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CURABILITY OF BREAST CANCER

SIR,-In their long-term follow-up of 704 breast-cancerpatients, Dr Brinkley and Dr Haybittle (July 19, p. 95)report that those who survived after twenty years showed adeath-rate no worse than that of a normal population, yet" 8 out of 23 deaths after twenty years were from cancerof the breast". Before accepting this as evidence thatsuch long survivors are more likely to die of breast cancerthan is a normal populatiori-and correspondingly less likelyto die of other causes-it would be of considerable interestto know more about this small group of 8 patients. Howold were they when they died ? Apart from the deathcertificate, how strong is the evidence (a) that they hadactive breast cancer at the time of death and (b) that thisalone was the cause of their death ? Since all 8 died fairlyrecently it perhaps might not be too difficult to obtain thisinformation, should it not already be available.Glasgow Institute of Radiotherapeutics

and Oncology,Glasgow G11 6NT. T. B. BREWIN.

** * This letter has been shown to Dr Brinkley andDr Haybittle, whose reply follows.-ED. L.

SIR,-The answers to Dr Brewin’s inquiries concerningthe eight patients in our series who died from cancer ofthe breast more than 20 years after treatment are as follows.Their ages at death were 63, 64, 64, 68, 73, 82, 83, and 94.In all cases cancer of the breast was listed on the deathcertificate. A close re-examination of their records showsthat in six cases there was strong evidence of active cancerpresent before death, and there was nothing to suggestthat this did not originate from cancer of the breast. Inone case, the 83-year-old, there was no indication ofrecurrence in the follow-up reports, and we now considerit very unlikely that death was due to breast cancer.

Evidence of recurrence before death in the 94-year-old isalso doubtful, but we are still trying in this case to obtainaccess to the case-notes from the geriatric hospital whereshe died.

In conclusion, therefore, we may say that a less pessimisticassessment of the case-histories would still leave at leastsix deaths after 20 years almost certainly due to cancer ofthe breast, a number still greatly in excess of that to beexpected in the normal population.

Physics Department,Addenbrooke’s Hospital,

Hills Road,Cambridge CB2 2QQ.

DIANA BRINKLEY

J. L. HAYBITTLE.

DIAGNOSIS OF DEEP-VEIN THROMBOSIS

SIR,-Dr Ludlam and his colleagues (Aug. 9, p. 259)report an increase of a

" p-thromboglobulin " in the plasma

of patients with acute deep-vein thrombosis (D.V.T.). Thistest takes 2 h and is specific for this particular proteinliberated from platelets. They very properly point outthat platelet activation by any of many other processes mayalso lead to the release of this globulin, and of courseplatelet factor 4 would also be released.We also have a test which can assist in the diagnosis of

acute D.v.T., and it takes only 5 min. It is a heparin/thrombin clotting-time of platelet-poor plasma and,provided that the patient’s thrombin clotting-time isnormal, this test measures the heparin-neutralising activity(H.N.A.) of the patient’s plasma.1 The test is non-specificbut it is influenced by factor 4 liberated from platelets andwe believe 2 that in these kinds of patients it may measure

1. O’Brien, J. R., Etherington, M., Jamieson, S., Lawford, P.,Sussex, J., Lincoln, S. V. J. clin. Path. (in the press).

2. O’Brien, J. R., Etherington, M., Jamieson, S., Lawford, P. Lancet,1974, ii, 656.

Heparin neutralising activity (i.e., heparin/thrombin clotting-time) in seconds in:

(1) patients with acute myocardialinfarction; (2) patients withchest pain proved not to have an infarct; (3) patients 3 monthsto 5 years after an infarct (post M.I.), and (4) controls closelymatched for age, smoking, occupation, &c. The means and twoS.D. are indicated.

factor 4 released into the plasma from " activated"platelets.

This test has been shown to be abnormal, with anexcess of H.N.A., in acute D.v.T.3 and in acute myocardialinfarction (M.l.). With Dr Ludlam’s test there was no

overlap between the controls and 7 patients with acuteD.v.T. We found almost no overlap in the first 55 patientswith acute M.I. when they were compared with controlsand with 32 other patients admitted with chest pain andsubsequently shown not to have M.I.; so our test mayprove useful clinically in these conditions. Abnormalitieswere also found, but to a lesser extent, in patients withgross atherosclerosis and in patients long after myocardialinfarction (figure).4,5 Thus perhaps it can reflect a chronic" hypercoagulable " or thrombosis-prone state as well asacute thrombotic involvement and diffuse intravascularcoagulation. eDr Ludlam’s test certainly, and ours probably, reflects

platelet involvement in acute thrombotic episodes, andeach measures different molecules which are, however,probably released in parallel. It is now most importantto find out in what other conditions these abnormalitiesoccur, how long they persist-their respective half-lives-and also which test, or modified test, will ultimately prove

3. Green, P. J. ibid. 1975, i, 799.4. O’Brien, J. R., Etherington, M., Jamieson, S., Lawford, P.,

Lincoln, S. V., Alkjaersig, N. J. Thromb. Diath. hœmorrh. (in thepress).

5. O’Brien, J. R. ibid. 1974, 32, 116.6. Fuster, V., Bowie, E. J., Kazmier, F. J., Owen, C. A. Thromb. Res.

1974, 4, 247.

458

most useful to the clinicians in acute and also in chronicthrombotic conditions and perhaps in atherosclerosis.

Portsmouth and South-EastHampshire District Pathology

Service,St. Mary’s Hospital,

Portsmouth PO3 6AG, Hampshire. J. R. O’BRIEN.

LOW-DOSE HEPARIN

SIR,-It was with great interest and expectation that Iread the article on low-dose heparin prophylaxis in post-operative patients (July 12, p. 45). Although a number ofpublications concerning the efficacy of such a regimen hadappeared previously, it had become apparent that a largemulticentre trial was necessary to show effectiveness in

reducing massive fatal pulmonary embolism. Such a

demonstration was evident in the trial results: 16 deathsdue to massive pulmonary embolism occurred in thecontrol group while only 2 occurred in the prophylaxisgroup. If all. emboli were considered, 22 pulmonaryemboli occurred in the control group contrasted with5 in the heparin group (a four-fold reduction).Although many of us working in this area became

convinced of the efficacy of this regimen on the basis of anumber of smaller series reports, a definitive trial was

necessary to overcome the inertia of non-prophylaxis,built up over many years. Now the definitive trial iscompleted and the data speak for themselves: low-doseheparin prophylaxis reduces death from massive pulmonaryembolism in postoperative patients.

It seemed to me most inappropriate and unfortunatethat your editorial discussing this trial (July 12, p. 63) wasnot commensurate to the task. It was clearly superficial,indifferent, and lacking in insight as to the clinical importof these results. In contrast, Professor Sherry 1 clearly andobjectively analysed the data from the vantagepoint of ascientist-clinician, expert in the field. He states... " Thus,the final link in establishing the validity of low-doseheparin prophylaxis for postoperative venous thrombo-embolism for those at high risk after general abdomino-thoracic surgical procedures has been provided. Its usenow on a large scale should be encouraged "...How unfortunate that Professor Sherry’s penetrating

analysis appeared in the New Englandlournal of Medicine,instead of in The Lancet!

Departments of Medicine,West Roxbury VeteransAdministration and

Peter Bent Brigham Hospitals;Harvard Medical School,

Boston, Massachusetts, U.S.A. ARTHUR A. SASAHARA.

* * * Yes, on existing evidence low-dose heparin isthe best means of preventing pulmonary embolism afterabdominothoracic operations. Now we need to identifythe groups in which other prophylactic measures are moreuseful than heparin. The latest disappointment is thatlow-dose heparin adds nothing to the effect of intermittentcalf compression.2-ED. L.

INFUSION THROMBOPHLEBITIS

SIR,-Mr Irvin (Aug. 16, p. 326) draws attention to oneof the major difficulties of any clinical study of infusionthrombophlebitis and bacterial contamination-namely,the large number of potential xtiological factors. Thereare many more variables than the type and pH of theinfusate which he mentions, and these can be consideredunder three headings: .

1. Sherry, S. New Engl. J. Med. 1975, 293, 300.2. Roberts, V. C., Cotton, L. T. Br. med. J. 1975, iii, 458.

Bacterial contamination may vary with the presence or absenceof an airway, the time taken to infuse the fluid after the containeris punctured, the addition of drugs to the infusate, the frequencyof changing the giving set, the use of a septic technique for cannulainsertion, skin sterilisation, and the use of topical antibiotics.

Chemical factors involving the infusate are its pH, osmolarity,and chemical composition. The fluid may be contaminated withthe plasticiser of polyvinyl-chloride containers or from therubber bung of glass bottles, and this contamination may increasewith the duration of container storage. In addition there is thechemical composition of the cannula itself to be considered.

Mechanical factors are the least amenable to analysis, for,besides the site of infusion and cannula size, there are the ever-changing rate of infusion, the amount of movement transmittedto the cannula, the varying calibre of the vein, the blood-flowpast the cannula, and the occurrence of venous stasis.

The impossibility of simultaneously analysing all thesevariables in any clinical study means that random allocationof patients is the only practical method of studying therelative importance of any of the variables in isolation.With regard to Mr Irvin’s specific criticism of our study

(July 26, p. 150)-that a higher proportion of patientsgiven the long Teflon’ cannulas had infusions of greaterthan 72 h duration-we would point out that our objectionto these cannulas is based on a significantly higher incidenceof thrombophlebitis at less than 36 h and significantlygreater incidence of bacterial contamination of the cannulasin infusions of less than 48 h duration. Our main message,however, is that the duration of the infusion is the factorof overriding importance in the production of thrombo-phlebitis, and in infusions lasting more than 72 h theincidence of thrombophlebitis is so high that any differencesdue to other factors cease to be apparent.Department of Surgery,Royal Victoria Infirmary,Newcastle upon Tyne,

NEI 4LP.

JACK COLLINCHRISTINE COLLIN.

SCHIZOPHRENIA

SiR,—I am afraid that Mrs Hemmings (Aug. 9, p. 276)allowed her enthusiasm for the biochemical aetiology ofschizophrenia to run away with her when she dismissedthe excellent study by Hirsch and Leff 1 as useless. Where

only about 60% of monozygotic pairs are concordant forschizophrenia, there are 40% who avoid illness throughthe effects of the environment. There is also ampleevidence from such studies as that by Birley and Brown 2that environmental factors cannot be ignored. It isobviously relevant and valuable to study the environmentalfactors which modify the expression of a schizophrenicgenotype, especially since individuals who carry the genebut do not develop the illness seem to be unusually creative. 3

Department of Psychiatry,St. George’s Hospital Medical

School,Clare House,

Blackshaw Road,London SW17. JOHN M. KELLETT.

SiR,—Your review (Aug. 2, p. 213) of the scientificcredibility of the theory that lays down the blame for thedevelopment of schizophrenia at the doorstep of the familyof the schizophrenic is indeed welcome. However, youfailed to offer an alternative explanation for those findingsof deviant communications and conceptual styles in thefirst-degree relatives of schizophrenic probands. These

1. Hirsch, S. R., Leff, J. P. Abnormalities in Parents of Schizophrenics.London, 1975.

2. Birley, J. L. T., Brown, G. W. Br. J. Psychiat. 1970, 116, 327.3. Heston, L. L. in The Schizophrenic Syndrome (edited by R.

Cancro); p. 535. New York, 1971.