- Email: [email protected]
L-ASPARAGINASE AND ALLOGRAFT IMMUNITY
1365 IMMUNOGLOBULIN LEVELS
*
BEFORE, DURING,
AND AFTER
ASN-ASE*
Patients 1, 2, 3, and 7 received penicillin every 15 days; patient 7 was given aspirin (80 mg./kg./day); case 2 received 2 blood-transfusions (150+ 150 ml. on the llth day and on the 22nd day); case 3 received 1 blood-transfusion (150 ml. on 10th day).
Different dosages the treatment well tolerated.
was
were
used, and in
cases
very short because the
drug
4 and 8 was not
The results obtained show that often the
immunoglobulin values increased. IgG and IgM increased by 25% or more in 5 out of 8 and in 6 out of 8 patients respectively; IgA increased by 25% or more in all. It was exceptional for immunoglobulin values to fall. We think it unlikely that the changes in immunoglobulin levels were caused by the collateral treatment (used only in cases 1, 2, 3, and 7). It seems more likely that Asn-ase, at the dosages employed, acted as an antigen. 16, 17 Possibly the enzyme also produces nonspecific immunological stimulation or favours release of immunoglobulins into the bloodstream. Pædiatric Clinic, University of Pavia, and Blood Research Foundation Centre,
Tortona, Italy.
G. R. BURGIO R. VACCARO M. CLARA GASPARONI A. ASTALDI, JR.
C 57B 1 /6 mice were divided into three groups. Group 1 received intraperitoneal injections of 1000 I.U. L-asparaginase per kg. daily. After7 days’ treatment a skin allograft from a DBA/2 donor was applied, and L-asparaginase treatment was continued daily until the graft was rejected. Group 2 received a skin allograft from a DBA/2 donor. 1000 i.u. L-asparaginase per kg. was given intraperitoneally 24 hours after grafting and continued daily until graft rejection. Group 3 received normal saline solution (0-4 ml. per mouse) for 7 days. On day 8, a skin allograft from a DBA/2 donor was applied and daily saline treatment continued until the graft was rejected. There was only slight prolongation of graft survival when L-asparaginase was given before the application of the allograft. L-Asparaginase given after the application of an allograft showed no significant increase in survival over saline controls (see accompanying table). INFLUENCE OF L-ASPARAGINASE ON GRAFT
REJECTION
L-ASPARAGINASE AND ALLOGRAFT IMMUNITY
SIR The inhibitory effect of L-asparaginase on tumours is well established,18 and it has been shown that Escherichia coli L-asparaginase suppresses phytohæmagglutinin-induced blastogenesis.19-21 In addition, L-asparaginase considerably suppresses the humoral response 22-24 ; and in one reported case 24 injection of high doses slightly suppressed skin-graft rejection. We have investigated the effects of conventional doses of L-asparaginase on allograft survival in mice. 16. Khan, A., Hill, J. M. J. Lab. clin. Med. 1969, 73, 846. 17. Beard, M. E. J. Br. med. J. 1970, i, 191. 18. Old, L. J., Boyse, E. A., Campbell, H. A., Bradley, R. S., Fidler, J., Teller, J. D. Cancer, N. Y. 1967, 20, 1066. 19. Astaldi, G., Burgio, G. R., Krc, J., Genova, R., Astaldi, A. A. Lancet, 1969, i, 423. 20. McElwain, T. J., Hayward, S. K. ibid. p. 527. 21. Astaldi, G., Burgio, G. R., Biscotti, G., Astaldi, A., Ferfoglio, L. ibid. 1969, ii, 275. 22. Schwartz, R. S. Nature, 1969, 224, 275. 23. Chakrabarty, A. K., Friedman, H. Science, N.Y. 1970, 167, 869. 24. Nelson, S. D., Lee, M. B., Bridges, J. M. Transplantation, 1970, 9, 566.
All animals grafted on day 8. † Mean ± standard deviation. ‡As determined by Student’s test. § Not significant. a related investigation, the im--nunosuppressive effects L-asparaginase were evaluated in canine cardiac allografts. The hearts of mongrel dogs were reimplanted in the necks of 2 recipient dogs. Restoration of the circulation was accomplished by anastomoses between the innominate and subclavian arteries of the donor heart with the proximal and distal segments of the carotid arteries of the recipients.25 Daily intravenous injections of L-asparaginase (1000 i.u. per kg.) were begun 5 days before transplantation and continued until the heart ceased to contract (rejection).
In
of
25.
Tennenbaum, J. I., St. Pierre, R. L., Vasko, J. S. Archs Surg. 1969, 99, 753.
1366 NUMB-CHIN SYNDROME
The hearts
rejected at 11.5 :1::2.5 days as compared with 7-6 1-6 days for six untreated control dogs. These observations are in contrast to a report showing decreased immune reactivity to an allografted tumour after L-asparaginase treatment.26 Possibly the tumour-allograft system is not analogous to the skin or solid-organ graft system, since even a slight immunosuppression, as seen with some of our animals, would be enough to allow progressive growth of the tumour. Apparently the immunosuppressive effects of L-asparaginase (even in excessive doses 24) on cellular immunity is at best minimal. The observations reported here are not as impressive as those of Shons et al.,21 who demonstrated prolonged survival of skin grafts in rabbits after the injection of L-asparaginase. The L-asparaginase was a gift from Merck Sharp and Dohme. This work was supported in part by the Life Insurance Medical Research Fund, the American Cancer Society, Inc., and a U.S.P.H.S. general research support grant.
Departments of Anatomy and Medicine, The Ohio State University
College of Medicine, Columbus, Ohio 43210.
SIR,-Dr. Thrush and Dr. Small (Oct. 31, p. 851) ask, benign a symptom is facial numbness ? Six of their
How
had grave illnesses. In support of their warning, I offer the following case-report. A 28-year-old woman noted aching in the region of the right temporomandibular joint which was initially severe but then lessened. Coincidentally she noted numbness of the right side of her chin and an odd feeling of the right side of her tongue. Objective loss of pain and touch perception was demonstrated in these areas. An X-ray of the base of the skull showed slight enlargement of the right foramen ovale. Later the numbness on the chin spread to involve the entire mandibular division of the trigeminal nerve, the right foramen ovale enlarged further, and a mass appeared behind the right tonsil. Intracranial exploration of the region of the foramen ovale revealed a circumscribed tumour, which was removed. Subsequent exploration of seven cases
the
R. L. ST. PIERRE J. I. TENNENBAUM R. M. FOLK.
right retrotonsillar region revealed a similar tumour. proved to be an embryonic rhabdomyosarcoma. Subsequently, widespread metastases appeared, and the patient died 1years later. The numb-chin syndromeemphasises the serious import of seemingly innocuous complaints. The tumour
University Hospital, Ann Arbor, Michigan 48104.
PASSIVE IMMUNOTHERAPY FOR NEUROBLASTOMA
SIR,-The prognosis of Wilms’ tumour and neuroblastoma is much better in infants under one year than in older children. In neuroblastoma the improved prognosis holds even in the presence of liver metastases. Furthermore, microscopic deposits of neuroblastoma are often found incidentally in the adrenals of infants up to the age of three months, but not thereafter. 28 These findings could be due to differences either in the tumours or in their hosts. There is some histological evidence that the tumours are slightly different in the younger age-groups. But humoral factors may also be important, and could indeed have induced the histological changes seen in some cases. The influence of cell-mediated immunity has been explored,29 but the role of cytotoxic antibody is less clear. It has already been pointed out that Burkitt’s tumour is unknown in infants under one year, and that this may be related to passive immunity.3O Similar passive immunological factors may account for the improved prognosis in infants with neuroblastoma. For this reason, a trial of passive immunisation is proposed for the older children with advanced neuroblastoma. Pooled immunoglobulin could be used. However, there is evidence that the mothers and close relatives of children with neuroblastoma are immune to neuroblastoma antigens.31 It has also been shown that at least the mothers have cytotoxic antibodies to these antigens.32 Consequently, it might be better to use immunoglobulin derived from such relatives. The rationale for this therapy would be at least as sound as that for giving vitamin B12. Finally, it is of interest that in a trial of intensive immunoglobulin therapy in three cases of advanced Hodgkin’s disease, one girl had a worth-while remission.33 She had normal serum-levels of immunoglobulins before treatment. Department of Therapeutic Radiology, Tufts-New England Medical Center, Boston, Mass. 02111.
W. S. B. LOWRY.
Schulten, J. K., Giraldo, G., Boyse, E. A., Oettgen, H. F. Lancet, 1969, ii, 645. 27. Shons, A., Jetzer, T., Najarian, J. S. Transplantation, 1970, 10, 280. 28. Beckwith, J. B., Perrin, E. V. Am. J. Path. 1963, 43, 1089. 29. Hellstrom, K. E., Hellstrom, I. Adv. Cancer Res. 1969, 12, 167. 30. Lowry, W. S. Lancet, 1969, ii, 910. 31. Hellstrom, I., Hellstrom, K. E., Bill, A. H., Pierce, G. E. Proc. 26.
32. 33.
natn. Acad. Sci. 1968, 60, 1231. Hellstrom, K. E. Int. J. Cancer (in the press). Lowry, W. S. Unpublished.
JOHN F. SIMPSON.
LEVODOPA IN POSTENCEPHALITIC PARKINSONISM
SIR,-Although a short therapeutic trial of levodopa in postencephalitic parkinsonism of long standing gave encouraging resultslonger trials have revealed a high incidence of adverse effects.3-5 Our further experience during a 24-week investigation of maximum tolerated doses of levodopa confirms that postencephalitic patients tolerate levodopa poorly, and that only a minority gain useful and enduring benefit. 50 patients took part in the trial; their disabilities and concurrent treatments were as described previously.2 16 patients showed sustained improvement while taking levodopa, 16 showed no overall change, and 18 developed intolerable adverse effects which persisted despite progressive dose reduction, and the drug had to be abandoned. The degree of sustained improvement, although small compared with that seen in idiopathic parkinsonism, was nevertheless important to patients and their nurses; for example, the only benefit seen in one patient was an ability to extend his neck, which was previously held rigid with his chin on his chest. This small change enabled him to be fed more easily. Others noticed improvement in daily activities such as walking and dressing. The adverse effects which limited the dose of levodopa were similar to those seen in other trials. 7 patients showed a definite early response, but the persistence of intolerable adverse effects necessitated progressive reduction of dose with loss of benefit. In patients who were obliged to abandon levodopa, the average duration of therapy was 11 weeks (range 1-19 weeks). The adverse effects were: severe vomiting (1 patient), psychiatric disturbances (8 patients), pain in thighs (1 patient), involuntary movements (5 patients), inability to swallow (1 patient), and respiratory abnormalities (2 patients). The respiratory abnormalities, Calverley, J. R., Mohnac, A. N. Archs intern. Med. 1963, 112, 819. Calne, D. B., Stern, G. M., Laurence, D. R., Sharkey, J., Armitage, P. Lancet, 1969, i, 744. 3. Sacks, O. W., Kohl, M., Schwartz, W., Messeloff, C. ibid. 1970, i, 1. 2.
1006. 4. 5.
Sacks, O. W., Kohl, M. ibid. 1970, ii, 215. Krasner, N., Cornelius, J. M. Br. med. J. 1970, iv,
496.
*
BEFORE, DURING,
AND AFTER
ASN-ASE*
Patients 1, 2, 3, and 7 received penicillin every 15 days; patient 7 was given aspirin (80 mg./kg./day); case 2 received 2 blood-transfusions (150+ 150 ml. on the llth day and on the 22nd day); case 3 received 1 blood-transfusion (150 ml. on 10th day).
Different dosages the treatment well tolerated.
was
were
used, and in
cases
very short because the
drug
4 and 8 was not
The results obtained show that often the
immunoglobulin values increased. IgG and IgM increased by 25% or more in 5 out of 8 and in 6 out of 8 patients respectively; IgA increased by 25% or more in all. It was exceptional for immunoglobulin values to fall. We think it unlikely that the changes in immunoglobulin levels were caused by the collateral treatment (used only in cases 1, 2, 3, and 7). It seems more likely that Asn-ase, at the dosages employed, acted as an antigen. 16, 17 Possibly the enzyme also produces nonspecific immunological stimulation or favours release of immunoglobulins into the bloodstream. Pædiatric Clinic, University of Pavia, and Blood Research Foundation Centre,
Tortona, Italy.
G. R. BURGIO R. VACCARO M. CLARA GASPARONI A. ASTALDI, JR.
C 57B 1 /6 mice were divided into three groups. Group 1 received intraperitoneal injections of 1000 I.U. L-asparaginase per kg. daily. After7 days’ treatment a skin allograft from a DBA/2 donor was applied, and L-asparaginase treatment was continued daily until the graft was rejected. Group 2 received a skin allograft from a DBA/2 donor. 1000 i.u. L-asparaginase per kg. was given intraperitoneally 24 hours after grafting and continued daily until graft rejection. Group 3 received normal saline solution (0-4 ml. per mouse) for 7 days. On day 8, a skin allograft from a DBA/2 donor was applied and daily saline treatment continued until the graft was rejected. There was only slight prolongation of graft survival when L-asparaginase was given before the application of the allograft. L-Asparaginase given after the application of an allograft showed no significant increase in survival over saline controls (see accompanying table). INFLUENCE OF L-ASPARAGINASE ON GRAFT
REJECTION
L-ASPARAGINASE AND ALLOGRAFT IMMUNITY
SIR The inhibitory effect of L-asparaginase on tumours is well established,18 and it has been shown that Escherichia coli L-asparaginase suppresses phytohæmagglutinin-induced blastogenesis.19-21 In addition, L-asparaginase considerably suppresses the humoral response 22-24 ; and in one reported case 24 injection of high doses slightly suppressed skin-graft rejection. We have investigated the effects of conventional doses of L-asparaginase on allograft survival in mice. 16. Khan, A., Hill, J. M. J. Lab. clin. Med. 1969, 73, 846. 17. Beard, M. E. J. Br. med. J. 1970, i, 191. 18. Old, L. J., Boyse, E. A., Campbell, H. A., Bradley, R. S., Fidler, J., Teller, J. D. Cancer, N. Y. 1967, 20, 1066. 19. Astaldi, G., Burgio, G. R., Krc, J., Genova, R., Astaldi, A. A. Lancet, 1969, i, 423. 20. McElwain, T. J., Hayward, S. K. ibid. p. 527. 21. Astaldi, G., Burgio, G. R., Biscotti, G., Astaldi, A., Ferfoglio, L. ibid. 1969, ii, 275. 22. Schwartz, R. S. Nature, 1969, 224, 275. 23. Chakrabarty, A. K., Friedman, H. Science, N.Y. 1970, 167, 869. 24. Nelson, S. D., Lee, M. B., Bridges, J. M. Transplantation, 1970, 9, 566.
All animals grafted on day 8. † Mean ± standard deviation. ‡As determined by Student’s test. § Not significant. a related investigation, the im--nunosuppressive effects L-asparaginase were evaluated in canine cardiac allografts. The hearts of mongrel dogs were reimplanted in the necks of 2 recipient dogs. Restoration of the circulation was accomplished by anastomoses between the innominate and subclavian arteries of the donor heart with the proximal and distal segments of the carotid arteries of the recipients.25 Daily intravenous injections of L-asparaginase (1000 i.u. per kg.) were begun 5 days before transplantation and continued until the heart ceased to contract (rejection).
In
of
25.
Tennenbaum, J. I., St. Pierre, R. L., Vasko, J. S. Archs Surg. 1969, 99, 753.
1366 NUMB-CHIN SYNDROME
The hearts
rejected at 11.5 :1::2.5 days as compared with 7-6 1-6 days for six untreated control dogs. These observations are in contrast to a report showing decreased immune reactivity to an allografted tumour after L-asparaginase treatment.26 Possibly the tumour-allograft system is not analogous to the skin or solid-organ graft system, since even a slight immunosuppression, as seen with some of our animals, would be enough to allow progressive growth of the tumour. Apparently the immunosuppressive effects of L-asparaginase (even in excessive doses 24) on cellular immunity is at best minimal. The observations reported here are not as impressive as those of Shons et al.,21 who demonstrated prolonged survival of skin grafts in rabbits after the injection of L-asparaginase. The L-asparaginase was a gift from Merck Sharp and Dohme. This work was supported in part by the Life Insurance Medical Research Fund, the American Cancer Society, Inc., and a U.S.P.H.S. general research support grant.
Departments of Anatomy and Medicine, The Ohio State University
College of Medicine, Columbus, Ohio 43210.
SIR,-Dr. Thrush and Dr. Small (Oct. 31, p. 851) ask, benign a symptom is facial numbness ? Six of their
How
had grave illnesses. In support of their warning, I offer the following case-report. A 28-year-old woman noted aching in the region of the right temporomandibular joint which was initially severe but then lessened. Coincidentally she noted numbness of the right side of her chin and an odd feeling of the right side of her tongue. Objective loss of pain and touch perception was demonstrated in these areas. An X-ray of the base of the skull showed slight enlargement of the right foramen ovale. Later the numbness on the chin spread to involve the entire mandibular division of the trigeminal nerve, the right foramen ovale enlarged further, and a mass appeared behind the right tonsil. Intracranial exploration of the region of the foramen ovale revealed a circumscribed tumour, which was removed. Subsequent exploration of seven cases
the
R. L. ST. PIERRE J. I. TENNENBAUM R. M. FOLK.
right retrotonsillar region revealed a similar tumour. proved to be an embryonic rhabdomyosarcoma. Subsequently, widespread metastases appeared, and the patient died 1years later. The numb-chin syndromeemphasises the serious import of seemingly innocuous complaints. The tumour
University Hospital, Ann Arbor, Michigan 48104.
PASSIVE IMMUNOTHERAPY FOR NEUROBLASTOMA
SIR,-The prognosis of Wilms’ tumour and neuroblastoma is much better in infants under one year than in older children. In neuroblastoma the improved prognosis holds even in the presence of liver metastases. Furthermore, microscopic deposits of neuroblastoma are often found incidentally in the adrenals of infants up to the age of three months, but not thereafter. 28 These findings could be due to differences either in the tumours or in their hosts. There is some histological evidence that the tumours are slightly different in the younger age-groups. But humoral factors may also be important, and could indeed have induced the histological changes seen in some cases. The influence of cell-mediated immunity has been explored,29 but the role of cytotoxic antibody is less clear. It has already been pointed out that Burkitt’s tumour is unknown in infants under one year, and that this may be related to passive immunity.3O Similar passive immunological factors may account for the improved prognosis in infants with neuroblastoma. For this reason, a trial of passive immunisation is proposed for the older children with advanced neuroblastoma. Pooled immunoglobulin could be used. However, there is evidence that the mothers and close relatives of children with neuroblastoma are immune to neuroblastoma antigens.31 It has also been shown that at least the mothers have cytotoxic antibodies to these antigens.32 Consequently, it might be better to use immunoglobulin derived from such relatives. The rationale for this therapy would be at least as sound as that for giving vitamin B12. Finally, it is of interest that in a trial of intensive immunoglobulin therapy in three cases of advanced Hodgkin’s disease, one girl had a worth-while remission.33 She had normal serum-levels of immunoglobulins before treatment. Department of Therapeutic Radiology, Tufts-New England Medical Center, Boston, Mass. 02111.
W. S. B. LOWRY.
Schulten, J. K., Giraldo, G., Boyse, E. A., Oettgen, H. F. Lancet, 1969, ii, 645. 27. Shons, A., Jetzer, T., Najarian, J. S. Transplantation, 1970, 10, 280. 28. Beckwith, J. B., Perrin, E. V. Am. J. Path. 1963, 43, 1089. 29. Hellstrom, K. E., Hellstrom, I. Adv. Cancer Res. 1969, 12, 167. 30. Lowry, W. S. Lancet, 1969, ii, 910. 31. Hellstrom, I., Hellstrom, K. E., Bill, A. H., Pierce, G. E. Proc. 26.
32. 33.
natn. Acad. Sci. 1968, 60, 1231. Hellstrom, K. E. Int. J. Cancer (in the press). Lowry, W. S. Unpublished.
JOHN F. SIMPSON.
LEVODOPA IN POSTENCEPHALITIC PARKINSONISM
SIR,-Although a short therapeutic trial of levodopa in postencephalitic parkinsonism of long standing gave encouraging resultslonger trials have revealed a high incidence of adverse effects.3-5 Our further experience during a 24-week investigation of maximum tolerated doses of levodopa confirms that postencephalitic patients tolerate levodopa poorly, and that only a minority gain useful and enduring benefit. 50 patients took part in the trial; their disabilities and concurrent treatments were as described previously.2 16 patients showed sustained improvement while taking levodopa, 16 showed no overall change, and 18 developed intolerable adverse effects which persisted despite progressive dose reduction, and the drug had to be abandoned. The degree of sustained improvement, although small compared with that seen in idiopathic parkinsonism, was nevertheless important to patients and their nurses; for example, the only benefit seen in one patient was an ability to extend his neck, which was previously held rigid with his chin on his chest. This small change enabled him to be fed more easily. Others noticed improvement in daily activities such as walking and dressing. The adverse effects which limited the dose of levodopa were similar to those seen in other trials. 7 patients showed a definite early response, but the persistence of intolerable adverse effects necessitated progressive reduction of dose with loss of benefit. In patients who were obliged to abandon levodopa, the average duration of therapy was 11 weeks (range 1-19 weeks). The adverse effects were: severe vomiting (1 patient), psychiatric disturbances (8 patients), pain in thighs (1 patient), involuntary movements (5 patients), inability to swallow (1 patient), and respiratory abnormalities (2 patients). The respiratory abnormalities, Calverley, J. R., Mohnac, A. N. Archs intern. Med. 1963, 112, 819. Calne, D. B., Stern, G. M., Laurence, D. R., Sharkey, J., Armitage, P. Lancet, 1969, i, 744. 3. Sacks, O. W., Kohl, M., Schwartz, W., Messeloff, C. ibid. 1970, i, 1. 2.
1006. 4. 5.
Sacks, O. W., Kohl, M. ibid. 1970, ii, 215. Krasner, N., Cornelius, J. M. Br. med. J. 1970, iv,
496.