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provides an ideal means of treating these commonlesions in the conscious patient. A review by Beardet al. claims that three-quarters of the cervicalerosions treated in the U.K. could be dealt with on an

outpatient basis. Outpatient treatment saves dis-

ruption in the patient’s home life, reduces inpatientwaiting-lists, and allows operating-theatres to be usedfor other procedures. Most patients do not experiencemuch discomfort from cervical cryosurgery. In oneseries of 142 women, only 3 had so much dis-comfort that treatment had to be discontinued 2 andcryosurgery seems to be acceptable to even the mostapprehensive woman. While the cryolesion is healingthe major side-effect is a watery discharge; thereis little bleeding or postoperative pain. Occasionallythe erosion is too large to be treated at one session, andabout one in ten patients need repeat therapy. Healingis good and patients have had normal pregnanciesand deliveries afterwards, although most of the

follow-ups so far have been for only a few years.While cryosurgery for benign cervical lesions is

standard in many departments, there is no agree-ment on the management of cervical carcinoma-in-situ.Proponents of freezing suggest that tissue is

destroyed to the correct depth for in-situ lesions,that future childbearing is not affected, that blood-loss is minimal, and that admission to hospitalmay be unnecessary. All this may be true, but,since there is usually no visible area of disease on thecervix, most gynaecologists still believe that the true

diagnosis of carcinoma-in-situ, and the exclusion of aninvasive growth, demands a wide biopsy. Multiplepunch-biopsies can miss the affected area; thereforea ring or cone of tissue is desirable. In the hands ofsome gynaecologists colposcopy irnproves localisation,but many are uncertain of the ability of a surfaceagent to deal with a process which can follow cervical

glands deep into tissue. Healing of surface tissuescould cover up carcinoma-in-situ deeper in the glands,preventing the escape of abnormal cells. In addition,the changes in cervical epithelium from dysplasia,through in-situ, to frank invasion are slow; and,although local freezing may have temporarily stoppedthe lesion, it may only have delayed the evolution ofpotential cervical cancer. Creasman et al. have

reported a series of patients with severe dysplasia orcarcinoma-in-situ of the cervix treated thoroughlywith cryosurgery of whom 19% had residual abnormaltissue at subsequent biopsy or hysterectomy. Nielsenand Stakeman 4 have described persistent carcinoma-in-situ at hysterectomy in 9 out of 11 women who hadhad thorough cryotherapy four to ten weeks earlier.

Perhaps the answer lies in a compromise betweensurgery and freezing. Crisp et al. employed shallow-knife conisation or selected biopsy of the cervixfollowed by immediate cryosurgery. Of 26 patientswho had carcinoma-in-situ, 9 at subsequent hysterec-tomy had no residual lesions and the remaining 17 had

1. Beard, R. J., Chamberlain, G., Holt, E. Br. J. Hosp. Med. 1973,9, 521.

2. Young, C., Malvern, J., Chamberlain, G. J. Obstet. Gynœc. Br.Commonw. 1972, 79, 753.

3. Creasman, W. T., Facog, J. C., Weed, J. C., Curry, S. L., Johnston,W. W., Parker, R. T. Obstet. Gynec. N. Y. 1973, 41, 501.

4. Nielsen, N. C., Stakeman, G. Lancet, Sept. 15, 1973, p. 627.5. Crisp, W. E., Smith, M. S., Asadourian, L., Warrerberg, C. B.

Am. J. Obstet. Gynec. 1970, 107, 737.

had persistent class-i cervical smears. The value of

cryosurgery for in-situ lesions of the cervix seems in

doubt, and the problems of surgical conisation remain.Since in-situ lesions progress slowly, the best way ofdeciding whether cryotherapy can replace conven-

tional but damaging conisation would be a randomisedtrial run at one or more of the larger gynxcologicalcentres. If the new treatment can then be shown toeradicate carcinoma-in-situ and to cause fewer side-effects, it is a better therapy. " Some things can belearned only by statistical comparison ", said Osler,and had he lived in this decade he would have put hisweight behind the wider use of prospective randomisedtrials to judge new treatments.

CHALONES: POSSIBLY AN HORSE

THE mechanisms involved in the development ofcancers should become clearer when more is knownabout fundamental growth processes, especially thosewhich put an end to cell proliferation when tissueregeneration is complete. Why does the healingprocess stop when the preinjury functional status ofa tissue or organ is restored ? From the viewpoint ofcibernetics it is difficult to believe that the extent of

regenerative growth is not controlled by negative-feedback systems. Chalone research, which is basicallyresearch into the nature of these feedback systems,was the subject of a conference in Augusta, Michigan,in June, 1972.1

Schafer first used the term chalone to describe anendocrine product which inhibits or diminishes

activity, as distinct from a hormone which excites orincreases activity. But the term as used by Schafer didnot find general acceptance. In 1962, Bullough 2

adopted it to describe a substance extractable fromskin which inhibits mitosis specifically in epidermalcells. Three years ago a spate of papers describingnecrosis and inhibition of mitosis in tumour tissue in

response to extracts from normal tissues, and specula-tion that the effects were due to the presence of

tissue-specific chalones in those extracts, led Iversen 3to review the likely value of chalones in thetreatment of cancer. His verdict at that time bears

quotation: " ... since we do not yet know the normalbiochemistry and physiology or the chemical con-

stitution of the chalones, it seems much too early tomake optimistic statements about the relationshipbetween chalones and the treatment of cancer. Everyeffort should be directed toward the possible dis-

covery of the chemical constitution of chalones andthe mechanism of action at the cellular and molecularlevel." Iversen pointed out that excessive mitosis isnot necessarily the main attribute of neoplasia. Cell

proliferation is relatively slow in many cancers com-pared with that in some normal tissues, and theinvasive and metastasising properties of cancer may notbe subject to control by chalones. Possibly cancersare attributable to development of cell resistance tothe inhibiting effect of chalones, in which case onecould not expect chalones to be of value in the treat-

1. Chalones: Concepts and Current Researches. Edited by BERNARD K.FORSCHER and JOHN C. HOUCK. Natn. Cancer Inst. Monogr. 1973,no. 38. $5.10.

2. Bullough, W. S. Biol. Rev. 1962, 37, 307.3. Iversen, O. H. Cancer Res. 1970, 30, 1481.

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ment of such growths. In his introductory remarksto the 1972 conference J. C. Houck pinpoints twoimportant characteristics of chalones. Firstly, like

hormones, they are tissue-specific but not species-specific. And secondly, they are not cytotoxic; theirinhibition of mitosis is reversible. Later in the pro-ceedings Dame Honor Fell draws attention to the

question of how chalones are destroyed. She suggests,on the basis of her own previous work, that lysosomalhydrolases are likely to be implicated. 4

Biological evidence of mitotic inhibition by tissueextracts from skin, lymphocytes, granulocytes, fibro-blasts, liver, kidney, and melanocytes is discussed,but in some cases the chalone concept seems over-stretched. For instance, P. Bichel speculates that achalone may determine the failure of transplantedascites-tumour cells to continue to proliferate in-

definitely. Experiments in parabiotic mice showedthat ascites-tumour growth was almost completelyprevented in one parabiote when the other bore thesame ascites tumour that had reached the growthplateau. Ultrafiltrates of ascitic fluid revealed a

G2-phase mitotic inhibitor with a molecular weight ofbetween 1000 and 10,000 and a G1 inhibitor with amolecular weight of between 10,000 and 50,000.

Information about the chemical structure andnature of chalones presents a motley picture. The

purest form of the epidermal chalone studied byBullough and Laurence has a molecular weight ofbetween 30,000 and 40,000. Elgjo’s 5 work, however,indicates that there may be two factors-a G2inhibitor extractable from basal cells and a G1inhibitor extractable from keratinising cells-andMarks 6 suggests that the G1 inhibitor is a glyco-protein with an apparent molecular weight of 100,000-300,000. This glycoprotein consists, according to

Marks, of a thick protein coat which can be removedby proteolytic digestion and a small (molecularweight 10,000-20,000) glycopeptide core. Epidermalchalone has been found not only in the skin but alsoin a wide variety of normal human and animal tissuesand secretions, including lung and urine, and in somecancerous tissues. 7

Second only to epidermal chalones, leucocytechalones have attracted attention because of the hopethat a lymphocyte chalone might be useful as an

immunosuppressant. Houck and Irausquin 8 reportthat they have found a non-cytotoxic, non-species-specific, lymphocyte-specific mitotic inhibitor whichis a glycoprotein of molecular weight 30,000-50,000.This chalone inhibits mitosis stimulated by phyto-haemagglutinin and mitosis by human leukeemic

lymphocytes in culture. Garcia-Giralt and col-

leagues 9 report that an alcoholic extract of calf spleen,which perhaps contains the chalone investigated byHouck, inhibits lymphocyte proliferation in vivo andprevents graft-versus-host reaction under certaindefined conditions. Others 10 have reported pro-

4. Fell, H. B. Natn. Cancer Inst. Monogr. 1973, no. 38, p. 77.5. Elgjo, K. ibid. p. 71.6. Marks, F. ibid. p. 79.7. Laurence, E. B. ibid. p. 37.8. Houck, J. C., Irausquin, H. ibid. p. 117.9. Garcia-Giralt, E., Rella, W., Morales, V. H., Diaz-Rubio, E.,

Richaud, F. ibid. p. 123.10. Chung, A. C., Hufnagel, C. A. ibid. p. 131.

longation of xenograft survival as a result of theadministration of lymphocyte chalone.

Uncritical biological assessment, sometimes basedsolely on studies on cells grown in vitro, has raised adust about the subject of chalones ever since the termwas reintroduced ten years ago by Bullough. Theconference in Augusta established the respectabilityof the subject, and, although much of importance isstill unknown, a pattern is beginning to emerge. AsIversen in his summing-up says, " We can only echothe hope expressed in the Arabian proverb, Whenthe dust falleth, thou wilst see whether thou ridest anhorse or an ass ’."

HEAVY SMOKING AND C.E.A.THE casual medical reader might be forgiven for not

being surprised at the report on p. 1238 of an associ-ation between heavy cigarette smoking and carcino-embryonic antigen (C.E.A.) in the serum. After all,he could argue, there seems to be hardly any diseasethat smoking does not produce, and the number ofdiseases with which the presence of C.E.A. in the bloodhas not been shown to be a factor seems to be shrinkingfast. Dr Stevens and his associates refer to a wide

variety of conditions in which circulating C.E.A. hasbeen found, including no less than three diseases ofwhich smoking is known to be a causal factor: chronicbronchitis, emphysema, and lung cancer. Hall et aLl

lately detected C.E.A. in both the urine and plasma ofpatients with another smoking-associated disease-cancer of the urinary bladder. Since low levels ofc.E.A. may be present in normal subjects, it may notbe justifiable to regard, as Stevens and his colleaguesdo, levels of 5 ng. per ml. of serum as abnormal.Evidence is accumulating which suggests that c.E.A.

may be released non-specifically from inflammatoryand hypertrophic lesions. Whether this is the reasonfor raised C.E.A. levels in pancreatitis is not known. 2

It seems, therefore, premature to suggest that theC.E.A. may indicate precancerous changes in bronchialepithelium. All that it would be wise to say, on existingevidence, is that, in a heavy cigarette smoker who isfree from cancer of the colon, cirrhosis, pancreatitis,or other conditions known to be associated with C.E.A.,an increase in the antigen may be attributable to

emphysema, chronic bronchitis, or lung cancer. Sucha statement is obviously not very helpful either to thesmoker or to his physician.A puzzling feature of the findings of Stevens et al.

is that the association between raised C.E.A. and

smoking is almost as striking for pipe and cigar smokersas for cigarette smokers, and yet most of the smoking-related diseases are less common in these classes ofsmokers. If these workers can now follow up the 110

heavy cigarette smokers in their study, and if in doingso they find that the 15 with raised C.E.A. levels suffera worse fate than the 95 without raised levels, theirobservations may lead to useful advances in the earlydetection of one or other smoking-related diseases.

Certainly, smoking habits should in future be takeninto account in the interpretation of raised blood-c.E.A.levels.

1. Hall, R. R., Laurence, D. J. R., Darcy, D., Stevens, U., James, R.,Roberts, S., Neville, A. M. Br. med. J. 1972, iii, 609.

2. Delwiche, R., Zamcheck, N., Marcon, N. Cancer, 1973, 31, 328.