816

phases of the cycle. We would encourage others who are

unconvinced to register prospectively the day of the cycle on whicheach procedure is performed in order that this important questioncan be answered.

Hedley Atkins Breast Unit,ICRF Clinical Oncology Unit,Guy’s Hospital,London SE1 9RT, UK

R. A. BADWEI. S. FENTIMANZ. SAADA. BENTLEY

M. A. RICHARDSW. GREGORYM. A. CHAUDARYR. D. RUBENS

1. Powles TJ, Ashley SE, North AG, et al. Timing of surgery m breast cancer. Lancet1991; 337: 1603-04.

2. Senie RT, Rosen PP, Rhodes P, et al. Timing of breast cancer excision during themenstrual cycle influences duration of disease-free survival. Ann Intern Med 1991;115: 337-42.

Svane localisation of non-palpable breastlesions

SiR,—Your Aug 10 editorial (p 352) lucidly presents issues raisedby the increasing number of non-palpable breast lesions which haveaccompanied the wide application of screening mammography. Wehave attempted most of the localisation procedures described in theeditorial and agree that all leave something to be desired. However,you do not include what we find to be a highly effective techniquefor locating non-palpable breast cancers for surgical excision. Thisfailure to include a Swedish approach has been a long-standingproblem in British and American medicine. 1

In 1983 Dr Gunilla Svane (director of mammography services atthe Karolinska Institute and Hospital) described the use of carbonto tattoo the lesion under stereoscopic observation.2 We use theSvane technique, which entails a simple installation of carbon,tattooing the lesion in depth. We leave a carbon tract with a smalltattoo at the skin surface, allowing the surgeon to follow the tract andexcise the small area identified at mammography. Lesions as smallas 3 mm have been marked and removed at surgery. The Svanemethod is far more accurate than any hook wire technique, since ituses a three-dimensional calculation. The ability to instill thecarbon and then do the surgery later is advantangeous to radiologistand surgeon. The patient does not have to have a wire placed withinthe breast. The stability of inert carbon in tissue has distinctadvantages over methylene-blue marking, which diffuses throughthe breast substance.We perform carbon installation with stereotaxic fine-needle

aspirations which yield suspicious cells and in lesions that are somammographically characteristic that subsequent surgical biopsywill be necessary. The carbon localisation technique has been usedat the Karolinska Hospital by Svane and her colleagues for over 10years on more than 1000 patients. We have been using this methodfor only a year and have found it far superior to alternativetechniques. Why has the Svane method not been more readilyaccepted? It is accurate, safe, complication-free, and readilyappreciated by patients.

Departments of Radiology,Pathology, and Surgery,

Michigan State University,East Lansing, Michigan 48824, USA

E. JAMES POTCHENARLENE SIERRACHARLES MACKENZIE

JANET OSUCH

1. Fox CH. Innovation in medical diagnosis: the Scandinavian curiosity. Lancet 1979; i.1387-88.

2. Svane G. A stereotaxic technique for preoperative marking of non-palpable breastlesions. Acta Radiol 1983; 24: 145-51.

Treatment of severe postnatal depressionwith oestradiol skin patches

SIR,-Research into the possible hormonal contribution to

psychological symptoms premenstrually and during theclimacteric’ has demonstrated a substantial therapeutic effect ofoestrogens on mood and associated symptoms in both.2-4 Theincreased prevalence of affective disorder in the puerperium,another time of pronounced hormonal change, also raises the

possibility of an association between changes in circulating steroid

Mean change in EPDS score.

Each subject’s EPDS score at one, two, and three months isshown as achange from baseline score.

hormones and depressed mood. Various mechanisms by whichoestrogens may affect neurotransmitter systems have been

proposed,5 and oestrogen withdrawal postpartum has been

suggested to provoke affective psychotic breakdown throughinteraction with central dopaminergic systems.6We are conducting a double-blind, placebo-controlled study of

transdermal oestradiol therapy for severe non-psychotic postnataldepression. Because of the unexpectedly high drop-out rate

independent interim analysis of the data from the first 35 patientswas done.

Subjects were included in the study if onset of depression waswithin twelve weeks postpartum, delivery was within the previous18 months, they were not breastfeeding, and had had no hormonaltreatment since delivery. The use of psychoactive drugs was not anexclusion criterion provided that there had been no change intreatment in the preceding six weeks. Fully informed consent andagreement to use non-hormonal contraception for the duration ofthe study were also obtained. At entry, subjects had to score 14 ormore on the Edinburgh postnatal depression scale (EPDS), and allhad a diagnosis of major depressive disorder according to theresearch diagnostic criteria (RDC) on the basis of a standardisedpsychiatric interview with use of the schedule for affective disordersand schizophrenia8 (SADS).

Patients were randomised to active treatment with transdermaloestradiol patches delivering 200 ug of 17-(3-oestradiol per day, or toidentical placebo patches. Cyclical dydrogesterone 10 mg daily wasadded for twelve days per month after three months’ unopposedoestrogen in the active group, to reduce the risk of endometrial

hyperplasia. Monthly progress measures included the EPDS,SADS (change version), clinical psychiatric and gynaecologicalassessments, and measurement of plasma oestradiol and folliclestimulating hormone. After six months treatment was discontinuedand a vabra curettage was done to exclude endometrial disease.

Monthly follow-up continued for a further three months with thesemeasures.

Of the first 35 patients recruited, 18 in the active group and 7 inthe placebo group remain in the study, the other 10 having droppedout. 7 of the drop-outs were receiving placebo treatment and left thestudy within two months. The remaining 3 were in the active groupand stopped treatment between four and six months. These

drop-out rates differed significantly (p < 0,01, t-test). Initial EPDSscores did not significantly differ between drop-outs and currentpatients. However, postal and telephone follow-up revealeddifferences in subsequent EPDS scores between active and placebodrop-outs. In the placebo drop-outs EPDS scores were persistentlyhigh, and reasons cited for drop-out included social and financialfactors as well as disappointment at subjective failure to improve. Inthe active group, however, the EPDS scores were uniformly low (6,7, and 4) and reasons cited for drop-out included satisfactorysubjective improvement.The two groups showed important differences in response to the

first three months’ treatment (figure). The active group showed astriking improvement in EPDS scores (from 21 to 11) within thefirst month of treatment which was maintained at three months (9).The placebo group showed only a minor improvement over the first

817

three months (23 to 17) which may have partly resulted fromspontaneous resolution of depression.Plasma oestradiol concentrations, although significantly higher in

the active group (p < 0-05), remained well within the physiologicalrange, reaching a mean value of 680 pmol/1 at three months. Thefrequency of adverse effects ( < 5 %) was encouragingly low, with nodifference between active and placebo groups, and so far no patienthas dropped out because of side-effects. Furthermore, no

pathological endometrial changes have been detected at the routinevabra curettage.

In view of these encouraging preliminary results, we aim tocontinue the study, assessing fully the efficacy and safety oftransdermal oestrogen and identifying prognostic variables in suchtreatment.

Menopause Clinic,Dulwich Hospital ANNE F. HENDERSON

Institute of Psychiatry,De Crespigny Park,London SE5

ALAIN J. P. GREGOIRER. CHANNI KUMAR

Menopause Clinic,Dulwich Hospital,London SE22 8PT, UK JOHN W. W. STUDD

1. Studd JWW, Watson NR, Montgomery J. Depression and the menopause. Br Med J1990; 300: 1653.

2. Magos AL, Brincat M, Studd JWW. Treatment of the premenstrual syndrome bysubcutaneous oestradiol implants and cyclical oral norethisterone: placebocontrolled study. Br Med J 1986; 292: 1629-33.

3. Watson NR, Studd JWW, Savvas M. Treatment of severe premenstrual syndromewith oestradiol patches and cyclical oral norethisterone. Lancet 1989; i: 730-32.

4. Montgomery JC, Brincat M, Tapp A, et al. Effect of oestrogen and testosteroneimplants on psychological disorders m the climacteric. Lancet 1987; i. 297-99.

5 Deakin JFW. Relevance of hormone CNS interactions to psychological changes in thepuerperium. In: Kumar R, Brockington IF, eds. Motherhood and mental illness,vol 2. London Wright, 1988: 113-32.

6 Wieck A, Kumar R, Hirst AD, Marks MN, Campbell IC, Checkley SA. Increasedsensitivity of dopamine receptors and recurrence of affective psychosis afterchildbirth. Br Med J (in press).

7. Cox JL, Holden JN, Sagovsky R. Detection of post-natal depression development ofthe ten item Edinburgh post-natal depression scale. Br J Psychiatry 1987; 150:782-86

8. Endicott J, Spitzer RL. A diagnostic interview: the schedule for affective disorders andschizophrenia. Arch Gen Psychiatry 1978; 35: 837-44.

BM-1, a platelet aggregation inhibitor frommackerel

SIR,-A substance composed of protein containing a smallamount of lipid and carbohydrate has isolated and purified from afish (chub mackerel) after treatment with proteolytic enzyme. Thesubstance (BM-1), which is chemically different from

eicosapentaenoic acid (EPA), inhibits platelet aggregation in vitro.The molecular weight of BM-1 is less than 3500 (high-pressureliquid chromatography), and gas-liquid chromatography revealedno EPA. The constituents are:

Water 378%, protein 61 3%. lipid 04%, carbohydrate 0-5%.

Eight healthy males took 6 g BM-1 daily for 30 days. Plateletswere isolated from peripheral blood drawn into acid-citratedextrose (ACD) in a ratio of 1 ’5 ml per 8-5 ml whole blood, andcentrifuged at 120g for 12 min at 22&deg;C to obtain platelet-rich plasma(PRP). To test platelet aggregation we added 0 45 ml PRP and 0 05ml ADP (final concentration 20 olfl) or 0-05 ml collagen (3g/ml). A dual channel aggregometer (Payton) was used and theheight (h) of the aggregation curve at 4 min incubation withaggregating agents, the slope of the aggregation curve (8), and thelag time in aggregation were measured.

Platelet aggregation induced by ADP and collagen was

significantly inhibited by BM-1 (figure).

Effects of BM-1 on ADP and collagen induced aggregation.

Arrows indicate addition of aggregation agents.(A) before taking BM-1.(B) after taking 6 g BM-1 daily for 30 days.

The effects of BM-1 on cytoplasm free calcium were investigatedwith the intracellularly trapped fluorescent indicator ’Fura-2’.Thrombin-induced cytoplasm free calcium was inhibited by BM-1,when BM-1 was removed from the medium the rise in free calciumin platelets was not inhibited.

First Department of Internal Medicine,and Department of Immunology,

Kurume University School of Medicine,Kurume Fukuoka 830, Japan

JUNICHI HONDAMITSUNORI IWAMOTOSHIGEKI SHICHIJOKOTARO OIZUMIMITSUO YOKOYAMA

Screening for cervical cancer by directinspection

SIR,-Dr Sehgal and colleagues (Aug 3, p 282) do not provide ameasure of the false-positive rate. Although 52% of the so-calledcancers were suspected from visual inspection, they have not told uswhat proportion of the normal population have a suspicious-lookingcervix. From everyday clinical experience most gynaecologistswould expect this to be rather high, invalidating direct inspection asa useful test even in parts of the world where a cytological screeningprogramme is not possible.

This is similar to the flaw in the paper you published from Singeret aP and which was later retracted In that study the cutoff valuefor the test was placed 1 SD above the mean, thereby ensuring afalse-positive rate of 32%-a fact which passed without comment.

Royal Postgraduate Medical School,Institute of Obstetrics and Gynaecology,Hammersmith Hospital,London W12 0NN, UK W. P. SOUTTER

1. Singer A, Tay SK, Griffin JF, Wickens DG, Dormandy TL. Diagnosis of cervicalintraepithelial neoplasia by the estimation of octadeca-9-11-dienoic add. Lancet1987; i: 537-39.

2. Fairbank J, Ridgway L, Griffin J, Wickens D, Singer A, Dormandy TL.Octadeca-9-11-dienoic acid in the diagnosis of cervical intraepithelial neoplasia.Lancet 1988; ii: 329-30.

**This letter has been shown to Dr Sehgal and colleagues, whosereply follows.-ED. L.

SIR,-We feel that there are two crucial aspects of any cervicalscreening programme, including one by direct inspection-theprevalence of suspicious-looking cervix (the high-risk category) inthe population and the rate of cancer in that category.With respect to the prevalence of the high-risk category

(described as false-positive by Dr Soutter), the proposed screeningstrategy for cervical cancer is to be undertaken in a symptom-freepopulation to detect cancers at an early stage. Such a population in aprimary health care setting is not likely to have a very highproportion of suspicious-looking cervices, as feared by Soutter. Wehave three data sets to substantiate this point. First, in 44 970women attending maternal and child health (MCH) centres inDelhi only 11 -4% (5135) had suspicious-looking cervices and 63%