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often in food samples from Linhsien County than in samples from a county where the disease was not especially common; and experiments suggested that Geotrichum candidum, a fungus contaminating pickled vegetables, might be co-carcinogenic for

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methylbenzylnitrosamine. NEPHROLOGY: FLORENCE A MUCH-DISCUSSED subject at the Sixth International Congress of Nephrology was membranoproliferative glomerulonephritis. In M.P.G.N. the glomeruli show modest proliferation of mesangial cells together with thickening of the capillary wall, with or without lobulation and at times with crescents. On silver impregnation staining the encircling mesangial cells give the capillary a double contour. Some groups prefer to call this lesion mesangiocapillary glomerulonephritis. By electron microscopy, or with an oil immersion lens and expert eye, three types of deposit can be seen-those lying in the subendothelial space, those under the epithelium, and those in the basement membrane. The basement-membrane deposits are particularly electron-dense and the nephritis exhibiting these changes has been labelled dense-deposit disease. This subgroup is important because, according to world experience, it invariably recurs in the donor kidney after transplantation.

The complement abnormalities commonly present in M.P.G.N. include hypocomplementsemia (due mainly to a low circulating C3); presence in the serum of some hypocomplementsemic patients of a factor which breaks down C3 in vitro and presumably in vivo (C3 nephritic factor, C3NeF); circulating breakdown products of C3; and both hypercatabolism and reduced synthesis of C3. C3NeF is a non-immune y-globulin with molecular weight 150,000. The argument goes that the hypocomplementsemia creates an immunodeficiency; complement is necessary for eradication of bacteria, and in complement deficiency bacterial antigens persist and become available for formation of soluble complexes. Why such unrecognised bacteria should lead to such a consistent histological picture is a mystery: and some patients with M.P.G.N. seem never to be hypocomplementsemic. An animal model of M.P.G.N. has been found. In a small flock of ewes mated to specific rams the lambs develop a spontaneous and fatal M.P.G.N. C3 is low at birth, but as yet C3NeF has not been detected. A familial trend might be expected in human M.P.G.N., but only one such family has been found (in which a father and sister were hypocomplementsemic). There is an association between M.P.G.N. and partial lipodystrophy (P.L.D.). Some patients with P.L.D. also have M.P.G.N. with hypocomplementasmia due to the presence of C3NeF. Other patients with P.L.D. have the complement abnormalities typical of M.P.G.N., though the urine, and the renal tissue in the few cases examined, have been normal. Patients with both P.L.D. and M.P.G.N. tend to have the dense-deposit variety of nephritis with low C3 but normal C4 levels. P.L.D. with complement deficiency alone is no threat to life; but M.P.G.N. with or without hypocomplementoemia leads to death or dialysis, the more rapidly

if there is persistent nephrosis or macroscopic haematuria. Not all dialysis and transplantation units can follow the recommended approach to chronic renal failure. Ideally, dialysis starts before the creatinine clearance falls below 5 ml. per minute, and children in particular should be transplanted as soon as possible. After the immediate surgical and immunosuppressive problems have receded, the survival of a graft kidney depends upon many factors other than HL-A matching (which was not seriously questioned at the congress). Patients who originally had M.P.G.N., Berger’s IgG/IgA glomerulonephritis, or focal glomerulosclerosis are particularly likely to develop glomerulonephritis in their allograft. Virus infections seem to be a factor in graft survival. In patients with post-transplant cytomegalovirus (c.M.v.) infection creatinine clearances are lower and graft nephrectomy for chronic rejection more common at 3, 6, and 12 months than in transplanted patients free of c.M.v. infection. In addition, there is a statistical association between epidemics of influenza B and adenovirus infections and acute kidney rejection. Long-term graft survival can be predicted from biopsy specimens. Thirty-five transplanted kidneys were biopsied 2 years after transplant, and function was reassessed 9 years after transplant. Thirteen of the thirty-five kidneys were morphologically normal at 2 years and all thirteen were functioning successfully at the end of follow-up. Of the twenty-two kidneys which had developed structural abnormalities by 2 years, only nine were still functioning 9 years after transplantation. As it is possible that glomerulonephritis and transplant nephropathies are mediated by circulating immune complexes, the quantitation of these is important. Measurement of such complexes may become possible by a radioimmunoassay which measures complex binding to cultured lymphoblastoid cells via complement receptors. Perhaps at the Seventh International Congress of Nephrology in Montreal in 1978 the kinetics of soluble-complex disease will be much clearer. ORAL CONTRACEPTIVES AND LIVER TUMOURS

CLINICIANS hoping for a clear-cut statement on the cancer risk of oral contraceptives will be disappointed in vol. vi of an I.A.R.C. review.1 A working group met at the International Agency for Cancer Research in February, 1974, and discussed diethylstilboestrol and testosterone in addition to oestrogens and progestagens. Animal work shows that sex hormones with cestrogenic or progestagenic activity do have

higher doses tested. Tumours were noted in several animal species, and the sites most commonly affected were liver, pituitary, breast, and female reproductive system. A lot of toxicological work done by drug manufacturers was gathered together by the Committee on Safety of Medicines in 1972.That review had been prompted by a report of hepatoma formation in rats on mestranol. carcinogenic potential, usually

at

the

1. I.A.R.C. Monographs on the Evaluation of Carcinogenesis Risk of Chemicals to Man: vol. VI, sex hormones. Obtainable from W.H.O. sales agents. 2. Committee on Safety of Medicines. Carcinogenicity Tests of Oral Contraceptives. H.M. Stationery Office, 1972.

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The committee concluded that there was little evidence that oestrogens and progestagens separately or together caused benign or malignant hepatomas in animals, and the general question of the carcinogenicity of oral contraceptives the committee was equally reassuring. In the human female, however, very few epidemiclogical studies of this problem have been done. Three months before the group met in Lyon there appeared the first of several reports (19 cases in The Lancet and British Medical Journal) of liver tumours in women on oral contraceptives. These tumours-benign histobut fatal-are often very rare in women of logically, The for an association evidence childbearing age. fall of short that may required by the I.A.R.C. and the C.S.M.; nevertheless, an up-to-date assessment of the risk of hepatoma in women on oral contracepon

tives would be welcome from

one or

both of these

bodies.

COLPOSCOPY ONE of the problems of cervical carcinoma-in-situ is overtreatment. The gynaecologist seeks on the one hand to identify those conditions which are truly premalignant and on the other hand to perform the least mutilating operation. In the United Kingdom, the most usual way of determining the significance of a cervical smear containing malignant or highly suspicious cells is to excise and examine the tissue from which the cells probably came. Since the gynaecologist cannot localise clinically the exact tissue which sheds the offending cells, he must take a biopsy specimen which includes the whole area at risk-an inverted cone circumscribing the external os and extending up the canal. This is a bloody operation which has risks of later infection and cervical stenosis, possibly leading to an increased risk of infertility, mid-trimester abortion, and difficulties at delivery.l If there was some safe and accurate way of localising the potentially neoplastic area, it might save this destructive and blind shelling-out of the cervix. Colposcopy offers this, and its use in experienced hands could reduce the need for wide conisation. A colposcope is essentially a binocular, low-powered microscope which can be manoeuvred to examine the whole cervical surface. A bivalve speculum opens the vagina and causes the cervix to gape, allowing an exaggerated view of the lower cervical canal. Swabbing with 3% acetic acid clears the mucus and cellular debris, allowing an impressive view of the surface epithelium, rather like flying high over the countryside on a cloudless day. Areas of abnormal cells stand out with their disordered growth patterns, their altered refractility of light, and the disturbed outlines of surface capillaries. The whole spectrum of atypical epithelium, dysplasia, carcinoma-in-situ, and invasive carcinoma can be identified since 90% of this transformation begins on the portio. The junction of the squamous and columnar epithelium is a critical area which unfortunately cannot be checked in about a tenth of women. Interpretation of colposcopic changes requires skill and experience, and lately the terminology has been rationalised so that uniformity may be expec1.

Hughes, J., Arwyn Evans,

M. D.

Br. J. Hosp. Med. 1969, 2, 989.

ted between different centres. In Continental Europe, Australia, and North and South America this instrument is used in most gynxcological departments. In some centres colposcopy is now the primary cervical screening device. It is claimed that the clinician can provide accurate screening except where the The procedure, lesion is entirely endocervical. a time and there is however, takes high false-positive

might lead to an increased number of 2 unnecessary biopsies.2 Comparisons of colposcopy and exfoliative cytology have usually shown similar pick-up rates for carcinoma-in-situ 3,4:cytology has fewer false-positives,5 but colposcopy is slightly superior in the detection of cervical dysplasia.4 With the increased number of adolescents producing abnormal smears, colposcopy may be a valuable alternative to conisation in this young pre-reproductive group. The small but worrying problem of followingup girls whose mothers may have taken stilboestrol in pregnancy can also be tackled by colposcopy. In the United Kingdom colposcopy is confined to a rate

which

few centres, where enthusiasts have obtained excellent results. 6,7 Drawbacks are the length of training necessary and the increased time which has to be spent with each patient. As a screening instrument it has never taken on in the U.K., where gynaecologists have become accustomed to the relatively simple technique of cervical smears, leaving the time-consuming diagnostic procedures to the pathologist. But colposcopy is more widely used after the finding of malignant cells on a smear-for localising accurately the affected region of the cervix. As many as 85% of patients with abnormal cervical exfoliative cytology can be shown not to have invasive carcinoma.8 Probably conisation is still required in these circumstances, but a shallower or more localised excision becomes reasonable; colposcopy-directed biopsy allows carcinoma-in-situ to be removed with the minimum of healthy cervix 9 and is of particular value in the interpretation of positive smears in pregnancy.’ Some say that colposcopy has almost eliminated the need for conisation during pregnancy.99 At present, however, the evidence in favour of any lesser surgical treatment of carcinoma-insitu such as punch-excision, cautery, or cryosurgery alone, is not very convincing, although cervical dysplasia may well respond to such therapies."-13 Colposcopy, even if used for pre-biopsy localisation only, would put an insupportable extra load on a routine gynxcological department. In certain centres, however, one staff member could be given time for proper training. It would then stand as a consultation service for an area, and to that centre might be referred all women with positive Papanicolaou smears who require cervical biopsy. 2. Odell, L. D., Merrick, F. W., Ortiz, R. Acta cytol. 1968, 12, 305. 3. Navratil, E., Burghardt, E., Banardi, F. Am. J. Obstet. Gynec. 1958, 75, 1292. 4. Scott, J. W., Brass, P., Seekinger, D. ibid. 1969, 103, 935. 5. Van Haam, E. Acta cytol. 1962, 6, 508. 6. Singer, A. Br. J. Obstet. Gynœc. 1975, 82, 81. 7. Jordan, J. A. Practitioner, 1969, 202, 351. 8. Ostergard, D. R., Gondos, B. Am. J. Obstet. Gynec. 1973, 115, 783. 9. Stafl, A., Mattingly, R. F. Obstet. Gynec. 1973, 41, 168. 10. De Petrillo, A. D., Townsend, M. D., Morrow, C. P., Lickrish, G. M., Di Saia, P. J., Roy, M. Am. J. Obstet. Gynec. 1975, 121, 441. 11. Richart, R. M. Cancer, 1966, 19, 1635. 12. Richart, R. M., Sciarra, J. J. Am. J. Obstet. Gynec. 1968, 101, 200. 13. Kaufmann, R. H., Connor, J. S. ibid. 1971, 109, 1167.

Editorial: Oral contraceptives and liver tumours.

1414 often in food samples from Linhsien County than in samples from a county where the disease was not especially common; and experiments suggested...
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