605 that the IgG3 anti-Rh was in the second peak. In the other two cases, an anti-Rh of the IgA class appeared. In these six pregnancies analysis of amniotic fluid remained in Liley’s zone B, and the babies were born at about 35 weeks’ gestation in good condition. They were treated by postnatal exchange transfusions. The seventh case, a twin pregnancy, was of particular interest because the twins were Rh negative. Despite the absence of fetomaternal conflict, the evolution of the anti-Rh gammaglobulin pattern in the maternal serum during E.M.O.T. was the same as that in the other women. The IgG1 anti-Rh titre was depressed, an IgG3 molecule appeared and disappeared, and a part of the anti-Rh specificity was of the IgA class. This response was relatively stable and persisted for several months after delivery (i.e., after the end of the oral treatment which probably produced the Rh/anti-Rh conflict). The apparent efficiency of E.M.O.T. may be due either to intestinal antibody consumption or to some effect on immunological regulation. The effect of oral antigen administration is ’vell-known in primary response, but it is not so well documented in secondary response. This project was an attempt to replace or diminish an IgG response by a local IgA response. Oral therapy in one case produced a permanent primary IgM-type response and in the other cases a new IgA-type anti-Rh, probably produced by continuous stimulation of the intestinal immunological system, appeared. In all the patients the pre-existing circulating secondary antibody was depressed and the anamnestic reaction of the parenteral system was suppressed. Hæmatology Service, Blood Transfusion Centre, Centre Hospitalier Universitaire 31052 Toulouse, France
Blood Typing Centre C.H.U. Purpan
A 60-year-old woman had a pigmented melanotic mole removed from her right leg in July, 1976. Recurrent metastases were resected from lymph-nodes in the right groin 12, 17, and 23 months later. She became systemically ill in October, 1978, and multiple liver and lung metastases were noted on liver scan and chest X-ray. Dacarbazine (D.T.I.C.) 850 mg/m2 was given as a single intravenous dose, but 3 weeks later a new lung lesion had appeared and the other metastatic lung lesions had increased in size, the largest lesion increasing from 25 to 30 mm in diameter. We then tried a course of oral pimozide 4 mg daily for 1 week, 8 mg/day for the secmd week, and 12 mg daily after that. After 4 weeks of pimozide (7 weeks after the dose of D.T.LC.) lung lesions were perceptibly smaller by 1-2 mm. 1 week later, lung lesions were smaller by 50%, and serum-alkaline-phosphatase had fallen from 194 to 98 i.u./I (normal range 30-85). After 8 weeks of pimozide therapy (11 weeks after the D.T.I.C.) the lung lesions were no longer visible and a liver scan showed greater than 50% reduction in the size of lesions. Side-effects of treatment have included lethargy, xerostomia, and xerophthalmia. Pimozide dosage has been tapered off and stopped, and she remains in partial remission 20 weeks after starting pimozide. This response may have been a delayed one to the single dose of D.T.I.C. or the result of a spontaneous regression of her melanoma, but it is also possible that pimozide has led to a partial remission of metastatic disease in this postmenopausal patient with pigmented metastases. Further studies of pimozide in patients with metastatic malignant melanoma and of the mechanisms of action of pimozide in B16 melanoma in mice have been started. Division of Oncology,
Purpan,
S. J. BIERME
C.N.R.S., M. BLANC
Immunology Service, C.H.U. Purpan
M. ABBAL
Gynæcology and Obstetics Service, Hôpital La Grave, Toulouse
A. FOURNIE
TREATMENT OF METASTATIC MALIGNANT MELANOMA WITH PIMOZIDE
SIR,-Treatment of metastatic malignant melanoma with
cytotoxic drugs has been unsatisfactory, with brief responses seen in only a minority of patients.’ Recently, evidence has emerged that malignant melanoma may be a hormonally responsive tumour: oestrogen receptors have been described in the cytoplasm of human melanoma tissue,2 hormonal therapy has been shown to cause regression of metastatic melanoma in a small number of patients,3 and in B16 melanoma in mice administration of drugs that inhibit the enzyme dopa decarboxy-
lase results in lower levels of dopamine and inhibition of growth of pigmented tUmours.4 Pimozide is a neuroleptic agent of the diphenylbutylpiperidine category that inhibits pituitary releasing factors in rats.5 In man, pimozide has been used in the treatment of generalised lipodystrophy with elimination of corticotrophin and luteinising hormone releasing factors from the general circulation.6 Pimozide is also a potent dopamine inhibitor. We have used pimozide to treat a postmenopausal woman with metastatic pigmented malignant melanoma and have observed a partial remission of measurable disease. 1. Everall, J. D., Dowd, P. M. Lancet, 1977, ii, 286. 2 Fisher, R.J., Neifeld, J. P., Lippman, M. E. ibid. 1976,ii,337. 3 Fisher, R. J., Young, R. C., Lippman, M. E. Proc. Am. Soc. clin. Oncol. 1978,19,339 4. Wick,M. M. Nature, 1977, 269, 513. 5. Upton, G. V., Corbin, A. Yale J. Biol. Med. 1973, 46, 314. 6 Corbin, A, Upton, G. V., Mabry, C. C., Hollingsworth, D. R. Acta endocr. 1974, 77, 209.
Department of Medicine, Virginia, Richmond, Virginia, U.S.A. Department of Medicine, Toronto Western Hospital, University of Toronto, Medical College of
Toronto, Ontario M5T 2S8, Canada
ROBERT N. TAUB
MICHAEL A. BAKER
HEPATIC DYSFUNCTION IN PATIENT WITH FETAL ALCOHOL SYNDROME
SiR,—The main features of abnormal infants born to alcoholic mothers are prenatal and postnatal growth retardation, retarded motor and intellectual development, and facial anomalies. Other problems, such as congenital heart-disease and hypospadias, are often seen,’ but liver dysfunction in the fetal alcohol syndrome has not been described.2 Our patient, a girl, is the first child of a 21-year-old alcoholic mother, who consumed about 2 litres of strong beer a day. During the pregnancy the fetus was small for gestational age. 3-4 weeks before term the child was born without complications, weight 1100 g, length 40 cm. Jitteriness was observed during the first days of life. Serumcalcium and blood-sugar values were normal. Despite adequate gavage feeding her growth was modest. Psychomotor development was also slow. At 16 months her weight was z 79 kg, length 69 cm, cranial circumference 39 cm. She could stand without support but was unable to walk. Her developmental quotient was 45 in a Cattel test. Microcephaly, short palpebral fissures, low-set ears, hypoplastic mandible, wide mouth, and anteverted nostrils completed the impression of a patient with the fetal alcohol ’
syndrome. Shortly after
birth hepatomegaly without splenomegaly was observed. The patient never became jaundiced and serum-bilirubin remained low at 4-9µmol/l (mean of six determinations), Jones, K. L., Smith, D. W., Ulleland, C. N., Streissguth, A. D. Lancet, 1973, i,1267. 2. Clarren, S. K., Smith, D. W. New Engl. J. Med. 1978, 298, 1063. 1.
606
an ambiguous sign, described in combination with extrahepatic atresia, virus hepatitis, cirrhosis, and galactosEemia.3 Hepatic dysfunction has not previously been described in
is
connection with fetal alcohol syndrome-perhaps it has been overlooked because of silent symptoms or perhaps it is a very rare complication of the syndrome. Neither the biochemical nor the histological features support a fortuitous association of non-alcoholic liver damage in a patient with fetal alcohol syndrome as the explanation in this case. The case-history has been reported in Danish, as one of the two first cases of fetal alcohol syndrome observed in Denmark.4 Section of Clinical Genetics, Department of Paediatrics and Laboratory of Pædiatric Pathology,
Rigshospitalet, 2100 Copenhagen, Denmark
JØN MØLLER NIELS JACOB BRANDT INGE TYGSTRUP
MEGALOBLASTIC ANÆMIA WITH NORMAL MEAN CELL VOLUME Portal space with several small tubular structures-so-called bileduct proliferation.
(Hsematoxylin and eosin; reduced to 2/3 of x 400).
the normal range being 7-15 umol/1 (1 mol/l=0-0113 mg/dl). Aspartate aminotransferase was raised (99-160 U/l, normal
Blood Typing Centre C.H.U. Purpan
A 60-year-old woman had a pigmented melanotic mole removed from her right leg in July, 1976. Recurrent metastases were resected from lymph-nodes in the right groin 12, 17, and 23 months later. She became systemically ill in October, 1978, and multiple liver and lung metastases were noted on liver scan and chest X-ray. Dacarbazine (D.T.I.C.) 850 mg/m2 was given as a single intravenous dose, but 3 weeks later a new lung lesion had appeared and the other metastatic lung lesions had increased in size, the largest lesion increasing from 25 to 30 mm in diameter. We then tried a course of oral pimozide 4 mg daily for 1 week, 8 mg/day for the secmd week, and 12 mg daily after that. After 4 weeks of pimozide (7 weeks after the dose of D.T.LC.) lung lesions were perceptibly smaller by 1-2 mm. 1 week later, lung lesions were smaller by 50%, and serum-alkaline-phosphatase had fallen from 194 to 98 i.u./I (normal range 30-85). After 8 weeks of pimozide therapy (11 weeks after the D.T.I.C.) the lung lesions were no longer visible and a liver scan showed greater than 50% reduction in the size of lesions. Side-effects of treatment have included lethargy, xerostomia, and xerophthalmia. Pimozide dosage has been tapered off and stopped, and she remains in partial remission 20 weeks after starting pimozide. This response may have been a delayed one to the single dose of D.T.I.C. or the result of a spontaneous regression of her melanoma, but it is also possible that pimozide has led to a partial remission of metastatic disease in this postmenopausal patient with pigmented metastases. Further studies of pimozide in patients with metastatic malignant melanoma and of the mechanisms of action of pimozide in B16 melanoma in mice have been started. Division of Oncology,
Purpan,
S. J. BIERME
C.N.R.S., M. BLANC
Immunology Service, C.H.U. Purpan
M. ABBAL
Gynæcology and Obstetics Service, Hôpital La Grave, Toulouse
A. FOURNIE
TREATMENT OF METASTATIC MALIGNANT MELANOMA WITH PIMOZIDE
SIR,-Treatment of metastatic malignant melanoma with
cytotoxic drugs has been unsatisfactory, with brief responses seen in only a minority of patients.’ Recently, evidence has emerged that malignant melanoma may be a hormonally responsive tumour: oestrogen receptors have been described in the cytoplasm of human melanoma tissue,2 hormonal therapy has been shown to cause regression of metastatic melanoma in a small number of patients,3 and in B16 melanoma in mice administration of drugs that inhibit the enzyme dopa decarboxy-
lase results in lower levels of dopamine and inhibition of growth of pigmented tUmours.4 Pimozide is a neuroleptic agent of the diphenylbutylpiperidine category that inhibits pituitary releasing factors in rats.5 In man, pimozide has been used in the treatment of generalised lipodystrophy with elimination of corticotrophin and luteinising hormone releasing factors from the general circulation.6 Pimozide is also a potent dopamine inhibitor. We have used pimozide to treat a postmenopausal woman with metastatic pigmented malignant melanoma and have observed a partial remission of measurable disease. 1. Everall, J. D., Dowd, P. M. Lancet, 1977, ii, 286. 2 Fisher, R.J., Neifeld, J. P., Lippman, M. E. ibid. 1976,ii,337. 3 Fisher, R. J., Young, R. C., Lippman, M. E. Proc. Am. Soc. clin. Oncol. 1978,19,339 4. Wick,M. M. Nature, 1977, 269, 513. 5. Upton, G. V., Corbin, A. Yale J. Biol. Med. 1973, 46, 314. 6 Corbin, A, Upton, G. V., Mabry, C. C., Hollingsworth, D. R. Acta endocr. 1974, 77, 209.
Department of Medicine, Virginia, Richmond, Virginia, U.S.A. Department of Medicine, Toronto Western Hospital, University of Toronto, Medical College of
Toronto, Ontario M5T 2S8, Canada
ROBERT N. TAUB
MICHAEL A. BAKER
HEPATIC DYSFUNCTION IN PATIENT WITH FETAL ALCOHOL SYNDROME
SiR,—The main features of abnormal infants born to alcoholic mothers are prenatal and postnatal growth retardation, retarded motor and intellectual development, and facial anomalies. Other problems, such as congenital heart-disease and hypospadias, are often seen,’ but liver dysfunction in the fetal alcohol syndrome has not been described.2 Our patient, a girl, is the first child of a 21-year-old alcoholic mother, who consumed about 2 litres of strong beer a day. During the pregnancy the fetus was small for gestational age. 3-4 weeks before term the child was born without complications, weight 1100 g, length 40 cm. Jitteriness was observed during the first days of life. Serumcalcium and blood-sugar values were normal. Despite adequate gavage feeding her growth was modest. Psychomotor development was also slow. At 16 months her weight was z 79 kg, length 69 cm, cranial circumference 39 cm. She could stand without support but was unable to walk. Her developmental quotient was 45 in a Cattel test. Microcephaly, short palpebral fissures, low-set ears, hypoplastic mandible, wide mouth, and anteverted nostrils completed the impression of a patient with the fetal alcohol ’
syndrome. Shortly after
birth hepatomegaly without splenomegaly was observed. The patient never became jaundiced and serum-bilirubin remained low at 4-9µmol/l (mean of six determinations), Jones, K. L., Smith, D. W., Ulleland, C. N., Streissguth, A. D. Lancet, 1973, i,1267. 2. Clarren, S. K., Smith, D. W. New Engl. J. Med. 1978, 298, 1063. 1.
606
an ambiguous sign, described in combination with extrahepatic atresia, virus hepatitis, cirrhosis, and galactosEemia.3 Hepatic dysfunction has not previously been described in
is
connection with fetal alcohol syndrome-perhaps it has been overlooked because of silent symptoms or perhaps it is a very rare complication of the syndrome. Neither the biochemical nor the histological features support a fortuitous association of non-alcoholic liver damage in a patient with fetal alcohol syndrome as the explanation in this case. The case-history has been reported in Danish, as one of the two first cases of fetal alcohol syndrome observed in Denmark.4 Section of Clinical Genetics, Department of Paediatrics and Laboratory of Pædiatric Pathology,
Rigshospitalet, 2100 Copenhagen, Denmark
JØN MØLLER NIELS JACOB BRANDT INGE TYGSTRUP
MEGALOBLASTIC ANÆMIA WITH NORMAL MEAN CELL VOLUME Portal space with several small tubular structures-so-called bileduct proliferation.
(Hsematoxylin and eosin; reduced to 2/3 of x 400).
the normal range being 7-15 umol/1 (1 mol/l=0-0113 mg/dl). Aspartate aminotransferase was raised (99-160 U/l, normal
