graham, J. B., Estes, H. Medicine, Baltimore, 1966, 77, 45. Bang, H. O., Dyerberg, J., Nielsen, A. B. Lancet, 1971, i, 1143. Ewing, A. M., Freeman, N. K., Lindgren, F. T. in Advances in Lipid Research (edited by R. Paoletti and D. Kritchevsky); vol. III, p. 25. New York, 1965. Green, R. A., Humphrey, E., Close, H., Patno, M. E. Am. J. Med. 1969, 46, 516. Wolf, J., Spear, P., Yesner, R., Patno, M. E. ibid. 1960, 29, 1008.
with a regression-rate higher than 50%,8 and since combination chemotherapy is probably more effective than single-agent treatment in small-cell carcinoma,9-11 a combination including cyclophosphamide would have been a much better choice for a randomised study. This is in retrospect particularly important, in view of the excessive mortality in the patients over age 55 treated by chemotherapy, which implies intolerance to the treatment used (nitrogen mustard, vinblastine, procarbazine, and predni-
solone). In addition, it has to be pointed out that a direct comparison, using survival between the two modalities of treatment, is hampered by the fact that almost a third of the patients (10/32) treated with radiotherapy received in addition. We agree with the conclusion of Laing et al. that, in view of the systemic nature of the disease at onset, a combination of chemotherapy and radiotherapy is worth evaluating. We would not, however, want readers to believe that their investigation has conclusively demonstrated lack of efficacy of current chemotherapeutic regimens for small-cell carcinoma of the lung, and the superiority of local radiotherapy. Division of Medical Oncology,
chemotherapy
Albert Einstein College of Medicine, Bronx, N.Y. 10461, U.S.A. Medical Department C, Bispebjerg Hospital, and Finsen Institute, Copenhagen, Denmark.
FRANCO M. MUGGIA. HEINE H. HANSEN.
PER DOMBERNOWSKY.
MANAGEMENT OF INTRACRANIAL ANEURYSMS Atkinson SIR,-Mr (Jan. 4, p. 5) described a new to the management of intracranial aneurysms. approach While his approach may well be beneficial, I think that he got his arguments wrong. He stresses the role of atherosclerosis-even so far as to call this " the main event to haemorrhage from intracranial aneurysms". To the contrary I feel that by him (and by many of my clinical colleagues) far too much stress is laid upon atherosclerosis in this respect. In my view, the two main aetiological factors in the bursting of intracranial vessels, whether subarachnoid or intracranial, are weak spots in the vessel walls and arterial hyp-rtension. With the exception of mycotic and (if they exist at all) primary atherosclerotic aneurysms, the weak spots may be assumed to be of congenital origin and their evolution into microaneurysms or even macroscopically visible aneurysms to be an effect of systemic hypertension. 11 Atherosclerotic changes in the neighbourhood of or within aneurysms are easily interpreted as secondary to the occurrence of eddy-formation (and may have some contributory significance in the way suggested by Mr Atkinson). Development of atherosclerosis, far from leading to haemorrhage, in general seems rather to protect against it-this would account for the increase in lesions resulting from vascular insufficiency with increasing age, whereas haemorrhages show an earlier peak. In my view, as in Mr Atkinson’s, lowering the intraarterial pressure is beneficial. My reason for arguing against his principles lies in the different practical consequences of both views: emphasis on hypertension entails
leading
Selawry, O. S., Hansen, H. H. in Cancer Medicine (edited by J. F. Holland and E. Frei); p. 1506. Philadelphia, 1973. 9. Hansen, H. H., Selawry, O. S., Carr, D., Sealy, R., Simon, R. Proceedings of 11th International Cancer Congress, Florence,
8.
1974, p. 592. Edmonson, J. H., Stolbach, L., Mittelman, A., Lagakos, S. W. ibid. p. 591. 11. Alberto, P. Cancer Chemother. Rep. 1973, 4, 199. 12. Cole, F. M., Yates, P. O. J. Path. Bact. 1967, 93, 393.
10.
693
high priority for control of blood-pressure as the main preventive measure when intracranial haemorrhage is concerned, whereas concentrating on the role of atherosclerosis may conceivably lead to a more defeatist attitude. Division of Neuropathology, Department of Pathology, University of Groningen,
Oostersingel 63, Groningen, Netherlands.
EBEL
J. EBELS.
INDOMETHACIN AND CLOSURE OF THE DUCTUS ARTERIOSUS SIR,-Professor Elliott and his colleagues (Jan. 18, p. 140) reported improvement in arterial oxygenation following the of prostaglandin El in two infants with cyanotic congenital heart-disease. They attributed this improvement to a dilatation of the ductus arteriosus. The use ofp.G.E1 in this manner is well supported by previous in-vitroand use
in-vivo 2,3 studies, and with further careful research it may prove useful in the palliative treatment of well-selected cases of severe cyanotic heart-disease by temporising until a definitive and preferable controlled shunt/valve procedure can be completed.
The use of indomethacin in case 1 to " arrest the closure of the ductus arteriosus " was associated with a prompt
of indomethacin in case 1 is not well supported by laboratory data and does not appear justifiable. Past observations of ductal closure in utero ó,6 and studies with shown inprostaglandin-synthetase inhibitors in rats have Thus the utero contraction of the ductus arteriosus.’7 finding of a presumed closure of the infant’s ductus following indomethacin is not unexpected and points out7 an essential difference between in-vitro 4 and in-vivo’ studies. Indomethacin probably induces ductal contraction in utero by depleting endogenous prostaglandin in the ductal wall. This may increase the sensitivity of the ductus to oxygen, and contraction is then possible at the low fetal p02 in utero. Possibly, vasomotor tone in the ductus may also be affected by changes in adrenergic output, since prostaglandins decrease 8,9 and indomethacin increases The
use
norepinephrine (noradrenaline) release.1o The demonstration of in-utero ductal closure following indomethacinmay indicate a possible means to facilitate postnatal closure of a persistently patent ductus in selected cases. But further toxicity studies and detailed laboratory investigation of the effects of indomethacin and other inhibitors on the newborn are strongly recommended. Caution is also needed in studies where prostaglandinsynthetase inhibitors are used to inhibit premature labour. Department of Pediatrics, Karolinska Sjukhuset, Stockholm 60, Sweden.
GEORGE L. SHARPE.
ÆTIOLOGY OF PATENT DUCTUS ARTERIOSUS SiR$-Rothman and Fyler 11 reported a seasonal variation in ventricular septal defect, especially when it was associated with patent ductus arteriosus (P.D.A.), whereas Bartsocas 12 could demonstrate no such seasonal trend for P.D.A. Since Rutstein et al.13 suggested maternal rubella as the environmental factor for P.D.A., we have taken a careful history from all our patients with P.D.A., regarding infectious disease during pregnancy. In studying more than 200 patients with P.D.A. we could not find a single case in which there had been a rubella infection during pregnancy.14 This might be due to the fact that in Germany rubella is a disease of children and not as common in adults as it may be in the U.S.A. Interestingly enough, we have just encountered a family with high frequency of P.D.A.: two sisters, 42 and 51 years old, and the 12-year-old daughter of one of them all had signs of P.D.A. by heart catheterisation. The diagnosis was confirmed by operation in all three. Again, we could find no indication of rubella in the lst and 2nd generation Injection of 1
ILg. per g. P.G.F,e[ subcutaneously in 50 jjti. of saline at 30, 90, and 150 minutes after delivery produced cedema seen in the newborn rat on the right. The control pup on the left received 50 1. saline at the same times.
during gestation. Thus, hereditary transmission might be tors
for
(see accompanying figure). 1. 2. 3. 4.
Coceani, F., Olley, P. M. Can. J. Physiol. Pharmac. 1973, 51, 220. Sharpe, G. L., Larsson, K. S. Teratology, 1974, 10, 324. Sharpe, G. L., Larsson, K. S. J. Steroid Biochem. 1974, 5, 400. Starling, M. B., Elliott, R. B. Prostaglandins, 1974, 8, 187.
of the fac-
Medizinische Universitäts-Klinik, Lehrstuhl Innere Medizin
(Kardiologie), reversal in the previous improvement obtained by p.G.E1. This use of indomethacin was based on in-vitro studies by the same groupand was intended to inhibit endogenous P.G.F2a which they supposed was responsible for ductal closure. Prostaglandins from both the E and F series have been shown to relax the ductus arteriosus.1-3 Repeated administration of prostaglandin can produce acute reversible oedema in rats and may provoke other side-effects
one
P.D.A.
53 Bonn 1, Venusberg, West Germany.
HERMANN OCHS A. SCHAEDE.
5. Arcilla, R. A., Thilenius, O. G., Ranniger, K. J. Pediat. 1969, 75, 74. 6. Kohler, H. G. Archs Dis. Childh. 1967, 42, 335. 7. Sharpe, G. L., Thalme, B., Larsson, K. S. Prostaglandins, 1974, 8, 363. 8. Steinberg, D. Ann. N.Y. Acad. Sci. 1967, 139, 897. 9. Hedqvist, P., Brundin, J. Life Sci. 1969, 8, 389. 10. Fredholm, B., Hedqvist, P. Acta physiol. scand. 1973, 87, 570. 11. Rothman, K. J., Fyler, D. C. Lancet, 1974, ii, 193. 12. Bartsocas, C. S. ibid. Jan. 11, 1975, p. 109. 13. Rutstein, D. D., Nickerson, R. J., Heald, F. P. Am. J. Dis. Child. 1952, 84, 199. 14. Schaede, A., Taucher, M., Hilger, H. H. Arch. Kreislaufforsch. 1967, 54, 215.
SIR,-We agree with the hypothesis of Dr G. J. Miller and Dr N. E. Miller (Jan. 4, p. 16) about a possible antiatherogenic role of plasma - high - density - lipoproteins (H.D.L.). Both Glueck1 and ourselves2 have lately recognised a familial hyperlipoproteinmmia in which most of the cholesterol is carried as H.D.L. (oc) cholesterol. In members of these families no signs of cardiovascular involvement have been found. Moreover, in our series, few patients with familial type-IIA hyperlipoproteinarmia have xanthomata, unlike such patients from other countries. Also, the frequency of ischaemic heart-disease among the families in our series is rather low. Other authors have supported the view that essential hypercholesterolaemia is a " relatively benign trait 11.3 In this respect, it is interesting that, in our patients with type-II hyperlipoproteinsemia, values of H.D.L.cholesterol are higher than those quoted by previous authors.
A reciprocal behaviour of low-density-lipoprotein (L.D.L.)cholesterol and H.D.L.-cholesterol is not supported by our
findings, as we have recorded a positive correlation (r= +0-31) between the two parameters. A positive correlation has been previously quoted in Eskimos4 and in one American group. The complex process of lipid influx and efflux in the arterial wall is shown best by the ratio of plasma-levels of L.D.L.H.D.L. cholesterol.
The trend of the ratio from the highest values in type the lowest value in normal people seems to correlate better with the expected frequencies of cardiovascular disease in hyperlipoproteinamlia states. IIA to
Regional Hospital, Unit for Atherosclerosis and
Hyperlipæmias, Venice, Italy.
P. AVOGARO G. CAZZOLATO M. PAIS.
TREATMENT OF SMALL-CELL CARCINOMA OF BRONCHUS SIR,-A randomised study evaluating the results of treatment with radiotherapy versus chemotherapy in small-cell carcinoma of the bronchus is a timely and laudable effort (Jan. 18, p. 129). It is unfortunate, however, that Dr Laing and his co-workers selected as their chemotherapy a treatment that includes the more toxic but probably less effective alkylating agent nitrogen mustard,8 and a drug (prednisolone) that may have deleterious effects on the survival of patients with lung cancer, as reported in a randomised study by the Veterans Administration
Lung Cancer Study Group.’7
Cyclophosphamide seems to be the most effective single agent in the treatment of small-cell anaplastic carcinoma, 1. 2. 3.
4. 5.
6. 7.
Glueck, C. J. Clin. Res. (in the press). Avogaro, P., Cazzolato, G. Atherosclerosis (in the press). Harlan, W. R., Graham, J. B., Estes, H. Medicine, Baltimore, 1966, 77, 45. Bang, H. O., Dyerberg, J., Nielsen, A. B. Lancet, 1971, i, 1143. Ewing, A. M., Freeman, N. K., Lindgren, F. T. in Advances in Lipid Research (edited by R. Paoletti and D. Kritchevsky); vol. III, p. 25. New York, 1965. Green, R. A., Humphrey, E., Close, H., Patno, M. E. Am. J. Med. 1969, 46, 516. Wolf, J., Spear, P., Yesner, R., Patno, M. E. ibid. 1960, 29, 1008.
with a regression-rate higher than 50%,8 and since combination chemotherapy is probably more effective than single-agent treatment in small-cell carcinoma,9-11 a combination including cyclophosphamide would have been a much better choice for a randomised study. This is in retrospect particularly important, in view of the excessive mortality in the patients over age 55 treated by chemotherapy, which implies intolerance to the treatment used (nitrogen mustard, vinblastine, procarbazine, and predni-
solone). In addition, it has to be pointed out that a direct comparison, using survival between the two modalities of treatment, is hampered by the fact that almost a third of the patients (10/32) treated with radiotherapy received in addition. We agree with the conclusion of Laing et al. that, in view of the systemic nature of the disease at onset, a combination of chemotherapy and radiotherapy is worth evaluating. We would not, however, want readers to believe that their investigation has conclusively demonstrated lack of efficacy of current chemotherapeutic regimens for small-cell carcinoma of the lung, and the superiority of local radiotherapy. Division of Medical Oncology,
chemotherapy
Albert Einstein College of Medicine, Bronx, N.Y. 10461, U.S.A. Medical Department C, Bispebjerg Hospital, and Finsen Institute, Copenhagen, Denmark.
FRANCO M. MUGGIA. HEINE H. HANSEN.
PER DOMBERNOWSKY.
MANAGEMENT OF INTRACRANIAL ANEURYSMS Atkinson SIR,-Mr (Jan. 4, p. 5) described a new to the management of intracranial aneurysms. approach While his approach may well be beneficial, I think that he got his arguments wrong. He stresses the role of atherosclerosis-even so far as to call this " the main event to haemorrhage from intracranial aneurysms". To the contrary I feel that by him (and by many of my clinical colleagues) far too much stress is laid upon atherosclerosis in this respect. In my view, the two main aetiological factors in the bursting of intracranial vessels, whether subarachnoid or intracranial, are weak spots in the vessel walls and arterial hyp-rtension. With the exception of mycotic and (if they exist at all) primary atherosclerotic aneurysms, the weak spots may be assumed to be of congenital origin and their evolution into microaneurysms or even macroscopically visible aneurysms to be an effect of systemic hypertension. 11 Atherosclerotic changes in the neighbourhood of or within aneurysms are easily interpreted as secondary to the occurrence of eddy-formation (and may have some contributory significance in the way suggested by Mr Atkinson). Development of atherosclerosis, far from leading to haemorrhage, in general seems rather to protect against it-this would account for the increase in lesions resulting from vascular insufficiency with increasing age, whereas haemorrhages show an earlier peak. In my view, as in Mr Atkinson’s, lowering the intraarterial pressure is beneficial. My reason for arguing against his principles lies in the different practical consequences of both views: emphasis on hypertension entails
leading
Selawry, O. S., Hansen, H. H. in Cancer Medicine (edited by J. F. Holland and E. Frei); p. 1506. Philadelphia, 1973. 9. Hansen, H. H., Selawry, O. S., Carr, D., Sealy, R., Simon, R. Proceedings of 11th International Cancer Congress, Florence,
8.
1974, p. 592. Edmonson, J. H., Stolbach, L., Mittelman, A., Lagakos, S. W. ibid. p. 591. 11. Alberto, P. Cancer Chemother. Rep. 1973, 4, 199. 12. Cole, F. M., Yates, P. O. J. Path. Bact. 1967, 93, 393.
10.
693
high priority for control of blood-pressure as the main preventive measure when intracranial haemorrhage is concerned, whereas concentrating on the role of atherosclerosis may conceivably lead to a more defeatist attitude. Division of Neuropathology, Department of Pathology, University of Groningen,
Oostersingel 63, Groningen, Netherlands.
EBEL
J. EBELS.
INDOMETHACIN AND CLOSURE OF THE DUCTUS ARTERIOSUS SIR,-Professor Elliott and his colleagues (Jan. 18, p. 140) reported improvement in arterial oxygenation following the of prostaglandin El in two infants with cyanotic congenital heart-disease. They attributed this improvement to a dilatation of the ductus arteriosus. The use ofp.G.E1 in this manner is well supported by previous in-vitroand use
in-vivo 2,3 studies, and with further careful research it may prove useful in the palliative treatment of well-selected cases of severe cyanotic heart-disease by temporising until a definitive and preferable controlled shunt/valve procedure can be completed.
The use of indomethacin in case 1 to " arrest the closure of the ductus arteriosus " was associated with a prompt
of indomethacin in case 1 is not well supported by laboratory data and does not appear justifiable. Past observations of ductal closure in utero ó,6 and studies with shown inprostaglandin-synthetase inhibitors in rats have Thus the utero contraction of the ductus arteriosus.’7 finding of a presumed closure of the infant’s ductus following indomethacin is not unexpected and points out7 an essential difference between in-vitro 4 and in-vivo’ studies. Indomethacin probably induces ductal contraction in utero by depleting endogenous prostaglandin in the ductal wall. This may increase the sensitivity of the ductus to oxygen, and contraction is then possible at the low fetal p02 in utero. Possibly, vasomotor tone in the ductus may also be affected by changes in adrenergic output, since prostaglandins decrease 8,9 and indomethacin increases The
use
norepinephrine (noradrenaline) release.1o The demonstration of in-utero ductal closure following indomethacinmay indicate a possible means to facilitate postnatal closure of a persistently patent ductus in selected cases. But further toxicity studies and detailed laboratory investigation of the effects of indomethacin and other inhibitors on the newborn are strongly recommended. Caution is also needed in studies where prostaglandinsynthetase inhibitors are used to inhibit premature labour. Department of Pediatrics, Karolinska Sjukhuset, Stockholm 60, Sweden.
GEORGE L. SHARPE.
ÆTIOLOGY OF PATENT DUCTUS ARTERIOSUS SiR$-Rothman and Fyler 11 reported a seasonal variation in ventricular septal defect, especially when it was associated with patent ductus arteriosus (P.D.A.), whereas Bartsocas 12 could demonstrate no such seasonal trend for P.D.A. Since Rutstein et al.13 suggested maternal rubella as the environmental factor for P.D.A., we have taken a careful history from all our patients with P.D.A., regarding infectious disease during pregnancy. In studying more than 200 patients with P.D.A. we could not find a single case in which there had been a rubella infection during pregnancy.14 This might be due to the fact that in Germany rubella is a disease of children and not as common in adults as it may be in the U.S.A. Interestingly enough, we have just encountered a family with high frequency of P.D.A.: two sisters, 42 and 51 years old, and the 12-year-old daughter of one of them all had signs of P.D.A. by heart catheterisation. The diagnosis was confirmed by operation in all three. Again, we could find no indication of rubella in the lst and 2nd generation Injection of 1
ILg. per g. P.G.F,e[ subcutaneously in 50 jjti. of saline at 30, 90, and 150 minutes after delivery produced cedema seen in the newborn rat on the right. The control pup on the left received 50 1. saline at the same times.
during gestation. Thus, hereditary transmission might be tors
for
(see accompanying figure). 1. 2. 3. 4.
Coceani, F., Olley, P. M. Can. J. Physiol. Pharmac. 1973, 51, 220. Sharpe, G. L., Larsson, K. S. Teratology, 1974, 10, 324. Sharpe, G. L., Larsson, K. S. J. Steroid Biochem. 1974, 5, 400. Starling, M. B., Elliott, R. B. Prostaglandins, 1974, 8, 187.
of the fac-
Medizinische Universitäts-Klinik, Lehrstuhl Innere Medizin
(Kardiologie), reversal in the previous improvement obtained by p.G.E1. This use of indomethacin was based on in-vitro studies by the same groupand was intended to inhibit endogenous P.G.F2a which they supposed was responsible for ductal closure. Prostaglandins from both the E and F series have been shown to relax the ductus arteriosus.1-3 Repeated administration of prostaglandin can produce acute reversible oedema in rats and may provoke other side-effects
one
P.D.A.
53 Bonn 1, Venusberg, West Germany.
HERMANN OCHS A. SCHAEDE.
5. Arcilla, R. A., Thilenius, O. G., Ranniger, K. J. Pediat. 1969, 75, 74. 6. Kohler, H. G. Archs Dis. Childh. 1967, 42, 335. 7. Sharpe, G. L., Thalme, B., Larsson, K. S. Prostaglandins, 1974, 8, 363. 8. Steinberg, D. Ann. N.Y. Acad. Sci. 1967, 139, 897. 9. Hedqvist, P., Brundin, J. Life Sci. 1969, 8, 389. 10. Fredholm, B., Hedqvist, P. Acta physiol. scand. 1973, 87, 570. 11. Rothman, K. J., Fyler, D. C. Lancet, 1974, ii, 193. 12. Bartsocas, C. S. ibid. Jan. 11, 1975, p. 109. 13. Rutstein, D. D., Nickerson, R. J., Heald, F. P. Am. J. Dis. Child. 1952, 84, 199. 14. Schaede, A., Taucher, M., Hilger, H. H. Arch. Kreislaufforsch. 1967, 54, 215.