RADIOSENSITIVITY OF IN-SITU CARCINOMA OF BREAST

282 define their

of this term. Many of our false negatives were in combination of vascular and cellular rejection but nevertheless most of them benefited from pulse methylprednisolone and this must surely be the ultimate yardstick by which such tests should be judged. use

patients with

a

C. P. GIBBONS C. B. BROWN A. T. RAFTERY

Royal Hallamshire Hospital, Sheffield S10 2JF 1. Salaman JR, Griffin

PJ. Fine needle intrarenal manometry:

cyclosporin-treated recipients of kidney transplants.

a new

Lancet

test for

1983; ii:

rejection in

709-1

RADIOSENSITIVITY OF IN-SITU CARCINOMA OF BREAST in situ does not reveal aggressive-invasive and it may be assumed that it is less radiosensitive than invasive carcinoma. However, Dr Ribeiro (June 1, p 1275) states that there are no radiobiological data available showing that carcinoma in situ is less radiosensitive than invasive carcinoma. Rather, indirect evidence indicates that carcinoma in situ is as radiosensitive as invasive carcinoma. Survival from breast cancer is not different between patients treated with radical mastectomy as opposed to conservative therapy (ie, lumpectomy and radiotherapy) (see figure). In 25—45% of patients with invasive carcinoma,

SIR,-Carcinoma

growth

TAMOXIFEN AND CONTRALATERAL BREAST CANCER of tamoxifen in delaying recurrence and it is used as an adjuvant in early breast cancer has stimulated interest in the possibility that it might be a useful drug for preventing primary disease in women who are at high risk of breast cancer. The annual incidence of a primary tumour in the contralateral breast of women with previous breast cancer is about 8 per 1000,1 making them a very high risk group. Examining the occurrence of second primary cancers in patients in randomised adjuvant trials of tamoxifen offers an opportunity for studying the ability of this drug to prevent or delay the onset of these tumours. This effect could be accomplished by controlling clinically undetectable microcancers, arresting preneoplastic lesions, or correcting abnormal hormonal environments which predispose to high risk. We have analysed primary contralateral breast cancer as the first event in the Cancer Research Campaign’s 2 x 2 adjuvant trial in which patients were double randomised to receive daily tamoxifen for 2 years or not and a 5-day course of cyclophosphamide or not. Follow-up was censored at the time of any recurrence or at death, if this happened without previous recurrence. 13 such contralateral cancers have been observed, 10 in the arms not containing tamoxifen and 3 in the tamoxifen arms, and the difference was marginally significant on life-table analysis (p=0-05). No difference was observed when the patients were split according to whether or not they were allocated to receive cyclophosphamide (5 vs 8, respectively). The cumulative incidence is shown in the figure, the rate being about 2% at 2-year follow-up in the control group.

SiR,—The

success

reducing mortality when

Breast

cancer

survival.

Survival curves are depicted for a control population (A), patients with stage I and stage II breast cancer (0=excision plus radiotherapy, *=radical mastectomy), and patients who refused breast cancer treatment (A). These curves are compiled averages from more than 4000 patients in seventeen

published

reports.

multifocal disease (half, carcinoma in situ) exists; this is left behind in patients with lumpectomy.l Because of equal survival, radiotherapy after lumpectomy must be an effective treatment for residual invasive and in-situ carcinoma. Accordingly, patients with carcinoma in situ may be spared mutilating surgery in favour of surgical excision and radiotherapy. Department

of Obstetrics-Gynecology,

School

of Medicine, University of New Mexico, Albuquerque, New Mexico 87131, USA 1. Vorherr H.

Pathobiology

of breast cancer: Treatment 219—35

HELMUTH VORHERR implications. Eur J

Obstet

Gynecol Reprod Biol 1984; 17:

Cumulative incidence of contralateral breast

cancer

in

patients

in

controlled trials of adjuvant tamoxifen.

were treated for only two years in the trial and very little is available after this time. Besides verification of this observation in large data sets, it will be important to see if the difference is sustained after withdrawal of tamoxifen.

Patients

follow-up

Clinical Trials Centre,

Rayne Institute, King’s College School of Medicine and Dentistry,

J. CUZICK M. BAUM,

London SE5 9NU

for the Cancer Research Campaign II Working Party

1

Chaudary MA, Millis RR, Hoskins EOL, et al. Bilateral primary breast prospective study of disease incidence. Br J Surg 1984; 71: 711-14.

cancer a

SiR,—Dr Riberio objects to your statement (April 27, p 964) that in-situ breast cancer may be radioresistant. I would like to present evidence in support of your contention. Schnitt and co-workers,lI for example, have found that the rate of recurrence following segmental mastectomy and radical radiotherapy in patients whose tumours contained a significant amount of in-situ cancer of any type was significantly higher than in those whose tumours did not. This high failure rate remained unaffected by the use of higher doses of radiation (6000 rads) by means of a booster. Likewise, an extremely high frequency of new recurrences has been noted after a full course of radiotherapy in patients with urinary bladder cancer with an insitu component.2 Others3 have also found that primary in-situ carcinoma of the bladder is radioresistant. This experience accords completely with the dictum of Bergonie and Tribondeau4that has stood the test of time-that the radiosensitivity of cells and tissues is

283

proportional to their reproductive capacity and inversely proportional to their degree of differentiation. Lobular carcinomain-situ which becomes invasive, probably in 20 or more years,5 may be one of the slowest proliferating lesions known, so its radioresistance is understandable. Departments of Surgery, Mount Vernon Hospital and New York Medical

College,

ANAXAGORAS PAPAIOANNOU

Valhalla, New York

SJ, Connolly JL, Harris JR, Hellman S, Cohen RB. Pathologic predictors of early recurrence in stage I and II breast cancer treated by primary radiation therapy.

1. Schntt

Cancer 1984; 53: 1048-57. 2.

WolfH, Olsen PR, H6igaard F. Ureteral dysplasia concomitant with bladder tumours: A determinant for future

radiotherapy Lancer 1985,

new

occurrences in

patients

treated

by

full-course

i: 1005-08.

DC, Farrow GM, Riffe CC, Segura JW, Zincke H. Carcinoma in situ of the bladder. Cancer 1980; 45: 1842-48. 4. Bergome J, Tnbondeau L. Action des rayons X sur le testicule. Arch. d’Electr. Med Bordeauz 1906: 779-91. 5 Rosen PP Lobular carcinoma in situ and mtraductal carcinoma of the breast. In: McDivitt R, Oberman H, Ozello L, Kaufman N, eds. The Breast. Baltimore, Wlll1ams Wilkms, 1984. 3 Utz

HEALTH STATISTICS IN ISRAEL

SIR,-Dr Woolhandler and Dr Himmelstein (June 15, p 1375), in their article on militarism and mortality, exclude Israel from their study, lumping her with South Africa, as countries that "do not report health statistics for a large proportion of the population". Israel’s health statistics do include vital statistics for the total population, including both the Jewish majority and the non-Jewish minority; these figures are reported in the Central Bureau of Statistics’ annual Statistical Abstracts of Israel and are cited by the Demographic Yearbook, World Health Statistics Annual, and other UN/WHO publications. Mortality data for Jews and non-Jews by age, cause, and district of residence are published in addition to data on hospital admission. The infant mortality rate (IMR) for the non-Jewish population of Israel has declined more rapidly than that of the Jewish population in the past decade.’ Israel’s IMR for the non. Jewish population is now similar to that of various population groups in the United States2 and in Britain.3There is substantial regional and socioeconomic variation of the IMR for the Jewish population as

well.1

Social indicators for the Israel population show major improvements in standards of living among the non-Jewish population as well as for the Jewish population.4Vital statistics and social economic indicators for the West Bank and Gaza are reported 5

WHO annually. Woolhandler and Himmelstein incorrectly link South Africa with Israel together in their exclusion. If this was intentional, it might have been designed to make some kind of political point. We in Israel do suffer from the effect of high military spending necessitated by living in a tough neighbourhood, but this is not manifest in the non-reporting of health statistics.

endocrine tissues is the primary event in autoimmune disorders and that this is an effect of virally-induced IFN. Firstly, it is unlikely that a viral infection per se could account for the induction of class II MHC antigens on tissue cells. As you infer, only y-IFN is capable of inducing cellular class II antigen expression, while a and 0-IFN are virtually ineffective in this respect. 1,2 Viral infections stimulate production of predominantly a and 0-IFN but y-IFN can be produced only by mitogenic or antigenic stimulation of primed T lymphocytes and not directly in response to a viral challenge.2,3 Certainly, one could envisage the possibility that activation of virus-specific T lymphocytes might result in a little y-IFN production in vivo, but it would seem improbable that this mechanism could account for the markedly enhanced class II antigen expression observed in autoimmune lesions. This idea is supported by the fact that there are no reports of enhanced class II expression in disorders with a purely viral on

aetiology. My second comment concerns the issue of whether expression of class II MHC antigens on non-lymphoid cells has a primary or secondary function in local immune responses. Enhanced expression of class II antigens not only occurs on appropriate target cells during allograft rejection4 and autoimmunity but is also found in many different organs during immune responses against antigens which are unrelated to the tissues themselves, including parasitic infections, contact sensitivity, and graft-versus-host reaction. 5-7 Furthermore, we have shown that class II MHC alloantigens on intestinal epithelial cells do not influence the development of intestinal damage during a graft vs host reaction in mice (unpublished). Together, these observations indicate that the induction of class II MHC antigens on tissue cells is not an essential primary event in triggering a destructive immune response, but rather is secondary to raised levels of y-IFN found as part of a generalised release of T-lymphocyte-derived lymphokines. I would suggest therefore that enhanced expression of class II MHC antigens in autoimmune diseases merely reflects the involvement of effector T lymphocytes in the tissue pathology and that it is still necesary to consider other causes for the aberrant activation of these autoreactive lymphocytes. Nevertheless, the possibility that secondary increases in class II MHC antigen expression could worsen the autodestructive process cannot be ignored and warrants careful experimental consideration. Department of Bacteriology and Immunology University of Glasgow, Glasgow, Scotland

ALLAN MCI. MOWAT

to

3.

T. H. TULCHINSKY

Tulchinsky TH, Infant mortality in Israel. Statistical Bulletin Ministry of Health, Jerusalem, September, 1983. 2. Health United States. Washington. US Public Health Service, 1980. 3 Morris JN Social inequality undiminished. Lancet 1979; i: 87-89. 4 Central Bureau of Statistics Social profile of Israel Jerusalem, 1981. 5. Ministry of Health. Report on health and health services in Judaea, Samaria and Gaza, 1

Steeg PS, Moore RN, Johnson HM, Oppenheim JJ. Regulation of murine macrophage Ia antigen expression by a lymphokine with immune interferon activity. J Exp Med

1982; 156: 1780-93. 2. Trinchieri G, Perussia B. Immune interferon:

4.

Ministry of Health, Jerusalem, Israel

1984-1985, Jerusalem,

1.

5. 6. 7.

a pleiotropic lymphokine with multiple effects. Immunol Today 1985; 6: 131-36. Younger JS, Salvin SB. Production and properties of migration inhibitory factor and interferon in the circulation of mice with delayed type hypersensitivity. JImmunol 1983; 111: 1914—22. de Waal RMW, Bogman MJJ, Maas CN, Cornelissen LMH, Tax WJM, Koene RAP. Variable expression of Ia antigens on the vascular endothelium of mouse skin allografts. Nature 1983; 303: 426-27. Barclay AN, Mason DW. Induction of Ia antigen in rat epidermal cells and gut epithelium by immunological stimuli. J Exp Med 1982; 156: 1665-76. Suitters AJ, Lampert IA. Class II antigen induction in the liver of rats with graft-versushost disease. Transplantation 1984; 38: 194-96. Wadgymar A, Urmson J, Baumal R, Halloran PF. Changes in Ia expression in mouse kidney during acute graft-vs-host disease. J Immunol 1984; 132: 1826-32.

1985.

COLOUR

INTERFERON AND CLASS II MHC ANTIGEN EXPRESSION IN AUTOIMMUNITY

SiR,-Your editorial, What Triggers Autoimmunity (July 13, p 18), raises some interesting points and presents an attractive hypothesis about the role ofvirally-induced interferon(s) (IFN) in the induction of class II MHC antigens on non-lymphoid tissue cells with consequent activation of autoreactive T lymphocytes. This concept also received support from Dr Burman and colleagues (p 100) in their report on autoimmune thyroiditis following interferon therapy. Nevertheless, certain points must be considered before accepting fully the idea that the induction of class II MHC antigens

SLIDES, COLOUR BLINDNESS

SIR,-There is a small but practical point arising from Dr Kinnear’s review of Fletcher and Voke’s excellent book, Defective Colour VisTOn (June 29, p 1485). Since 8% of men in European countries are colour blind, and 75% of these have a defect in the deutan series involving green and red, those who present colour slides of tables and graphs at meetings should be persuaded to avoid these colours and stick to black/white or white/blue. If this is adhered to, 8% of the viewing audience will have less excuse for somnolent inattention. Hull

Royal Infirmary, Hull HU3 2JZ

J.M. S. PEARCE