- Email: [email protected]
E.B. VIRUS AND BURKITT'S LYMPHOMA
742
independent of each other.1 In a long-term series of readings on one individual these deviations are, in fact, unlikely to be independently distributed. If one observation is somewhat above the mean it is likely that neighbouring observations will also be somewhat higher than expected.2 In these circumstances an assumption of independence will lead to many spurious claims of statistical significance. It is usually difficult to decide in a particular situation whether or not the deviations are independent. In the absence of a-priori information such an assessment can be made only through measurements recorded during an initial period when the patient is in a " steady state Very often, however, this is not a practical possibility. When the clinician is ignorant of the nature of the deviations he would do better to work with his cusum chart without any probability statements rather than to rely heavily on possibly erroneous statistical significances. M.R.C. Statistical Research and Services Unit, 115 Gower Street, London WC1E 6AS.
L. FREEDMAN.
R. H., Goldsmith, P. L. Cumulative Sum Techniques. Mathematical and Statistical Techniques for Industry; monograph no. 3. Edinburgh, 1964. 2. Armitage, P. Statistical Methods in Medical Research; p. 347. Oxford, 1971.
1.
Woodward,
B-CELL MITOGEN IN HYPERGAMMAGLOBULINÆAMIA IN MALARIA AND TRYPANOSOMIASIS
SIR,-Dr Greenwood (March 16, p. 435) speculated on the possibility that a B-cell mitogen exists in plasmodia and trypanosomes which may be responsible for the hypergammaglobulinsemia and autoantibody production in malaria and sleeping-sickness.1 In this regard, we have studied the in-vitro proliferative response to a malaria antigen preparation of lymphocytes from 15 patients with documented previous infections with Plasmodium falciparum, normal controls without malaria exposure, and normal cord-blood samples.1 The antigen was prepared by obtaining an aqueous extract of saponin-lysed, crushed erythrocytes from owl monkeys (Aotus trivirgatus) infected with P. falciparum. At low (1 {.tg. protein per culture) concentrations of this preparation, a specific proliferative response was seen only in people with a history of malaria. In contrast, at higher concentrations (10 g. per culture) lymphocytes from 7 of 9 control individuals and 2 of 4 cord-blood specimens showed significant non-specific proliferation. These results would indicate that indeed a specific antigen as well as non-specific mitogen is contained in our heterogeneous malaria antigen preparation. We are investigating whether this mitogenic principle is a B-cell or T-cell mitogen, and it is quite possible that the mitogen stimulates a polyclonal population of B-cells non-specifically, as suggested by Dr Greenwood. Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20014, U.S.A. 1.
Wyler, D. J., Oppenheim, J. J. J.
DAVID Immun.
J. WYLER.
(in the press).
could result in a situation where the malaria-infected individual is so busy producing these non-specific and useless antibodies that he is unable to recognise or respond to the threat posed by the development of a small clone of malignant lymphoid cells. As a result these cells escape destruction for a sufficient period of time to establish the
malignant lymphomatous
process.
We can therefore extend Greenwood’s statement, " Stimulation of a pronounced and disordered immunoglobulin response could, however, benefit the parasite by swamping a specific immunological response aimed at its destruction," to the concept that another processnamely, Burkitt’s lymphoma-could equally be benefited. 1430 Esplanade, ALBERT E. WARRENS. Chico, California 95926, U.S.A. E.B. VIRUS AND BURKITT’S LYMPHOMA
SIR,-Last year we reported1 the lack of association between Epstein-Barr virus (E.B.v.) infection and American Burkitt’s lymphoma. In response, Dr Levine and Dr O’Conor wrote2 that the absence of E.B.v. antibody in a significant number of patients with this disease is not sufficient cause for excluding this virus as a possible aetiological agent. They emphasise their findings3 that in a subgroup of the American cases resembling Burkitt’s lymphoma-those occurring in children under 8 years of age-E.B.v. antibody titres were considerably higher than in controls. It is important to recognise that their subgroup consisted of 7 individuals whose antibody titres were compared with those of a larger number of controls (not individually matched). The obvious pitfall in drawing any conclusion from a sample of this size was well stated in their paper: " the number is too small to make reliable conclusions possible ". Our own series was sufficiently large to permit statistical analysis of differences in E.B.v. antibody titres in the sera of American Burkitt’s lymphoma patients and age-matched and sex-matched controls. No significant differences were found. In addition, the disinitial group of 12 American patients parity between an " (referred to2 as a small subgroup ") studied by Levine and co-workers who were serologically identical to controls,4 and a subsequent group of 17 whom they feel show significant differences from controls,3 is not explained. This intra-group variation raises questions regarding variability in the assay employed, differences in the control groups used, or changing factors in the selection of cases. This anomaly should be confronted before conclusions are drawn about comparisons of the group as a whole with other groups. Furthermore, Dr Levine is a co-author of a recent report indicating the absence of E.B.v. genome in American Burkitt’s lymphoma tumours.Ó The authors of this study state: " The apparent absence of the viral DNA in the American tumour tissue seems to militate against a role for EBV in American Burkitt’s lymphoma." We agree with this interpretation, and feel it supports our contention, on seroepidemiological grounds, that E.B.v. is unlikely to be responsible for Burkitt’s lymphoma in the United States. Memorial Sloan-Kettering Cancer Center, New York, N.Y., U.S.A.
YASHAR HIRSHAUT.
National Cancer
BURKITT’S LYMPHOMA AND DISORDERED IMMUNOGLOBULIN RESPONSE
SiRj—Dr Greenwood’s paper may help to explain the relationship between malaria and Burkitt’s lymphoma. The correlation of Burkitt’s lymphoma with areas of high malaria infestation is well known. The suggestion by Dr Greenwood that the very large amount of serum-immunoglobulins produced in response to malaria are non-specific
Institute, Bethesda, Maryland. Santa Clara Valley Medical Center, San Jose, California.
MARTIN H. COHEN. DAVID A. STEVENS.
1. Hirshaut, Y., Cohen, M. H., Stevens, D. A. Lancet, 1973, ii, 114. 2. Levine, P. H., O’Conor, G. ibid. p. 850. 3. Levine, P. H., O’Conor, G. T., Berard, C. W. Cancer, 1972, 30, 610. 4. Levine P. H., Ablashi, D. V., Berard, C. W., Carbone, P. P., Waggoner, D. W., Malan, L. ibid. 1971, 27, 416. 5. Pagano, J. S., Huang, C. H., Levine, P. New Engl. J. Med. 1973, 289, 1395.
independent of each other.1 In a long-term series of readings on one individual these deviations are, in fact, unlikely to be independently distributed. If one observation is somewhat above the mean it is likely that neighbouring observations will also be somewhat higher than expected.2 In these circumstances an assumption of independence will lead to many spurious claims of statistical significance. It is usually difficult to decide in a particular situation whether or not the deviations are independent. In the absence of a-priori information such an assessment can be made only through measurements recorded during an initial period when the patient is in a " steady state Very often, however, this is not a practical possibility. When the clinician is ignorant of the nature of the deviations he would do better to work with his cusum chart without any probability statements rather than to rely heavily on possibly erroneous statistical significances. M.R.C. Statistical Research and Services Unit, 115 Gower Street, London WC1E 6AS.
L. FREEDMAN.
R. H., Goldsmith, P. L. Cumulative Sum Techniques. Mathematical and Statistical Techniques for Industry; monograph no. 3. Edinburgh, 1964. 2. Armitage, P. Statistical Methods in Medical Research; p. 347. Oxford, 1971.
1.
Woodward,
B-CELL MITOGEN IN HYPERGAMMAGLOBULINÆAMIA IN MALARIA AND TRYPANOSOMIASIS
SIR,-Dr Greenwood (March 16, p. 435) speculated on the possibility that a B-cell mitogen exists in plasmodia and trypanosomes which may be responsible for the hypergammaglobulinsemia and autoantibody production in malaria and sleeping-sickness.1 In this regard, we have studied the in-vitro proliferative response to a malaria antigen preparation of lymphocytes from 15 patients with documented previous infections with Plasmodium falciparum, normal controls without malaria exposure, and normal cord-blood samples.1 The antigen was prepared by obtaining an aqueous extract of saponin-lysed, crushed erythrocytes from owl monkeys (Aotus trivirgatus) infected with P. falciparum. At low (1 {.tg. protein per culture) concentrations of this preparation, a specific proliferative response was seen only in people with a history of malaria. In contrast, at higher concentrations (10 g. per culture) lymphocytes from 7 of 9 control individuals and 2 of 4 cord-blood specimens showed significant non-specific proliferation. These results would indicate that indeed a specific antigen as well as non-specific mitogen is contained in our heterogeneous malaria antigen preparation. We are investigating whether this mitogenic principle is a B-cell or T-cell mitogen, and it is quite possible that the mitogen stimulates a polyclonal population of B-cells non-specifically, as suggested by Dr Greenwood. Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20014, U.S.A. 1.
Wyler, D. J., Oppenheim, J. J. J.
DAVID Immun.
J. WYLER.
(in the press).
could result in a situation where the malaria-infected individual is so busy producing these non-specific and useless antibodies that he is unable to recognise or respond to the threat posed by the development of a small clone of malignant lymphoid cells. As a result these cells escape destruction for a sufficient period of time to establish the
malignant lymphomatous
process.
We can therefore extend Greenwood’s statement, " Stimulation of a pronounced and disordered immunoglobulin response could, however, benefit the parasite by swamping a specific immunological response aimed at its destruction," to the concept that another processnamely, Burkitt’s lymphoma-could equally be benefited. 1430 Esplanade, ALBERT E. WARRENS. Chico, California 95926, U.S.A. E.B. VIRUS AND BURKITT’S LYMPHOMA
SIR,-Last year we reported1 the lack of association between Epstein-Barr virus (E.B.v.) infection and American Burkitt’s lymphoma. In response, Dr Levine and Dr O’Conor wrote2 that the absence of E.B.v. antibody in a significant number of patients with this disease is not sufficient cause for excluding this virus as a possible aetiological agent. They emphasise their findings3 that in a subgroup of the American cases resembling Burkitt’s lymphoma-those occurring in children under 8 years of age-E.B.v. antibody titres were considerably higher than in controls. It is important to recognise that their subgroup consisted of 7 individuals whose antibody titres were compared with those of a larger number of controls (not individually matched). The obvious pitfall in drawing any conclusion from a sample of this size was well stated in their paper: " the number is too small to make reliable conclusions possible ". Our own series was sufficiently large to permit statistical analysis of differences in E.B.v. antibody titres in the sera of American Burkitt’s lymphoma patients and age-matched and sex-matched controls. No significant differences were found. In addition, the disinitial group of 12 American patients parity between an " (referred to2 as a small subgroup ") studied by Levine and co-workers who were serologically identical to controls,4 and a subsequent group of 17 whom they feel show significant differences from controls,3 is not explained. This intra-group variation raises questions regarding variability in the assay employed, differences in the control groups used, or changing factors in the selection of cases. This anomaly should be confronted before conclusions are drawn about comparisons of the group as a whole with other groups. Furthermore, Dr Levine is a co-author of a recent report indicating the absence of E.B.v. genome in American Burkitt’s lymphoma tumours.Ó The authors of this study state: " The apparent absence of the viral DNA in the American tumour tissue seems to militate against a role for EBV in American Burkitt’s lymphoma." We agree with this interpretation, and feel it supports our contention, on seroepidemiological grounds, that E.B.v. is unlikely to be responsible for Burkitt’s lymphoma in the United States. Memorial Sloan-Kettering Cancer Center, New York, N.Y., U.S.A.
YASHAR HIRSHAUT.
National Cancer
BURKITT’S LYMPHOMA AND DISORDERED IMMUNOGLOBULIN RESPONSE
SiRj—Dr Greenwood’s paper may help to explain the relationship between malaria and Burkitt’s lymphoma. The correlation of Burkitt’s lymphoma with areas of high malaria infestation is well known. The suggestion by Dr Greenwood that the very large amount of serum-immunoglobulins produced in response to malaria are non-specific
Institute, Bethesda, Maryland. Santa Clara Valley Medical Center, San Jose, California.
MARTIN H. COHEN. DAVID A. STEVENS.
1. Hirshaut, Y., Cohen, M. H., Stevens, D. A. Lancet, 1973, ii, 114. 2. Levine, P. H., O’Conor, G. ibid. p. 850. 3. Levine, P. H., O’Conor, G. T., Berard, C. W. Cancer, 1972, 30, 610. 4. Levine P. H., Ablashi, D. V., Berard, C. W., Carbone, P. P., Waggoner, D. W., Malan, L. ibid. 1971, 27, 416. 5. Pagano, J. S., Huang, C. H., Levine, P. New Engl. J. Med. 1973, 289, 1395.