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NEURAL-TUBE MALFORMATIONS IN OFFSPRING OF SPINA-BIFIDA PATIENTS
685 abnormalities in a study of influences in the fetal environment.
congenital
Department of Child Health, Southampton General Hospital, Southampton SO9 4XY.
possible teratogenic
SIR,—Iwish DAVID C. SIGGERS.
NEURAL-TUBE MALFORMATIONS IN OFFSPRING OF SPINA-BIFIDA PATIENTS two of us reported a follow-up of 202 and women surviving after operation in infancy for spina bifida cystica and estimated that the risk of neuraltube malformations in their offspring was of the order of 3%. There is, therefore, a case for screening of the pregnancy by ultrasound and by amniotic-fluid oc-fetoprotein (A.F.P.) estimation, where either parent had spina
SIR,-In 1973
men
bifida cystica. A further patient in this series, a married woman of 19 years with paraplegia was found last month to have a raised A.F.P. level in amniotic fluid at 15 and 17 weeks, respectively. The pregnancy was terminated and the fetus found to have a lumbosacral meningomyelocele and bilateral talipes
equinovarus. M.R.C. Clinical Genetics Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH. Institute of Obstetrics, Queen Charlotte’s Maternity Hospital, London W6.
HEPATOMA ASSOCIATED WITH ANDROGENIC STEROIDS
C. O. CARTER K. A. EVANS.
S. CAMPBELL.
IRON DEFICIENCY AND INFECTION
SIR,—The paper by Dr Masawe and others (Aug. 10, p. 314) and the letter by Dr Stein (Dec. 28, p. 1567) must raise at least two questions: (1) Is it not the lack of available iron which causes so-called anergic bedsores in psychogeriatric patients ? ; and (2) what is the role of iron deficiency in the
general adaptation syndrome ? Considering the anergic bedsore, it is amazing to see a huge decubital ulcer with bare calcaneous bone, with the insertion of Achilles tendon, blood-vessels, and nerves exposed like an anatomical preparation, but no inflammatory reaction in the healthy surrounding tissue or general symptoms; and when the patient is asked how he is, he answers, without irony, " just fine ". Is it not the lack of available iron or perhaps of other biogenic factors which prevents bacterial growth ? Without an appropriate reaction producing local and general changes, it would be difficult to imagine how the ulcer can heal. Almost all our patients with anergic bedsores have hypochromic anxmia, but not always a hsemoglobin level below 10 g. per 100 ml. I remember patients in whom a blood-transfusion or massive doses of B or C vitamins obviously turned the anergic process into an active one; the patient suddenly became pyrexial, the dry necrotic lesion changed to a moist one, and the patient died in the clinical picture of sepsis. We are facing a paradox in that a substance otherwise necessary for the organism may, under certain conditions, be contraindicated. In certain psychiatric illnesses, and particularly in psychogeriatric ones, the mechanism of the general adaptation syndrome is changed towards energy: the patient does not react to the stressor because he does not feel pain, has no insight, judgment, or fear, and a lack of iron or other biogenic factors may reinforce the asymptomatic, anergic character of the condition. Montreal, Quebec, Canada H4H 1R3.
histological illustrations as showing unequivocal hepatocellular carcinoma (case 2 of Johnson et al.2). Necropsies done on 5 cases and metastases were found in none of them. ot-fetoprotein estimations were carried out in 6 cases of which 5 were negative. a-fetoprotein was present only in the 1 case reported by Henderson et al.8 This is all the more surprising as 7 of these 9 patients were under the age of 30. In our experience 30 of 34 patients in this age-group were positiveand similar high rates have also been reported by others.9,loThis leaves us with 2 acceptable cases of hepatocellular carcinoma in association with androgenic steroid treatment. The evidence for a role of oral contraceptive steroids in the aetiology of benign liver-cell adenomas and other non-malignant lesions of the liver is rather stronger,l
were
1.
2. 3. 4. 5.
6. 7.
1.
Carter, C. O., Evans, K. A. Lancet, 1973, ii, 924.
8.
S. HONTELA.
the report of 3 cases of et al.1 It is said
2 patients during four and seven years of observation and that it regressed in 1 of these 2 and another 3rd patient. Bony metastasis occurred in 1 patient who is still alive and well three years later, and so are the other 2 patients. All three tumours are said to have shown well-differentiated hepatocellular carcinoma, but this is not supported by histological illustrations. The biopsy specimen from the bony metastasis was not available to the authors. a-fetoprotein was tested for and was absent in all 3 cases. The authors also quote a case reported by Johnson et al. in which the tumour regressed. This was a 6-year-old girl, treated with oxymetholone for three years, who died six months after a tumour in the liver was found at laparotomy. The serum a-fetoprotein test was negative and no necropsy was carried out. Hepatocellular carcinoma, no matter how differentiated, is a relentlessly progressive malignant disease. In our experience of 153 cases, only 20% were alive two months after presentation and all but 1 were known to be dead at eleven months. The median survival time was only one month.33 These figures are similar to those reported by others.4,5 Spontaneous regression is exceedingly rare in malignant neoplasms once they have become manifest, and I am unaware of any case of proven cancer which has regressed as a result of withdrawal of a known or putative causative agent. A review of case-reports of hepatocellular carcinoma in association with androgenic steroid therapy cited by Farrell et al. can be summarised as follows. 9 cases have been reported, in 8 of which histological examination was done (reproduced in 3) and a-fetoprotein estimation was carried out in 6. Since the matter is of some importance, I suggest that unequivocal histological appearances 6 and/or a positive a-fetoprotein test should be required before the diagnosis is accepted. As a pathologist with experience of some 700 cases of primary liver cancer, I can only accept 1 of the 3 cases which have been documented with
Douglas Hospital, 6875 LaSalle Boulevard,
to comment on
androgen-induced hepatoma by Farrell that the tumour progressed slowly in
Farrell, G. C., Joshua, D. E., Uren, R. F., Baird, P. J., Perkins, K. W., Kronenberg, H. Lancet, Feb. 22, 1975, i, 430. Johnson, F. L., Feagler, J. R., Lerner, K. G., Majerus, P. W., Siegel, M., Hartmann, J. R., Thomas, E. D. ibid. 1972, ii, 1273. Primack, A., Vogel, C. L., Kyalwazi, S. K., Ziegler, J. L., Simon, R., Anthony, P. P. Cancer (in the press). Chan, K. T. Ann. R. Coll. Surg. Engl. 1967, 41, 253. Malt, R. A., Van Vroonhoven, J. J., Kakumoto, Y. Surgery Gynec. Obstet. 1972, 135, 361. Anthony, P. P. J. Path. 1973, 110, 37. Vogel, C. L., Primack, A., McIntire, K. R., Carbone, P. P., Anthony, P. P., Cancer, 1974, 33, 959. Henderson, J. T., Richmond, J., Sumerling, M. D. Lancet, 1973, i,
934. 9. Mawas, C., Buffe, D., Burtin, P. ibid. 1970, i, 1292. 10. Bagshawe, A., Parker, A. M. ibid. 1970, ii, 268. 11. Br. med. J. 1974, iii, 3.
congenital
Department of Child Health, Southampton General Hospital, Southampton SO9 4XY.
possible teratogenic
SIR,—Iwish DAVID C. SIGGERS.
NEURAL-TUBE MALFORMATIONS IN OFFSPRING OF SPINA-BIFIDA PATIENTS two of us reported a follow-up of 202 and women surviving after operation in infancy for spina bifida cystica and estimated that the risk of neuraltube malformations in their offspring was of the order of 3%. There is, therefore, a case for screening of the pregnancy by ultrasound and by amniotic-fluid oc-fetoprotein (A.F.P.) estimation, where either parent had spina
SIR,-In 1973
men
bifida cystica. A further patient in this series, a married woman of 19 years with paraplegia was found last month to have a raised A.F.P. level in amniotic fluid at 15 and 17 weeks, respectively. The pregnancy was terminated and the fetus found to have a lumbosacral meningomyelocele and bilateral talipes
equinovarus. M.R.C. Clinical Genetics Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH. Institute of Obstetrics, Queen Charlotte’s Maternity Hospital, London W6.
HEPATOMA ASSOCIATED WITH ANDROGENIC STEROIDS
C. O. CARTER K. A. EVANS.
S. CAMPBELL.
IRON DEFICIENCY AND INFECTION
SIR,—The paper by Dr Masawe and others (Aug. 10, p. 314) and the letter by Dr Stein (Dec. 28, p. 1567) must raise at least two questions: (1) Is it not the lack of available iron which causes so-called anergic bedsores in psychogeriatric patients ? ; and (2) what is the role of iron deficiency in the
general adaptation syndrome ? Considering the anergic bedsore, it is amazing to see a huge decubital ulcer with bare calcaneous bone, with the insertion of Achilles tendon, blood-vessels, and nerves exposed like an anatomical preparation, but no inflammatory reaction in the healthy surrounding tissue or general symptoms; and when the patient is asked how he is, he answers, without irony, " just fine ". Is it not the lack of available iron or perhaps of other biogenic factors which prevents bacterial growth ? Without an appropriate reaction producing local and general changes, it would be difficult to imagine how the ulcer can heal. Almost all our patients with anergic bedsores have hypochromic anxmia, but not always a hsemoglobin level below 10 g. per 100 ml. I remember patients in whom a blood-transfusion or massive doses of B or C vitamins obviously turned the anergic process into an active one; the patient suddenly became pyrexial, the dry necrotic lesion changed to a moist one, and the patient died in the clinical picture of sepsis. We are facing a paradox in that a substance otherwise necessary for the organism may, under certain conditions, be contraindicated. In certain psychiatric illnesses, and particularly in psychogeriatric ones, the mechanism of the general adaptation syndrome is changed towards energy: the patient does not react to the stressor because he does not feel pain, has no insight, judgment, or fear, and a lack of iron or other biogenic factors may reinforce the asymptomatic, anergic character of the condition. Montreal, Quebec, Canada H4H 1R3.
histological illustrations as showing unequivocal hepatocellular carcinoma (case 2 of Johnson et al.2). Necropsies done on 5 cases and metastases were found in none of them. ot-fetoprotein estimations were carried out in 6 cases of which 5 were negative. a-fetoprotein was present only in the 1 case reported by Henderson et al.8 This is all the more surprising as 7 of these 9 patients were under the age of 30. In our experience 30 of 34 patients in this age-group were positiveand similar high rates have also been reported by others.9,loThis leaves us with 2 acceptable cases of hepatocellular carcinoma in association with androgenic steroid treatment. The evidence for a role of oral contraceptive steroids in the aetiology of benign liver-cell adenomas and other non-malignant lesions of the liver is rather stronger,l
were
1.
2. 3. 4. 5.
6. 7.
1.
Carter, C. O., Evans, K. A. Lancet, 1973, ii, 924.
8.
S. HONTELA.
the report of 3 cases of et al.1 It is said
2 patients during four and seven years of observation and that it regressed in 1 of these 2 and another 3rd patient. Bony metastasis occurred in 1 patient who is still alive and well three years later, and so are the other 2 patients. All three tumours are said to have shown well-differentiated hepatocellular carcinoma, but this is not supported by histological illustrations. The biopsy specimen from the bony metastasis was not available to the authors. a-fetoprotein was tested for and was absent in all 3 cases. The authors also quote a case reported by Johnson et al. in which the tumour regressed. This was a 6-year-old girl, treated with oxymetholone for three years, who died six months after a tumour in the liver was found at laparotomy. The serum a-fetoprotein test was negative and no necropsy was carried out. Hepatocellular carcinoma, no matter how differentiated, is a relentlessly progressive malignant disease. In our experience of 153 cases, only 20% were alive two months after presentation and all but 1 were known to be dead at eleven months. The median survival time was only one month.33 These figures are similar to those reported by others.4,5 Spontaneous regression is exceedingly rare in malignant neoplasms once they have become manifest, and I am unaware of any case of proven cancer which has regressed as a result of withdrawal of a known or putative causative agent. A review of case-reports of hepatocellular carcinoma in association with androgenic steroid therapy cited by Farrell et al. can be summarised as follows. 9 cases have been reported, in 8 of which histological examination was done (reproduced in 3) and a-fetoprotein estimation was carried out in 6. Since the matter is of some importance, I suggest that unequivocal histological appearances 6 and/or a positive a-fetoprotein test should be required before the diagnosis is accepted. As a pathologist with experience of some 700 cases of primary liver cancer, I can only accept 1 of the 3 cases which have been documented with
Douglas Hospital, 6875 LaSalle Boulevard,
to comment on
androgen-induced hepatoma by Farrell that the tumour progressed slowly in
Farrell, G. C., Joshua, D. E., Uren, R. F., Baird, P. J., Perkins, K. W., Kronenberg, H. Lancet, Feb. 22, 1975, i, 430. Johnson, F. L., Feagler, J. R., Lerner, K. G., Majerus, P. W., Siegel, M., Hartmann, J. R., Thomas, E. D. ibid. 1972, ii, 1273. Primack, A., Vogel, C. L., Kyalwazi, S. K., Ziegler, J. L., Simon, R., Anthony, P. P. Cancer (in the press). Chan, K. T. Ann. R. Coll. Surg. Engl. 1967, 41, 253. Malt, R. A., Van Vroonhoven, J. J., Kakumoto, Y. Surgery Gynec. Obstet. 1972, 135, 361. Anthony, P. P. J. Path. 1973, 110, 37. Vogel, C. L., Primack, A., McIntire, K. R., Carbone, P. P., Anthony, P. P., Cancer, 1974, 33, 959. Henderson, J. T., Richmond, J., Sumerling, M. D. Lancet, 1973, i,
934. 9. Mawas, C., Buffe, D., Burtin, P. ibid. 1970, i, 1292. 10. Bagshawe, A., Parker, A. M. ibid. 1970, ii, 268. 11. Br. med. J. 1974, iii, 3.