PATHOGENIC ENTAMŒBA HISTOLYTICA

1038 U.S. TRENDS IN MORTALITY FROM CARCINOMA OF CERVIX

SIR,-Yulel has reported a decrease in the number of deaths due to cancer of the cervix among women aged 35-54 years in England and Wales between 1970 and 1976. Among younger women the number of such deaths rose during the same period, a trend attributed in part to the "early onset of sexual activity", "increased use of non-barrier contraceptives" and "the possiblity that pre-invasive phase of carcinoma of the cervix may be shorter in younger women". These findings prompted a review of U.S. data. Table I shows annual mortality-rates by 10-year and other age-groups for the period 1970-76 and the corresponding

(U.S.) BY POPULATION)

MORTALITY-RATES FROM CARCINOMA OF THE CERVIX

(PER

AGE AND YEAR

1000 000

FEMALE

The above findings warrant further studies on the future pattern of cervical-cancer mortality and on the reasons for the observed increase in carcinoma of the cervix in young women. Division of Biometrics, Food and Drug Administration, Rockville, Maryland 20857, U.S.A.

C. ANELLO C.LAO

PATHOGENIC ENTAMŒBA HISTOLYTICA

SIR,-It was gratifying to read your editorial of Feb. 10 (p. 303) commenting on advances in the evaluation of pathogenicity in strains of amoebae. Of course, if the amceba is caught with his hands in the till-i.e., with ingested erythrocytesthere can be little doubt of its guilt. In insisting on such a criterion for the label Entamceba histolytica, the pioneers taught better than they knew. Had such a dictum been sustained, much misdiagnosis and consequent suffering would have been avoided.

I

Source: Vital Statistics of the United States (Yearbook 1970-76); mortality, vol. 11, part A. Division of Vital Statistics, National Center for Health Statistics. (For example, in the 1971 yearbook, the U.S. female population is from table 6-3, technical appendix. The deaths are from table 1-26. The age-groups are reconstructed.) Rates are rounded off to one decimal point for ages 25 or more.

*Computed assuming linear trend. tp<0.01. TABLE II-PERCENT. HYSTERECTOMIES

(ALL RACES)

FOR

EVER-MARRIED WOMEN BY AGE AND YEAR

i

*Standard

error

i

i

of estimate exceeds 25; of estimate.

coefficients calculated from the data. Above age 25 years, the mortality-rate decreased, and this is not likely to be due to chance. For women below 25 years of age there was an apparent increase: this is consistent only for 1974-76 and the rates in this age-group are based on small numbers (11-25 cases per year), so the mortality-rates calculated for the under-25 age-group are not as stable as those for older women. The increase could be fortuitous: nevertheless an increase in cervical-cancer death-rates among U.S. women below the age of 25cannot be excluded. We contacted the Family Growth Survey Branch, Division of Vital Statistics, National Center for Health Statistics, to determine whether or not this finding might be a reflection of different patterns of hysterectomies for the different agegroups. The Family Growth Branch provided data from two surveys. Table n shows the percent. of hysterectomies for the years 1973 and 1976. An increase in the percent. of hysterectomies occurred for all age-groups, and changes in hysterectomy patterns are unlikely to account for the apparent rise in cervical-cancer mortality among women below the age of 25.

regression

1

Yule, R Lancet, 1978,i, 1031.

Clinically, a firm distinction must be made between "luminal amcebiasis", in which E. histolytica is just as commensal as are Entamceba coli, Endolimax nana, Entamaeba hartmartni, and other amoebae able to live in the human gut, and "invasive amoebiasis". Since the only progenitors of cysts are commensal, invasive amoebiasis should never be diagnosis on the sole finding of cysts, even when it has been proved culturally2 that the cysts are indeed those of E. histolytica. Luckily serology will show whether the patient has been invaded within the previous few years. The absence of antibodies practically excludes invasion, but their presence must be evaluated in the light of other evidence. With the ease and efficacy of modern therapy and the length of time needed to cultivate amoebae, it might be considered "academic" to determine whether or not a cultured strain is pathogenic (invasive). This is not true, for if the mechanism underlying the situation is to be identified, it is essential that distinction-commensal or pathogen-be made on all experimental material. Animal models, though useful, have not proved altogether satisfactory, as they all depend on artificial procedures. Thus the discoveries of cytotoxicity,3 of toxins4 and of specific isoenzymes5 are indeed steps forward. It would be of interest to know the relationship of these factors to the antibodies produced in invasive amoebiasis. As you point out, our objective is the elimination of invasive amoebiasis, which has a more restricted distribution than has the parasite. With the notable and informative exception of Loon Lake in Saskatchewandisease is confined to the tropics and subtropics. Affected areas all have, besides poor hygiene, an additional factor-overcrowding. This implies that the trigger which induces the amceba to invade requires a quicker route from anus to mouth than do the cysts of E. histolytica. The nature of this trigger has yet to be determined. No-one has found factors operative on the host, but what of those affecting the amoeba ? Invasive ammbx and malignant cells have much in common. By exceeding the bounds of hospitality, neither shows any regard for its host nor for its own sustained posterity. Unchecked, such invasion may lead to death of the host and racial suicide for themselves. Such change in behaviour may well be due to genetic transformation brought about by some external agent. Transformations of this nature are well known. A prophage can convert Corynebacterium diphtherice to a virulent form; 1

Richards, C. S., Goldman, M., Cannon, L. T. Am. J. trop. Med Hyg 1966,

15, 648. 2.

Chévez, A., Sepúlveda, B., Segura, M., Corona, D., Diaz, J in Proc mt Conf. Amebiasis (October, 1975); p. 447. Instituto Mexicano del Seguro Social, Mexico, 1976. 3. Bos, H. J. Trans. R Soc. trop. Med. Hyg. 1979, 73, 120 4. Sargeaunt, P G., Williams, J. E., Greene, J. D. ibid. 1978, 72, 519 5. Meerovitch, T. C. H., Eaton, R D. P. Am J. trop. Med Hyg. 1965, 14, 719

1039 from one strain of pneumococci can change the behavof other strains. Genetic engineering, with all its dangers, depends on such prowess. Now that progress has been made towards easier determination of pathogenicity in strains of E. histolytica, the way is open for attempts to transform (or transduce) commensal strains into invasive E. histolytica, and so to identify the obviously labile trigger agent. D.x.A.

iour

causative link is almost unthinkable. Moreover, the background of reported cases of gastric cancer associated with a history of duodenal ulcer,4the sequence of events in their first case provides no substantial grounds for suspecting that cimetidine treatment triggered the cancer. All in all, I feel that the juxtaposition of the three case reports and the speculation(s) with regard to the formation of a gastric carcinogen from cimetidine is both misleading and

Thus,

a

against

scientifically unjustifiable.

Amœbiasis Research Unit, Durban, South Africa

R. ELSDON-DEW*

4

Kings Road, SW19 8QN

FRANCIS J. C. ROE

Wimbledon *Present address. Kwazulu

Pathology Laboratory Services,

Private

Bag X9020,

Pietermariszburg 3200, South Africa.

RADIATION DOSES AFTER THREE MILE ISLAND

CIMETIDINE AND GASTRIC CANCER

SIR,-The manufacturers of cimetidine, Smith Kline & French Laboratories, have asked me to comment on the paper by Mr Elder and his colleagues on p. 1005 of this week’s issue. Several important points need to be made. Firstly, insofar as cimetidine can ease symptoms caused by gastric cancer, there is a danger that its use will delay the diagnosis of malignancy. In their data sheet on ’Tagamet’ the manufacturers of cimetidine specifically warn users of this danger,’ and reports of such cases have been published’ prior to the three now described by Elder et alIt is right that such cases should be publicised to remind clinicians of the need to check the accuracy of diagnosis before embarking on cimetidine therapy and to maintain close observation of patients while treatment continues. Another feature of the paper is of more debatable merit, however. It is well-known that many drugs which are secondary (or tertiary) amines (or amides) might, theoretically at least, be converted to nitroso-derivatives within the highly acidic conditions of the stomach by reaction with nitrite from saliva, food, drinking water, tobacco smoke, and such.2 Cimetidme falls into this category, but whether nitrosation occurs in vivo, and, if so, the extent to which it occurs, are unknown. Furthermore, there is no evidence that any nitroso-compound which could conceivably be formed from cimetidine in the stomach would behave biologically like N-methyl-N’-nitro-N-nitrosoguanidine, irrespective of its arguably analogous chemical structure. While such uncertainties exist it is difficult to iustify the speculations in Elder’s paper. N-nitrosamines are remarkable for the specificity of their organotropy and one really could not predict that a ’mono nitrosocimetidine’ would be especially likely to cause cancers specifically of the stomach. Indeed, this is irrelevant: if the administration of cimetidine led to the production of biologically significant quantities of a carcinogenic nitrosamine, one would be concerned, irrespective of its particular organotropy. Clearly it is data and not speculations that are needed. Is cimetidine nitrosated to a significant extent in vivo? Is the product formed carcinogenic? If so, which is or are) the target organ(s)? One way of obtaining such information is to study the effect of the drug in laboratory animals. This has been done in a large, well-designed, multi-dose, long-term study in rats without evidence of increased risk of malignancy.2 The results of this study provide persuasive evidence that, in doses equivalent to over 60 times those used chmcatly, cimetidine is safe from the viewpoint of carcinogenicity. No experienced cancer researcher would expect cancer to arise in a human as a consequence of exposure to even a potent chemical carcinogen within a period from first exposure measured in weeks or months. The intervals from first exposure to cimetidine to diagnosisof gastric cancer in the three cases reported by Elder et al. ranged from 10 weeks to 11 months. 1 Taylor, R H.,

Menzies-Gow, N., Lowell, D., La Brooy, S. J., Misiewicz, J Lancet, 1978, i, 686. 2 Tjinsky, W. Cancer Res. 1974, 34, 255. 3. Brmblecombe, R. W., Duncan, W. A. M., Durant, G. J., Emmett, J. C., Ganellin, C. R., Leslie, G. B., Parsons, M. E. Gastroenterology 1978, 74, 339-347.

recent accident the Three Mile Island nuclear power station in Pennsylvania includes data on the radiation exposure of members of the public. According to information received from Federal agencies in the United States, the value quoted of 80 mrem is the estimated maximum exposure to any individual and is not the average to the population in the area. Furthermore, the collective dose to the population of approximately 2 million living within a radius of 50 miles (80 km) of the plant has been estimated at between 2000 and 3000 person-rem. According to the most recent estimates of UNSCEAR and I.C.R.P., this implies that there is about one chance in four that there will eventually be one extra death from cancer in this population in addition to the expectation of approximately 500 000 deaths from cancers from all causes.

SiR,—Your editorial of April 28 about the

at

National

Radiological

Protection

Harwell, Didcot, Oxfordshire OX11 0RQ

Board,

A. S. MCLEAN

&agr;2-ANTIPLASMIN INHIBITOR DEFICIENCY SiR,-Koie et al.l described the first case of deficiency of OC2-antiplasmin (the designation used for the fast-acting plasmin inhibitor in plasma previously called antiplasmin, &agr;2-plasmin inhibitor, or primary plasmin inhibitor as suggested by the International Committee on Thrombosis and Haemostasis in Thromb. Haemostas. 1978, 39, 524) in a patient who presented with haemorrhagic diathesis. Plasma-fibrinogen and fibrinogen-degradation products in serum were, however, normal. Koie et al. suggested that the bleeding in their patient might be due to increased fibrinolysis of the hxmostatic plugs in the absence of the fast-acting plasmin inhibitor. The absence of systemic fibrinogen breakdown was explained by the presence of other protease inhibitors in the circulation. Dr Lipinski and Dr Gurewich (Feb. 10, p. 329) suggest another explanation. They and othersz had observed that, in the presence of increased plasminogen-activator levels in the blood, fibrinolysis is much more enhanced than fibrinogenolysis. This preferential action on fibrin is explained by postulating the formation of an antiactivator-activator complex which dissociates in the presence of fibrin. The evidence for the existence of a specific inhibitor of plasminogen activator in the blood remains, however, indirect, and such a substance has not been isolated or characterised. During the past few years specific interactions at the molecular level have been demonstrated between the different components of the fibrinolytic system. The developments permit a molecular model for the directed action of the fibrinolytic system towards fibrin in vivo.3 In this model, the fibrinolytic sys4.

Ellts, D. J., Kingston, R. D., Brookes, V. S., Waterhouse, J. A. H. Br. J.

Surg. 1979, 66, 117. Kamiya, T., Ogata, K., Takamatsu, J., Kohakura, M. Lancet, 1978, ii, 1334. 2. Müllertz, S. Acta physiol. scand. 1956, 38, suppl. 10. 3. Wiman, B., Collen, D. Nature, 1978, 272, 549. 1. Koie, K.,