- Email: [email protected]
PELVIC CANCER
1361
ficant depression of serum cholesterol and triglycerides without side-effects. OLIVER described this combina" tion as " an orally active androsterone and suggested from preliminary observations that the administration of C.P.LB. alone had no significant effect on serumlipids. At the Buxton symposium, however, he described clear evidence from several cross-over studies that C.P.LB. alone is as effective as atromid in reducing serum cholesterol and triglyceride levels in man. At this symposium (the proceedings of which will be published in the Journal of Atherosclerosis Research) reports from workers in Britain, the United States, Scandinavia, and various European countries showed that C.P .LB. and atromid produce several other effects on lipids. The Sf 20-400, or triglyceride-rich, class of lipoproteins is significantly decreased regardless of the initial value, and to a greater extent than with thyroxine analogues. Certain classes of high-density lipoproteins are increased. The alpha-beta lipoprotein ratio is increased. The total exchangeable lipoprotein pool and the catabolic rate of this pool are decreased. The height and duration of postprandial lipxmia are also decreased. Specific measurements of lipoprotein lipase activity indicate that this is also increased. In addition to these effects on lipid metabolism, atromid influences some factors which are believed to be associated with thrombus formation. C.P.LB. has not yet been adequately studied in this respect. Atromid reduces platelet stickiness and probably prolongs platelet survival. Clot-lysis time is also reduced. Plasmafibrinogen levels are probably reduced. Atromid prevents the shortening of recalcified clotting-time which occurs during postprandial lipxmia. An earlier observation 23 that the requirements of anticoagulants were reduced when patients receiving these drugs are given atromid or C.P .LB. was confirmed, and one study suggested that atromid has less effect on serum-lipids in
patients receiving phenindione. Studies on diabetic patients
have shown that the to the use of of diabetes is no contraindication presence atromid or c.P.i.B. Moreover, there may be a synergistic action between atromid and chlorpropamide or between atromid and the sulphonylurea drugs. The reduction of triglyceride levels has been associated with improvement of exudative diabetic retinopathy, although some concomitant increase in hxmorrhage was also reported. In all, 1300 patients have now received either atromid or c.r.i.B. The death-rate is certainly no greater and may be rather less than that which would be expected. Surprisingly, more than half the deaths occurred in the first three months of treatment; and closer investigation of the causes of death is needed, particularly since the weight of some patients increases. This may be due to fluid retention, and OLIVER reported 4 cases of left ventricular failure. The serum-lipid levels do not respond in all cases, and 10-15% may be refractory; indeed, a small proportion of patients may actually have a rise in triglyceride levels, and theoretically this might contribute 23.
Oliver, M. F., Roberts, S. D., Hayes, D., Pantridge, J. F., Suzman, M. M., Bersohn, I. ibid. Jan. 19, 1963, p. 143.
the deaths soon after the start of treatment. No acquired resistance was reported; but of those patients who were initially refractory or who had a rise in triglyceride levels, several apparently had either idiopathic or familial hypercholesterolaemia or hypertriglyceridxmia. A seven-month controlled trial in patients with cerebrovascular diseases suggested that atromid may have reduced the incidence of transient ischaemic strokes and possibly also of cerebral infarcts, but it is far too early yet to reach any conclusion from this trial. Neither atromid nor C.P.I.B. appears to have any significant toxic effects; nausea occurred in 8% and diarrhoea in 3% of patients, but neither of these side-effects was constant or troublesome. Transient elevation of serumglutamic-oxaloacetic-transaminase (S.G.O.T.) has already been observed 22 ; and this was again reported, but was regarded by F. WROBLEWSKI as an indication of metabolic activity and not as a sign of hepatotoxicity. A period of consolidation is now required, and determined efforts must be made to find out more about the mechanism of action. The need for adding androsterone to C.P.I.B. has already been questioned, and we need now to determine whether the effect of C.I.P .B. is equivalent to that of atromid on other parameters as well as serum lipids. The possibility that C.P.I.B. acid displaces certain albumin-bound acids and increases the concentration of thyroxine in the liver will have to be carefully investigated. It is essential also that lipid and sterol balance studies should be undertaken in order to establish whether lipids and sterols are actually lost from the body. All in all, the drug looks promising; and when more is known about its action, the establishment of long-term trials of its effect in the treatment and prophylaxis ofischasmic heart-disease may be considered. to
Annotations PELVIC CANCER
AT last Saturday’s meeting in London of the British section of the International College of Surgeons, Sir Denis Browne presided and Prof. M. Louros, of Athens, was guest of honour. Pelvic cancer at all ages was reviewed in 11 papers by leading authorities. Many of the facts were grim and emphasised changing trends in medicine. For example, at the two extremes of life, cancer was the commonest cause of death of children in hospital, and cancer of the prostate could be detected in 30% of men over 50. At the age of 90 few men were free from the disease. Fortunately its biological potential decreased with age, so that, while growth might be rapid in the younger patient, the old man might remain free of symptoms. Only 50% of hard prostatic nodules felt in patients over the age of 50 were malignant. Transrectal biopsy was advised as the best diagnostic method. Rectovesical fistul2e were not uncommon after this operation, but fungation into the rectum did not occur and nituule closed spontaneously. (Estrogens acted by changing the active growth of the young man into the latent phase commonly seen in the elderly. Subcapsular orchidectomy was indicated only when oestrogens ceased to be effective and obstruction made intervention essential. Until then, stilboestrol in doses of 45-100 mg. daily was advised.
1362
Some
striking results were reported from Great Ormond
Street. Whereas 57 out of 58 small children with a neuroblastoma had died within a few months without treatment, and 17 out of 25 treated surgically had died, there had been 32 survivors out of 74 unselected patients given 1 mg. of vitamin B12 every second day, with or without operation. Embryological and pathological studies had shown that tumours arising from the urogenital sinus could originate from a wide area, and adequate treatment therefore demanded extensive excision. After operation 7 out of 14 patients with rhabdomyosarcoma of bladder or vagina (sarcoma botryoides) were alive and well three years later. In the male the same lesion was fatal in all 6 patients treated for rhabdomyosarcoma of the prostate. Detailed studies of the pelvic spread of cancer of the rectum and uterus at St. Mark’s Hospital and in Oxford demonstrated points of similarity and added weight to the view that a radical attack was needed on the primary condition. In rectal tumours the recurrence-rate was 19-7% with an anaplastic growth, compared with 5’7% in a well-differentiated tumour. Restorative operations and anterior resection were contraindicated when the
anaplastic. agreed that patients with malignant disease had prognosis when they were treated in clinics staffed to provide all the skills and weapons and equipped now available against cancer. The disadvantages for the patient and relatives of travelling to a distant hospital were heavily outweighed by the improved prospects.
tumour was
It was the best
common-there is a forward slip of a lumbar vertebra (usually the fourth) with osteoarthritic changes in the posterior joints; the displacement is seldom severe. Spondylolisthesis from defects in the neural archusually with loss of continuity in the pars interarticularis -is the type which has attracted most attention, but it is certainly not the commonest cause of displacement, and it may be present at least for many years without a significant shift of the vertebral body. Whether the defect in the pars interarticularis is congenital in origin is doubtful, and there is little evidence that it is commonly produced by an injury. Newman favours the view that the loss of continuity is due to a stress fracture. True traumatic spondylolisthesis is very uncommon, as is displacement from defects in bone structure, such as osteogenesis imperfecta or Paget’s disease. Many patients with spondylolisthesis go through life with little or no discomfort, and in others the symptoms can be relieved by a supporting belt. If there is severe pain, spinal fusion may become necessary. A posterior fusion must extend from the spine of the fourth lumbar vertebra to the sacrum; and, since the spinous process of the latter is often defective, pseudarthroses at the lower end of the graft are prone to arise. Anterior lumbosacral fusion has the merit of the direct approach, and if the body of the fifth lumbar vertebra can be successfully sacralised the symptoms are usually relieved.
SPONDYLOLISTHESIS
FORWARD displacement of the fifth lumbar vertebra on the sacrum has for two centuries been recognised as a cause of difficulty in labour. At first the displacement was thought to be due to dislocation of the lumbosacral joint; but Hartmannnoted that the displacement of the vertebral body was not accompanied by displacement of the spinous process, and Neugebauer, 23 after extensive dissection of postmortem specimens, concluded that the displacement might be due either to elongation of the neural arch or to loss of continuity between the superior and inferior articular facets. Radiology has permitted more accurate assessment of the extent of vertebral displacement, and focused attention on defects in the pars interarticularis as the main cause of spondylolisthesis, but the cause of the defects in the pars interarticularis has remained in question. There is no direct evidence that they are developmental in origin, and they are now generally thought to arise either as a result of minor trauma which produces a stress fracture, or as a result of abnormal mechanical strains. The obliquity of the lumbosacral joint tends to make the fifth lumbar vertebra slide forwards on the sacrum; this is resisted by the lumbo-sacral facets and the strength of the pedicles and neural arches. Spondylolisthesis is uncommon at a higher level in the lumbar spine, and vertebral displacement is usually slight. Newman4 recognises five different types of spondylolisthesis. In the congenital form, which is common, there is a defect in the sacral facets. The neural arch of the fifth lumbar vertebra becomes attenuated, and displacement is often severe. In the degenerative group-also 1. 2. 3.
Hartmann, G. Mschr. Geburtsh. Gynäk. 1865, 25, 465. Neugebauer, F. L. Zbl. ges. Gynäk. 1881, 5, 260.
A New Contribution to the History and Etiology of The New Sydenham Society. London, 1888. Newman, P. H. Ann. R. Coll. Surg. Engl. 1955, 16, 305.
Neugebauer,
F. L.
Spondylolisthesis.
4.
WOUND SLOUGHS
WHILE many of the principles involved in the healing of wounds have been and are being extensively studied,! detailed aspects are also receiving special attention-such as sutures.2 The latest subject to be investigated is the structure of the slough or scab covering the surface of a wound. If most of us had thought of this, we had probably assumed that it was composed of condensed fibrin or serum and necrotic white cells of the blood. But James3 showed that the scab contains a high concentration of an aminoacid, hydroxyproline, which is found to a high concentration only in collagen, much less in elastin, and is virtually absent from all other tissue proteins. Zaphir 4 confirmed this in another series of experimental wounds, and, as the aminoacid is not present in a free state, suggested that it came from collagen, particularly at the necrotic edge of the wound. Now, in a detailed histological study of the development of scabs in experimental wounds, Hadfield5 shows that a layer of collagen in the floor of the wound becomes embedded in a voluminous exudate, and the exposed superficial parts of collagen become swollen and hyalinised, losing their staining reactions, while the deeper fibres, protected by the exudate, retain their normal size and staining reactions. The many polymorphs throughout the exudate become concentrated immediately under this layer of swollen hyalinised collagen and form a line of demarcation. The proteolytic enzymes of the polymorphs do not digest this collagen as they would do if it were chemically denatured collagen, and Hadfield suggests that the transformation it has undergone is related to simple exposure. It loses its staining properties and becomes gradually drier until it is finally sloughed off. While the theoretical explanation of this process is still 1. See Lancet, 1960, ii, 248. 2. ibid. 1961, ii, 416. 3. James, D. W. J. Path. Bact. 1955, 69, 33. 4. Zaphir, M. ibid. 1962, 84, 79. 5. Hadfield, G. Brit. J. Surg. 1963, 50, 649.
ficant depression of serum cholesterol and triglycerides without side-effects. OLIVER described this combina" tion as " an orally active androsterone and suggested from preliminary observations that the administration of C.P.LB. alone had no significant effect on serumlipids. At the Buxton symposium, however, he described clear evidence from several cross-over studies that C.P.LB. alone is as effective as atromid in reducing serum cholesterol and triglyceride levels in man. At this symposium (the proceedings of which will be published in the Journal of Atherosclerosis Research) reports from workers in Britain, the United States, Scandinavia, and various European countries showed that C.P .LB. and atromid produce several other effects on lipids. The Sf 20-400, or triglyceride-rich, class of lipoproteins is significantly decreased regardless of the initial value, and to a greater extent than with thyroxine analogues. Certain classes of high-density lipoproteins are increased. The alpha-beta lipoprotein ratio is increased. The total exchangeable lipoprotein pool and the catabolic rate of this pool are decreased. The height and duration of postprandial lipxmia are also decreased. Specific measurements of lipoprotein lipase activity indicate that this is also increased. In addition to these effects on lipid metabolism, atromid influences some factors which are believed to be associated with thrombus formation. C.P.LB. has not yet been adequately studied in this respect. Atromid reduces platelet stickiness and probably prolongs platelet survival. Clot-lysis time is also reduced. Plasmafibrinogen levels are probably reduced. Atromid prevents the shortening of recalcified clotting-time which occurs during postprandial lipxmia. An earlier observation 23 that the requirements of anticoagulants were reduced when patients receiving these drugs are given atromid or C.P .LB. was confirmed, and one study suggested that atromid has less effect on serum-lipids in
patients receiving phenindione. Studies on diabetic patients
have shown that the to the use of of diabetes is no contraindication presence atromid or c.P.i.B. Moreover, there may be a synergistic action between atromid and chlorpropamide or between atromid and the sulphonylurea drugs. The reduction of triglyceride levels has been associated with improvement of exudative diabetic retinopathy, although some concomitant increase in hxmorrhage was also reported. In all, 1300 patients have now received either atromid or c.r.i.B. The death-rate is certainly no greater and may be rather less than that which would be expected. Surprisingly, more than half the deaths occurred in the first three months of treatment; and closer investigation of the causes of death is needed, particularly since the weight of some patients increases. This may be due to fluid retention, and OLIVER reported 4 cases of left ventricular failure. The serum-lipid levels do not respond in all cases, and 10-15% may be refractory; indeed, a small proportion of patients may actually have a rise in triglyceride levels, and theoretically this might contribute 23.
Oliver, M. F., Roberts, S. D., Hayes, D., Pantridge, J. F., Suzman, M. M., Bersohn, I. ibid. Jan. 19, 1963, p. 143.
the deaths soon after the start of treatment. No acquired resistance was reported; but of those patients who were initially refractory or who had a rise in triglyceride levels, several apparently had either idiopathic or familial hypercholesterolaemia or hypertriglyceridxmia. A seven-month controlled trial in patients with cerebrovascular diseases suggested that atromid may have reduced the incidence of transient ischaemic strokes and possibly also of cerebral infarcts, but it is far too early yet to reach any conclusion from this trial. Neither atromid nor C.P.I.B. appears to have any significant toxic effects; nausea occurred in 8% and diarrhoea in 3% of patients, but neither of these side-effects was constant or troublesome. Transient elevation of serumglutamic-oxaloacetic-transaminase (S.G.O.T.) has already been observed 22 ; and this was again reported, but was regarded by F. WROBLEWSKI as an indication of metabolic activity and not as a sign of hepatotoxicity. A period of consolidation is now required, and determined efforts must be made to find out more about the mechanism of action. The need for adding androsterone to C.P.I.B. has already been questioned, and we need now to determine whether the effect of C.I.P .B. is equivalent to that of atromid on other parameters as well as serum lipids. The possibility that C.P.I.B. acid displaces certain albumin-bound acids and increases the concentration of thyroxine in the liver will have to be carefully investigated. It is essential also that lipid and sterol balance studies should be undertaken in order to establish whether lipids and sterols are actually lost from the body. All in all, the drug looks promising; and when more is known about its action, the establishment of long-term trials of its effect in the treatment and prophylaxis ofischasmic heart-disease may be considered. to
Annotations PELVIC CANCER
AT last Saturday’s meeting in London of the British section of the International College of Surgeons, Sir Denis Browne presided and Prof. M. Louros, of Athens, was guest of honour. Pelvic cancer at all ages was reviewed in 11 papers by leading authorities. Many of the facts were grim and emphasised changing trends in medicine. For example, at the two extremes of life, cancer was the commonest cause of death of children in hospital, and cancer of the prostate could be detected in 30% of men over 50. At the age of 90 few men were free from the disease. Fortunately its biological potential decreased with age, so that, while growth might be rapid in the younger patient, the old man might remain free of symptoms. Only 50% of hard prostatic nodules felt in patients over the age of 50 were malignant. Transrectal biopsy was advised as the best diagnostic method. Rectovesical fistul2e were not uncommon after this operation, but fungation into the rectum did not occur and nituule closed spontaneously. (Estrogens acted by changing the active growth of the young man into the latent phase commonly seen in the elderly. Subcapsular orchidectomy was indicated only when oestrogens ceased to be effective and obstruction made intervention essential. Until then, stilboestrol in doses of 45-100 mg. daily was advised.
1362
Some
striking results were reported from Great Ormond
Street. Whereas 57 out of 58 small children with a neuroblastoma had died within a few months without treatment, and 17 out of 25 treated surgically had died, there had been 32 survivors out of 74 unselected patients given 1 mg. of vitamin B12 every second day, with or without operation. Embryological and pathological studies had shown that tumours arising from the urogenital sinus could originate from a wide area, and adequate treatment therefore demanded extensive excision. After operation 7 out of 14 patients with rhabdomyosarcoma of bladder or vagina (sarcoma botryoides) were alive and well three years later. In the male the same lesion was fatal in all 6 patients treated for rhabdomyosarcoma of the prostate. Detailed studies of the pelvic spread of cancer of the rectum and uterus at St. Mark’s Hospital and in Oxford demonstrated points of similarity and added weight to the view that a radical attack was needed on the primary condition. In rectal tumours the recurrence-rate was 19-7% with an anaplastic growth, compared with 5’7% in a well-differentiated tumour. Restorative operations and anterior resection were contraindicated when the
anaplastic. agreed that patients with malignant disease had prognosis when they were treated in clinics staffed to provide all the skills and weapons and equipped now available against cancer. The disadvantages for the patient and relatives of travelling to a distant hospital were heavily outweighed by the improved prospects.
tumour was
It was the best
common-there is a forward slip of a lumbar vertebra (usually the fourth) with osteoarthritic changes in the posterior joints; the displacement is seldom severe. Spondylolisthesis from defects in the neural archusually with loss of continuity in the pars interarticularis -is the type which has attracted most attention, but it is certainly not the commonest cause of displacement, and it may be present at least for many years without a significant shift of the vertebral body. Whether the defect in the pars interarticularis is congenital in origin is doubtful, and there is little evidence that it is commonly produced by an injury. Newman favours the view that the loss of continuity is due to a stress fracture. True traumatic spondylolisthesis is very uncommon, as is displacement from defects in bone structure, such as osteogenesis imperfecta or Paget’s disease. Many patients with spondylolisthesis go through life with little or no discomfort, and in others the symptoms can be relieved by a supporting belt. If there is severe pain, spinal fusion may become necessary. A posterior fusion must extend from the spine of the fourth lumbar vertebra to the sacrum; and, since the spinous process of the latter is often defective, pseudarthroses at the lower end of the graft are prone to arise. Anterior lumbosacral fusion has the merit of the direct approach, and if the body of the fifth lumbar vertebra can be successfully sacralised the symptoms are usually relieved.
SPONDYLOLISTHESIS
FORWARD displacement of the fifth lumbar vertebra on the sacrum has for two centuries been recognised as a cause of difficulty in labour. At first the displacement was thought to be due to dislocation of the lumbosacral joint; but Hartmannnoted that the displacement of the vertebral body was not accompanied by displacement of the spinous process, and Neugebauer, 23 after extensive dissection of postmortem specimens, concluded that the displacement might be due either to elongation of the neural arch or to loss of continuity between the superior and inferior articular facets. Radiology has permitted more accurate assessment of the extent of vertebral displacement, and focused attention on defects in the pars interarticularis as the main cause of spondylolisthesis, but the cause of the defects in the pars interarticularis has remained in question. There is no direct evidence that they are developmental in origin, and they are now generally thought to arise either as a result of minor trauma which produces a stress fracture, or as a result of abnormal mechanical strains. The obliquity of the lumbosacral joint tends to make the fifth lumbar vertebra slide forwards on the sacrum; this is resisted by the lumbo-sacral facets and the strength of the pedicles and neural arches. Spondylolisthesis is uncommon at a higher level in the lumbar spine, and vertebral displacement is usually slight. Newman4 recognises five different types of spondylolisthesis. In the congenital form, which is common, there is a defect in the sacral facets. The neural arch of the fifth lumbar vertebra becomes attenuated, and displacement is often severe. In the degenerative group-also 1. 2. 3.
Hartmann, G. Mschr. Geburtsh. Gynäk. 1865, 25, 465. Neugebauer, F. L. Zbl. ges. Gynäk. 1881, 5, 260.
A New Contribution to the History and Etiology of The New Sydenham Society. London, 1888. Newman, P. H. Ann. R. Coll. Surg. Engl. 1955, 16, 305.
Neugebauer,
F. L.
Spondylolisthesis.
4.
WOUND SLOUGHS
WHILE many of the principles involved in the healing of wounds have been and are being extensively studied,! detailed aspects are also receiving special attention-such as sutures.2 The latest subject to be investigated is the structure of the slough or scab covering the surface of a wound. If most of us had thought of this, we had probably assumed that it was composed of condensed fibrin or serum and necrotic white cells of the blood. But James3 showed that the scab contains a high concentration of an aminoacid, hydroxyproline, which is found to a high concentration only in collagen, much less in elastin, and is virtually absent from all other tissue proteins. Zaphir 4 confirmed this in another series of experimental wounds, and, as the aminoacid is not present in a free state, suggested that it came from collagen, particularly at the necrotic edge of the wound. Now, in a detailed histological study of the development of scabs in experimental wounds, Hadfield5 shows that a layer of collagen in the floor of the wound becomes embedded in a voluminous exudate, and the exposed superficial parts of collagen become swollen and hyalinised, losing their staining reactions, while the deeper fibres, protected by the exudate, retain their normal size and staining reactions. The many polymorphs throughout the exudate become concentrated immediately under this layer of swollen hyalinised collagen and form a line of demarcation. The proteolytic enzymes of the polymorphs do not digest this collagen as they would do if it were chemically denatured collagen, and Hadfield suggests that the transformation it has undergone is related to simple exposure. It loses its staining properties and becomes gradually drier until it is finally sloughed off. While the theoretical explanation of this process is still 1. See Lancet, 1960, ii, 248. 2. ibid. 1961, ii, 416. 3. James, D. W. J. Path. Bact. 1955, 69, 33. 4. Zaphir, M. ibid. 1962, 84, 79. 5. Hadfield, G. Brit. J. Surg. 1963, 50, 649.