THIOPROLINE

597 stains for CEA would seem to be no better than standard histochemical methods in the differential diagnosis of endocervical or endometrial adenocarcinoma.

peroxidase

Departments of Laboratory Medicine and Obstetrics and Gynecology, Naval Regional Medical Center, Portsmouth, Virginia 23708, U.S.A.

D. ROBERT DUFOUR RICHARD J. STOCK

yield cysteine and formaldehyde, the formaldehyde being rapidly absorbed and responsible for the toxicity. Our pharmacokinetic studies seem to show that after intravenous injection the drug is rapidly eiiminated intact in the urine, and this is why we propose to administer thioproline to cancer patients at a dose of 40 mg/kg per day by injection acid in the stomach

to

every 6 h. Clinica Puerta de Hierro,

and Professor Goldenberg (Jan. 26, p. 213) and Lieut.-Commanders Dufour and Stock (this issue) challenge our conclusion that immunoperoxidase staining of tissue CEA can help in the distinction between endocervical and endometrial adenocarcinomas. van Nagell et al.’ reported a lower frequency (36%) of CEA-positives than we did (80%) for endocervical adenocarcinoma. Our series was much larger, and the patient material may have been different: 55% of our patients had advanced disease (stage n or more),2 and others3 have observed that serum CEA level is almost always raised in advanced endocervical adenocarcinoma, but rarely in local disease. Furthermore, CEA contains multiple antigenic sites,4 and antisera may have different specificities. We found that endocervical adenocarcinomas which are associated with endometrial adenocarcinoma are CEA-negative, and no such case was included in our material. We would be happy to send tissue specimens of our material to van Nagell and Goldenberg to clarify how much the techniques and antisera have affected the reported discrepancy. Dufour and Stock raise an important point. In absolute terms, endometrial adenocarcinomas would contribute twice as many CEA-positives as would endocervical adenocarcinomas unless adenosquamous carcinomas and squamous metaplasia are carefully ruled out. However, after these exclusions, and that of mesonephroid adenocarcinomas, as in our series, the predictive value is considerably higher than they suggest. Furthermore, if the predictive value of CEA-negative results is used in the same fashion, 99% of CEA-negative adenocarcinomas would be endometrial.

SIR,-Professor

van

Nagell

Department of Pathology, University of Helsinki, 00290 Helsinki 29, Finland Departments of Obstetrics, Gynæcology, and Reproductive Physiology, St Bartholomew’s Hospital Medical College, London EC1A 7BE

TORSTEN WAHLSTRÖM

MARKKU SEPPÄLÄ

THIOPROLINE

SiR,-Dr Garnier and colleagues (Feb. 16, p. 365) draw attention to the toxicity of thiazolidine-4-carboxylic acid (thioproline) when taken by mouth by children. During our toxicological studies on the sodium salt of L-4-thiazolidine carboxylic acid we noted that the oral form was more toxic than the intravenous form. This fact, together with the fact that Dr Brugarolas and I (Jan. 12, p. 68) found that the oral form of thioproline seems to have no antitumour activity, makes me wonder if there is a considerable hydrolysis of thiazolidine-4-carboxylic 1. van

Nagell JR, Jr, Donaldson ES, Gay EC, Hudson S, Sharkey RM, Primus FJ, Powell DF, Goldenberg DM. Carcinoembryonic antigen in carcinoma of the uterine cervix. II Tissue localisation and correlation with plasma antigen concentration. Cancer 1979; 44: 944-48.

2. Korhonen MO. Adenocarcinoma of the uterine cervix: An evaluation of the available diagnostic methods. Acta Pathol Microbiol Scand A 1978; suppl 264: 1-59. 3. Kjorstad KE, Orjaseter H. Studies on carcinoembryonic antigen levels in patients with adenocarcinoma of the uterus. Cancer 1977; 40: 2953-56. 4. Hammarström S, Svenberg T, Sunblad G. Immunochemical studies on carcinoembryonic antigen (CEA): Number of antigenic determinants and relationship to a glycoprotein from normal human bile. In: Fishman WH, Sell S, eds. Oncodevelopmental gene expression. New York: Academic Press, 1976: 559-65.

MARIO GOSÁLVEZ

Madrid-35, Spain

SiR,-I have followed with interest Lancet contributions on the possible anti-tumour action of thioproline (Jan. 12, p. 68) and on the toxicity of this agent (Feb. 16, p. 365), and the usefulness of screening related adducts (Feb. 16, p. 365). Thioproline is the parent compound of an extensive series of substances already studied by various laboratories and for differing purposes. The non-enzymic reversible interaction of a,&bgr;-unsaturated aldehydes with cysteine (and other thiol-containing substances) has been reported on extensively by Schauenstein and Esterbauer’s group in Graz.’ The thiazolidine and furan derivatives produced by interaction of 4-hydroxy-alk-2-en-l-als with cysteine have been studied over many years for antitumour action on animal tumours,I,2 and some of the parent hydroxy-unsaturated aldehydes have also been tested on human cancer.3,4 The initial stimulus for these animal studies was generated by the knowledge that such unsaturated aldehydes are formed as products of lipid peroxidation5 and that the cysteine adducts are less toxic than the parent aldehyde.l,2 These unsaturated aldehydes have similarities to the ketoaldehyde, methylglyoxal, which has been proposed by Szent-Gyorgyi6 to have a key role in helping to reverse the behaviour of tumour cell membranes back towards a normal pattern. In this respect, it is worth noting that methylglyoxal has been shown to inhibit membrane adenyl cyclase at micromolar concentrations (M. U. Dianzani, L. Paradisi, and C. Panagini, unpub-

lished). Thioproline (thiazolidine-4-carboxylic acid)

restores contact

inhibition of hela cells in culture and has attracted considerable interest "to learn whether the first drug to attack cancer by curing diseased cells rather than killing them is as effective as it seemed to be in initial trials."8 Implicit in this remark is a principle long held by Albert Szent-Gvörgyi6 who, in his work over many years, has stressed the importance of changing the membrane behaviour of tumour cells back towards that observed in the corresponding normal cells-in effect, restoring normal control and social behaviour without the need for significant cytotoxicity. Thus there is a lot of published information relevant to the current interesting work on thioproline. In particular, the stimulation in vivo of lipid peroxidation, with the subsequent formation of unsaturated aldehydic products, offers exciting possibilities for the in situ formation of thiazolidine adducts, E, Esterbauer H, Zollner H. Aldehydes in biological systems: London: Pion, 1977. 2. Conroy PJ, Nodes JT, Slater TF, White GW. The inhibitory effects of a 4-hydroxy-pentenal: cysteine adduct against sarcoma 180 cells in mice. 1. Schauenstein

Eur. Cancer 1977;13: 55 63. 3. Musger A. Cited by Schauenstein et al. (ref. 1). 4. Ratzenhofer M, Richter K, Schauenstein E. Effects of 4-hydroxypentenal on the non-cancerous and the cancerous ectocervix uterihominis. Exp Pathol

1975, 11: 83-106. 5. Schauenstein E. Autoxidation of structure

and

polyunsaturated esters in water: chemical biological activity of the products. J Lipid Res 1967; 8:

417-28. 6.

A. Electronic biology and cancer. New York: Marcel Dekker, 1976. The living state and cancer In: Wolstenholme GEW, FitzSimons DW, Whelan J, eds. Submolecular biology and cancer: Ciba Foundation Symp no. 67. Amsterdam: Excerpta Medica, 1979: 3-18. 7. Gosalvez M, Vivero C, Alverez I. Restoration of ’contact inhibition’ in tumour cells in tissue culture by treatment with thiazolidine-4-carboxylic acid. Biochem Soc Transact 1979; 7: 191-92. 8. Debelius H. Optimism over first results of anti-cancer drug. Times Feb. 22, 1980.

Szent-Györgyi

598

especially since lipid peroxidation is reduced in many experimental tumours9 so that endogenous production of such unsaturated aldehydes is very much decreased by that route. Department of Biochemistry, Brunel University, Uxbridge, Middlesex UB8 3PH

T. F. SLATER

CORONARY HEART MORTALITY IS STILL INCREASING IN SWITZERLAND

SIR,-In your editorial of Jan. 26 (p. 183) you refer twice paper dealing with some aspects of cardiovascular disease (CVD) mortality in Switzerland.’ The first time, you make a cautious statement: "Among low-coronary countries, Japan and possibly also Switzerland ... have shown a decrease" followed by an explanation of the meaning of the "possibly" which fits ours. A decline of coronary heart mortality cannot be easily deduced from data that use several classification systo a

The seventh and former International Classification of Diseases (ICD) cannot be compared with the eighth which first fully distinguishes ischsemic heart disease (ICD 410-414) from other CVD. Since 1969, this classification has been used in Switzerland and it is now possible to look for a trend in ischasmic heart disease (IHD) death rates during the past 10 years. In the male population of Swiss aged 45-84-the important foreign emigration during the 1970s makes it difficult to consider the entire resident population-according to an estimate of the odds ratio standardised for age by the Mantel-Haenszel procedure, the IHD death rate increased by 9.7% (0-99 confidence interval: 5.6-14.0%) from 1969-1970 to 1977-1978. This result is consistent with a recent publication2 and with an tems.

on-going cohort mortality study.3 The second time, your refer to an inverse relationship between animal fat consumption and ischaemic heart disease mortality in Switzerland. In fact, when considering the past 10 years, this association is direct. Truly there is no "anomalous"

picture. Institut Universitaire de Médecine Sociale et Préventive,

Hôpital Sandoz, 1011 Lausanne, Switzerland

J. ALEXANDER B. JUNOD

RESUSCITATION FROM CARDIAC ARREST

SIR,-Dr Weisfeldt and his colleagues (Jan. 26, p. 175) have done another brilliant study of resuscitation of cardiac arrest by rhythmic chest compression, showing that cardiac emptying is produced, not merely by the force of the sternum, but by the entire intrathoracic pressure as exerted by the lungs on the heart. However, their procedure is unnecessarily complicated. The air-filled lungs behave as a fluid, transmitting applied pressure in all directions. Thus, if the trachea is blocked and a firm binder is applied to the abdomen, force to depress the sternum must raise the pressure in the thorax. It would seem unnecessary to use a pressure-cycled ventilator. Indeed, simultaneous application of the opposing pressures (sternal and endotracheal) might result in little or no tidal flow, which would not be evident in the 30 s trials. Weisfeldt et al. give no measure of tidal air flow. A better procedure would be the use of a piston-type respirator displacing about 800 ml air during a 3 s inspiratory phase; 9. Burlakova EB. Bioantioxidants and synthetic inhibitors of radical processes. Russian Chemical Rev 1975; 44: 871-80. 1. Guberan E. Surprising decline of cardiovascular mortality in Switzerland:

1951-1976. J Epidem Commun Health 1979; 33: 114-20. 2. Gass R. L’influence des facteurs géographiques démographiques et socioéconomiques sur la mortalité par cardiopathies ischémiques en Suisse. Rev

Epidem Santé Publ 1979; 27: 315-29. 3. Junod B, Alexander J, Wietlisbach V. Evolution par cohorte et autres facteurs associés à la mortalité par maladies ischémiques du coeur en Suisse—To be presented at the 48th meeting of the Swiss Society of Internal Medicine, Lugano, May 8-10, 1980.

then, during a 2 s expiratory phase the exhaust port should be vented through a positive end-expiratory pressure (PEEP) valve, and adjustable up to 80 mm Hg (110 cm water). A pressure gauge on the line between the pump and endotracheal tube will indicate the intrathoracic pressure reached during chest compression, and this should drop to zero during the upstroke. A tight abdominal binder, by preventing downward displacement of the diaphragm, will help raise the intrathoracic pressure. If the gauge does not drop to zero during the upstroke, that will indicate overinflation of the lungs and require reduction of the PEEP or reduction of the tidal volume of the ventilation pump. Thus, chest compression of 60/min and ventilation of 12/min results in five cardiac compressions, three during inspiration and two during expiration. Actual expiration will occupy only the two ’chest compression phases of 0.6 s each. Additional augmentation of blood flow can be achieved with counterpulsation pressure applied to the extremities during each 0-4 s phase of sternal rise, using either pneumatic trousers (MAST type) or a hydraulic device (Cardiassist Cor-

poration). 8552 Canton Center

Road,

SAM LERMAN

Canton, Michigan 48187, U.S.A.

NEW LOOK AT CLOSED CARDIAC MASSAGE

SIR,-Dr Chandra and colleagues (Jan. 26,

p.

175) provide

ideas about the haemodynamics of external cardiac compression. Why do we in the U.K. stop cardiac massage to ventilate, and then begin again? A brief look at the history of closed chest cardiac massage gives a clue to this anachronism. In 1960 Kouwenhoven et al.l described closed chest cardiac massage in five cases, four of which were anaesthetic mishaps. They did not describe how they maintained ventilation during cardiac massage. Safar et al. massaged four times and then stopped during ventilation. Is this the paper on which the British base their technique? A later paper by Harris and Safar] suggests continuing cardiac massage without cessation, and interposing ventilation quickly between massages. This is the current American approach$·6 with refinements such as maintaining pressure on the precordium for 50% of cycle time; there must be a distinct pause at maximal compression.’ Work in dogs has shown that there is no problem with oxygenation of blood if ventilation is combined with continuous cardiac

refreshing new

massage.8 With mouth-to-mouth resuscitation it may be worthwhile cardiac massage for a short while to be sure that the chest inflates. One may feel we in the U.K. have been left behind in advances in cardiac resuscitation--or does a very large chest inflation, when cardiac massage has stopped, raise airway pressure levels to those cited by Chandra et al. and so improve blood flow?

stopping

Department of Anæsthetics Frenchay Hospital, Bristol BS16 1LE

WILLIAM SELLERS

WB, Jude JR, Knickerbocker GG. Closed chest cardiac massage. JAMA 1960; 173: 1064-67. Safar P, Brown TC, Holtey WJ, Wilder RJ. Ventilation and circulation with closed-chest cardiac massage in man. JAMA 1961; 176: 674-76.

1. Kouwenhoven 2.

3. Harris LC, Kirimli B, Safar P. Ventilation-cardiac compression rates and ratios in cardiopulmonary resuscitation. Anœsthesiology 1967; 28: 806-12. 4. Standards for cardiopulmonary resuscitation and emergency cardiac care

JAMA 1974; 227: 833-68. 5. Cecil’s textbook of medicine. 15th ed. 1979: 1055-56. 6. Taylor GJ, Tucker WM, Greene HL, Rudikoff MT, Weisfeldt ML. Importance of prolonged compession during cardiopulmonary resuscitation in man. N Engl J Med 1977; 296: 1515-17. 7. Wilder RJ, Weir D, Rush BF, Ravitch MM. Methods of co-ordinating ventilation and closed chest cardiac massage in the dog. Surgery 1963; 53: 186-94.