1116

ticularly to show whether, in an at-risk male fetus, significantly raised S.C.K. is always associated with abnormal muscle histology whereas a normal S.C.K. level is not, and whether a normal fetal S.C.K. always betokens a normal child. Certainty in genetic counselling may become possible only when the basic biochemical defect has been clearly identified and is demonstrable in amniotic fluid or its contained cells or in fetal blood. Evidence from various sources suggests that the biochemical defect in this disorder may well reside in cell membranes, and in particular be demonstrable in red cells. This approach may one day provide a more reliable test.

UBIQUITOUS HUMAN CHORIONIC GONADOTROPHIN? THE recruitment of endocrinologists and immunologists to cancer research has resulted in a plethora of new approaches to the fundamental and clinicopathological study of human neoplasia. Human tumours release a wide variety of products which, as well as accounting for many cancer-associated clinical features, provide means of monitoring disease activity and the effects of treatment.’ Gonadotrophins are secreted by normal and neoplastic trophoblast and have long been measured for diagnosis, monitoring, and classification of tumours with trophoblastic elements.2 Lately, raised plasmagonadotrophins have been reported also in patients with "non-endocrine" tumours, particularly of the gastrointestinal tract,3-5 though the frequency in neoplasia as a whole is low. Kahn and his associates,6 studying pancreatic tumours, claim that gonadotrophin production is a property of malignant but not benign functioning islet-

cell tumours. Does this mean that secretion of H.C.G. or H.c.G.-like material indicates malignant transformation? If so, why, in islet-cell carcinoma, does H.c.G. appear only in association with other hormones? If H.C.G. is malignancy-associated what is the real nature of the H.C.G.-like material detected in diverse normal adult tissues.4,7-9 The structural complexity of H.C.G. and the many difficulties in its measurement make these questions very hard to answer. The four glycoprotein hormones-follicle-stimulating hormone (F.S.H.), luteinising hormone (L.H.), thyroidstimulating hormone (T.S.H.), and human chorionic gonadotrophin (H.C.G.)—possess a common quaternary structure characterised by two dissimilar polypeptide chains called the a and &bgr; subunits. 10, 11 The oc chains of L.H., T.S.H., and F.S.H. are structurally identical and, despite minor structural differences, are immunologi1. 2.

Neville, A. M., Cooper, E. H. Ann. clin. Biochem. 1976, 13, 283. Bagshawe, K. D. in Cancer Related Antigens (edited by P. Franchimont); p.

251. Amsterdam, 1976. Braunstein, G. D., Vaitukaitis, J. L., Carbone, P. P., Ross, G. T. Ann. intern. Med. 1973, 78, 39. 4. Vaitukaitis, J. L., Ross, G. T., Braunstein, G. D., Rayford, P. L. Rec. Progr. Hormone Res. 1976, 32, 289. 5. Tormey, D. C., Waalkes, T. P., Simon, R. M. Cancer, 1977, 39, 2391. 6. Kahn, C. R., Rosen, S. W., Weintraub, D. B., Fajans, S. S., Gorden, P. New Engl. J. Med. 1977, 297, 565. 7. Yoshimoto, Y., Wolfsen, A. R., Odell, W. D. Science, 1977, 197, 575. 8. Braunstein, G. D., Rasor, J., Wade, M. E. New Engl. J. Med. 1975, 293, 3.

1339. 9. Chen, H-C., Hodgen, G. D., Matsura, S., Lin, L. J., Gross, E., Reichert, L. E., Birken, S., Canfield, R. E., Ross, G. T. Proc. natn. Acad. Sci.,

cally indistinguishable from the x chain of H.c.G. The p chain of each of the glycoprotein hormones is unique and is responsible for both biological and immunological activity. Neither the oc nor thechain alone possesses bioactivity, but an r:1. chain may be combined with any of the specificchains to produce a biologically active hormone whose specificity is determined by the &bgr; chain. Radioimmunoassays employing antisera directed towards the specific &bgr; subunits may allow distinction not only of the appropriatesubunit but also of the corresponding whole molecule.4 Although distinction of -L.H. from &bgr;-H.C.G. is difficult, since they have similar structure for most of their length, this can be achieved with an antiserum raised against the unique C-terminal-aminoacid residues of

&bgr;-H.C.G.8

There

are

thus numerous’im-

munological ways of measuring H.C.G. and its subunits. Differing specificities of the reagents chosen may explain some of the discrepancies in reported occurrence of H.c:G. and H.c.G.-like materials in normal and neoplastic states.

Trophoblastic neoplasms producing whole H.c.G. are said to respond readily to conventional chemotherapy, while tumours releasing subunits as well as H.C.G. tend not to respond.4Hence, measurement of H.c.G. and H.C.G.-subunit production may be useful in prognosis. Longitudinal studies of secretion by other tumours remain to be done. These results suggest that prognosis may be determined by the functional properties of the tumour cells themselves or by the effect of the tumour products upon the host. H.c.G. is reported to be immunosuppressive,12 but it is the subunits rather than H.c.G. itself which seem to influence prognosis. Though thep subunit is without endocrine bioactivity, perhaps it can influence other host-cell functions such as immunity? Subunit release may merely reflect the functionally less differentiated nature of the tumour cells. If so, then it is surprising to find gonadotrophin production with functioning but not with non-functioning islet-cell carcinomas.6

Despite this evidence and the apparently stable heritable property of H.C.G. production by many tumour-cell lines,13 it would be premature to equate H.C.G. or H.C.G.like materials solely with malignancy. H.c.G.-like materials have been reported present in raised amounts in various gastrointestinal diseases associated with inflammation and repair.4 H.C.G. may occur also in normal tissues. The most convincing evidence for this was obtained with a radioimmunoassay directed towards the unique C-terminal part of the &bgr;-H.C.G.:9 it revealed the C terminal, in small amounts, in pituitary and urine of normal subjects. Some workers have found H.c.G.-like material in the normal testis, colon, and liver;7,8 others have failed to detect it in liver.4 In certain tumours, and in the normal colon and liver, detectable H.c.G.-like material seems to be devoid of carbohydrate sidechains.7 Removal of sialic acid reduces the biological half-life of H.C.G., but the molecule still retains in-vitro bioactivity.4 However, nothing is known of the properties of H.C.G. from which further monosaccharide residues have been removed. Thus, much of the uncertainty about the presence,

U.S.A. 1976, 73, 2885.

Howard, S. M., Shome, B., Cornell, J. S. Rec. Progr. Hormone Res. 1971, 27, 165. 11. Canfield, R. E., Morgan, F. J., Kammerman, S., Bell, J. J., Agosto, G. M. ibid. p. 121. 10. Pierce, J. G., Liao, Th.,

12.

Adcock, E. W., Teasdale, F., August, C. S., Cox, S., Meschia, G., Battaglia, F. C., Naughton, M. A. Science, 1973, 181, 845. 13. Chou, J. T., Robinson, J. C., Wang, S-S. Nature, 1977, 268, 543.

1117

absence, and distribution of H.C.G. and H.C.G.-like molefrom the diversity of reagent of and lack convincing chemical data on the probes of the materials nature being assayed. Perhaps the term material H.c.G.-like encompasses several different subwith stances immunological cross-reactivity. Future work in this area must include immunochemistry and attempts to ascertain, at a histological level, the normal .and neoplastic cell types responsible for production of H.C.G. and H.C.G.-like materials. At present the verdict for ubiquitous H.c.G. is "not proven". cules

seems to emanate

INTESTINAL FISTULAS French surgeons have been greatly interested in fistulas ever since Ambroise Pare treated the "inflamed, swollen wounds issuing from the guts" of his 16th century battle casualties. This Gallic influence is maintained in the opening paper of the Barber’s Company symposium on intestinal fistulas. Monod-Brocal analyses the dramatic fall in mortality (from 60% to 30%, or even to 10% in selected series), during the past decade in the treatment of small-bowel fistulas, of which 90% result from some form of surgical operation. He attributes this improvement to three major therapeutic advances-parenteral nutrition; low-flow enteric nutrition (usually with elemental diets); and irrigation with lactic acid. Few would disagree with the first two factors, but the Tremolieres technique2 of lactic-acid irrigation of the fistulous wound is probably less important than the local mechanical protective measures described by Irving3 in the second paper of the symposium. Sump drainage can now be replaced or supplemented in most patients by combinations of a modern stoma appliance, karaya gum or paste, and ’Stomahesive’ (a compressed wafer of gelatin, pectin, and methylcellulose which can be cut to shape around the fistulous opening). There is much scope for ingenuity in this work, and a nurse who supervises all fistulas can become a valued expert in any hospital. Early aggressive surgery has little place in enterocutaneous fistulas. For at least four weeks surgery should be restricted if possible to treatment of general peritonitis, drainage of abscesses, creation of a feeding enterostomy (usually a jejunostomy), and defunctioning of diseased bowel. During these weeks, the patient is maintained by intensive nutritional support.4 This may be parenteral (intravenous) or enteral. During the first few days of resuscitation and control of sepsis the intravenous route is usually necessary, but later, as the patient improves, it may be possible to change to enteral feeding by nasogastric intubation or surgically fashioned jejunostomy. Only the commercially produced (and very expensive) elemental diets are discussed, although they are probably no better in most cases than the cheaper substitutes which can be made up in any good hospital diet-kitchen.5 Despite all such valiant attempts to maintain nutrition, some 20-30% of the fistulas will not close spontaneously and so come to definitive operation which can "encompass the whole of gastro-enterological surgical practice." Whilst the outlook for intestinal fistula is 1. Monod-Broca, P. Br. J. Surg. 1977, 64, 685. 2. Trémolières, J., Bonfils, S., Gross, J. Arch. Mal. Appar. dig. 1961, 50, 636. 3. Irving, M. Br. J. Surg. 1977, 64, 690. 4. Holmes, J. T. ibid. p. 695. 5. Allison, S. P., Woolfson, A. M. J. Lancet, 1975, ii, 507.

today better than it was even ten years ago, one of surgery’s most disheartening sights is still the elderly, patient, with cancer or Crohn’s disease, who, a few days after emergency intestinal resection, produces that first dreaded spot of malodorous bile on his wound dressings CARDIOMYOPATHY AND CORONARY-ARTERY DISEASE

congestive cardiomyopathy conjures up the obscure disease of cardiac muscle whose of an picture unknown. cause is Patients with this disorder present with unexplained heart-failure, clinical and radiological evidence of cardiomegaly, diminished left-ventricularwall movement, and reduced left-ventricular ejection fractions.’ An identical clinical picture may, however, arise in some patients with coronary-artery diseasesometimes in the absence of a history of angina or myocardial infarction.2-4 The prognosis is poor and examination of the hearts of such patients shows focal areas of myocardial fibrosis interspersed with normal-looking myocardium.4 In life, cardiac radioisotope scanning with thallium-201 has been suggested as a way of separating the cardiomyopathy associated with coronary-artery disease from primary congestive cardiomyopathy. Dash and others6 have tried to quantify more precisely the relationship between chronic heart-failure and coronaryartery disease. 30 of 84 patients with coronary-artery disease were found to have a "cardiomyopathic syndrome due to coronary artery disease". This was-defined as heart-failure caused by multiple and widespread abnormalities of left-ventricular-wall motion due to coronary-artery disease, resulting in a reduction of left-ventricular ejection fraction to less than 50%. Excluded were patients with mechanical causes for their heart-failure such as disorders of the mitral-valve apparatus, damage to the interventricular septum, ventricular aneurysms, or poor movement of the left-ventricular wall localised to one segment. This syndrome was found to be specifically related to the extent of proximal coronary-artery disease and to the occurrence of previous multiple myocardial infarctions. The cardiomyopathy found in diabetics, although commoner than in non-diaTHE term

betics, seems indistinguishable.’ This pattern of obscure chronic heart-failure with the clinical picture of congestive cardiomyopathy fits into the end-stage of the natural history of coronary-artery disease. Before congestive cardiomyopathy is diagnosed, therefore, coronary-artery disease should be excluded. Although coronary-artery vein bypass grafting should be avoided in such patients, since it carries an increased surgical risk,4 one surgical teamS judges that cardiac transplantation has a place in this group. 1. 2. 3. 4.

Goodwin, J. F., Oakley, C. M. Br. Heart J. 1972, 34, 545. Raftery, E. B., Banks, D. C., Oram, S. Lancet, 1969, ii, 1147. Burch, G. E., Tsui, C. Y., Harb, J. M. Am. Heart J. 1972, 83, 340. Yatteau, R. F., Peter, R. H., Behar, V. S., Bartel, A. G., Rosati, R. A., Kong, Y. Am. J. Cardiol. 1974, 34, 520. 5. Bulkley, B. H., Hutchins, G. M., Bailey, I., Strauss, H. W., Pitt, B. Circulation, 1977, 55, 753. 6. Dash, H., Johnson, R. A., Dinsmore, R. E., Harthorne, J. W. Br. Heart J. 1977, 39, 733. 7. Dash, H., Johnson, R. A., Dinsmore, R. E., Harthorne, J. W. ibid. p. 740. 8. Rider, A. K., Copeland, J. G., Hunt, S. A., Mason, J., Specter, M. J., Winkle, R. A., Bieber, C. P., Billingham, M. E., Dong, E., Griepp, R. B., Schroeder, J. S., Stinson, E. B., Harrison, D. C., Shumway, N. E. Circulation, 1975, 52, 531.

Ubiquitous human chorionic gonadotrophin?

1116 ticularly to show whether, in an at-risk male fetus, significantly raised S.C.K. is always associated with abnormal muscle histology whereas a n...
317KB Sizes 0 Downloads 0 Views