107

the patient had pains in his knee and ankle joints, abdominaldiscomfort, and a rash over both feet. He was pyrexial (37-5°C) andhad a maculopapular vasculitic rash, confined to his shins, ankles,and the dorsum of both feet. Urinalysis revealed haematuria andproteinuria +; the red blood cells were confirmed on urine

microscopy.Blood and urine cultures were negative. Plasma urea, electrolytes

and creatinine were unchanged. Autoantibodies, rheumatoid factor,and anti-neutrophil cytoplasmic antibodies were negative.Immunoglobulins and complement were normal. Skin biopsyrevealed a leucocytoclastic vasculitis with deposition of IgA andcomplement (C3) within dermal capillary walls.

Urinalysis returned to normal by day 12. The patient wasdischarged on day 13 with the rash resolving but with persistingarthralgia.These results are consistent with Henoch-Schonlein-like

vasculitis triggered by APSAC. Such a vasculitis can lead to seriousrenal and systemic damage. We recommend urinalysis as part of thelate follow-up of patients on fibrinolytic therapy during themanagement of myocardial infarction. This should apply to thenewer agents, such as APSAC, as well as to SK.

Duchess of Cornwall Renal Unit,Truro, Cornwall TR1 3LJ, UK

A. ALI

J. N. BARNESA. J. W. DAVISONE. H. MOSTAFIDY. SIVATHONDAN

False alarms of breast cancer

SIR,-Dr Devitt’s article (Nov 25,-p 1257) raises several issues.While questioning the real cost of searching for breast carcinoma, heassesses the morbidity associated with false alarms and suggestsmethods of decreasing morbidity.We believe Devitt’s data suggest that the analysis of a personal

series may well reflect local attitudes rather than generally acceptedprinciples. Devitt says that "87% (2532/2923) of signs/symptoms ofbreast cancer were false alarms". We ask, what are the signs andsymptoms of breast cancer? In our experience, most patients havesigns and symptoms of non-specific breast disease, and with propercommunication should not experience the same anguish as thosewith breast cancer. Delay in referral and definitive managementmay cause unnecessary anxiety. At our unit, where about 1200 newpatients are seen annually, urgent referrals can be seen within 4days. Fine-needle aspiration cytology (omitted in Devitt’s

investigation) and conventional mammography are available at 72 h,and a definitive diagnosis can be made one week after the initialpractitioner visit. In the absence of cytological confirmation webelieve that the patient should be "told that she may have breastcancer" only when there is very firm clinical evidence of cancer.Devitt does not mention biopsy specimen compression and imageenhancement, which enable early confirmation that areas ofabnormal density without microcalcification have been excised.We feel that self-examination of the breast should be encouraged

from an early age in women at risk. Routine physical examinationbefore the age of 45 is not standard practice in the UK, and breastcancer in this age group is therefore often discovered by the patient.Many women do not comply with breast self-examination,’ andearly cancers will therefore be missed. Women aged 45 or less whovisit their general practitioner for other reasons could have theirbreasts examined routinely. Of the last 100 non-screen detectedcancers at our unit 19 were seen in women aged under 45, and all but2 were classified as over Tia. 89 % of these cancers would have beenpalpable.We think Devitt is incorrect to discourage routine

mammography before the age of 60. Studies in North America andSweden have clearly demonstrated reduced mortality in the over 50age groUpS.2,3 Whether early detection and screening are

worthwhile needs to be established. Various groups have concludedthat a properly organised service that uses mammography reducesdeaths in women aged 50-64 years.4.5

Benefit from mammographic screening for women under 50years is unclear. Data from the Health Insurance Plan study6

showed mortality reductions of 31 % for women aged 40-44 yearsand 14% for women aged 45-49, but since few women were seenlate in follow-up, a substantial mortality reduction was not proven.Devitt’s 44% frequency of screen detected cancers and similarTNM pathological staging between accidental andmammographically detected cancers contrasts with the findings ofothers.7 In addition, mammography has become more sensitive andsafe. Reports have shown 55 cancers per 1000 women screened,’66 per 1000 (UK breast screening programme, unpublished), and2 73 per 1000.

Perhaps Devitt’s principal message in the need for improvementin public attitudes towards breast cancer, while educating personneltowards greater awareness of the associated potential morbidity.Despite the UK Government’s recognition of the need forcounsellors and correct information and advice, most patients withdiagnosed breast cancer do not yet have this help preoperatively on aproperly funded basis.

Academic Department of Surgery,Royal Free Hospital and Medical School,London NW3 2QG

D. J. HEHIRS. P. PARBHOO

1. UK Breast Cancer Group: trial of early-detection of breast cancer. Br J Cancer 1981;44: 618.

2. Shapiro S. The status of breast cancer screening: a quarter of a century of research.World J Surg 1989; 13: 9-18.

3. Tabar L, Fagerberg CJG, Gad A. Reduction in mortality from breast cancer after massscreening with mammography. Lancet 1985; i: 830-32.

4. Netherlands Ministry of Welfare, Health and Cultural Affairs, Health and SafetyDirectorate of the Commission of the European Community. Report of aninternational workshop on health policy in relation to mass screening for breastcancer by mammography. Meeting, Noordwijk, Netherlands, December, 1986.

5. Working group report to the Health Ministers of England, Wales, Scotland andNorthern Ireland. Breast cancer screening. London: HM Stationery Office, 1987.

6. Habbema J, et al. Age specific reduction in breast cancer mortality by screening: ananalysis of the results of the Health Insurance Plan of Greater New York study. JNatl Cancer Inst 1986; 77: 317.

7. Baker LH. Breast cancer detection demonstration projects’ five year summary report.Cancer 1982; 32: 194-225.

Long-term blood glucose control anddiabetic retinopathy

SiR,—Dr McCance and colleagues (Oct 7, p 824) conclude thatHbAl measurement over time, besides being a good indicator oflong-term plasma glucose concentration, can predict either

development or progression of retinopathy in insulin-dependentdiabetic subjects. However, a link between metabolic control andvascular complications seems to be an oversimplified conclusionwith respect to McCance and colleagues’ table vn. Indeed, from themultiple regression analysis in that table (left without comment), itis apparent that not only HbAl but also age and sex, among otherfactors, have significant weight in the determination of diabeticretinopathy. No information is presented on the sex ratio in thediabetic group, although it is claimed that this variable plays animportant part in both the pathogenesis of diabetes and thedevelopment of its complications.’ 1 HbAl has proved to differbetween diabetic female and male subjects despite similar plasmaglucose concentrations, thus suggesting a role for gender inmetabolic contro!.2 From McCance and colleagues’ table vu it alsoseems that age is negatively related to retinopathy; patients withretinopathy were significantly older than those without retinopathy.Retinopathy cannot be completely explained by the level ofmetabolic control since the highest frequency of backgroundretinopathy in cohort III (13-18 years of diabetes) is associated witha mean HbA, value much the same as or lower than that of cohortsII and I (7-12 years and 1-6 years of diabetes, respectively).Moreover, subjects without retinopathy show similar mean HbAlvalues, independently of age and duration of disease, suggestingother factors are implicated in the determination of retinopathy or inprotection from its progression. The severity of retinopathy is

presented as causally linked to an increased HbA1 mean value,without any mention of the possible affect of other variables.New findings on the glucose transporter indicate that the

glycosylation process is dependent not only on plasma glucoseconcentration but also on the presence of either external stimuli3.4 or

108

intrinsic membrane abnormalities which, directly or indirectly(through lipid bilayer modification), affect the expression andfunctioning of the glucose transporter as well as of other intrinsicplasma membrane proteins.5 Thus, it is not surprising that anincrease in HbA1 has been shown in various pathological conditionsunrelated to increased plasma glucose concentrations6,7 and that arelation between HbA1 and membrane red blood cell (Na-/ /K’)ATPase activity has also been seen in diabetic patients.8 Sincesex-related differences have also been reported in membraneenzyme activities of red blood cells of normal subjects,9 it is likelythat differences in glucose transport activity in diabetic patientsresult from genetically linked differences in membrane structure. Inaddition to the increased growth-stimulating property of diabeticplasma,lO this may account for the accelerated rate of vascularproliferation seen in insulin-dependent diabetes.

Department of Pharmacology,University of Padua, Padua, Italy,and Institute of Internal Medicine,

University of Padua

P. FINOTTIA. PICCOLI

1. Editorial. Sex and juvenile diabetes. Br Med J 1977; 1: 594-95.2. Stickland MH, Paton RC, Wales J. Haemoglobin A1c concentration in men and women

with diabetes. Br Med J 1984; 289: 733.3. Kitagawa T, Tanaa M, Akamatsu Y. Regulation of glucose transporter mRNA by

serum, growth factor and phorbol ester in quiescent mouse fibroblasts. BiochimBiophys Acta 1989; 980: 100-08.

4. Fujii H, Miwa I, Okuda J, Tamura A, Fujii T. Glucose transport into humanerythrocytes treated with phospholipase A2 or C. Biochim Biophys Acta 1986; 883:77-82.

5. Carruthers A, Melchior DL. Effects of lipid environment on membrane transport: thehuman erythrocyte sugar transport protein/lipid bilayer system. Ann Rev Physiol1988; 50: 257-71.

6. Wettres S, Arnqvist H, Von Scenck H. Abnormal concentration of stable HbA1 innon-diabetic patients. Diab Metab 1984; 10: 299-303.

7. Fournier AM, Gadia MT, Kubrusly DB, Skyler JS, Sosenko JM. Blood pressure,insulin and glycaemia in non-diabetic subjects. Am J Med 1986; 80: 861-84.

8. Finotri P, Palatini P. Reduction of eruthrocyte (Na+-K+)ATPase activity in type I(insulin-dependent) diabetic subjects and its activation by homologous plasma.Diobetologia 1986; 29: 623-29.

9. Finotti P, Verbaro R. Sex differences in erythrocyte membrane ATPase activitiesevidenced by exposing the cells to different hemolytic solutions. Meth Find ExpClin Pharmacol 1989; 11: 263-67.

10. Petty RG, Pearson JD, Morgan DML, Mahler RF. Stimulation of endothelial cellgrowth by sera from diabetic patients with retinopathy. Lancet 1988; i: 208-11.

Deaths of heroin addicts starting on amethadone maintenance programme

SiR,—The main function of our institute is the investigation ofsudden and unexpected deaths in the State of Victoria. We haveestablished that a substantial number of heroin addicts die within afew days of starting a methadone maintenance programme. Wedescribe here our investigations of these deaths.

10 cadavers (3 female, 7 male), aged 18 to 36 at death, who wereknown to have been heroin addicts and on methadone maintenance,were received at the institute in the five months to November, 1989.In 5 cases examination by forensic pathologists revealed no

life-threatening anatomical abnormalities. In the other 5

bronchopneumonia of varying severity was present. In all casesthere was evidence of chronic persistent hepatitis. Methadone wasdetected in all cadavers (mean concentration in blood 0-71 mg/1,range 0-30-2-52). The concentrations are within the range reportedfor deaths attributed to methadone use.l Other drugs were detectedin 6 cadavers: benzodiazepines in 3, morphine in 3, alcohol in 2, andpropoxyphene in 1. In 4 subjects the presence of additional drugspossibly contributed to their death-these were the morphine-positive subjects and 1 whose blood alcohol was 0 13 g/dl.Methadone had been begun in all 10 subjects between 2 and 6

days before death. The mean prescribed dose at the time of deathwas about 60 mg. Others have advised caution about starting dosesgreater than 30 mg.2,3 We have no evidence that the subjectsreceived any additional methadone from other sources. Methadoneis prescribed only on a daily basis, and the patient usually takes thedrug in the presence of the dispensing pharmacist. There are about900 heroin addicts on the methadone programme in Victoria.We are not aware of other reports of deaths attributed to

methadone occurring in association with the start of methadone

treatment. Although the presence of chronic persistent hepatitis inintravenous drug addicts is unremarkable, liver disease can reducethe clearance of methadone.4 Therefore these subjects could havehad a reduced clearance allowing methadone to reach higher thanexpected blood concentrations. We recommend that considerationbe given not only to the screening of subjects for entry into amethadone maintenance programme (including testing of liverfunction and urine testing for the presence of drugs) but also to theuse of lower starting doses. We recognise the difficulties inherent inmethadone maintenance programmes, but these steps may decreasethe likelihood of such deaths.

Victorian Institute of Forensic Pathology,South Melbourne,Victoria 3205, Australia

OLAF H. DRUMMERMARIE SYRJANENKENNETH OPESKINSTEPHEN CORDNER

1. Segal RJ, Catherman RL. Methadone: a cause of death. J Forensic Sci 1974; 19: 64-74.2. Milner G. Methadone. Med J Aust 1976, 2: 551-53.3. Gardner R. Methadone misuse and death by overdosage. Br J Addict 1970; 65:

113-18.4. Sawe J. High-dose morphine and methadone in cancer patients: clinical

pharmacokinetic considerations of oral treatment. Clin Pharmacokin 1986; 11:87-106.

Urokinase plasminogen activator andprognosis in breast cancer

SIR,-Evidence from animal tumours suggests that proteolyticenzymes are implicated in cancer invasion and metastasis.l,2 One ofthese proteases is the urokinase form of plasminogen activator(UK-PA). Dr Janicke and colleagues (Oct 28, p 1049) show thatUK-PA antigen values are significantly higher in breast carcinomasthan in benign tumours and that these high levels correlate

significantly with early disease recurrence. With an enzyme activityassay, we have reported similar findings for UK-PA-ie, breastcarcinomas had significantly higher UK-PA activity than hadbenign samples3 and, furthermore, that patients with high levels ofUK-PA had a shorter disease-free interval than patients with lowlevels.4 We now report further findings of UK-PA activity withrespect to overall patient survival.

After a median follow-up of 35 months, patients with highUK-PA activity (over 0-5 IU per mg protein) had a significantlygreater risk of early death than those with low levels (univariateanalysis with proportional hazards general linear model procedure:relative risk 3-92, 95% confidence intervals [CI] 1-45-10-2,p=0-0056, n=119). In multivariate analysis, UK-PA as a

prognostic factor was independent of tumour size, axillary nodestatus, and oestrogen receptor status (relative risk 27-1, 95% CI1 -13-648, p=0041).We conlude therefore that UK-PA, whether assayed by

immunoassay or catalytic assay, is a new prognostic marker in breastcancer. Another protease, cathepsin D has also been reported to besuch a marker in breast cancer .5,6 We suggest that other proteasesimplicated in cancer spread should also be investigated as

prognostic markers in breast cancers. Indeed, certain proteasesmight be prognostic markers for solid tumours in general.

Departments of Nuclear Medicineand Medical Oncology,and Education and Research Centre,

St Vincent’s Hospital,Dublin 4, Ireland;St Luke’s Hospital, Dublin;

and Department of Surgery,University College, Dublin

MICHAEL J. DUFFYDAVID REILLYCATHRIONA O’SULLIVANNIALL O’HIGGINSJAMES J. FENNELLY

1. Duffy MJ. Do proteases play a role m cancer invasion and metastasis? Eur J CancerClin Oncol 1987; 23: 583-89.

2. Zucker S. A critical appraisal of the role of proteolytic enzymes in cancer invasionemphasis on tumor surface proteinases. Cancer Invest 1988; 6: 219-31.

3. O’Grady P, Lijnen HR, Duffy MJ. Multiple forms of plasminogen activator in humanbreast tumours. Cancer Res 1985; 45: 6216-18.

4. Duffy MJ, O’Grady P, Devaney D, O’Siorain L, Fennelly JJ, Lijnen HJ.Urokinase-plasmmogen activator, a marker for aggressive breast carcinomasCancer 1988; 62: 531-33.

5. Thorpe SM, Rochefort H, Garcia M, et al. Association between high concentrations of 52% cathepsin D and poor prognosis in primary breast cancer. Cancer Res 1989; 49:6008-14.

6. Spyratos F, Maudelonde T, Brouilett J-P, et al. Cathepsin D: an independentprognostic factor for metastasis of breast cancer. Lancet 1989; ii: 1115-18.