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RISK OF FAMILIAL BREAST CANCER

SIR,-Dr Ottman and colleagues (Sept 3, p 556) providedprobability estimates of breast cancer developing between variousages in the sisters and mothers of breast cancer patients, accordingto the patients’ age at diagnosis and laterality of disease. Theseprobabilities were considered essential for counselling womenabout breast cancer risks. Some of the probabilities were

surprisingly high, particularly those applying to sisters of patientswith bilateral, premenopausal disease diagnosed before age 41. Forexample, the probability of a 30-year-old sister having breast cancerby age 60 years was 59% and by age 70 it was 100%. Ottman et alrecognised that the standard errors of some of the estimates werelarge; even so probabilities of this magnitude could, withoutqualification, lead to undue concern by a woman or perhaps to anunwarranted recommendation for prophylactic mastectomy.We estimated breast cancer probabilities from a sample of 699

sisters of patients, using the same methods as Ottman andco-workers. For brevity we show only two age-at-diagnosis classes.Although our patients were selected for having a family history ofthe disease, our probabilities for sisters of patients with

premenopausal bilateral disease were much more conservative thanOttman’s and did not exceed 24% (table). Differences were alsoevident for the other disease categories except for postmenopausal,unilateral disease where there was general agreement.

PROBABILITY (%) OF BREAST CANCER DEVELOPING IN SISTERS OFPATIENTS WITHIN CERTAIN AGE INTERVALS, GIVEN THE PATIENT’S

AGE AT DIAGNOSIS AND CANCER IN ONE OR BOTH BREASTS

*MDAH=present study; n=number ofsisters at risk; number with breast cancer is inparentheses.

These differences could relate to different sampling proceduresand reference populations in the two studies. Our patients wereselected for a family history of breast cancer in a first and seconddegree relative, with no selection for vital status, age or year ofdiagnosis, or laterality. Their patients were population based, butthey were selected for age and year of diagnosis and one group wasselected for early bilateral disease. Since early occurring andmultiple or bilateral disease characterise hereditary forms ofcancer,2 their data could have been biased towards the inheritedforms of breast cancer and thus high probabilities. Whatever thereason, the differences between the two studies underscore the needfor additional data especially from an unselected series of breastcancer patients. They also underscore the need for caution inapplying probability estimates from a single and/or restricted sourceof patients and relatives for general counselling of women abouttheir breast cancer risks.Our results will be presented in full elsewhere.

Department of Genetics,University of Texas,M D Anderson Hospital,Houston, Texas 77030, USA

DAVID E. ANDERSONMICHAEL BADZIOCH

1. Anderson DE. Genetic study of breast cancer: identification of a high risk group.Cancer 1974; 34: 1090-97.

2. Knudson AG Jr, Strong LC, Anderson DE. Heredity and cancer in man. Progr MedGenet 1973; 9: 113-58.

DESFERRIOXAMINE TO IMPROVE CARDIACFUNCTION IN IRON-OVERLOADED PATIENTS WITH

THALASSAEMIA MAJOR

SIR,-The accepted treatment for iron overload due to regulartransfusion therapy is the daily use of desferrioxamine bysubcutaneous infusion over 8-12 h.I,2 However, patients withthalassaemia major who receive desferrioxamine are still at risk fromthe effects of iron deposition in the heart,3 manifesting as atrial orventricular arrhythmias4 or progressive and intractable heartfailure. Although there is a recent report of patients withsymptomless cardiac dysfunction due to iron overload improving ontreatment with desferrioxamine,6 there are no published datashowing that established symptomatic cardiac toxicity may beimproved or reversed by this drug.Five transfusion-dependent thalassaemic patients with symptoms

and signs of myocardial iron toxicity, or who had reduced left-ventricular ejection fraction (LVEF) as measured by radionuclideangiocardiography, 7 were treated with higher doses ofdesferrioxamine than previously used (up to 200 mg/kg daily) for6-12 months. In three of these there was considerable symptomaticbenefit and objective evidence of improvement in cardiac function,including a reduction in cardiothoracic ratio on chest X-ray andincrease in LVEF (see table). None of these three patients wasreceiving diuretics or digoxin at the time of either study, and thehaemoglobin was maintained at > 12 g/dl. The fourth patient, whosesymptoms of cardiac failure at first improved, died with

deteriorating liver function tests; and the fifth has recently died withprogressive cardiac disease despite the excretion of more than 10 gof iron over 3 months. The other three patients are alive 18 monthsafter the initial cardiac investigations.

RESULTS

There has been only a slight reduction in alanine transaminaseand serum ferritin levels in all cases. Vitamin C 100-200 mg wasintroduced after 1 week; this increased urinary iron excretion by100-150% and we did not notice the deterioration in cardiacfunction previously reported when larger doses of vitamin C andsmaller doses of desferrioxamine were used.These patients provide some evidence that impaired cardiac

function due to iron overload may be improved and survival

1. Propper RD, Cooper R, Rufo RR, et al. Continuous subcutaneous administration ofdesferrioxamme in patients with iron overload. N Engl J Med 1977; 297: 418-23

2. Husain MAM, Flynn DM, Green N, Husein S, Hoffbrand AV. Subcutaneous infusionand intramuscular injection of desferrioxamine in patients with iron overload.Lancet 1976; ii: 1278-80.

3. Nienhuis AW, Griffith P, Straweynski H, et al. Evaluation of cardiac function inpatients with thalassemia major. Ann NY Acad Sci 1980, 344: 387-96

4. Kaye SB, Owen M. Cardiac arrhythmias in thalassemia major. Evaluation of chelationtherapy using ambulatory ECG monitoring. Br Med J 1978; i: 242-46.

5. Ehlers KH, Levin AR, Makerson AL, et al. Longitudinal study of cardiac function inthalassemia major Ann NY Acad Sci 1980; 344: 297-404.

6 Freeman AP, Giles RW, Berdoukas V, Walsh W, Choy D, Murray PC. Early leftventricular dysfunction and chelation therapy in thalassemia. Ann Intern Med 1983;99: 450-54.

7 Goris ML, Briardet PA, Hutter E. Automation and operator-independent dataprocessing of cardiac and pulmonary function: methods and results in informationprocessing in medical imaging. Proc VIth Int Conf INSERM 1979; 88: 477-88

8. Henry WL. Thalassemia major: molecular and clinical aspects (moderator NienhuisAW) Ann Intern Med 1979; 91: 883-97

393

prolonged by intensive therapy with desferrioxamine. This is incontrast to the series reported by Henry" who found that fourpatients with reduced LVEF died within 6 months of presentation.This suggests that it may be possible to remove sufficient iron fromthe heart to improve cardiac function by intensification ofdesferrioxamine therapy. However, two patients have had severereversible retinal degeneration which did not recur on

reintroduction of the drug at lower doses.9 We now use a maximumdaily dose of 125 mg/kg given over 24 h by Hickman line, addingvitamin C 200 mg daily orally after 1 week of therapy with regularophthalmic and cardiac assessment. We suggest that patients withevidence of iron-induced cardiac toxicity should be treated as soonas cardiac dysfunction is detected and would recommendcontinuation of treatment either until urinary iron excretion fallssubstantially, suggesting an emptying of the postulated chelatableiron pool,’ or until cardiac function improves.Department of Haematology,University College London,London WC1;Department of Haematology,Middlesex Hospital, London Wl,Department of Paediatrics,University College Hospital;and Department of Cardiology,

Middlesex Hospital

R. E. MARCUS*SALLY C. DAVIESH. M. BANTOCKS. R. UNDERWOODS. WALTONE. R. HUEHNS

"Present address. MRC Leukaemia Unit, Royal Postgraduate Medical School, LondonW12 0HS.

STREPTOCOCCAL SEPSIS IN BONE MARROWTRANSPLANT PATIENTS

SIR,-We read with interest the report of Dr Cohen and hiscolleagues (Dec 24/31, p 1452) on viridans streptococci septicaemiain neutropenic patients. Historically, we too have seen primarilygram-negative infections in severely neutropenic patients; however,there has been an increasing incidence of gram-positive infectionssince 1980 in patients undergoing bone marrow transplantation(BMT). Viridans streptococcus has become a very common bloodisolate, exceeded only by Staphylococcus epidermidis. Review of 209consecutive patients on the BMT unit with positive blood culturesreveals the following figures for viridans streptococcus: in 1980, 8out of 39 patients (21%); in 1981, 8 out of 57 (14%); in 1982, 16 outof 74 (22%); and in the first 6 months of 1983, 14 out of 39 (37%).These patients were undergoing therapy for a variety of disorders,including leukaemia, aplastic anaemia, myelodysplasia,neuroblastoma, lymphoma, and osteopetrosis. The organismsisolated were S mitis 20 isolates, S sanguis 16, S anginosus 5,S morbillorum 3, S salivarius 2, and non-speciated 3. aKoM 5,6’ morbillorum 3, M/KMn’M.! 2, and non-speciated 3.We have identified a subpopulation of patients who have an

inordinately high incidence of viridans streptococcus sepsis with anunusually severe clinical course. Between March, 1982, and April,1983, 10 patients with acute lymphocytic leukaemia (ALL) receivedintensive cytoreductive therapy with high-dose cyclophosphamideand total body irradiation followed by rescue with autologousmarrow treated with monoclonal antibodies and complement toremove residual leukaemic cells. 9 out of the 10 patients acquiredsevere a-streptococcal infections, 1 of which was fatal, within 7 daysof BMT. The infectious syndrome was sudden in onset and thefeatures included shock, pneumonia (resembling adult respiratorydistress syndrome), encephalopathy without meningitis, &plusmn; palmardesquamation in association with viridans streptococcus sepsis. Ofnote was the development of the infection early in the transplantcourse, often before the development of mucositis or a prolongedstate of neutropenia. These patients were compared with those whoreceived allogeneic transplant for the same disease, with the sameconditioning therapy, and with the same presence of an indwellingcentral line. In that group of patients, in the same time period, thefrequency of streptococcal sepsis was 12 - 507o (<0’ 001). Patients inboth groups received prophylactic co-trimoxazole and ticarcillinplus tobramycin empirically at the onset of fever.We have not identified the cause for this increased risk for gram-

positive infections in patients undergoing autologous BMT. One

9. Davies SC, Marcus RE, Hungerford JL, Miller MH, Arden GB, Huehns ER. Oculartoxicity of high-dose intravenous desferrioxamine. Lancet 1982; ii: 181-84

10. Hershko C, Rachmilewitz EA. Mechanism of action of desferrioxamine-inducedchelation in thalassaemia. Br J Haematol 1979, 42: 125-32.

might suppose that the marrow itself becomes contaminated duringmanipulation. However, results of extensive culturing of themarrow throughout the process can not be correlated with clinicalinfection. In an effort to decrease these infections, we have alteredmarrow processing with the addition of antibiotics in vitro, and allpatients have received prophylactic vancomycin. Subsequently, 7patients have received autologous treated marrow grafts and nonehas acquired streptococcal sepsis (<0 - 02). 1

We agree that the susceptible neutropenic patient should receiveempirical gram-positive coverage at the first sign of sepsis.Furthermore, patients who may be at increased risk of gram-positiveinfections may benefit from prophylactic therapy. Prospectiverandomised studies are now being conducted to address thesequestions.

Bone Marrow Transplantation Programand Departments of Pediatrics and Medicine,

University of Minnesota,Minneapolis, Minnesota 5 5455, USA

JEAN HENSLEEBRUCE BOSTROMDANIEL WEISDORFNORMA RAMSAYPHILLIP MCGLAVE

JOHN KERSEY

SUDDEN DEATH IN SQUASH PLAYERSSiR,-In their investigation of 30 sudden deaths in squash players

(Jan 21, p 148) Dr Northcote and colleagues found 23 from coronaryheart disease (CHD), and among these individuals 15 smoked morethan ten cigarettes a day. This is nearly twice the frequency ofcigarette smoking in the population as a whole, and is very muchhigher than the usual frequency of smoking among people who takeexercise. I am surprised that Northcote et al do not discuss the roleof smoking in these deaths from CHD.The smoking history is not given for the other 7 cases but 6 of

these were thought to be cardiac deaths and there is ample evidenceto incriminate cigarette smoking as a possible factor in all types ofsudden cardiac death. Cigarette smoking is associated withincreased carboxyhaemoglobin levels, up to 10% or even 15%; Iwith the release of catecholamines, which raise the heart rate andblood pressure, increase the risk of arrhythmia, and increase plateletadhesiveness and blood lipid concentrations;2 and with raised bloodviscosity, associated with increases in fibrinogen levels,haematocrit, and red cell volume. The sportsman who smokes thushas a dangerous triad of risk factors for cardiac hypoxia andarrhythmia. Furthermore, squash is often taken up veryenthusiastically by middle-aged unfit men; it is highly competitiveand demands fast reactions, thus causing the release of largequantities of catecholamines; and it is a demanding sport that candrive even fit people into large oxygen debt.The importance of deep breathing has been underemphasised in

the prevention of sudden deaths in sportsmen. The rarity of cardiacdeath in the swimming pool is probably due to the reflex

hyperventilation induced by contact with water. By the same tokenthe danger of isometric exercise is probably due mainly to reflexbreath holding which accompanies tonic muscular contractionrather than to the accompanying rise in blood pressure. Anysustained muscle contraction or vigorous exercise should be

accompanied by deliberate hyperventilation.I suggest that the prevention of sudden death in squash players

and other sportsmen will depend on three factors: stoppingsmoking, graduated training ("get fit to play squash, don’t playsquash to get fit"), and deep breathing.Bridgend General Hospital,Bridgend, Mid Glamorgan A. W. FOWLER

SIR,-More than 1 million people in the UK play squash once amonth or more. Competitions have lately been expanded to includeveteran and even vintage groups. Some of the older players are veryfit. However, there are risks in unwisely ambitious competitionschedules. Mr A. P. H. Chalmers of the Squash Rackets Associationtells me of one sudden death in a regular player of 62 who had to playfour matches in 48 hours. Older competitors may, like younger men,be careless of their own health: another death (not reported in Dr

1. Astrup P. Some physiological and pathological effects of moderate carbon monoxideexposure. Br Med J 1972; iv: 447-52.

2. Ball K. Smoking and the heart. Lancet 1974; n: 822-26.3. Dintenfass L. Elevation of blood viscosity, aggregation of red cells, haematocrit values

and fibrinogen levels in cigarette smokers. Med J Aust 1975; i: 616-20.