327
apparently widespread habit, and we must hope that youngsters will not follow the dangerous example now being set by English and Australian test cricketers. The controversy over short-pitched bowling and the risk of injury to batsmen goes on, while in gum chewing we have a real danger to cricketers that could easily be eliminated. University Department of Surgery, General Hospital,
Nottingham NG1
6HA
J. B. BOURKE
X-ASSOCIATED IMMUNOCOMPETENCE The Lancet on hepatitis B virus have revealed a marked predominance of males affected by membranous nephropathy (M.N.)’ and hepatocarcinoma (H.C.j.2 A third article indicates a possible influence of H.B.v. on the sex ratio.3 Despite there being a male:female ratio of greater than 4:1 for M.N. and H.c., the possibility that the male predominance of these disorders could be due to X-associated immunodeficiency to H.B.v. was not considered.!.2 9 of the 11 Japanese patients with M.N.’ were males and all were positive for HB surface antigen (HBJ whereas none had anti-HB, in serum. 6 of the 11 mothers of the children were positive for REs and one had anti-HBs’ It seems to me that this male predominance of M.N. could be associated with inferior immunocompetence to H.B.v. of males as compared to females. Immunodeficiency could be partly responsible for the predominance of males with H.B.v. and associated M.N. and H.c. J. L. Sullivan and I have recently reviewed evidence (to be published elsewhere) which demonstrates immunological bases for superior immunocompetence and survival of females. Males experience more frequent and severe illness and higher mortality from many common infectious and neoplastic disorders than do females. This superior immunocompetence probably compensates for the immunosuppression which accompanies pregnancy.4 Females have higher serum-IgM concentrations, superior ability to form antibodies to infectious agents, and experience lower incidence of viral and bacteriological infectious diseases. Similarly, females have a lower incidence of most malignancies. Defective immune responses in males could account for their being frequent carriers of viruses such as H.B.v. Heptatitis B carrier states occur three times more frequently in males than in females.5 In contrast, antibody to HBs develops approximately three times more often in females than in males.6 Drew et al.7 have postulated cross-reactivity between H.B.v. and a human male-determined tissue antigen as being responsible for the sex ratio. They have suggested that males, being self-tolerant, possess weaker immune defences against H.B.v., resulting in disproportionate losses of male infants. Possibly, another factor to be evaluated is the apparent lack of immunocompetence of males to H.B.v. caused by mutant X-linked recessive immunoregulatory genes or weaker immune responsiveness than females from differences in hormonal milieu. Our study of cirrhosis and H.c. at Boston City Hospital during 1917-68 had revealed a striking male predominance which was associated with cirrhosis and chronic alcoholism.8 After having personally observed numerous alcoholic vagrants drinking in Boston, we had speculated that H.B.v. could have acted synergistically with alcoholism to provoke cirrhosis and H.c. The study performed by Trichopoulos et al. has revealed
SIR,—Recent articles in
(H.B.v.)
a high prevalence of active or past H.B.v. infections in 80 Greek patients with H.c., and 86% of the patients were males. They found active infection with H.B.v. as detected by the presence of HB, or anti-HB core antigen, but anti-HBs was lacking. Despite the lack of anti-BHs Trichopoulos et al. did not speculate that immunodeficiency to H.B.v. could have been a major factor in the emergence of H.c. Considerable effort has been directed toward finding human oncogenic viruses, but with little success.9 Our studies of the X-linked lymphoproliferative syndrome and immune deficiency to Epstein-Barr virus with fatal infectious mononucleosis or malignant lymphoma in males is a model for viral induced oncogenesis. 10 Supporting evidence stems from acquired immunodeficiency in transplant recipients as being a factor in the frequent occurrence of opportunistic lymphomas in this population." It seems plausible that the predominance of males with H.B.v. and hepatocarcinoma could be due to immunoincompetence which is based on mutant X-linked recessive immunoregulatory genes, differences in hormonal
milieu, or acquired immunodeficiency. University of Massachusetts Medical Center
Worcester, Massachusetts 01605, U.S.A
DAVID T. PURTILO
PREGNANCY, BREAST-CANCER RISK, AND MATERNAL-FETAL GENETICS
SIR,-In reviewing the epidemiological evidence linking pregnancy and breast-cancer risk I believe the data suggest that pregnancy has a biphasic effect on subsequent breastcancer risk-an adverse effect in the short run and a beneficial effect in the long run. The biological explanation for this may lie in the immunological similarity between fetal and malignant cells, described by Castro et al. and others. The epidemiological evidence linking pregnancy to breastcancer risk is extensive and controversial. A comprehensive review of the evidence is not possible here. In general, single women2 have higher rates of breast cancer than do married women, and this is thought to be a beneficial after-effect of pregnancy.3 There is a small but, I believe, biologically important exception to this pattern. The rates of breast cancer in single and married women cross each other about 35 or 40 years of age. This was first reported by Deelman4and later by Lilienfeld.2 From the mid-20’s, when breast-cancer rates begin to rise, until about 35 or 40 years of age, married women have a higher rate of breast cancer than single women. Single women have higher rates from 35 or 40 on. The table presents data from the New York Cancer Registry and shows the proportion of single women among breast-cancer cases and nonbreast-cancer cases, by age-group. There is a deficit of single women among the breast-cancer cases until 40 years of age, and a slight excess thereafter. This is consistent with the crossover shown previously by Deelman and Lilienfeld. If one accepts that the basic reason for the different rates between married and single women is some effect from pregnancy, then it is not unreasonable to suggest that pregnancy can increase the risk of breast cancer for a short and limited period of time. A second piece of epidemiological evidence suggesting that pregnancy promotes before it protects involves the sex of the first offspring among breast-cancer patients. Juret et al.5 reported that breast-cancer patients whose first child was a son
1. Tekekoshi, Y.,
Shida, N., Saheki, Y., Tanaka, M., Satake, Y., Matsumoto, S. Lancet, 1978, ii, 1065. 2. Trichopoulos, D., Gerety, R. J., Sparos, L., Tabor, E., Xirouchaki, E., Munoz, N., Linsell, C. A. ibid. 1978, ii, 1211. 3. Lancet, 1978, ii, 1241. 4. Purtilo, D. T., Hallgren, H. M., Yunis, E. J. ibid. 1972, i, 767. 5. Goodman, M., and others. Pediatrics, 1971, 48, 907. 6. London, W. T., Drew, J. S. Proc. natn. Acad. Sci. U.S.A. 1977, 74, 2561. 7. Drew, J. S., London, W. T., Lustbader, E. D., Hesser, J. E., Blumberg, B. S.Science, 1978, 201, 687. 8. Purtilo, D. T., Gottleib, L. S. Cancer, 1973, 32, 458.
9. Klein, P. A., Smith, R. T. Ann. Rev. Med. 1977, 28, 311. 10. Purtilo, D. T., and others. New Engl. J. Med 1977, 297, 1077. 11. Penn, I. Transplant. Proc. 1977, 9, 1133. 1. Castro, J. E., Lance, E. M., Medawar, P. B., and others. Nature, 1973, 243, 225. 2. Lilienfeld, A. M. Cancer Res.
1963, 23, 1503.
3. MacMahon, B., Cole, P., Brown, J. J. Natn. Cancer Inst. 1973, 4. Deelman, H. T. Z. Krebsforsch. 1920, 17, 164. 5. Juret, P., and others. Lancet, 1978, i, 415.
30, 21.
328 1970-77
REGISTRY DATA FOR NEW YORK STATE EXCLUSIVE OF
NEW YORK CITY
(WHITE WOMEN)
groups
are
required before it
tion screening,
as
can be recommended for Moncada et al. claim.
popula-
Department of Dermatology, Bristol Royal Infirmary,
J. L. BURTON
Bristol BS2 8HW
PHAGE TYPING OF GROUP B STREPTOCOCCI
*
Excludes breast cancer and carcinoma M=married.
(in situ) of cervix.
S=single.
prognosis than those whose first child was a In studying young breast-cancer patients (
apparently widespread habit, and we must hope that youngsters will not follow the dangerous example now being set by English and Australian test cricketers. The controversy over short-pitched bowling and the risk of injury to batsmen goes on, while in gum chewing we have a real danger to cricketers that could easily be eliminated. University Department of Surgery, General Hospital,
Nottingham NG1
6HA
J. B. BOURKE
X-ASSOCIATED IMMUNOCOMPETENCE The Lancet on hepatitis B virus have revealed a marked predominance of males affected by membranous nephropathy (M.N.)’ and hepatocarcinoma (H.C.j.2 A third article indicates a possible influence of H.B.v. on the sex ratio.3 Despite there being a male:female ratio of greater than 4:1 for M.N. and H.c., the possibility that the male predominance of these disorders could be due to X-associated immunodeficiency to H.B.v. was not considered.!.2 9 of the 11 Japanese patients with M.N.’ were males and all were positive for HB surface antigen (HBJ whereas none had anti-HB, in serum. 6 of the 11 mothers of the children were positive for REs and one had anti-HBs’ It seems to me that this male predominance of M.N. could be associated with inferior immunocompetence to H.B.v. of males as compared to females. Immunodeficiency could be partly responsible for the predominance of males with H.B.v. and associated M.N. and H.c. J. L. Sullivan and I have recently reviewed evidence (to be published elsewhere) which demonstrates immunological bases for superior immunocompetence and survival of females. Males experience more frequent and severe illness and higher mortality from many common infectious and neoplastic disorders than do females. This superior immunocompetence probably compensates for the immunosuppression which accompanies pregnancy.4 Females have higher serum-IgM concentrations, superior ability to form antibodies to infectious agents, and experience lower incidence of viral and bacteriological infectious diseases. Similarly, females have a lower incidence of most malignancies. Defective immune responses in males could account for their being frequent carriers of viruses such as H.B.v. Heptatitis B carrier states occur three times more frequently in males than in females.5 In contrast, antibody to HBs develops approximately three times more often in females than in males.6 Drew et al.7 have postulated cross-reactivity between H.B.v. and a human male-determined tissue antigen as being responsible for the sex ratio. They have suggested that males, being self-tolerant, possess weaker immune defences against H.B.v., resulting in disproportionate losses of male infants. Possibly, another factor to be evaluated is the apparent lack of immunocompetence of males to H.B.v. caused by mutant X-linked recessive immunoregulatory genes or weaker immune responsiveness than females from differences in hormonal milieu. Our study of cirrhosis and H.c. at Boston City Hospital during 1917-68 had revealed a striking male predominance which was associated with cirrhosis and chronic alcoholism.8 After having personally observed numerous alcoholic vagrants drinking in Boston, we had speculated that H.B.v. could have acted synergistically with alcoholism to provoke cirrhosis and H.c. The study performed by Trichopoulos et al. has revealed
SIR,—Recent articles in
(H.B.v.)
a high prevalence of active or past H.B.v. infections in 80 Greek patients with H.c., and 86% of the patients were males. They found active infection with H.B.v. as detected by the presence of HB, or anti-HB core antigen, but anti-HBs was lacking. Despite the lack of anti-BHs Trichopoulos et al. did not speculate that immunodeficiency to H.B.v. could have been a major factor in the emergence of H.c. Considerable effort has been directed toward finding human oncogenic viruses, but with little success.9 Our studies of the X-linked lymphoproliferative syndrome and immune deficiency to Epstein-Barr virus with fatal infectious mononucleosis or malignant lymphoma in males is a model for viral induced oncogenesis. 10 Supporting evidence stems from acquired immunodeficiency in transplant recipients as being a factor in the frequent occurrence of opportunistic lymphomas in this population." It seems plausible that the predominance of males with H.B.v. and hepatocarcinoma could be due to immunoincompetence which is based on mutant X-linked recessive immunoregulatory genes, differences in hormonal
milieu, or acquired immunodeficiency. University of Massachusetts Medical Center
Worcester, Massachusetts 01605, U.S.A
DAVID T. PURTILO
PREGNANCY, BREAST-CANCER RISK, AND MATERNAL-FETAL GENETICS
SIR,-In reviewing the epidemiological evidence linking pregnancy and breast-cancer risk I believe the data suggest that pregnancy has a biphasic effect on subsequent breastcancer risk-an adverse effect in the short run and a beneficial effect in the long run. The biological explanation for this may lie in the immunological similarity between fetal and malignant cells, described by Castro et al. and others. The epidemiological evidence linking pregnancy to breastcancer risk is extensive and controversial. A comprehensive review of the evidence is not possible here. In general, single women2 have higher rates of breast cancer than do married women, and this is thought to be a beneficial after-effect of pregnancy.3 There is a small but, I believe, biologically important exception to this pattern. The rates of breast cancer in single and married women cross each other about 35 or 40 years of age. This was first reported by Deelman4and later by Lilienfeld.2 From the mid-20’s, when breast-cancer rates begin to rise, until about 35 or 40 years of age, married women have a higher rate of breast cancer than single women. Single women have higher rates from 35 or 40 on. The table presents data from the New York Cancer Registry and shows the proportion of single women among breast-cancer cases and nonbreast-cancer cases, by age-group. There is a deficit of single women among the breast-cancer cases until 40 years of age, and a slight excess thereafter. This is consistent with the crossover shown previously by Deelman and Lilienfeld. If one accepts that the basic reason for the different rates between married and single women is some effect from pregnancy, then it is not unreasonable to suggest that pregnancy can increase the risk of breast cancer for a short and limited period of time. A second piece of epidemiological evidence suggesting that pregnancy promotes before it protects involves the sex of the first offspring among breast-cancer patients. Juret et al.5 reported that breast-cancer patients whose first child was a son
1. Tekekoshi, Y.,
Shida, N., Saheki, Y., Tanaka, M., Satake, Y., Matsumoto, S. Lancet, 1978, ii, 1065. 2. Trichopoulos, D., Gerety, R. J., Sparos, L., Tabor, E., Xirouchaki, E., Munoz, N., Linsell, C. A. ibid. 1978, ii, 1211. 3. Lancet, 1978, ii, 1241. 4. Purtilo, D. T., Hallgren, H. M., Yunis, E. J. ibid. 1972, i, 767. 5. Goodman, M., and others. Pediatrics, 1971, 48, 907. 6. London, W. T., Drew, J. S. Proc. natn. Acad. Sci. U.S.A. 1977, 74, 2561. 7. Drew, J. S., London, W. T., Lustbader, E. D., Hesser, J. E., Blumberg, B. S.Science, 1978, 201, 687. 8. Purtilo, D. T., Gottleib, L. S. Cancer, 1973, 32, 458.
9. Klein, P. A., Smith, R. T. Ann. Rev. Med. 1977, 28, 311. 10. Purtilo, D. T., and others. New Engl. J. Med 1977, 297, 1077. 11. Penn, I. Transplant. Proc. 1977, 9, 1133. 1. Castro, J. E., Lance, E. M., Medawar, P. B., and others. Nature, 1973, 243, 225. 2. Lilienfeld, A. M. Cancer Res.
1963, 23, 1503.
3. MacMahon, B., Cole, P., Brown, J. J. Natn. Cancer Inst. 1973, 4. Deelman, H. T. Z. Krebsforsch. 1920, 17, 164. 5. Juret, P., and others. Lancet, 1978, i, 415.
30, 21.
328 1970-77
REGISTRY DATA FOR NEW YORK STATE EXCLUSIVE OF
NEW YORK CITY
(WHITE WOMEN)
groups
are
required before it
tion screening,
as
can be recommended for Moncada et al. claim.
popula-
Department of Dermatology, Bristol Royal Infirmary,
J. L. BURTON
Bristol BS2 8HW
PHAGE TYPING OF GROUP B STREPTOCOCCI
*
Excludes breast cancer and carcinoma M=married.
(in situ) of cervix.
S=single.
prognosis than those whose first child was a In studying young breast-cancer patients (
