1367 THROMBOSIS AND FACTOR-IX CONCENTRATES
SiR,-The danger of thrombotic complications after the use of some commercial preparations of factor-ix concentrate in Christmas disease has been well reported.’-3 In Britain, the Oxford material DE(1)4 and the similar Edinburgh product DEFIX,5 which are clinical concentrates of the coagulation factors ix, n, and x, are widely used and are considered safe.6 We have seen a deep-vein thrombosis develop postoperatively in a patient with Christmas disease receiving regular infusions of
DE(1). A 63-year-old man with severe Christmas disease (factor ix level less than 1%) was admitted for a retropubic prostatectomy. During the immediate preoperative and first 10 postoperative days he received an average of 31-9 i.u. factor-ix activity per kg body-weight in each infusion from three batches of the Oxford DE(1) concentrate, this maintaining his factor-ix level above 50% during the first 5 days and above 15% over the next 5 days. He was given aminocaproic acid (E.A.C.A.) in a dose of 12 g per day from the sixth to the tenth postoperative days. Liver-function tests were normal throughout the postoperative period. On the fifth postoperative day, he had left-sided heel and calf pain, and by the tenth day, there was further clinical evidence of a deep-vein thrombosis which was confirmed by phlebography. Infusions of factor-ix concentrate and E.A.C.A. therapy were discontinued and subcutaneous heparin, 5000 i.u. twice a day was started with subsequent clinical improvement. Compared with some commercial concentrates, the British products have a very good record with over three hundred patients having been treated and only two patients (both postoperative) having thromboembolic complications.’ A report from Oxford8 showed that none of 72 patients with Christmas disease treated with type DE(1) concentrate, varying in amount from 16 to 117 i.u. of factor ix activity per kg body-weight, showed any clinical signs of intravascular clotting. Our case suggests that the British preparations of factor-ix concentrates--despite tests indicating freedom from thrombogenicity-still carry a slight risk of inducing thromboembolism, especially in the immediate postoperative period after major surgery. Department of Hæmatology, Middlesex Hospital, London W1P 7LD
S. J. MACHIN B. R. MILLER
DOXORUBICIN FOR LIVER CANCER
SIR,-The report from Dr Johnson and colleagues (May 13,
1006) on the treatment of primary liver-cell cancer with doxorubicin seems encouraging. In 1976 we treated eleven such patients, classed according to the Kampala symposium criteria9 as stage I (four patients), stage 11 (three) and stage III (four) with doxorubicin at the dosage tried by Johnson et al. All our patients died at 1-15 months (mean 5-45 months). Although pain disappeared in five of ten patients, there was no sign of remission, as judged by liver scan. cx,7fetoprotein levels fell in the three patients with long survival (14, 15, and 9 months) but did not return to normal in any patient. Our limited experience suggests that doxorubicin may help some patients with liver-cell cancer but we cannot confirm complete remission such as that described in four patients by p.
1. Kasper, C. K. New Engl. J. Med. 1973, 289, 160. 2. Kasper, C. K. Thrombos. Diath. hœmorrh. 1975, 33, 640. 3. Stieinberg, M. H., Dreling, B. J. New Engl. J. Med 1973, 289, 592. 4. Dike, G. W. R., Bidwell, E, Rizza, C. R. Br. J. Hœmat. 1972, 22, 469. 5. Middleton, S. H., Bennett, I. H., Smith, J. K. Vox Sang. 1973, 24, 441. 6. Lancet, 1975, ii, 855. 7. Bidwell, E., Rizza, C. R., Dike, G. W. R., Snape, T. J. Thrombos. Hœmostas. 1976, 35, 488. 8. Lane, J. L., Rizza, C. R., Snape, T. J. Br. J. Hœmat. 1975, 30, 435. 9.
Vogel, C. L., Linsell, C. A. J. natn. Cancer
Inst. 1972,
48, 567.
et al. Confirmation of controlled series.
Johnson
improved survival requires
a
J. VILASECA J. GUARDIA
Department of Internal Medicine, Ciudad Sanitaria de la Seguridad Social, Universidad Autónoma, Barcelona, Spain
R. BACARDÍ
J. MONNÉ
CHRONIC ACTIVE HEPATITIS AND EXTRAHEPATIC MALIGNANCY
SIR,-Extrahepatic malignant tumours have been reported in the course of chronic active hepatitis (c.A.H.).’ In our series of 32 cases of C.A.H., confirmed by laboratory and histological findings, 4 malignant tumours (12.5%) have been diagnosed. Case1
with antigen-positive C.A.H.., found at the age of given prednisolone 20 mg daily, gradually decreasing to a maintenance dose of 5 mg daily, for 27 months. At the age of 70 the patient died of cancer of the peritoneum with hepatic metastases, secondary to cancer of the ovary. A
65,
woman
was
Case 2 A man with antigen-positive viral hepatitis which proceeded C.A.H., discovered at the age of 56 and untreated for 19 months, was given 20 mg prednisolone daily for 2 years, after which prednisolone (30 mg daily) and azathioprine (100 mg daily) were given together for 10 months. At the age of 60 the to
patient died of a malignant lymphoma. Case 3 A
man
of 76
with antigen-positive
treated with decover 7 months
c.A.H. was
in a dose of 40 mg daily reased to a maintenance dose of 15 mg daily, in all. A year after the clinical onset of C.A.H. a tal polyp was found.
prednisolone given
gradually
malignant
rec-
Case 4 A man of 69 with antigen-negative c.A.H. without smoothmuscle antibodies was given prednisolone in a dose of 30 mg daily, then 20 mg daily over 4 months, followed by prednisolone 20 mg daily with azathioprine 50 mg daily for 9 months. 2 years after the onset of C.A.H., when the patient was 71, carcinoma of the tongue was discovered. Our 32 c..H. patients had a mean age of 57 (range 28-80). All received corticosteroid therapy. They were followed up for an average of 26 months (range 3 months to 10 years). In these patients 4 extrahepatic tumours were seen over a period of 26 months. In the age-group 55-64 the annual incidence of cancer in France is 76 per 100000.2 In our group of 32 patients followed up for 26 months the incidence of cancer would be expected to be well below 1 (0.05). Even allowing for the difference between hospitals and general populations this association between C.A.H. and malignant tumour seems unlikely to be due to chance. Immunosuppression may predispose to malignant tumours, but this is not likely to be the sole factor. In our group, the doses were small and duration of treatment brief, both for the cortico-steroids and for azathioprine. This regimen is very different from those used in kidney transplants, where a high incidence of cancer has been observed. Service d’Hépatologie et Hôpital Antoine Béclère, 92141 Clamart, France; and Unité de Recherches
de
Gastroentérologie,
J. C. CHAPUT C. BUFFET L. PAPOZ J. P. ETIENNE
Statistitiques,
I.N.S.E.R.M., Villejuif, France
1. Viteri, A., Vernace, S. J., Schaffner, F. Gastroenterology, 1976, 71, 1075.
2. Enquête
Permanente Cancer. Résultats
I.N.S.E.R.M., Paris, 1976.
et
survie à
long
terme
1976.
_
SiR,-The danger of thrombotic complications after the use of some commercial preparations of factor-ix concentrate in Christmas disease has been well reported.’-3 In Britain, the Oxford material DE(1)4 and the similar Edinburgh product DEFIX,5 which are clinical concentrates of the coagulation factors ix, n, and x, are widely used and are considered safe.6 We have seen a deep-vein thrombosis develop postoperatively in a patient with Christmas disease receiving regular infusions of
DE(1). A 63-year-old man with severe Christmas disease (factor ix level less than 1%) was admitted for a retropubic prostatectomy. During the immediate preoperative and first 10 postoperative days he received an average of 31-9 i.u. factor-ix activity per kg body-weight in each infusion from three batches of the Oxford DE(1) concentrate, this maintaining his factor-ix level above 50% during the first 5 days and above 15% over the next 5 days. He was given aminocaproic acid (E.A.C.A.) in a dose of 12 g per day from the sixth to the tenth postoperative days. Liver-function tests were normal throughout the postoperative period. On the fifth postoperative day, he had left-sided heel and calf pain, and by the tenth day, there was further clinical evidence of a deep-vein thrombosis which was confirmed by phlebography. Infusions of factor-ix concentrate and E.A.C.A. therapy were discontinued and subcutaneous heparin, 5000 i.u. twice a day was started with subsequent clinical improvement. Compared with some commercial concentrates, the British products have a very good record with over three hundred patients having been treated and only two patients (both postoperative) having thromboembolic complications.’ A report from Oxford8 showed that none of 72 patients with Christmas disease treated with type DE(1) concentrate, varying in amount from 16 to 117 i.u. of factor ix activity per kg body-weight, showed any clinical signs of intravascular clotting. Our case suggests that the British preparations of factor-ix concentrates--despite tests indicating freedom from thrombogenicity-still carry a slight risk of inducing thromboembolism, especially in the immediate postoperative period after major surgery. Department of Hæmatology, Middlesex Hospital, London W1P 7LD
S. J. MACHIN B. R. MILLER
DOXORUBICIN FOR LIVER CANCER
SIR,-The report from Dr Johnson and colleagues (May 13,
1006) on the treatment of primary liver-cell cancer with doxorubicin seems encouraging. In 1976 we treated eleven such patients, classed according to the Kampala symposium criteria9 as stage I (four patients), stage 11 (three) and stage III (four) with doxorubicin at the dosage tried by Johnson et al. All our patients died at 1-15 months (mean 5-45 months). Although pain disappeared in five of ten patients, there was no sign of remission, as judged by liver scan. cx,7fetoprotein levels fell in the three patients with long survival (14, 15, and 9 months) but did not return to normal in any patient. Our limited experience suggests that doxorubicin may help some patients with liver-cell cancer but we cannot confirm complete remission such as that described in four patients by p.
1. Kasper, C. K. New Engl. J. Med. 1973, 289, 160. 2. Kasper, C. K. Thrombos. Diath. hœmorrh. 1975, 33, 640. 3. Stieinberg, M. H., Dreling, B. J. New Engl. J. Med 1973, 289, 592. 4. Dike, G. W. R., Bidwell, E, Rizza, C. R. Br. J. Hœmat. 1972, 22, 469. 5. Middleton, S. H., Bennett, I. H., Smith, J. K. Vox Sang. 1973, 24, 441. 6. Lancet, 1975, ii, 855. 7. Bidwell, E., Rizza, C. R., Dike, G. W. R., Snape, T. J. Thrombos. Hœmostas. 1976, 35, 488. 8. Lane, J. L., Rizza, C. R., Snape, T. J. Br. J. Hœmat. 1975, 30, 435. 9.
Vogel, C. L., Linsell, C. A. J. natn. Cancer
Inst. 1972,
48, 567.
et al. Confirmation of controlled series.
Johnson
improved survival requires
a
J. VILASECA J. GUARDIA
Department of Internal Medicine, Ciudad Sanitaria de la Seguridad Social, Universidad Autónoma, Barcelona, Spain
R. BACARDÍ
J. MONNÉ
CHRONIC ACTIVE HEPATITIS AND EXTRAHEPATIC MALIGNANCY
SIR,-Extrahepatic malignant tumours have been reported in the course of chronic active hepatitis (c.A.H.).’ In our series of 32 cases of C.A.H., confirmed by laboratory and histological findings, 4 malignant tumours (12.5%) have been diagnosed. Case1
with antigen-positive C.A.H.., found at the age of given prednisolone 20 mg daily, gradually decreasing to a maintenance dose of 5 mg daily, for 27 months. At the age of 70 the patient died of cancer of the peritoneum with hepatic metastases, secondary to cancer of the ovary. A
65,
woman
was
Case 2 A man with antigen-positive viral hepatitis which proceeded C.A.H., discovered at the age of 56 and untreated for 19 months, was given 20 mg prednisolone daily for 2 years, after which prednisolone (30 mg daily) and azathioprine (100 mg daily) were given together for 10 months. At the age of 60 the to
patient died of a malignant lymphoma. Case 3 A
man
of 76
with antigen-positive
treated with decover 7 months
c.A.H. was
in a dose of 40 mg daily reased to a maintenance dose of 15 mg daily, in all. A year after the clinical onset of C.A.H. a tal polyp was found.
prednisolone given
gradually
malignant
rec-
Case 4 A man of 69 with antigen-negative c.A.H. without smoothmuscle antibodies was given prednisolone in a dose of 30 mg daily, then 20 mg daily over 4 months, followed by prednisolone 20 mg daily with azathioprine 50 mg daily for 9 months. 2 years after the onset of C.A.H., when the patient was 71, carcinoma of the tongue was discovered. Our 32 c..H. patients had a mean age of 57 (range 28-80). All received corticosteroid therapy. They were followed up for an average of 26 months (range 3 months to 10 years). In these patients 4 extrahepatic tumours were seen over a period of 26 months. In the age-group 55-64 the annual incidence of cancer in France is 76 per 100000.2 In our group of 32 patients followed up for 26 months the incidence of cancer would be expected to be well below 1 (0.05). Even allowing for the difference between hospitals and general populations this association between C.A.H. and malignant tumour seems unlikely to be due to chance. Immunosuppression may predispose to malignant tumours, but this is not likely to be the sole factor. In our group, the doses were small and duration of treatment brief, both for the cortico-steroids and for azathioprine. This regimen is very different from those used in kidney transplants, where a high incidence of cancer has been observed. Service d’Hépatologie et Hôpital Antoine Béclère, 92141 Clamart, France; and Unité de Recherches
de
Gastroentérologie,
J. C. CHAPUT C. BUFFET L. PAPOZ J. P. ETIENNE
Statistitiques,
I.N.S.E.R.M., Villejuif, France
1. Viteri, A., Vernace, S. J., Schaffner, F. Gastroenterology, 1976, 71, 1075.
2. Enquête
Permanente Cancer. Résultats
I.N.S.E.R.M., Paris, 1976.
et
survie à
long
terme
1976.
_
