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ORAL CONTRACEPTIVES AND BREAST CANCER

SiR,—By the courtesy of the editors of The Lancet and the BritishMedical Journal, and with the agreement of the authors concerned, Ihave been able to study the publications by Dr Paul and colleagues,of New Zealand, in this week’s BMJ and by Dr Meirik andco-workers in today’s Lancet (p 650).

It is clear that both of these studies have been well conducted andthat concern might be felt regarding their conflicting results. Bothstudies come from countries with a high rate of oral contraceptiveuse; both add to the already considerable body of knowledgeregarding the possible effect of oral contraceptive use on the risk ofbreast cancer. Neither study can yet draw that body of knowledge toan acceptable conclusion because there are important aspects of theproblem, such as the effects of very long latency periods, whichmust remain under continued study.Of the new studies, that by Meirik and his group in Sweden and

Norway included 422 patients with cancer of the breast and 722age-matched controls. No statistically significant association wasfound between the use of oral contraceptives for 7 completed yearsor less and premenopausal breast cancer. However, the study didsuggest a possible risk from very-long-term use of oral

contraceptives, and the relative risk of breast cancer after 12 or moreyears of oral contraceptive use was found to be 2-2 (95 % confidenceinterval 1-2-4-0).The study of Paul and colleagues in New Zealand included 433

patients with breast cancer and 897 controls. It produced somewhatdifferent findings and Paul et al conclude that their study providesstrong evidence against the hypothesis that the use of oral

contraceptives at young ages increases the risk of breast cancer.Even so, there was some suggestion of increased risk in youngwomen with prolonged oral contraceptive use, exceeding 10 years.Both of these studies need to be viewed against the background of

the very much larger Cancer and Steroid Hormone (CASH) studyof the US Centers for Disease Control, the latest on this being in theNew England Journal of Medicine (Aug 14, p 405). This massivestudy, involving 4711 women with newly diagnosed breast cancerunder age 55 and 4676 controls, showed that the duration of oralcontraceptive use did not influence the risk of breast cancer. In fact,the relative risk of breast cancer in women who had used oral

contraceptives for 15 or more years was 0-6, significantly less than1 -0. Thus, this study, the largest available to date and roughly tentimes larger than either of the newly reported studies, suggests thatoral contraceptives, even when used for very long periods, do notincrease the risk of breast cancer.These several studies will very shortly be carefully reviewed by

the Committee on Safety of Medicines, whose views will be madeknown. In the interim, it seems appropriate to suggest that thepresently available information should not lead to any alteration ofcurrent practice regarding the use of oral contraceptives.Committee on Safety of Medicines,Market Towers,1 Nine Elms Lane,London SW8 5NQ

ABRAHAM GOLDBERG,Chairman

**A further editorial on this controversy appears on p 665-ED L.

CATHETER FRACTURES IN IMPLANTABLEVASCULAR ACCESS SYSTEMS

SIR,-Dr Martin and colleagues (Aug 2, p 293) report a catheterfracture in a totally implantable ’Port-A-Cath’ vascular accesssystem 8 months after implantation in an 8-year-old child withcystic fibrosis. While this is a most distressing incident, it should beput into perspective. Catheter fracture with possible embolisation isa well-recognised complication of all long-term indwelling cathetersystems. 1,2 Techniques to retrieve the embolised catheter fragmentsare also well reported.3 3

Several mechanisms for catheter fracture have been postulated.Aitken and Minton4 state that catheters placed by the percutaneoussubclavian method may be compressed or "pinched off" as theypass through the areolar tissue in the narrow space between theclavicle and the first rib. It has been estimated that 1 % of catheters

placed by this technique result in fracture.2 To reduce the risk ofmechanical shearing at the costo-clavicular angle if percutaneous

subclavian placement is done, it is recommended4 that needlepuncture be made no more medially than the midclavicular point.

Catheter fracture may also result from overenthusiastic flushingof a blocked catheter. Excessive pressures can easily be generated bysmall-volume syringes, resulting in catheter ballooning and

rupture. This appears to be the possible cause in the case reportedby Martin et al.

Implantable access systems are steadily gaining acceptance as analternative to percutaneous catheters for long-term central venousaccess. Patients prefer them cosmetically and the incidence ofinfection may be reduced.5 However, as with all implantabledevices, the systems are not entirely complication-free.Medical Department,Hospital Products Division,Pharmacia Inc,Piscataway, New Jersey 08854, USA GRAHAM S. MAY

1. Richardson JD, Grover FL, Trinkle JK. Intravenous catheter emboli. Experiencewith twenty cases and collective review. Am J Surg 1974; 128: 722-27.

2. Rubenstein RB, Alberty RE, Michels LG, Pederson RW, Rosenthal D. Hickmancatheter separation. J Parent Ent Nutr 1985; 9: 754-57.

3. Fisher RG, Ferreyro R. Evaluation of current techniques for non-surgical removal ofintravascular iatrogenic foreign bodies. Am J Roentgenol 1978; 130: 548.

4. Aitken DA, Minton JP. The "pinch-off sign". A warning of impending problems withpermanent subclavian catheters. Am J Surg 1984; 148: 633-36.

5. Champault G. Catheters totalement implantables pour chimiothérapie anticancéreuse:Expérience française de 325 cas. J Chir (Paris) 1985; 122: 269-72.

CYCLOSPORIN AND IDIOPATHIC NEPHROTICSYNDROME

SIR,-Dr Hoyer and colleagues (Aug 9, p 335) report experiencewith cyclosporin treatment in children with idiopathic nephroticsyndrome (INS). Over the past 18 months we have treated 13 casesof INS in adults with cyclosporin, after failure of steroids. Ourresults confirm and complement those of Hoyer et al in children andof Meyrier et al in adults. In INS with minimal change disease(MCD) or with focal segmental glomerulosclerosis (FSGS) steroidtherapy is not always effective. Some patients are steroid dependent;some are or become steroid-resistant, mainly in the FSGS group,with risks of progression to renal failure. Prolonged high-dosesteroid therapy may be complicated by infection, metabolic

disorders, and thromboembolism. Alkylating agents are sometimesefficient (mainly in the steroid-dependent group), but may involvesevere haematological disorders or gonadal effects, and carry therisk of cancer. Disturbances of T-lymphocyte function in INS withexcess production of lymphokines2,3 prompted trials with

cyclosporin, a drug that acts selectively on Th cells, inhibitinginterleukin-2 production.4 The following protocol was established(with Sandoz) for this pilot study. Prednisone was continued at 10mg daily. The starting dosage of cyclosporin was 3 mg/kg daily asone morning dose; it was increased to 5 mg/kg on the basis of plasmalevels, measured once a week, 24 h after a cyclosporin dose. Theplanned duration of the first treatment was 3 months. In case ofrelapses, cyclosporin was reintroduced at the same dosage.The 13 adults had had INS for 2-20 years. 10 were steroid

resistant (7 MCD, 3 FSGS) and 3 were steroid dependent (allMCD) with a high threshold of steroid efficacy. Initial 24 h

proteinuria was consistently over 6 g, with normal renal functionand blood pressure. Proteinuria decreased in 3-6 weeks:

proteinuria disappeared (complete remission) in 7 cases, all withMCD (3 steroid dependent) and fell below 3 g in 24 h in 5 steroid-resistant cases (2 MCD, 3 FSGS), with a return to normal serumalbumin levels in all 12. In 1 steroid-resistant MCD case, no changein proteinuria was observed; this patient had unusual laboratorydata (a poor selectivity index [28%], presence of urinary fibrinogendegradation products, and low creatinine clearance [55 ml/min]).The other 12 cases relapsed 2-6 weeks after the end of treatment,proteinuria rising rapidly to pretreatment levels. Cyclosporin at 5mg/kg daily was followed by disappearance of proteinuria in 6 of the7 previous cases of complete remission, and by a reduction to below3 g in 24 h in 6 cases, with the same time interval as for the first cure.Cyclosporin treatment was continued for a total duration of 12months.

In these 13 cases of INS with no tendency to spontaneousregression, cyclosporin demonstrated in 12 patients a favourable

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influence on the course of the disease. These results were achievedwith low cyclosporin plasma levels (25 -130 ng/ml) with no sign ofnephrotoxicity or hepatotoxicity; moderate hypertrichosis wasobserved 3 times and moderate gingival hyperplasia with

gingivorrhagia 5 times.We do not yet know for how long this treatment must be

continued or the criteria for reducing the dosage or stoppingcyclosporin, or what happens after cyclosporin is withdrawn.

Department of Nephrology,Hôpital Henri Mondor,94010 Créteil, France

C. LAGRUE

J. LAURENTD. BELGHITIR. ROBEVA

1. Meyrier A, Simon P, Perret G, Gondamin-Meyrier MC. Remission of idiopathicnephrotic syndrome after treatment with cyclosporin A. Br Med J 1986; 292:789-92

2. Lagrue G, Xheneumont S, Branellec A, et al. A vascular permeability factor elaboratedfrom lymphocytes: Demonstration in patients with nephrotic syndrome. Biol Med1975, 23: 37-40.

3. Lagrue G, Laurent J, Belghit D. Immunopathologie de la nephrose lipoidique.Nephrologie 1982; 3: 40-45.

4 Borel J, Lafferty K. Ciclosporin: Speculation about its mechanism of action.

Transplant Proc 1983; 15: 1881-85.

IS CHRONIC RENAL TRANSPLANT REJECTION ANON-IMMUNOLOGICAL PHENOMENON?

SiR,—Dr Feehally and co-workers (Aug 30, p 486) concludefrom their study of five renal transplant recipients that non-immune mechanisms are dominant in chronic transplant failure.After an immunological injury hyperfiltration through remnantnephrons may be responsible for the predictable decline in

transplant function. In our study1 of six patients with impairedrenal transplant function due to chronic rejection underconventional immunosuppressive treatment we found in five aconstant rate of loss of transplant function, assessed by a linearrelation between log serum creatinine and time. When azathioprinewas stopped there was no break in the slope of the curve in thesepatients. Thus at a time when azathioprine had been withdrawn andduring the course of chronic progressive transplant renal

insufficiency, immunological mechanisms did not seem to play amajor part in the mathematically predictable loss of transplantfailure. Our findings fit in well with Feehally and colleagues’hypothesis that in chronic graft failure progression results (at least inpart) from hyperfiltration.1st Medical Department,Landeskrankenhaus,A-9026 Klagenfurt, Austria PAUL SCHMIDT

1. Schmidt P, Kopsa H, Balcke P, Zazgornik J, Pils P. Cadaveric renal graft acceptancewithout azathioprine. Proc EDTA 1979; 16: 388-94.

POLIOMYELITIS IN FINLAND

SIR,-Your June 21 editorial (p 1421) and Dr Hovi and hiscolleagues’ article (p 1427) present an interesting analysis of therecent poliomyelitis outbreak in Finland. We agree with yourconclusion that the type 3 virus epidemic was caused mainly by thedeclining herd immunity of an immunised population. We wish,however, to make a few cautionary remarks about the role of theantigenic variation of type 3 polioviruses in this outbreak and thefuture use of polio vaccines, inactivated (IPV) or live, oral (OPV).

Serological studies during the past 25 years,’-3 have clearlydemonstrated that, while type differences among poliovirus strainsisolated in various parts of the world are very common, the majorantigen of each poliovirus type is remarkably stable. Because of thisantigen stability IPV and OPV, when administered judiciously,were found to be excellent immunogens and protected againstparalytic disease caused by all three types of poliovirus. Highlyspecific monoclonal antibodies prepared with various type 3poliovirus strains detected further antigenic differences amongthese strains;4 yet the antigenically different Saukett strain used inthe production of IPV induced high antibody levels to Sabin’s Leon

strain used in the production of OPV and vice versa. Serologicalstudies on sera obtained in the Netherlands after immunisation witha potent IPV (Dr A. L. van Wezel, personal communication) and inthe USA after immunisation with OPV (Dr P. Albrecht, personalcommunication) revealed high serum antibody titres against therecent Finnish type 3 strains. These findings are similar to thosereported by Hovi and colleagues, who found that sera from infantscollected one month after administration of two doses of a new

potent IPV had almost identical levels of neutralising antibodies tothe vaccine and the Finnish type 3 strains. Thus any change in thecomposition of the type 3 component of either IPV or OPV wouldnot be warranted.We believe that the outbreak in Finland points to vaccine failure

due to an inadequate IPV preparation produced in monkey kidneycell cultures without virus concentration. This is further supportedby the fact that in neighbouring Sweden, which has been using IPVof a different origin for many years, no poliomyelitis cases caused bytype 3 virus were reported at the time of the Finnish outbreak.

Bureau of Biologics,Health Protection Branch,Department of National Health and Welfare,Ottawa, Ontario K1A 0L2, Canada

J. FURESZG. CONTRERAS

1. Furesz J, Armstrong RE, Contreras G, Wachmann B. Genetic characterization ofpoliovirus isolates in Canada, 1962-1981. Rev Infect Dis 1984; 6 (suppl 2): S528-34.

2. Nakano JH, Hatch MH, Thieme ML, Nottay B. Parameters for differentiatingvaccine-derived and wild poliovirus strains. Prog Med Virol 1978; 24: 178-206

3. van Wezel AL, Hazendonk AG. Intratypic serodifferentiation of poliomyelitis virusstrains by strain-specific antisera. Intervirology 1979; 11: 2-8.

4. Magrath DI, Evans DMA, Ferguson M, et al. Antigenic and molecular properties oftype 3 poliovirus responsible for an outbreak of poliomyelitis m a vaccinatedpopulation. J Gen Virol 1986; 67: 899-905.

FAILURE OF HIGH INTRAUTERINE INSEMINATIONOF HUSBAND’S SEMEN

SIR,-In 1984 Kerin et all reported that high intrauterineinsemination of prepared husband’s semen (AIH) was an effectivetreatment for male infertility. We have found the techniqueineffective.Ten infertile couples, in whom the only diagnosed abnormality

was in the semen analysis, were recruited to the study. All thewomen had biphasic body temperature charts, normal luteal phaseplasma progesterone concentrations, normal plasma prolactin andthyroid function tests, a normal hysterosalpingogram, and normaldye laparoscopy. The women had a single menstrual cycleinvestigated by daily ultrasonic delineation of follicular growth andrupture combined with synchronous estimation of plasma gonado-tropin and oestradiol and salivary progesterone concentrations. Allthese cycles were normal, by our criteria .2

6 of the men were asthenozoospermic, 1 was teratozoospermic, 1was oligozoospermic, and in 2 there was a negative post-coital test(PCT). Asthenozoospermia was defined as a progressive motility ofless than 40%, teratozoospermia was less than 40% normal spermson light microscopy, oligozoospermia was a concentration of lessthan 20 million sperms/ml,3 and a negative PCT was when nomotile sperms were visible per high-power field in cervical mucus12 h after intercourse.4 The semen was either washed or washed and

migrated in the manner described by Kerin and co-workers. Aftermigration the median density was 43 million/ml (range 2-31) andthe median rapid motility was 49 % (range 22-72). The beginning ofthe mid-cycle gonadotropin surge was documented either by rapidradioimmunoassay of plasma luteinising hormone (LH) or urinaryLH dipsticks (’Ovusticks’; Monoclonal Antibodies, Oxford).High intrauterine insemination of 03 ml of prepared semen was

performed within 24 h of the beginning of the LH surge with atomcat catheter (Monoject, St Louis, Missouri, USA) in themanner described by Kerin et al. Timed insemination occurred in atotal of three cycles in all women. Each insemination was followedby a control cycle where intercourse was timed according to thefertile period.No pregnancy resulted in either the 30 treatment or the 30 control

cycles. These results conflict with the high rate of success reportedby Kerin et al. We feel that there are two possible explanations. The