250
important. Advanced reticulum-cell sarcoma (diffuse hisiiocytic lymphoma) is thought to be invariably fatal and only temporarily responsive to chemotherapy.u,12 We had only three patients with long-term disease-free survival in our first trial of M.O.P.P. in non-Hodgkin’s lymphoma; in most patients with lymphocytic lymphomas the regimen was relatively ineffective 13 Because of these early results further patients with diffuse histiocytic lymphoma were treated with M.O.P.P. or C.-M.O.P.P.
and constitute the present series. We know
only one other series with long-term survival, first reported in 1972 14 and updated 15: six of eight patients with diffuse histiocytic lymphoma achieved a complete of
remission with a drug combination. All had advanced disease, and five of the six patients remained free of disease after all treatment was discontinued from 39+ to 51 + months at the time of the report in March of 1974, with a median time free of disease of 43 + months. Median survival for patients with stage ill and IV reticulum-cell sarcoma or histiocytic lymphoma has been 6-9 months in most series, including those from Stanford University and the National Cancer Institute .6, 11 These data suggest that, because of the aggressive nature of the disease and its rapid evolution, most patients with advanced tumour die within 2 years of diagnosis. Against this background the unusually long survival of the complete responders in our series is striking, though the median survival for the series as a whole is 9 months. The median survival of patients with stage-n disease is approximately double that of patients with advanced tumour.17 However, the slopes of the survival curves for patients with localised and advanced disease become similar between 2 and 3 years. One interpretation of the data is that most patients with apparently localised histiocytic lymphoma have undetected disease outside normal radiation fields, and that the difference in median survival-time reflects the time for disease outside the radiation field-and, therefore, untreated by radiotherapy-to become clinically apparent. It seems that patients who are alive 2 years after the end of treatment and are free of all evidence of disease rarely relapse, as evidenced by the flat survival curves beyond 2-3 years reported here and in the literature. These patients seem to be well beyond the high-risk period of relapse and may be thought of as cured of their primary disease. This definition, previously used onlyin radiotherapy studies,ls also seems applicable to patients who achieve a complete remission by drug treatment. In our series 37% of patients with advanced diffuse histiocytic lymphoma treated with M.O.P.P. or c.-M.o.p.p. have had prolonged disease-free survivals. These results exceed those achieved by radiotherapy in localised (stage 11) disIf advanced diffuse histioease in most studies cytic lymphoma is a drug-curable disease in a significant fraction of patients, combination chemotherapy deserves a trial, with or without radiotherapy, in patients with stage 11 nodal and extranodal primary when the tumour-cell volume is small and hence chances of successful eradication of tumour by drugs should be greatly enhanced. Requests for reprints should,be addressed to V. T. DeVita.
HETEROZYGOUS ALPHA1-ANTITRYPSIN DEFICIENCY AND CIRRHOSIS IN ADULTS, A FORTUITOUS ASSOCIATION T. MORIN
J.-P. MARTIN
G. FELDMANN
B. RUEFF
C. ROPARTZ J.-P. BENHAMOU Research Unit (I.N.S.E.R.M.), Hepatic Pathophysiology Hôpital Beaujon, Clichy; and Departmental Blood Transfusion Centre and Research Group on the Genetics of Human Proteins (I.N.S.E.R.M.),
Bois-Guillaume, France Pi (protease inhibitor) genotype was determined in 394 healthy blooddonors, 132 adult patients with alcoholic cirrhosis, and 37 adult patients with cryptogenic cirrhosis. The frequency of the heterozygous genotype with a single allele Pi Z (heterozygous alpha1-antitrypsin deficiency) was not different in blood-donors and in patients with cirrhosis. This finding suggests that the association of this heterozygous genotype with cirrhosis is not causal but fortuitous and that this heterozygous genotype does not increase susceptibility to cirrhosis due to other causes, in particular alcoholism.
Summary
Introduction THE pattern of
serum
alphai-antitrypsin (al-A.T.)
is
genetically determined by a number of codominant alleles 1; these alleles constitute the Pi (protease inhibiallele is Pi M,I,3 and the is homozygous one Pi frequent genotype Pi ZZ (homozygous a1-A.T. deGenotype is associated with a ficiency) high risk of severe emdisease in adult and child.*** liver physema and/or The heterozygous genotype with a single allele Pi Z (heterozygous al-A.T. deficiency) has been reported in association with cirrhosis, and it has been suggested that this heterozygous genotype might increase suscep-
tor) system.2 The
most
frequent
the most MM.l.3
DR DEVITA AND OTHERS : REFERENCES
Kaplan, H. S. Harvey Lect. 1970, 64, 215. Lukes, R. J., Butler, J. J., Hicks, E. D. Cancer, 1966, 19, 317. Rappaport, H. Atlas of Tumour Pathology; section II, fasc. 8, p. 101. Armed Forces Institute of Pathology, Washington, 1966. 4. Ferguson, D. J., Allen, L. W., Griem, M. L., Moran, M. E., Rappaport, J., Ultmann, J. E. Archs intern. Med. 1973, 131, 356. 5. Johnson, R. E., Chretian, P. B., O’Conor, G. T., DeVita, V. T., Thomas, L. B. Radiology, 1974, 110, 665. 6. Schein, P. S., Chabner, B. A., Canellos, G. P., Young, R. C., Berard, C., DeVita, V. T. Blood, 1974, 43, 181. 7. Berard, C. W., in Williams, W. J., Beutler, E., Erslev, A. J., Rundles, W. (editors). Hematology; p. 901. New York, 1972. 8. Jones, S. E., Fuks, Z., Bull, M., Kadin, M. E., Dorfman, R. F., Kaplan, H. S., Rosenberg, S. A., Kim, H. Cancer, 1973, 31, 806. 9. DeVita, V. T., Serpick, A. A., Carbone, P. P. Ann. intern. Med. 1970, 73, 881. 10. Carbone, P. P., Kaplan, H. S., Musshoff, K., Smithers, D. W., Tubiana, M. Cancer Res. 1971, 31, 1860. 11. Muggia, F. M., Ultmann, J. E. Cancer, 1972, 30, 454. 12. Fuks, Z., Kaplan, H. S. Radiology, 1973, 108, 675. 13. Lowenbraum, S., DeVita, V. T., Serpick, A. A. Cancer, 1970, 25, 1. 2. 3.
1018.
Levitt, M., Marsh, J. C., DeConti, R. C., Mitchell, M. S., Skeel, R. T., Farber, L. R., Bertino, J. R. ibid. 1972, 29, 630. 15. Berd, D., Cornog, J., Dorfman, R., Bertino, J., DeConti, R., Marsh, J., Levitt, M. Abstr. Proc. Am. Soc. clin. Onc. 1974, 15, 175. 16. Jones, S. E., Rosenberg, S. A., Kaplan, H. S., Kadin, M. E., Dorfman, R. F. Cancer, 1972, 30, 31. 17. Jones, S. E., Fuks, Z., Kaplan, H. S., Rosenberg, S. A. ibid. 1973, 32, 682. 18. Newall, J., Freidman, M. Radiology, 1970, 97, 99. 14.
251 TABLE
I-FREQUENCY OF THE DIFFERENT Pi GENOTYPES IN BLOOD-DONORS AND IN PATIENTS WITH ALCOHOLIC
OR CRYPTOGENIC CIRRHOSIS
The frequency of Pi genotypes MM, MS, MZ, and " other " is not statistically different in blood-donors and in patients with either alcoholic cryptogenic cirrhosis (X2 for 3 degrees of freedom 1-22 and 1-94, p > 0-70 and > 0-50, respectively).
tibility to cirrhosis associated with other causes.7,9 However, neither cirrhosis nor the heterozygous genotype with a single allele Pi Z are uncommon, and a cannot be excluded. We have the compared frequency of the different Pi genotypes, in particular the heterozygous genotype with a single allele Pi Z, in healthy adults and in patients with
fortuitous association
cirrhosis.
Patients, Controls, and
Methods
Healthy adults and patients with cirrhosis, all from northern France, mainly Normandy and Paris, were investigated. There were 394 unselected, apparently healthy blood-donors, and 169 adults with cirrhosis of the liver. In 105 patients, the cirrhosis was histologically proven, and in the remainder the diagnosis was based on clinical examination, liver-function tests, and peritoneoscopy. In 132 patients, cirrhosis was considered to be the consequence of chronic alcoholism: daily alcohol intake was 100 g. or more and no other cause of cirrhosis had been found. In 37, the cause of the cirrhosis was obscure (cryptogenic). The pattern of serum ai-A.T. was determined in duplicate according to the method of Fagerhol and Laurell.2 The percentages of the different Pi genotypes and of the different Pi alleles in the group of blood-donors, and in the subgroups of patients with alcoholic or cryptogenic cirrhosis, were compared by using the x2-test.
or
different in healthy adults and in patients with cirrhosis suggests strongly that the reported association between cirrhosis and heterozygous
important. Advanced reticulum-cell sarcoma (diffuse hisiiocytic lymphoma) is thought to be invariably fatal and only temporarily responsive to chemotherapy.u,12 We had only three patients with long-term disease-free survival in our first trial of M.O.P.P. in non-Hodgkin’s lymphoma; in most patients with lymphocytic lymphomas the regimen was relatively ineffective 13 Because of these early results further patients with diffuse histiocytic lymphoma were treated with M.O.P.P. or C.-M.O.P.P.
and constitute the present series. We know
only one other series with long-term survival, first reported in 1972 14 and updated 15: six of eight patients with diffuse histiocytic lymphoma achieved a complete of
remission with a drug combination. All had advanced disease, and five of the six patients remained free of disease after all treatment was discontinued from 39+ to 51 + months at the time of the report in March of 1974, with a median time free of disease of 43 + months. Median survival for patients with stage ill and IV reticulum-cell sarcoma or histiocytic lymphoma has been 6-9 months in most series, including those from Stanford University and the National Cancer Institute .6, 11 These data suggest that, because of the aggressive nature of the disease and its rapid evolution, most patients with advanced tumour die within 2 years of diagnosis. Against this background the unusually long survival of the complete responders in our series is striking, though the median survival for the series as a whole is 9 months. The median survival of patients with stage-n disease is approximately double that of patients with advanced tumour.17 However, the slopes of the survival curves for patients with localised and advanced disease become similar between 2 and 3 years. One interpretation of the data is that most patients with apparently localised histiocytic lymphoma have undetected disease outside normal radiation fields, and that the difference in median survival-time reflects the time for disease outside the radiation field-and, therefore, untreated by radiotherapy-to become clinically apparent. It seems that patients who are alive 2 years after the end of treatment and are free of all evidence of disease rarely relapse, as evidenced by the flat survival curves beyond 2-3 years reported here and in the literature. These patients seem to be well beyond the high-risk period of relapse and may be thought of as cured of their primary disease. This definition, previously used onlyin radiotherapy studies,ls also seems applicable to patients who achieve a complete remission by drug treatment. In our series 37% of patients with advanced diffuse histiocytic lymphoma treated with M.O.P.P. or c.-M.o.p.p. have had prolonged disease-free survivals. These results exceed those achieved by radiotherapy in localised (stage 11) disIf advanced diffuse histioease in most studies cytic lymphoma is a drug-curable disease in a significant fraction of patients, combination chemotherapy deserves a trial, with or without radiotherapy, in patients with stage 11 nodal and extranodal primary when the tumour-cell volume is small and hence chances of successful eradication of tumour by drugs should be greatly enhanced. Requests for reprints should,be addressed to V. T. DeVita.
HETEROZYGOUS ALPHA1-ANTITRYPSIN DEFICIENCY AND CIRRHOSIS IN ADULTS, A FORTUITOUS ASSOCIATION T. MORIN
J.-P. MARTIN
G. FELDMANN
B. RUEFF
C. ROPARTZ J.-P. BENHAMOU Research Unit (I.N.S.E.R.M.), Hepatic Pathophysiology Hôpital Beaujon, Clichy; and Departmental Blood Transfusion Centre and Research Group on the Genetics of Human Proteins (I.N.S.E.R.M.),
Bois-Guillaume, France Pi (protease inhibitor) genotype was determined in 394 healthy blooddonors, 132 adult patients with alcoholic cirrhosis, and 37 adult patients with cryptogenic cirrhosis. The frequency of the heterozygous genotype with a single allele Pi Z (heterozygous alpha1-antitrypsin deficiency) was not different in blood-donors and in patients with cirrhosis. This finding suggests that the association of this heterozygous genotype with cirrhosis is not causal but fortuitous and that this heterozygous genotype does not increase susceptibility to cirrhosis due to other causes, in particular alcoholism.
Summary
Introduction THE pattern of
serum
alphai-antitrypsin (al-A.T.)
is
genetically determined by a number of codominant alleles 1; these alleles constitute the Pi (protease inhibiallele is Pi M,I,3 and the is homozygous one Pi frequent genotype Pi ZZ (homozygous a1-A.T. deGenotype is associated with a ficiency) high risk of severe emdisease in adult and child.*** liver physema and/or The heterozygous genotype with a single allele Pi Z (heterozygous al-A.T. deficiency) has been reported in association with cirrhosis, and it has been suggested that this heterozygous genotype might increase suscep-
tor) system.2 The
most
frequent
the most MM.l.3
DR DEVITA AND OTHERS : REFERENCES
Kaplan, H. S. Harvey Lect. 1970, 64, 215. Lukes, R. J., Butler, J. J., Hicks, E. D. Cancer, 1966, 19, 317. Rappaport, H. Atlas of Tumour Pathology; section II, fasc. 8, p. 101. Armed Forces Institute of Pathology, Washington, 1966. 4. Ferguson, D. J., Allen, L. W., Griem, M. L., Moran, M. E., Rappaport, J., Ultmann, J. E. Archs intern. Med. 1973, 131, 356. 5. Johnson, R. E., Chretian, P. B., O’Conor, G. T., DeVita, V. T., Thomas, L. B. Radiology, 1974, 110, 665. 6. Schein, P. S., Chabner, B. A., Canellos, G. P., Young, R. C., Berard, C., DeVita, V. T. Blood, 1974, 43, 181. 7. Berard, C. W., in Williams, W. J., Beutler, E., Erslev, A. J., Rundles, W. (editors). Hematology; p. 901. New York, 1972. 8. Jones, S. E., Fuks, Z., Bull, M., Kadin, M. E., Dorfman, R. F., Kaplan, H. S., Rosenberg, S. A., Kim, H. Cancer, 1973, 31, 806. 9. DeVita, V. T., Serpick, A. A., Carbone, P. P. Ann. intern. Med. 1970, 73, 881. 10. Carbone, P. P., Kaplan, H. S., Musshoff, K., Smithers, D. W., Tubiana, M. Cancer Res. 1971, 31, 1860. 11. Muggia, F. M., Ultmann, J. E. Cancer, 1972, 30, 454. 12. Fuks, Z., Kaplan, H. S. Radiology, 1973, 108, 675. 13. Lowenbraum, S., DeVita, V. T., Serpick, A. A. Cancer, 1970, 25, 1. 2. 3.
1018.
Levitt, M., Marsh, J. C., DeConti, R. C., Mitchell, M. S., Skeel, R. T., Farber, L. R., Bertino, J. R. ibid. 1972, 29, 630. 15. Berd, D., Cornog, J., Dorfman, R., Bertino, J., DeConti, R., Marsh, J., Levitt, M. Abstr. Proc. Am. Soc. clin. Onc. 1974, 15, 175. 16. Jones, S. E., Rosenberg, S. A., Kaplan, H. S., Kadin, M. E., Dorfman, R. F. Cancer, 1972, 30, 31. 17. Jones, S. E., Fuks, Z., Kaplan, H. S., Rosenberg, S. A. ibid. 1973, 32, 682. 18. Newall, J., Freidman, M. Radiology, 1970, 97, 99. 14.
251 TABLE
I-FREQUENCY OF THE DIFFERENT Pi GENOTYPES IN BLOOD-DONORS AND IN PATIENTS WITH ALCOHOLIC
OR CRYPTOGENIC CIRRHOSIS
The frequency of Pi genotypes MM, MS, MZ, and " other " is not statistically different in blood-donors and in patients with either alcoholic cryptogenic cirrhosis (X2 for 3 degrees of freedom 1-22 and 1-94, p > 0-70 and > 0-50, respectively).
tibility to cirrhosis associated with other causes.7,9 However, neither cirrhosis nor the heterozygous genotype with a single allele Pi Z are uncommon, and a cannot be excluded. We have the compared frequency of the different Pi genotypes, in particular the heterozygous genotype with a single allele Pi Z, in healthy adults and in patients with
fortuitous association
cirrhosis.
Patients, Controls, and
Methods
Healthy adults and patients with cirrhosis, all from northern France, mainly Normandy and Paris, were investigated. There were 394 unselected, apparently healthy blood-donors, and 169 adults with cirrhosis of the liver. In 105 patients, the cirrhosis was histologically proven, and in the remainder the diagnosis was based on clinical examination, liver-function tests, and peritoneoscopy. In 132 patients, cirrhosis was considered to be the consequence of chronic alcoholism: daily alcohol intake was 100 g. or more and no other cause of cirrhosis had been found. In 37, the cause of the cirrhosis was obscure (cryptogenic). The pattern of serum ai-A.T. was determined in duplicate according to the method of Fagerhol and Laurell.2 The percentages of the different Pi genotypes and of the different Pi alleles in the group of blood-donors, and in the subgroups of patients with alcoholic or cryptogenic cirrhosis, were compared by using the x2-test.
or
different in healthy adults and in patients with cirrhosis suggests strongly that the reported association between cirrhosis and heterozygous
