- Email: [email protected]
INTRA-ARTERIAL HYALURONIDASE IN SEVERE PERIPHERAL ARTERIAL DISEASE
648
SIR,-Professor Smithells and his colleagues have opened the
chapter in the saga of neural-tube defects. Since a deficiency of some nutrient has been proposed as the source of nearly every ailment since antiquity, why not propose another? An unfortunate effect of this form of communication is that women will be induced to self-administer large quantities of vitamins, some of which may be teratogenic. I hope that future studies will incorporate properly selected controls treated with placebos and that nutritional assessment of the mother, before and during therapy, will be done. next
Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, U. S. 7A.
PAUL M. FERNHOFF
SIR,-A better design for Professor Smithells’ experiment the possible prevention of neural-tube defects (NTD) by periconceptional vitamin supplementation would have been a randomised trial of all the women who previously had one or on
infants with NTDs, were not yet pregnant, and were admitted to the study; half would have received full vitamin supplements and the other half no supplements. Although Smithells et al. give four explanations for their finding of a low NTD risk in offspring of fully supplemented mothers, there may be others which are unknown. It remains true that no valid randomised trial of possible measures for preventing NTD has ever been done.1
more
Department of Community Medicine, Queen’s University of Belfast, Belfast BT12 6BJ
J. H. ELWOOD
full blood count, liver function tests, urine analysis, and ECG were performed. Every patient had a chest X-ray. GL-enzyme is a highly purified preparation of hyaluronidase of bovine origin presented as a sterile freeze-dried powder (minimum activity 40 000 IU/mg protein, 50 000 IU per vial). Hyaluronidase increases capillary permeability and promotes increased diffusion through the extravascular space,8 reducing oedema and probably assisting in the delivery of oxygen to the ischaemic cells.5 Every patient had a palpable femoral pulse on the affected side; under local (five cases) or general anxsthetic (one case) the common femoral artery on the affected side was catheterised and direct peripheral arteriography was done. Only when the results indicated that surgical correction was not possible, was the decision taken to inject GL-enzyme, 200 000 units in 8 ml cold saline (4°C) over 1z-2 min into the common femoral artery. 1 min after completion of injection simultaneous blood samples were taken via catheters in the common femoral artery and common femoral vein. Samples were taken every minute for 10 min (figure). The temperature of the skin of the dorsum of the foot on the affected side in the first web was measured by thermocouple before, during, and after intra-arterial injection. Measurements were repeated 48 h after injection. Rest pain, analgesic consumption, walking ability, and the clinical appearance of the limb were all assessed clinically. Four out of six cases had relief of rest pain, partly or com-
Two required amputation. One patient who had partial relief of rest pain had a further injection with added benefit. Walking distance improved in two patients and was unchanged in two patients. Details are as follows:
pletely.
Case l.-Male, aged 54. Severe rest pain for 1 month. Gangrenous ulcer lateral border L foot. Skin temperature (foot) rose from 34°C to 37°C post-injection. 10 months later no rest pain; ulcer clean and almost healed; walking; claudication in L calf after 40 m. Case 2.-M, 68. Severe rest pain L foot for 5 months. Temp. change 29.8 to 31-6°C. 4 months later no rest pain; walking; claudication in L calf at 80 m.
G, Magyar S. Effect of hyaluronidase on capillary permeability, flow and passage of dye-labelled protein from plasma to lymph. Nature 1954; 102: 377-79.
8. Szabo
INTRA-ARTERIAL HYALURONIDASE IN SEVERE PERIPHERAL ARTERIAL DISEASE
lymph
SIR,-In severe peripheral arterial disease, usually with thrombosis of the superficial femoral artery, occlusion of branches of the popliteal artery often results in severe rest pain, inability to walk, and progressive distal infarction with gangrene.2 Few such cases are suitable for reconstructive arterial surgery.3 In severe myocardial ischsemia with infarction resulting from coronary artery occlusion, preliminary results with parenteral hyaluronidase, experimentally4·5and clinically,’ have been encouraging. Kloner et al.’’ suggest that the hyaluronidase reduced the size of the ischaemic zone adjacent to the infarcted tissues. We wondered if hyaluronidase would help in severe peripheral vascular disease. A highly purified preparation (’GL-Enzyme’; Biorex Laboratories) is now available. .
Six
patients were admitted to hospital for a few days before the study for assessment of rest pain and analgesic consumption
enzyme and, in
more conventional treatment such intravenous praxilene. Only patients deemed unsuitable for reconstructive surgery, and for whom amputation seemed the only alternative, were entered into this open pilot study. None had active infection or were on long term anticoagulants (these inactivate the hyaluronidase preparation used). No patient had had coronary artery surgery or prosthetic heart valve replacement. All gave informed consent. Before and after the injection of GL-enzyme as
some
cases, for trials with
surgical sympathectomy and
1. Elwood JM, Elwood JH. Epidemiology of anencephalus and spina bifida. Oxford: Oxford University Press, 1980. 2. Taylor GW. Chronic arterial occlusion: Clinical management. In: Smith R, ed. Clinical surgery. London: Butterworths, 1967: 54-77. 3. Eastcott HHG. Vascular surgery. London: Arnold; 1975. 4. Maclean D, Fishbein MC, Maroko PR, Braunwald E. Hyaluronidaseinduced reductions in myocardial infarct size. Science 1976; 194: 199-200. 5. Maroko PR, Libby P, Bloor CM, Sobil BE, Braunwald E. Reduction by
hyaluromdase of myocardial
necrosis following coronary artery occlusion. Circulation 1972; 46: 430-37. 6. Maroko PR, et al. Favorable effects of hyaluronidase on ECG evidence of necrosis in patients with acute myocardial infarction. N Engl J Med 1977; 296: 898-903. 7. Kloner RA, et al. Long-term preservation of ischemic myocardium in the dog by Hyaluronidase. Circulation 1978; 58: 220-26.
Levels of
GL-enzyme
in
venous
The consistently greater after arterial injection and pheral tissues.
(8)
and arterial blood
(0).
levels suggest pooling within limb subsequent release of enzyme from peri-
venous
649 Case 3.-M, 73. Severe rest pain L foot for one month. Infected ulcer L heel. Temp. change 31.4 to 296°C. 4 months later ulcer clean and almost healed; mild rest pain controlled with dextropropoxy-
phene/paracetamol (’Distalgesic’). Case 4.-M, 56. Severe rest pain for 3 months. Dry gangrene R lst and 2nd toes. Temp. change 32.5 to 395°C. No improvement; above knee amputation 9 days after treatment. Case 5.-M, 67. Severe rest pain R foot for 3 months. Gangrene R 3rd toe. Temp. change 30.5 to 315°C. No improvement; above knee amputation 7 days after treatment. Case 6.-F, 77. Severe rest pain in R foot for 2 months. No relief with analgesics. Gangrenous toes. Temp. change 31.2 to 32.8°C. 6 weeks later improved; dry gangrene of toes with line of demarcation; residual rest pain well controlled with distalgesic.
Intra-arterial prostacyclin9 or thymoxamine hydrochloride for up to 72 h may achieve worthwhile limb salvage and relief of rest pain. We have used GL-enzyme by slow bolus injection; repeated injections would be possible. The results of our pilot study suggest the need for a clinical trial of intra-arterial GLenzyme against, for example, prostacyclin or thymoxamine. We thank Dr Derek
Pope (Biorex Laboratories)
for the
GL-enzyme
assays.
University Department of Surgery Department of Clinical Radiology, Manchester Royal Infirmary, Manchester M13 9WL
JAMES B. ELDER ANDREW T. RAFTERY VICTOR COPE
ACUTE MONOBLASTIC LEUKÆMIA IN CHILD RECEIVING CHLORAMBUCIL FOR JUVENILE RHEUMATOID ARTHRITIS
SIR,-Neoplasia, notably leukaemia and lymphoma, has been reported in adults given immunosuppressive therapy after organ transplantation or for the treatment of other neoplasias or autoimmune disease. However, there have been few reports of malignancies in children receiving immunosuppressive ther1 apy for non-neoplastic disease.’ A 13-month-old boy was admitted in 1971 with fever, rash, splenomegaly, and arthritic joints. Symptoms and laboratory tests suggested a diagnosis of juvenile rheumatoid arthritis (JRA). Prednisolone (2 mg/kg daily) and aspirin treatment was continued for 2 years, but every time the corticosteroid dose was brought below 1 mg/kg a severe increase in inflammatory joint symptoms affecting progressively more joints ensued. The corticosteroid therapy caused cushingoid facies, short stature, and osteoporosis. In November, 1973, because of a decreased response and side-effects of high-dose corticosteroids, treatment with chlorambucil was added (0-25 mg/kg daily). The symptoms declined and the corticosteroid dose was reduced below 1 mg/kg daily in October, 1974, without relapse. However, in June, 1975, pancytopenia (Hb 8.8 g/dl, WBC 16 000/1 with 0% neutrophils, platelets 81 000/1) was noted, and a bone-marrow aspirate showed aplasia. Chlorambucil was stopped and the bone-marrow became normal within 6 weeks, except for a mild lymphopenia (500/.1) which persisted until November, 1975. The clinical signs of JRA remained mild and stable. Corticosteroid therapy was stopped in October, 1976. The child seemed to be in remission. 2 years after chlorambucil treatment was stopped (September, 1977) he had a fever, anxmia, a tooth abscess with trismus, hypertrophic gingivitis, and cervical and axillary adenopathy. ESR 160 mm/h, Hb 7 g/dl, WBC 9200/ul with 97% blast cells, platelets 90 000/1. Bonemarrow aspirate showed 69% blasts with a mild nucleocytoplasmic ratio and weakly stained with sudan-black, peroxidases, and non-specific esterases which were partly inhibited 9 Szczeklik
A, et al. Successful therapy of advanced arteriosclerosis obliterans with prostacyclin. Lancet 1979; i: 1111-14. 10 Rose SS. Intra-arterial perfusion in the treatment of rest pain and gangrene.
Br J Clin Pract 1979; 33: 233-30. 1. Grup WE, Makker SP, Engelfinger JR. Chlorambucil treatment of frequently relapsing nephrotic syndrome. N Engl J Med 1976; 295: 746.
with sodium fluoride. Electromicroscopy showed non-differentiated blasts with a notched nucleus and few lysosomes. Acute
monoblastic leukaemia was diagnosed. Rubidazone (2 mg/kg daily) induced a complete remission, and monthly injections of rubidazone and cytarabine and for 3 prophylactic CNS irradiation followed. He months but relapsed and died in May, 1978. In a recent review2 of forty children treated with chlorambucil for JRA, two other cases of acute leukaemia were noted Dr M. L. Pernette (unpublished), in a series of two hundred JRA cases not treated with chlorambucil, found no cases of malignant blood disorder. Chlorambucil thus seems to have contributed to the development of acute leukaemia in three children with JRA. However, the numbers are too small for us to say if chlorambucil therapy carries a greater risk of associated leukaemia in children with JRA than it does in children given the drug for diseases other than JRA.; Acute leukaemia has been observed in adults treated with chlorambucil for chronic arthritis,’ and the high dose given to our patient (1-55 g), the appearance of pancytopenia after chlorambucil was withdrawn but before the diagnosis of acute leukaemia, and the non-lymphoblastic type of leuksemia with rapid downhill course resembles the cases in adults.4 Several mechanisms have been postulated by which alkylating agents could predispose to leukxmia. Induction of chromosome abnormalities may give rise to malignant cells.5 Unfortunately, we could not obtain adequate chromosome preparations in this case. Aplastic marrow may predispose to acute myelogenous leukaemia,6 and the 6 weeks of bone-marrow aplasia noted in our patient may have played a part. Chlorambucil suppression, by suppressing immunological surveillancemight allow the emergence of malignant clones of cells or invasion by oncogenic viruses; lymphopenia persisted for 6 months in our case. But whatever the mechanism, the case we describe suggests that chlorambucil should not be given to patients with JRA until more is known about its effects in such children.
responded
Pædiatric Service B,
Centre Hospitalier Universitaire de Tours, 37000 Tours, France
Y. LEBRANCHU J. DRUCKER H. NIVET J. C. ROLLAND B. GRENIER
C.H.U. de Tours
O. LEJARS J. P. LAMAGNERE
Immunology and Haematology Unit, Hôpital des Enfants-Malades, Pans
D. BURIOT
Hæmato-Cancerology Unit,
ANTITHROMBIN III DEFICIENCY DURING ASPARAGINASE THERAPY
SIR,-Professor Pitney and colleagues (March 1, p. 493) describe two patients in whom a venous thrombosis developed after I-asparaginase therapy, probably related to an antithrombin III (AT III) deficiency. We have treated a patient with acute monoblastic leukxmia for 9 days with a total dose of 84 000 U I-asparaginase. The pretreatment AT III was 100% (95-150% chromogene substrate S-2238 Kabi, as described by 2. Buriot D, Prieur AM, Lebranchu Y, Mersserschmitt J, Griselli C. Leucémies aiguës après traitement par le Chlorambucil: à propos de trois observations chez des enfants atteints d’arthrite chronique juvénile. Arch Fr
Pédiat 1979; 36: 592. Guesry P, Kleinknecht C, Gagnadoux MF, Broyer M. Complications extragonadiques du Chlorambucil chez l’enfant (à propos de 300 observations de néphropathies glomérulaires traitées). Arch Fr Pédiat 1977; 34: 798. 4. Seidenfeld AM, Smythe HA, Ogryzlo MA Acute leukemia in rhumatoïd arthritis treated with cytotoxic agents. J Rheumatol 1976; 3: 295. 5. Sieber SM, Adamson RH. The clastogenic, mutagenic, teratogenic and carcinogenic effects of various antineoplastic agents. In. Pharmacological basis of cancer chemotherapy. Baltimore: William & Wilkins, 1975: 3. Lenoir G,
401-68. 6. Vigliani EC, Saita G. Benzene and leukemia. N Engl J Med 1964, 271: 872. 7. Penn, I Occurrence of Cancer in Immune Deficiencies. Cancer 1974; 34: 858.
SIR,-Professor Smithells and his colleagues have opened the
chapter in the saga of neural-tube defects. Since a deficiency of some nutrient has been proposed as the source of nearly every ailment since antiquity, why not propose another? An unfortunate effect of this form of communication is that women will be induced to self-administer large quantities of vitamins, some of which may be teratogenic. I hope that future studies will incorporate properly selected controls treated with placebos and that nutritional assessment of the mother, before and during therapy, will be done. next
Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, U. S. 7A.
PAUL M. FERNHOFF
SIR,-A better design for Professor Smithells’ experiment the possible prevention of neural-tube defects (NTD) by periconceptional vitamin supplementation would have been a randomised trial of all the women who previously had one or on
infants with NTDs, were not yet pregnant, and were admitted to the study; half would have received full vitamin supplements and the other half no supplements. Although Smithells et al. give four explanations for their finding of a low NTD risk in offspring of fully supplemented mothers, there may be others which are unknown. It remains true that no valid randomised trial of possible measures for preventing NTD has ever been done.1
more
Department of Community Medicine, Queen’s University of Belfast, Belfast BT12 6BJ
J. H. ELWOOD
full blood count, liver function tests, urine analysis, and ECG were performed. Every patient had a chest X-ray. GL-enzyme is a highly purified preparation of hyaluronidase of bovine origin presented as a sterile freeze-dried powder (minimum activity 40 000 IU/mg protein, 50 000 IU per vial). Hyaluronidase increases capillary permeability and promotes increased diffusion through the extravascular space,8 reducing oedema and probably assisting in the delivery of oxygen to the ischaemic cells.5 Every patient had a palpable femoral pulse on the affected side; under local (five cases) or general anxsthetic (one case) the common femoral artery on the affected side was catheterised and direct peripheral arteriography was done. Only when the results indicated that surgical correction was not possible, was the decision taken to inject GL-enzyme, 200 000 units in 8 ml cold saline (4°C) over 1z-2 min into the common femoral artery. 1 min after completion of injection simultaneous blood samples were taken via catheters in the common femoral artery and common femoral vein. Samples were taken every minute for 10 min (figure). The temperature of the skin of the dorsum of the foot on the affected side in the first web was measured by thermocouple before, during, and after intra-arterial injection. Measurements were repeated 48 h after injection. Rest pain, analgesic consumption, walking ability, and the clinical appearance of the limb were all assessed clinically. Four out of six cases had relief of rest pain, partly or com-
Two required amputation. One patient who had partial relief of rest pain had a further injection with added benefit. Walking distance improved in two patients and was unchanged in two patients. Details are as follows:
pletely.
Case l.-Male, aged 54. Severe rest pain for 1 month. Gangrenous ulcer lateral border L foot. Skin temperature (foot) rose from 34°C to 37°C post-injection. 10 months later no rest pain; ulcer clean and almost healed; walking; claudication in L calf after 40 m. Case 2.-M, 68. Severe rest pain L foot for 5 months. Temp. change 29.8 to 31-6°C. 4 months later no rest pain; walking; claudication in L calf at 80 m.
G, Magyar S. Effect of hyaluronidase on capillary permeability, flow and passage of dye-labelled protein from plasma to lymph. Nature 1954; 102: 377-79.
8. Szabo
INTRA-ARTERIAL HYALURONIDASE IN SEVERE PERIPHERAL ARTERIAL DISEASE
lymph
SIR,-In severe peripheral arterial disease, usually with thrombosis of the superficial femoral artery, occlusion of branches of the popliteal artery often results in severe rest pain, inability to walk, and progressive distal infarction with gangrene.2 Few such cases are suitable for reconstructive arterial surgery.3 In severe myocardial ischsemia with infarction resulting from coronary artery occlusion, preliminary results with parenteral hyaluronidase, experimentally4·5and clinically,’ have been encouraging. Kloner et al.’’ suggest that the hyaluronidase reduced the size of the ischaemic zone adjacent to the infarcted tissues. We wondered if hyaluronidase would help in severe peripheral vascular disease. A highly purified preparation (’GL-Enzyme’; Biorex Laboratories) is now available. .
Six
patients were admitted to hospital for a few days before the study for assessment of rest pain and analgesic consumption
enzyme and, in
more conventional treatment such intravenous praxilene. Only patients deemed unsuitable for reconstructive surgery, and for whom amputation seemed the only alternative, were entered into this open pilot study. None had active infection or were on long term anticoagulants (these inactivate the hyaluronidase preparation used). No patient had had coronary artery surgery or prosthetic heart valve replacement. All gave informed consent. Before and after the injection of GL-enzyme as
some
cases, for trials with
surgical sympathectomy and
1. Elwood JM, Elwood JH. Epidemiology of anencephalus and spina bifida. Oxford: Oxford University Press, 1980. 2. Taylor GW. Chronic arterial occlusion: Clinical management. In: Smith R, ed. Clinical surgery. London: Butterworths, 1967: 54-77. 3. Eastcott HHG. Vascular surgery. London: Arnold; 1975. 4. Maclean D, Fishbein MC, Maroko PR, Braunwald E. Hyaluronidaseinduced reductions in myocardial infarct size. Science 1976; 194: 199-200. 5. Maroko PR, Libby P, Bloor CM, Sobil BE, Braunwald E. Reduction by
hyaluromdase of myocardial
necrosis following coronary artery occlusion. Circulation 1972; 46: 430-37. 6. Maroko PR, et al. Favorable effects of hyaluronidase on ECG evidence of necrosis in patients with acute myocardial infarction. N Engl J Med 1977; 296: 898-903. 7. Kloner RA, et al. Long-term preservation of ischemic myocardium in the dog by Hyaluronidase. Circulation 1978; 58: 220-26.
Levels of
GL-enzyme
in
venous
The consistently greater after arterial injection and pheral tissues.
(8)
and arterial blood
(0).
levels suggest pooling within limb subsequent release of enzyme from peri-
venous
649 Case 3.-M, 73. Severe rest pain L foot for one month. Infected ulcer L heel. Temp. change 31.4 to 296°C. 4 months later ulcer clean and almost healed; mild rest pain controlled with dextropropoxy-
phene/paracetamol (’Distalgesic’). Case 4.-M, 56. Severe rest pain for 3 months. Dry gangrene R lst and 2nd toes. Temp. change 32.5 to 395°C. No improvement; above knee amputation 9 days after treatment. Case 5.-M, 67. Severe rest pain R foot for 3 months. Gangrene R 3rd toe. Temp. change 30.5 to 315°C. No improvement; above knee amputation 7 days after treatment. Case 6.-F, 77. Severe rest pain in R foot for 2 months. No relief with analgesics. Gangrenous toes. Temp. change 31.2 to 32.8°C. 6 weeks later improved; dry gangrene of toes with line of demarcation; residual rest pain well controlled with distalgesic.
Intra-arterial prostacyclin9 or thymoxamine hydrochloride for up to 72 h may achieve worthwhile limb salvage and relief of rest pain. We have used GL-enzyme by slow bolus injection; repeated injections would be possible. The results of our pilot study suggest the need for a clinical trial of intra-arterial GLenzyme against, for example, prostacyclin or thymoxamine. We thank Dr Derek
Pope (Biorex Laboratories)
for the
GL-enzyme
assays.
University Department of Surgery Department of Clinical Radiology, Manchester Royal Infirmary, Manchester M13 9WL
JAMES B. ELDER ANDREW T. RAFTERY VICTOR COPE
ACUTE MONOBLASTIC LEUKÆMIA IN CHILD RECEIVING CHLORAMBUCIL FOR JUVENILE RHEUMATOID ARTHRITIS
SIR,-Neoplasia, notably leukaemia and lymphoma, has been reported in adults given immunosuppressive therapy after organ transplantation or for the treatment of other neoplasias or autoimmune disease. However, there have been few reports of malignancies in children receiving immunosuppressive ther1 apy for non-neoplastic disease.’ A 13-month-old boy was admitted in 1971 with fever, rash, splenomegaly, and arthritic joints. Symptoms and laboratory tests suggested a diagnosis of juvenile rheumatoid arthritis (JRA). Prednisolone (2 mg/kg daily) and aspirin treatment was continued for 2 years, but every time the corticosteroid dose was brought below 1 mg/kg a severe increase in inflammatory joint symptoms affecting progressively more joints ensued. The corticosteroid therapy caused cushingoid facies, short stature, and osteoporosis. In November, 1973, because of a decreased response and side-effects of high-dose corticosteroids, treatment with chlorambucil was added (0-25 mg/kg daily). The symptoms declined and the corticosteroid dose was reduced below 1 mg/kg daily in October, 1974, without relapse. However, in June, 1975, pancytopenia (Hb 8.8 g/dl, WBC 16 000/1 with 0% neutrophils, platelets 81 000/1) was noted, and a bone-marrow aspirate showed aplasia. Chlorambucil was stopped and the bone-marrow became normal within 6 weeks, except for a mild lymphopenia (500/.1) which persisted until November, 1975. The clinical signs of JRA remained mild and stable. Corticosteroid therapy was stopped in October, 1976. The child seemed to be in remission. 2 years after chlorambucil treatment was stopped (September, 1977) he had a fever, anxmia, a tooth abscess with trismus, hypertrophic gingivitis, and cervical and axillary adenopathy. ESR 160 mm/h, Hb 7 g/dl, WBC 9200/ul with 97% blast cells, platelets 90 000/1. Bonemarrow aspirate showed 69% blasts with a mild nucleocytoplasmic ratio and weakly stained with sudan-black, peroxidases, and non-specific esterases which were partly inhibited 9 Szczeklik
A, et al. Successful therapy of advanced arteriosclerosis obliterans with prostacyclin. Lancet 1979; i: 1111-14. 10 Rose SS. Intra-arterial perfusion in the treatment of rest pain and gangrene.
Br J Clin Pract 1979; 33: 233-30. 1. Grup WE, Makker SP, Engelfinger JR. Chlorambucil treatment of frequently relapsing nephrotic syndrome. N Engl J Med 1976; 295: 746.
with sodium fluoride. Electromicroscopy showed non-differentiated blasts with a notched nucleus and few lysosomes. Acute
monoblastic leukaemia was diagnosed. Rubidazone (2 mg/kg daily) induced a complete remission, and monthly injections of rubidazone and cytarabine and for 3 prophylactic CNS irradiation followed. He months but relapsed and died in May, 1978. In a recent review2 of forty children treated with chlorambucil for JRA, two other cases of acute leukaemia were noted Dr M. L. Pernette (unpublished), in a series of two hundred JRA cases not treated with chlorambucil, found no cases of malignant blood disorder. Chlorambucil thus seems to have contributed to the development of acute leukaemia in three children with JRA. However, the numbers are too small for us to say if chlorambucil therapy carries a greater risk of associated leukaemia in children with JRA than it does in children given the drug for diseases other than JRA.; Acute leukaemia has been observed in adults treated with chlorambucil for chronic arthritis,’ and the high dose given to our patient (1-55 g), the appearance of pancytopenia after chlorambucil was withdrawn but before the diagnosis of acute leukaemia, and the non-lymphoblastic type of leuksemia with rapid downhill course resembles the cases in adults.4 Several mechanisms have been postulated by which alkylating agents could predispose to leukxmia. Induction of chromosome abnormalities may give rise to malignant cells.5 Unfortunately, we could not obtain adequate chromosome preparations in this case. Aplastic marrow may predispose to acute myelogenous leukaemia,6 and the 6 weeks of bone-marrow aplasia noted in our patient may have played a part. Chlorambucil suppression, by suppressing immunological surveillancemight allow the emergence of malignant clones of cells or invasion by oncogenic viruses; lymphopenia persisted for 6 months in our case. But whatever the mechanism, the case we describe suggests that chlorambucil should not be given to patients with JRA until more is known about its effects in such children.
responded
Pædiatric Service B,
Centre Hospitalier Universitaire de Tours, 37000 Tours, France
Y. LEBRANCHU J. DRUCKER H. NIVET J. C. ROLLAND B. GRENIER
C.H.U. de Tours
O. LEJARS J. P. LAMAGNERE
Immunology and Haematology Unit, Hôpital des Enfants-Malades, Pans
D. BURIOT
Hæmato-Cancerology Unit,
ANTITHROMBIN III DEFICIENCY DURING ASPARAGINASE THERAPY
SIR,-Professor Pitney and colleagues (March 1, p. 493) describe two patients in whom a venous thrombosis developed after I-asparaginase therapy, probably related to an antithrombin III (AT III) deficiency. We have treated a patient with acute monoblastic leukxmia for 9 days with a total dose of 84 000 U I-asparaginase. The pretreatment AT III was 100% (95-150% chromogene substrate S-2238 Kabi, as described by 2. Buriot D, Prieur AM, Lebranchu Y, Mersserschmitt J, Griselli C. Leucémies aiguës après traitement par le Chlorambucil: à propos de trois observations chez des enfants atteints d’arthrite chronique juvénile. Arch Fr
Pédiat 1979; 36: 592. Guesry P, Kleinknecht C, Gagnadoux MF, Broyer M. Complications extragonadiques du Chlorambucil chez l’enfant (à propos de 300 observations de néphropathies glomérulaires traitées). Arch Fr Pédiat 1977; 34: 798. 4. Seidenfeld AM, Smythe HA, Ogryzlo MA Acute leukemia in rhumatoïd arthritis treated with cytotoxic agents. J Rheumatol 1976; 3: 295. 5. Sieber SM, Adamson RH. The clastogenic, mutagenic, teratogenic and carcinogenic effects of various antineoplastic agents. In. Pharmacological basis of cancer chemotherapy. Baltimore: William & Wilkins, 1975: 3. Lenoir G,
401-68. 6. Vigliani EC, Saita G. Benzene and leukemia. N Engl J Med 1964, 271: 872. 7. Penn, I Occurrence of Cancer in Immune Deficiencies. Cancer 1974; 34: 858.