817

three months (23 to 17) which may have partly resulted from spontaneous resolution of depression. Plasma oestradiol concentrations, although significantly higher in the active group (p < 0-05), remained well within the physiological range, reaching a mean value of 680 pmol/1 at three months. The frequency of adverse effects ( < 5 %) was encouragingly low, with no difference between active and placebo groups, and so far no patient has dropped out because of side-effects. Furthermore, no pathological endometrial changes have been detected at the routine vabra curettage. In view of these encouraging preliminary results, we aim to continue the study, assessing fully the efficacy and safety of transdermal oestrogen and identifying prognostic variables in such treatment.

Menopause Clinic, Dulwich Hospital

ANNE F. HENDERSON

Institute of Psychiatry, De Crespigny Park, London SE5

ALAIN J. P. GREGOIRE R. 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 J 1990; 300: 1653. 2. Magos AL, Brincat M, Studd JWW. Treatment of the premenstrual syndrome by subcutaneous oestradiol implants and cyclical oral norethisterone: placebo controlled study. Br Med J 1986; 292: 1629-33. 3. Watson NR, Studd JWW, Savvas M. Treatment of severe premenstrual syndrome with oestradiol patches and cyclical oral norethisterone. Lancet 1989; i: 730-32. 4. Montgomery JC, Brincat M, Tapp A, et al. Effect of oestrogen and testosterone implants on psychological disorders m the climacteric. Lancet 1987; i. 297-99. 5 Deakin JFW. Relevance of hormone CNS interactions to psychological changes in the puerperium. 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. Increased sensitivity of dopamine receptors and recurrence of affective psychosis after childbirth. Br Med J (in press). 7. Cox JL, Holden JN, Sagovsky R. Detection of post-natal depression development of the 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 and schizophrenia. Arch Gen Psychiatry 1978; 35: 837-44.

BM-1,

a

platelet aggregation inhibitor from mackerel

SIR,-A substance composed of protein containing a small of lipid and carbohydrate has isolated and purified from a fish (chub mackerel) after treatment with proteolytic enzyme. The substance (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-pressure liquid chromatography), and gas-liquid chromatography revealed amount

no

EPA. The constituents

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.

Effects of BM-1

are:

on

ADP and

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

JUNICHI HONDA First Department of Internal Medicine, and Department of Immunology, Kurume University School of Medicine, Kurume Fukuoka 830, Japan

MITSUNORI IWAMOTO SHIGEKI SHICHIJO KOTARO OIZUMI MITSUO YOKOYAMA

Screening for cervical cancer by direct inspection SIR,-Dr Sehgal and colleagues (Aug 3, p 282) do not provide a of the false-positive rate. Although 52% of the so-called cancers were suspected from visual inspection, they have not told us what proportion of the normal population have a suspicious-looking cervix. From everyday clinical experience most gynaecologists would expect this to be rather high, invalidating direct inspection as a useful test even in parts of the world where a cytological screening programme is not possible. This is similar to the flaw in the paper you published from Singer et aP and which was later retracted In that study the cutoff value for the test was placed 1 SD above the mean, thereby ensuring a false-positive rate of 32%-a fact which passed without comment.

measure

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

W. P. SOUTTER

Water 378%, protein 61 3%. lipid 04%, carbohydrate 0-5%. 1.

Singer A, Tay SK, Griffin JF, Wickens DG, Dormandy TL. Diagnosis of cervical intraepithelial neoplasia by the estimation of octadeca-9-11-dienoic add. Lancet

1987; 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, whose reply follows.-ED. L. SIR,-We feel that there are two crucial aspects of any cervical

Eight healthy males took 6 g BM-1 daily for 30 days. Platelets were isolated from peripheral blood drawn into acid-citrate dextrose (ACD) in a ratio of 1 ’5 ml per 8-5 ml whole blood, and centrifuged at 120g for 12 min at 22°C to obtain platelet-rich plasma (PRP). To test platelet aggregation we added 0 45 ml PRP and 0 05 ml ADP (final concentration 20 olfl) or 0-05 ml collagen (3

g/ml). A dual channel aggregometer (Payton) was used and the height (h) of the aggregation curve at 4 min incubation with aggregating agents, the slope of the aggregation curve (8), and the lag time in aggregation were measured. Platelet aggregation induced by ADP and collagen

significantly inhibited by BM-1(figure).

was

screening programme, including one by direct inspection-the prevalence of suspicious-looking cervix (the high-risk category) in the 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 screening strategy for cervical cancer is to be undertaken in a symptom-free population to detect cancers at an early stage. Such a population in a primary health care setting is not likely to have a very high proportion of suspicious-looking cervices, as feared by Soutter. We have three data sets to substantiate this point. First, in 44 970 women attending maternal and child health (MCH) centres in Delhi only 11 -4% (5135) had suspicious-looking cervices and 63%

818

of cancers were in this group. Second, the Indian Council of Medical Research has funded many studies to test this screening strategy. One such study in a rural population of Tamil Nadu has shown suspicious cervical appearances in about 10% of the

population (Luthra UK, unpublished). Third, a cytology screening camp conducted by us at Gokul Puri Resettlement Colony, Delhi, revealed 59 (9%) suspicious-looking cervices out of 680 examined. Thus, although the prevalence rate of suspicious-looking cervices is about 10% in the normal population, women with symptoms and attending secondary or tertiary levels of health care might have a higher rate. Soutter does not say what is his reference population (primary health care or referred patient population) in which he suspects a higher proportion of suspicious-looking cervices. Indeed the referred patient population is not intended to be screened through direct inspection. Since India has a high cancer rate, its women with suspicious cervical appearances are likely to have a higher proportion of cancer than those in countries such as the UK, with a low cancer rate. Furthermore, this proportion is likely to differ in the cytologically screened versus non-screened population. The Indian population is almost totally unscreened and therefore a higher proportion of women with a suspicious-looking cervix would have cervical cancer. In our experience the rate of malignant disease is 29/1000 in women with suspicious-looking cervices attending MCH clinics, compared with only 1 ’53! 1000 in the same population with normal cervices. In Western countries that have some cytology screening, noncancerous findings are likely to be common since cancerous and precancerous lesions have already been treated. Thus screening through direct inspection is proposed in areas where the prevalence of cervical cancer is very high and the population is unscreened, and cytology screening facilities might not be available for many years. Institute of Cytology and Preventive Maulana Azad Medical College, Bahadur Shah Zafar Marg, New Delhi-110002, India

Oncology,

ASHOK SEHGAL VEENA SINGH USHA K. LUTHRA

Prediction of cervical carcinoma response to

radiotherapy SIR,-Local failure rates after radiotherapy in carcinoma of the cervix vary with tumour stage, ranging from around 5% for stage I to 40% for stage III. They are an important cause of death, and salvage at the time of recurrence is unusual. Prediction of patients with a high probability of recurrence could identify a subpopulation who might benefit from early surgical intervention or adjuvant chemotherapy. There is increasing interest in the possibility of predicting radioresistant tumours by culture of biopsy specimens and evaluation of radiosensitivity to a single dose of radiation in vitro (surviving fraction at 2 Gy, SF2 [number of colonies formed after 2 Gy -’ number of cells seeded at 2 Gy] -7- [number of colonies formed in control - number of cells seeded in control]).1,2 Data for 51 patients with carcinoma of the cervix treated in 1988/89 have been analysed prospectively for intrinsic radiosensitivity. 20, 22, and 9 patients were at tumour stages I, II, and III, respectively. All patients were treated with radical radiotherapy according to the Manchester protocol3 and the minimum treatment follow-up was 2 years. At the time of analysis 32 patients were disease free (including 2 intercurrent deaths), 10 had or had died from local failure (some with metastases), and 9 had or had died with metastatic disease only. Values for SF2 ranged from 0-14 to 0-97. Patients were divided into 2 groups-those with SF2 less than or greater than 055.’ A local control curve (figure) with these two arms showed that patients with radioresistant tumours (SF2 > 0-55) had a significantly lower probability of local control (p< 0-001), when local control curves were plotted for individual stages the difference remained significant. Stage alone was a poorer prognostic factor for local control (stages I, II, and III only; p=0-ll) than radiosensitivity. In all the analyses of local control probability, patients with metastases only were regarded as free of local recurrence at the time of death. Overall 2-year survival =

63%. These findings indicate that intrinsic radiosensitivity may be a useful predictor of local recurrence after radical radiotherapy. was

Tumour control curve for patients whose tumours gave SF2 values less than or greater than 0 55. Patients with metastatic disease were taken as free of local recurrence at the time of death. Reproduced (ref 4) with permission of Academic Press.

However, it should be recognised that the correlation of cell radiosensitivity with tumour control is relevant only to diseases in which radical radiotherapy is the primary (and preferably the only) treatment. Investigation of the predictive potential of radiosensitivity measurements for tumours treated by a combination of surgery and radiotherapyl is underway, and one of tumours treated by a combination of radiotherapy and chemotherapy is planned. It is also noteworthy that radiosensitivity testing will be important only if local recurrence levels are high (there is no indication from the data that SF2 measurements will predict for the likelihood of metastases). Finally, testing should be done by laboratories in which many clinical samples for the same disease(s) are readily available and when assay reproducibility and resolution have been established. Primary tumour specimens should be investigated with good assay quality-control, in patients receiving uniform radiotherapy, and with allowance for sufficient time in all patients for most local recurrences to have occurred. Cancer Research Campaign Department of Experimental Radiation Oncology, Paterson Institute for Cancer Research, and Department of Radiotherapy, Christie Hospital, Manchester M20 9BX, UK

CATHARINE M. L. WEST SUSAN E. DAVIDSON JOLYON H. HENDRY ROBIN D. HUNTER

1. Peters LJ. Inherent radiosensitivity of tumor and normal tissue cells as a predictor of human tumor response. Radiother Oncol 1990; 17: 177-90. 2. Davidson SE, West CML, Roberts SA, Hendry JH, Hunter RD. Radiosensitivity testing of primary cervical carcinoma: evaluation of intra- and inter-tumour heterogeneity. Radiother Oncol 1990; 18: 349-56. 3. Hunter RD. In: Pointon RCS, ed. The radiotherapy of malignant disease. Berlin: Springer Verlag, 1991: 279-308. 4. West CML, Davidson SE, Hunter RD. Surviving fraction at 2 Gy versus control of human cervical carcinoma: update of the Manchester study. In: Fry RJM, ed. Proceedings of the 9th International Congress of Radiation Research (in press).

Trends in cervical

cancer

mortality

SiR,-Beral and Boothl analysed the rates of cervical cancer mortality in England and Wales for 1950-83. On the basis of increasing rates at young ages and on the assumption of a birth cohort effect they predict increasing rates in women aged 35-55 until the end of the century, by which time the overall rate (for all ages) would have increased also. Villard et al2 subsequently examined age-specific mortality rates up to 1987, providing preliminary evidence that the predictions of Beral and Booth might have been too pessimistic. Although the rates did not generally show the predicted increase, there remained some concern over the important age group of women aged between 35 and 39. Furthermore, rates were fluctuating and it was difficult to discern any underlying trends. 1990 mortality data have just become available from the Office of Population Censuses and Surveys. There can now be little doubt