Efficacy of antibiotic prophylaxis for prevention of native-valve endocarditis

Saturday

18

January

1992

No 8786

ORIGINAL ARTICLES

Efficacy of antibiotic prophylaxis for prevention of native-valve endocarditis

Whether antibiotic prophylaxis can prevent bacterial endocarditis is hotly debated. In an attempt to settle this issue, we have assessed the efficacy of prophylaxis for bacterial endocarditis on native valves in a nationwide, case-control study in the Netherlands. Cases were patients with known cardiac disease in whom endocarditis developed within 180 days of a medical or dental procedure for which prophylaxis was indicated. Of a total of 438 patients with endocarditis diagnosed during 2 years, 48 were eligible for the study. Controls were patients with the same cardiac status in whom endocarditis did not develop within 180 days of a similar procedure; of a total of 889 controls from five hospitals, 200 were eligible. Overall, about 1 in 6 patients in both groups had received prophylaxis. The best estimate of protective efficacy was 49% for first-ever endocarditis occurring within 30 days of a procedure. Endocarditis developed within 30 days of a procedure in only 13% of patients with a previously diagnosed heart lesion which predisposed to the disease. The findings suggest that strict adherence to for recommendations accepted generally do little to decrease the total prophylaxis might number of patients with endocarditis in the

community.

assess the efficacy of antibiotic prophylaxis in man has not yet been done, mainly because the disease is rare and so a large series of patient would be needed.12 We have therefore used an alternative approach-ie, a case-control study-to assess the protective effect of antibiotic prophylaxis in subjects with native-valve and cardiovascular anomalies.

Subjects and

Subjects were eligible if they had native-valve and cardiovascular anomalies that increased their risk of getting endocarditis and that warranted antibiotic prophylaxis before certain medical or dental procedures.13-14 These lesions included congenital heart disease, coarctation of the aorta, rheumatic and other valvular dysfunction, and mitral valve prolapse with mitral regurgitation. Patients with prosthetic heart valves were excluded for two reasons. Firstly, these patients probably have a much higher risk of endocarditis and therefore are a different risk-group. Secondly, there were too few patients with a prosthetic heart valve for a case-control study. Cases had to have undergone, within 180 days of onset of symptoms, a medical or dental procedure that required prophylaxis, and controls had to have had such a procedure within 180 days of the day of the follow-up interview. We chose 180 days to allow subsequent stratification by 30 day intervals in the analysis. Indications for prophylaxis were derived from the guidelines of the Netherlands Heart Foundation, and are similar to recommendations in the UK and USA.13-17 Procedures, indications for prophylaxis, and antibiotics Subjects Information

prophylaxis

Introduction There is considerable controversy about the efficacy of antibiotic prophylaxis for prevention of bacterial endocarditis.l-6In the 1940s, sulphonamides and penicillin were successfully used to reduce the incidence and severity of bacteraemia in patients who had undergone dental or surgical procedures, but numerous reports of prophylaxis failure have since appeared.7 11 A controlled clinical trial to

methods

Eligibility

interviewed with a structured questionnaire. obtained on procedures for which antibiotic is indicated that had been done within 180 days of the were was

Departments of Clinical Microbiology, (J T. M. der Meer, MD, Prof M F. Michel, MD), and of Epidemiology and Biostatistics (Prof H A. Valkenburg, MD), Erasmus University, Rotterdam; and Departments of Infectious Diseases (J. T. M. van der Meer, MD, W van Wijk, MSc, J. Thompson, MD) and Clinical Epidemiology (Prof J. P Vandenbroucke, MD), Leiden University Hospital, Leiden, Netherlands. Correspondence to Dr Jan T. M van der Meer, Department of Infectious Diseases, Building 1, C5-P, University Hospital, PO 9600, 2300 RC Leiden, the Netherlands. ADDRESSES: van

136

onset of disease (cases) or interview (controls). Procedures were named one at a time and the patient was requested to answer "yes" or "no". Questions were reworded only when a subject did not understand the question. When a subject had had more than one procedure, that closest to the onset of symptoms or interview was entered. Proxy responders-ie, spouses and general practitionerswere used for cases who were too ill to be interviewed or had died before they could be visited. All information about recent procedures and the use of prophylaxis was checked with medical and dental specialists, including pharmacists.

TABLEI-PROCEDURES AND MICROORGANISMS IN CASES OF ENDOCARDITIS

Cases From Nov 1, 1986, to Nov 1, 1988, all patients who were consecutively admitted to hospital in the Netherlands (14 491 138 inhabitants) and who were suspected of having bacterial endocarditis were reported to one of us (J. v. d. M.) by the microbiologists who were aware of these patients through submitted blood cultures. While the patient was in hospital, we asked the treating physician to explain the purpose of the study, and sought permission to visit the hospital for a review of the medical records and an interview with the patient. Data about previous diagnoses of heart disease, physical examination, and laboratory results were obtained. The patient was interviewed about recent medical or dental procedures and the use of prophylaxis. We defined day of onset as the first day on which a temperature of 38°C or more was recorded, accompanied by symptoms that finally led to admission to hospital, or the date of the first visit to a doctor for the same complaints. During 2 years, 559 patients suspected of having endocarditis were reported. 210 patients were excluded, 121 because they did not meet the diagnostic criteria for endocarditis as described by Von Reyn et al,18 and 89 because they had endocarditis on a prosthetic valve. Of the 349 patients who had native-valve endocarditis, 197 (56%) had previously had heart disease. Proxy responders were interviewed for 10 of these 197 patients. 54 patients (27%) had undergone, in the 180 days before onset of symptoms, a medical or dental procedure with an indication for prophylaxis. For 6 of these 54, a causal relation between the procedure and endocarditis was ruled out because it was unlikely that the agent isolated from the blood originated from the area of the procedure (Streptococcus bovis

isolated after a dental procedure [2 patients]; a-haemolytic streptococci after cystoscopy without tracheal intubation [1], after removal of a sebaceous cyst [1], and after stitching of a head wound, [1]; and Candida parapsilosis after dental scaling [1]). The remaining 48 patients with endocarditis formed the case group: for 39 of these patients this episode of endocarditis was their first, and for 9 it was a recurrent episode. None of the proxy responders fell in the case group.

Controls selected from outpatients of the cardiology departments of the Leiden University Hospital and four regional hospitals in Arnhem. All patients with a cardiac lesion and increased risk of endocarditis were selected. These patients were subsequently given a number and a first sample was drawn with the help of random tables. An introductory letter was sent to the control subjects accompanied by a list of of procedures for which antibiotic prophylaxis is indicated. The purpose of this list was to refresh their memory and imitate the recall stimulus experienced by the patients with endocarditis. 192 to 5 days later, the controls were contacted by telephone and the structured questionnaire was completed. Telephone calls were made on weekdays and Saturdays between 0900 h and 2200 h to avoid selection according to job or disease Controls

were

*Nos in parentheses no of patients from whIch organism isolated tNo further identification possible tNo organism isolated diagnosis based on histology from surgery

the eligibility criteria (53 patients had died, 29 had a heart valve, 62 had moved house and could not be located, 102 could not be contacted by telephone, 418 had not undergone a procedure with an indication for prophylaxis in the previous 180 days, and 25 refused to take part). Overall, of 200 controls included in the analysis, none got endocarditis within 180 days of the procedure.

not meet

prosthetic

Analysis The incidence of bacterial endocarditis is low, and endocarditis as the result of a procedure develops in an even smaller number of patients. Therefore, sample size and calculations of power were based on the assumption that a clinically important reduction in risk due to prophylaxis would have to be at least 75%. We also assumed that 40% of the population at risk for endocaditis would be given prophylaxis. On the basis of these assumptions and a one-sided significance level of 5 %, we calculated that a group of 31 cases and 4 controls per case would be needed. The power of the study to detect a protective effect of prophylaxis of at least 75% would then be

90%. To obtain

an estimate of the protective effect of antibiotic odds ratios (ORs) were calculated by the MantelHaenszel method from data stratified for age and indication for prophylaxis. Data were analysed separately for cases with first-time episodes of endocarditis and those with recurrent episodes. For a rare disease the OR derived from a case-control study closely approximates the relative risk (RR) that would have been derived from a cohort study. The protective effect of a prophylactic

prophylaxis,

TABLE li-CHARACTERISTICS OF CASES AND CONTROLS

status.

Since endocarditis is age related and sex related, whereas cases and controls age related only /<>-23 were matched for age but not sex. Controls were eligible if they were in the same 5-year-age category as a case and had undergone a medical or dental procedure with an indication for prophylaxis within 180 days of the interview. If there were more than 4 controls per case, all controls were used. However, for some age strata there were fewer than 4. For these age strata, a second random sample was drawn. Letters were sent to 889 patients, 689 (77-5%) of whom did

prophylaxis compliance is

*Interval between procedure and onset of symptoms procedure and interview (controls)

(for cases) and

between

137

TABLE III-PROCEDURES AND INDICATION FOR AN EXPOSURE TO ANTIBIOTIC PROPHYLAXIS

Data are no of patients exposed per no of patients not exposed to antibiotics *Indication according to guidelines of Netherlands Heart Foundation tlndication for prophylaxis established with certainty, procedures include denta extractions, dental root work, digestive tract surgery. tlndication for prophylaxis not established with certainty, all patients in this group underwent dental scaling 91nterval between the procedure and onset of symptoms (cases) or mterview

(controls)

is then expressed as 1- RR. Test-based confidence intervals (CI) for ORs were calculated with the chi-square method derived by Mantel-Haenszel. Ratios and medians were compared by means of the chi-square test and the non-parametric MannWhitney U test, respectively.

measure

Results Cases The procedures and microorganisms associated with the of endocarditis are shown in table 1. Most of these patients had undergone a dental procedure (table n), and prophylaxis was definitely indicated in 28 of these 48 procedures. For the other 20 procedures, the indication for prophylaxis could not be determined with certainty since all concerned removal of tartar. According to the recommendation of the Netherlands Heart Foundation, prophylaxis is indicated for scaling when it includes the subgingival removal of tartar or when it is combined with polishing of the teeth. However, most dentists do not keep records of the extent of scaling, and it proved to be impossible to find out whether scaling included removal of subgingival calculus or polishing. The indication for prophylaxis for these 20 patients was therefore entered as "possible". Median interval between procedure and onset of symptoms was 72 5 days (range 3-170) for procedures with a possible indication for prophylaxis compared with 10 days (range 0-175) for other procedures (p < 0’001). Antibiotics were given before the procedure to 8 of the 48 cases (table in). Prophylaxis was given to 6 of these 8 cases in accordance with the recommendations of the Netherlands Heart Foundation. In the other 2 cases, the antibiotics did not accord with the recommendations but could be considered equivalent. Prophylaxis was given more often to patients who had had previous episodes of endocarditis than to those who had not (3/9 vs 5/39). cases

Controls 181 (91 %) of the 200 procedures in control subjects were dental. Prophylaxis was definitely indicated in 96 of them. In 104 procedures, the indication for prophylaxis was entered as "possible" because dental scaling was done and we could not determine whether subgingival calculus had been removed. The median interval between the procedure ind the day of the interview was 79 days for procedures with

..

-----.

-

Days

to

onset/interview

Cumulative percentage of interval between procedure and onset of symptoms or interview.

Top, cases (.) and controls (0) differed significantly (p < 0-001) in median interval between procedure and onset of symptoms (cases) or interview (controls), 30 and 75 days, respectively Bottom, when analysed separately according to certainty of indication for prophylaxis, this difference disappeared for procedures with a "possible" indication and increased for those with a (cases = 0, controls = L) (p<0’73) "definite" indication (cases = 0, controls = A) (p<0 0001). ).

possible indication (n = 104) and 67-5 days for those with a definite indication (n = 96). Of the 200 controls, 26 (13%) received prophylaxis before the procedure. Prophylaxis was given to 26% (25/96) of those undergoing a procedure with a definite indication for prophylaxis and to 1% (1/104) of those undergoing a procedure with a possible indication (table III). 15 of these controls received prophylaxis according to the guidelines of the Netherlands Heart Foundation, and in 11 controls the antibiotics given were not in accordance with these recommendations but were deemed equivalent. a

Analysis Patients with endocarditis potentially eligible as cases (197) and patients potentially eligible as controls (618) did not differ significantly with respect to number of procedures they had undergone in the previous 180 days (27-4% 32-4%, 95% CI for RR 0-66 to 1-09). Controls from the Leiden University Hospital were broadly similar to those from the Arnhem hospitals with respect to age and sex ratio (table n), and these groups did not differ significantly in type of procedure undergone or use of prophylaxis (95% CI for RR 03 to 15). Cases and controls were similar with respect to age (as would be expected from the matching procedure) and

138

proportion of dental procedures, but among the cases there were more men (p 0-05) (table II). The interval between procedure and onset of symptoms or interview was significantly shorter for cases than was the interval between procedure and interview for controls (figure, table II). This difference disappeared for procedures with a possible indication and increased for procedures with a definite indication when analysed separately according to indication. =

The difference suggests a causal relation between endocarditis and procedures with a high risk for bacteraemia, such as dental root work or dental extractions, but not between endocarditis and the scaling of teeth. There was hardly any difference in use of prophylaxis between cases and controls (table III). For procedures within 180 days of onset of symptoms, stratified for age and certainty of indication, the OR was 1-04 (90% CI 0-36 to 2-99) for first-time episodes and 3-63 (0-98 to 13-4) for recurrent episodes. For procedures within 30 days of onset the same stratified OR was 0-51 (0-11 to 2-29) for cases with first-time endocarditis and 2-13 (0-48 to 9-44) for recurrent episodes. The stratified OR of 0-51 for cases with first-time endocarditis and a procedure within 30 days of onset seems to provide the best estimate of the risk reduction obtained with prophylaxis, since 30 days is a more likely incubation period than 180 days (figure). Thus, on the assumption that the incubation period is 30 days, the protective effect of prophylaxis is 49%, although this is not statistically significant. Endocarditis developed within 30 days of a procedure in 25 (12-7%) of 197 patients with a previously diagnosed heart lesion predisposing to the disease

(table III). Discussion Most patients with endocarditis on a known cardiac lesion do not get the disease as a consequence of a dental or medical procedure. In our study, endocarditis developed within 30 days of a procedure in only 25 (12-7%) of 197 patients who had had heart disease. Thus, 9 out of 10 patients with heart disease contracted endocarditis in some other way. Additionally, since 5 of these 25 patients did receive prophylaxis, total compliance with prophylaxis might, at best, have prevented endocarditis in 20 patients or 6% of all patients with native-valve endocarditis. The low percentage of patients in whom endocarditis developed after a procedure cannot be ascribed to good compliance with prophylaxis. In practice, prophylaxis is infrequently given and most patients with a high-risk cardiac lesion undergo high-risk procedures without the use of antibiotics.24-27 Thus, risk of endocarditis as a consequence of a medical or dental procedure must be very small-so small that the protective effect of prophylaxis would have to be very high to warrant its use in patients with various cardiac lesions ranging from mitral valve prolapse with regurgitation to aortic stenosis. Two further observations suggest that the role of procedures in the cause of endocarditis is small. First, patients potentially eligible as controls and patients potentially eligible as cases had had a similar number of procedures, and, second, there was no significant difference between cases and controls with respect to type of procedure carried out. The findings also suggest that dental scaling represents a lower risk for endocarditis than do other dental procedures, such as dental root work or extraction. The power of the study to detect a significantly protective effect of 49% was small owing to several factors. First, the difference in prophylaxis compliance between the cases and controls was small, so that it was difficult to detect anything

less than a very large effect. Second, the study power was limited by the number of cases. Only 18 patients with native-valve endocarditis had previously had a cardiac lesion and had a first-time episode of endocarditis within 30 days of a procedure. However, to collect these cases, we had to survey all microbiology departments in the Netherlands (14-5 million inhabitants) for 2 years. To detect a protective effect of 49 % with statistical significance would require well over a hundred cases and several hundred controls. The study was large enough, however, to exclude a substantial protective effect of prophylaxis in the population to whom the intervention is offered. The possibility that some subgroups may benefit from the use of prophylaxis cannot be excluded. Since we matched controls from only 5 hospitals to cases from over 40 hospitals, the use of prophylaxis among controls might not be representative for the whole country. However, we chose controls from two different parts of the country and two types of hospital and analysed results for both groups separately. There was no significant difference in characteristics between patients from different places of origin, so the groups were merged and accepted as being representative for the source population. Our findings differ substantially from those of Imperiale et a1,2$who found a protective efficacy of prophylaxis of 91 %. However, their study was limited by the retrospective recruitment of cases from medical records over 6 years, which might have made it difficult to assess the time relation between procedures and onset of symptoms. Moreover, they had to exclude 35% of potential cases because they could not determine whether these patients had had a procedure within 12 weeks of admission, and the subjects’ recall about the use of prophylaxis was accepted when dental records did not uniformly show whether prophylaxis was

given. Our best estimate of protective efficacy of 49 % means that in a developed affluent and medically well organised country such as the Netherlands complete compliance with endocarditis prophylaxis might prevent about 5 cases of the disease a year. Thus, the dilemma is that whereas a protective efficacy of about 50% may be worthwhile for the individual patient, the effect is negligible on the scale of the whole population. Whether routine antibiotic prophylaxis is justifiable would require a cost-effective analysis that weighs the costs of antibiotic therapy for many patients against the costs, financially and clinically, of endocarditis in a few.29 We thank the Dutch microbiologists for their cooperation; Prof Ralph van Furth for his critical review of the manuscript; Prof A. V. G. Bruschke, Prof J. Rohmer, and the Arnhem cardiologists for allowing us to study patients under their care; and Mrs M. Kerst-Noest for her secretarial assistance. This study Foundation.

was

supported by

grant 35.007 from the Netherlands Heart

REFERENCES 1. Editorial. Prophylaxis of bacterial endocarditis. Faith, hope, and charitable interpretations. Lancet 1976; i: 519-20. 2. Petersdorf RG. Antimicrobial prophylaxis of bacterial endocarditis. Prudent caution or bacterial overkill? Am J Med 1978; 65: 220-23. 3. Kaplan EL. Bacterial endocarditis prophylaxis-tradition or necessity? Am J Cardiol 1986; 57: 478-79. 4. Kaye D. Prophylaxis for infective endocarditis: an update. Ann Intern Med 1986; 104: 419-23. 5. McGowan DA. A dental view of controversies in the prophylaxis of infective endocarditis. J Antimicrob Chemother 1987; 20 (suppl A): 105-09. 6. Oakley CM. Controversies in the prophylaxis of infective endocarditis: a cardiological view. J Antimicrob Chemother 1987; 20(suppl A): 99-104.

139

7. McGowan DA. Failure of

prophylaxis of infective endocarditis following dental treatment. J Antimicrob Chemother 1978; 4: 486-88. 8. Durak DT, Kaplan EL, Bisno AL. Apparent failures of endocarditis prophylaxis. Analysis of 52 cases submitted to a national registry. JAMA 1983; 250: 2318-22. 9. Denning DW, Cassidy M, Dougall A, Hillis WS. Failure of single dose amoxycillin as prophylaxis against endocarditis. Br Med J 1984; 289: 1499-500. 10. Walker MP. Infective endocarditis: dental implications, prevention and prophylaxis failure. Clin Prev Dent 1984; 6: 17-19. 11. Fekete T. Controversies in the prevention of infective endocarditis related to dental procedures. Dent Clin N Am 1990; 34: 79-90. 12. Durack DT. Prophylaxis of infective endocarditis. In: Mandell GU, Douglas RG, Bennett JE, eds. Principles and practice of infectious diseases, 2nd ed. New York: John Wiley & Sons, 1984: 539-44. 13. Michel MF, Thompson J, Boering G, Hess J, Van Putten PL. Revision of the guidelines of the Netherlands Heart Foundation for the prevention of endocarditis. Geneesmiddelen-bull 1986; 20: 53-56. 14. Shanson DC. Antibiotic prophylaxis of infective endocarditis in the United Kingdom and Europe. J Antimicrob Chemother 1987; 20 (suppl A): 119-31. 15. British Society for Antimicrobial Chemotherapy. Antibiotic prophylaxis of infective endocarditis: recommendations from the Endocarditis Working Party. Lancet 1990; 335: 88-89. 16. Dajani AS, Bisno AL, Chung KJ, et al. Prevention of bacterial endocarditis. Recommendations by the American Heart Association. JAMA 1990; 264: 2919-22. 17. Finch R. Chemoprophylaxis of infective endocarditis. Scand J Infect Dis 1990; 70 (suppl): 102-10. 18. Von Reyn CF, Levy BS, Arbeit RD, Friedland G, Crumpacker CS. Infective endocarditis: an analysis based on strict case definitions. Ann Intern Med 1981; 94: 505-18.

Methodologic problems and standards in case-control research. J Chron Dis 1979; 32: 35-41. Steckelberg JM, Melton LJ, Ilstrup DM, Rouse MS, Wilson WR.

19. Feinstein AR. 20.

Influence of referral bias on the apparent clinical spectrum of infection endocarditis. Am J Med 1990; 88: 529-28. 21. Lavis CJ, Khanderia BK, Seward JB, Tajik AJ, Taylor CL, Ballard DJ. Factors associated with the recommendation for endocarditis prophylaxis in mitral valve prolapse. JAMA 1989; 262: 3308-12. 22. Bayliss R, Clark C, Oakley CM, Somerville W, Whitfield AGW, Young SEJ. The microbiology and pathogenesis of infective endocarditis. Br Heart J 1983; 50: 513-19. 23. Baddour LM. Twelve-year review of recurrent native-valve infective endocarditis: a disease of the modern antibiotic era. Rev Infect Dis 1988; 10: 1163-70. 24. Jaspers MT, Little JW, Hartwick WL. Effectiveness of a dental school program in the prevention of infective endocarditis and other related

infections. J Dent Educ 1984; 48: 159-63. VA, Merry JW, Little JW, Jaspers MT. Compliance with guidelines for management of dental school patients susceptible to infective endocarditis. J Dent Educ 1987; 51: 229-32. 26. Brooks RG, Notario G, McCabe RE. Hospital survey of antimicrobial prophylaxis to prevent endocarditis in patients with prosthetic heart valves. Am J Med 1988; 18: 74-77. 27. Gutschik E, Lippert S. Dental procedures and endocarditis prophylaxis: experiences from 108 dental practices. Scand J Dent Res 1990; 98: 25. Murrah

144-48. Horwitz RI. Does prophylaxis prevent postdental infective endocarditis? A controlled evaluation of protective efficacy. Am J Med 1990; 88: 131-36. 29. Dinman BD. The reality and acceptance of risk. JAMA 1980; 244: 1226-28.

28. Imperiale TF,

Loss of heterozygosity on chromosome 7q and aggressive primary breast cancer

Genetic alterations are believed to be important in the origin and dissemination of breast cancer. Cytogenetic rearrangements on chromosome 7 are common in breast tumours. We used the c-met proto-oncogene probe, which detects sequences on chromosome 7q31, to analyse tumour and blood leucocyte DNA samples from 245 patients with primary breast cancers. The pmetH polymorphic probe detected a high frequency of allele loss the 121 informative among (40·5%) This genetic alteration (heterozygous) patients. was not significantly associated with standard prognostic features including tumour size, histopathological grade, and lymph-node or steroid receptor status. However, patients with loss of heterozygosity on chromosome 7q31 in primary tumour DNA had significantly shorter metastasisfree survival (p=0·00022) and overall survival (p=0·0036) after surgery than patients without this alteration. These findings indicate that this region of chromosome 7 might be the site of a breast tumour or metastasis suppressor gene. Introduction Somatic deletions of chromosomal sequences within specific regions of the cellular genome may be found in solid tumours: such deletions are thought to remove tumour suppressor genes or to reveal recessive mutations that affect

tumour suppressor genes. Molecular analysis of primary breast tumour DNA has shown loss of heterozygosity on chromosomal regions lp,12 lq/ 3pllp/ 13q, 17p/ 17q, and 18q.8 These observations suggest that several suppressor genes may influence the development and progression of breast cancer. Genetic analysis of various solid tumours indicates that many, if not all, regions of the genome that show loss of heterozygosity in primary breast tumour DNA may show similar changes in association with other carcinomas. For example, loss of heterozygosity has been found at region lp in colorectal9 and gastrointestinal1O carcinoma; at region Iq in colorectal carcinoma;" at 3p in small cell 12 and non-small-cell13 lung cancer and renal,t4 cervical,ls ovarian,t6 and testicular17 carcinoma; at llp in small cells and non-small-cell13 lung cancer and hepatocellular,t9 bladder 20 and ovarian16 carcinoma; at 13q in small-cell 12 and non-small-cell13 lung cancer and stomach2l carcinoma; at 17p in small cell 12 and non-smallcell13 lung cancer, and colorectal," bladder,22 and ovarian23 carcinoma; at 17q in ovarian carcinoma;23 and at region 18q in colorectal carcinoma." Many of the mutations that lead to loss of heterozygosity in DNA from breast carcinomas have an equally high incidence in lung and colorectal carcinomas. Could such

ADDRESSES Oncovirology Laboratory (I. Bièche, DSc, M. H. Champème, DSc, F. Matifas, CT, R. Lidereau, PhD), and Department of Medical Statistics (K Hacène, DSc), Centre René Huguenin, F-92211 St-Cloud, France; and Laboratory of Tumor Immunology and Biology, National Cancer Institute, Bethesda, MD 20892, USA (R. Callahan, PhD). Correspondence to Dr R. Lidereau, Laboratoire d’Oncovirologie, Centre René Huguenin, 5 rue Gaston Latouche, F-92211 St-Cloud, France.