- Email: [email protected]
PHENOBARBITONE, LIVER TUMOURS, AND THOROTRAST
37
compared with those obtained
from a females of the same age. We do group of non-pregnant is an that abnormal state nor do we not suggest pregnancy this was an abnormal state these that for particular imply subjects. We were aware that these results were normal for pregnant women. G. G. DUGGIN Renal Unit and Biochemistry NANCY E. DALE Department, R. C. LYNEHAM Royal Prince Alfred Hospital, R. A. EVANS Missenden Road, D. J. TILLER. Camperdown 2050, New South Wales. our
subjects
were
PHENOBARBITONE, LIVER TUMOURS, AND THOROTRAST
SIR,-Dr Schneiderman’s interpretation (Nov. 2, p. 1085) of the data on cancer in epilepsy patients1 suffers because of the necessary brevity of statistical details in medical journals, and because of some generalisations from American experience to Danish data. In the main, the Danish data showed cancer morbidity of about the expected values for patients treated less than ten years. For those treated over longer periods most cancers were fewer, while cancer of the liver showed some " excess, although not statistically significant. As a usually accepted " explanation Dr Schneiderman mentions that
institutionalisation, besides reducing exposure to oncogens, will also cause occasional under-reporting of deaths ascribed to one cause in a population known to have another, sometimes fatal, disease. This explanation does not apply to efficient research hospitals. The neuropsychiatric hospital, Filadelfia, served as the main centre for epilepsy treatment and research in Denmark from the late 1930s to the late 1950s, when treatment became less centralised. As indicated by the dates for the introduction of new drugs, the medical staff was alert to development, and research activities produced a series of publications. 2-7 From my experience during short-term appointments in 1930-32, I can testify to the high standard of Filadelfia’s case-records, maintained during the tenure of the chief physician, Stubbe Teglbjxrg, from 1928 to 1959. That his proverbial interest in the fate of his patients certainly included the risk of liver cancer is shown by the fact that he referred the use of ’Thorotrast’ (thorium dioxide) for angiography to neurosurgical units elsewhere following a warning in 1939which I based on a discussion in the Pathological Society for Great Britain and Ireland in November, 1938. Earlier application of this compound in a number of cases naturally turned attention at Filadelfia to liver cancer. Furthermore, since patients at Filadelfia developing cancer would be referred for treatment to other hospitals, there is no reason to suppose that reporting of cancer would be less efficient for them than average. With regard to the fraction known from death certificates, up to the introduction of international certificates a cancer present at death would in Denmark invariably be classified as the primary cause of death. As appears from table i,l consequently, cancers other than those with significant deviations from the expected values showed no reduction in frequency for patients treated less than ten years. Schneiderman agrees that the deficit in numbers for 1. 2. 3. 4. 5. 6.
Clemmesen, J., Frederiksen, V. F., Plum, C. M. Lancet, 1974, i, 705. Clemmesen, C. Acta psych. neurol. 1932, suppl. 3. Teglbjærg, H. P. S. ibid. 1936, suppl. 9. Faurbye, A. Blodets reaktion ved epilepsi. Copenhagen, 1942. Hendriksen, V. Spasmofili og epilepsi. Copenhagen, 1923. Munch-Petersen, C. J. Spinalvæskens sukkerindhold. Copenhagen, 1929.
Yde, A. Nyrefunktionen ved epilepsi. Copenhagen, 1938. 8. Clemmesen, J. Ugeskr. læg. 1939, 664; Selbie, F. Lancet, 1936, ii, 7.
847.
cervical uterine
compared with expected values is reduced sexual activity among epilepsy explainable by He at Filadelfia. adds that in a population with patients a low cervical-cancer rate one usually finds high breastcancer rates, suggesting that the low rates found at Filadelfia may be due to under-reporting, and thus disregarding long-established observations. In Denmark urban/rural comparison shows parallel occurrence of cervical and mammary carcinomas,9 and in Copenhagen the social trend for cervical carcinoma has no reverse counterpart for breast cancer, the latter showing no unambiguous social trend.10° Furthermore, age-standardised morbidity rates for Denmark, 1943-67, known to Schneiderman in proof, show parallel rising secular trends for the two sites in all urban and rural categories.ll No final explanation of this parallelism is yet available, but it may be noted that the age-distribution of cervical carcinoma in Denmark differs from that of many other countries. It is true that the total for other sites fail to reach the expected values for patients treated for more than ten years, with the exception of carcinoma of the liver. However, once having accepted cancers of different sites as of different causation, and thus forming a non-homogenous group, it seems somewhat illogical that Schneiderman attempts an estimate of liver cancer in proportion to their total (exclusive of brain tumours). Employing in this way the methods also used by Clemmesen et al., Schneiderman underlines that one more case of liver cancer would mean statistical significance-thus arriving at what may be termed hypothetical significancean evaluation we would hesitate to use in view of its consequences (for example, in estimating results in cancer cancer
therapy). It should be strongly emphasised that Clemmesen et al., among their cases of liver carcinoma, included a male patient, treated for less than ten years for epilepsy, and known to have received a dose of thorotrast equivalent to 440 rad in 1946-a dose that would have justified exclusion from the material because of its oncogenic effect. Since, nevertheless, Schneiderman seems to attach significance to the small excess of liver cancer, which, even including all cases, does not reach the level of statistical significance, we feel we should give further details of this and other cases for which the accurate dose of thorotrast is not known, together with cases not having received the compound: Males 28364: Born Oct. 13, 1903. Epilepsy diagnosed, 1936. Thorotrast 440 rad. 1946. Died Nov. 23, 1964. Cholangiocarcinoma. Cirrhosis hepatis. 11002: Born Oct. 10, 1915. Epilepsy diagnosed about 1926. Thorotrast 1938. Died April 7, 1965. Hepatocarcinoma. 17123: Born Sept. 14, 1930. Epilepsy diagnosed 1942. Thorotrast Nov. 30, 1942. Died July 17, 1967. Cholangiocarcinoma. 7783: Born Oct. 15, 1905. Epilepsy diagnosed 1947. Died April 18, 1967. Adenocarcinoma hepatis, probably cholangio-
carcinoma. Female 23198: Born March 3, 1899. Epilepsy diagnosed 1946. Died July 7, 1964. Necropsy: primary liver cancer (no histology).
Since the latest symposium on the toxicity of thorotrast 12 failed to determine the oncogenic dose of this compound, and with expected values for liver cancer of 1-1 for males and 0-7 for females treated with anticonvulsants for more than ten years, we trust that Dr Schneiderman will consider our statistics conservative, stating as we did that we found no evidence that phenobarbitone is 9. 10. 11. 12.
Clemmesen, J. J. natn. Cancer Inst. 1951, 12, 1. Clemmesen, J. Acta path. microbiol. scand. 1965, suppl. 174; ibid. 1969, suppl. 209. Clemmesen, J. ibid. 1974, suppl. 247. Proceedings of III International Meeting on Toxicity of Thorotrast, 1973. Danish Atomic Energy Commission Riso Rep. 294. Roskilde, Denmark.
38 to epileptics in high doses for more than a decade. He is right in saying, however, that we did not claim to have disproved that phenobarbitone is oncogenic, since we did not extrapolate to mice, guineapigs, rats, rabbits, and monkeys.
oncogenic when given
Cancer Registry, Danish Cancer Society, Finsen Institute,
Strandboulevard 49, Denmark.
Copenhagen 2100,
resistant. coaln1lase-DOsitive. Stabh.
JOHANNES CLEMMESEN.
VENTRICULAR FIBRILLATION IN HYPOTHERMIA SiR,—Dr Lloyd and Mr Mitchell (Nov. 30, p. 1294) may well be right in their hypothesis that ventricular fibrillation in hypothermia is due to a relatively greater degree of cooling of the conducting tissue which lies just under the endocardium.
However, they use the terms " nervous tissue " or neuromuscular " to describe the conducting tissue. The conducting system in mammalian myocardium consists of modified heart-muscle cells: nerve cells are not directly involved. "
Wellcome Medical Research Institute, Department of Medicine, University of Otago Medical School, Dunedin, New Zealand.
F. O. SIMPSON.
INTRAVENOUS CEPHRADINE IN SERIOUS PÆDIATRIC INFECTIONS SIR,—This is a follow-up letter to our reporton intravenous cephradine. To date, in an open clinical trial, we have treated 11 children with intravenous cephradine, doses ranging from 85 to 300 mg. per kg. body-weight per day. In 5, coagulase-positive Staphylococcus aureus In 2 was obtained from a variety of clinical specimens. patients, pneumococcal bacteraemia occurred simultaneously with lobar pneumonia (see accompanying table). 1 child had group-A oc-streptococcus bactersemia, in the presence of extensive cellulitis of the right lower extremity 1.
Macias,
E. G.
(case 8). No phlebitis or pain arose at the site of intravenous administration in any patients and Coombs-positive ansEmia or nephrotoxicity were not observed. The time of clinical improvement was closely parallel to the return to. negative culture-on average, 5-6 days after starting of intravenous cephradine. We believe that cephradine is an effective antibiotic in the treatment of serious peediatrit infections, particularly those produced by penicillin-
Lancet, 1973, ii, 683.
Department of Pediatrics, Section of Infectious Diseases, University of Texas Health Science Center at San Antonio, Texas 78284, U.S.A.
ENRIQUE G. MACIAS JERRY J. ELLER.
BODY NITROGEN AFTER TRAUMA
SIR,—The article by Dr O’Keefe and others (Nov. 2, p. 1035) on catabolic nitrogen loss will, we hope, be the first in a seriesexploring by isotopic techniques the flux of body nitrogen after trauma. They show that urinary urea nitrogen was little altered by operation in their 4 subjects but that protein breakdown was enhanced less than was the inhibition of protein synthesis. Thirty years ago we postulated an approximately linear
relationship between the extent of injury (measured by totality of tissue damage, blood loss, supervening infection, &c.) and the totality of metabolic response (e.g., catabolic nitrogen loss, water-salt conservation). In the past decade it has become clear that such linear relationships do not obtain for all the response parameters. Although minor degrees of injury (e.g., loss of 500 ml. of blood) are strong stimuli to salt and water conservation, they are but minor stimuli to the other components of the endocrine and metabolic responses. By contrast, severe injury with a maintained low-flow state and maximal catecholamine discharge (particularly if accompanied by infection) appears to constitute a near maximum stimulus to muscle catabolism. It is therefore our concern that the 4 patients studied by O’Keefe et al. were not representative of severe injury, and that conclusions from these findings should not be extended to the truly major injuries of military or civilian life. Evidence that protein nitrogen is lost from muscle after
TREATMENT OF INFECTIONS WITH INTRAVENOUS CEPHRADINE I
I
aureus.
I
* Incision and drainage performed. + Resistant to penicillin.
compared with those obtained
from a females of the same age. We do group of non-pregnant is an that abnormal state nor do we not suggest pregnancy this was an abnormal state these that for particular imply subjects. We were aware that these results were normal for pregnant women. G. G. DUGGIN Renal Unit and Biochemistry NANCY E. DALE Department, R. C. LYNEHAM Royal Prince Alfred Hospital, R. A. EVANS Missenden Road, D. J. TILLER. Camperdown 2050, New South Wales. our
subjects
were
PHENOBARBITONE, LIVER TUMOURS, AND THOROTRAST
SIR,-Dr Schneiderman’s interpretation (Nov. 2, p. 1085) of the data on cancer in epilepsy patients1 suffers because of the necessary brevity of statistical details in medical journals, and because of some generalisations from American experience to Danish data. In the main, the Danish data showed cancer morbidity of about the expected values for patients treated less than ten years. For those treated over longer periods most cancers were fewer, while cancer of the liver showed some " excess, although not statistically significant. As a usually accepted " explanation Dr Schneiderman mentions that
institutionalisation, besides reducing exposure to oncogens, will also cause occasional under-reporting of deaths ascribed to one cause in a population known to have another, sometimes fatal, disease. This explanation does not apply to efficient research hospitals. The neuropsychiatric hospital, Filadelfia, served as the main centre for epilepsy treatment and research in Denmark from the late 1930s to the late 1950s, when treatment became less centralised. As indicated by the dates for the introduction of new drugs, the medical staff was alert to development, and research activities produced a series of publications. 2-7 From my experience during short-term appointments in 1930-32, I can testify to the high standard of Filadelfia’s case-records, maintained during the tenure of the chief physician, Stubbe Teglbjxrg, from 1928 to 1959. That his proverbial interest in the fate of his patients certainly included the risk of liver cancer is shown by the fact that he referred the use of ’Thorotrast’ (thorium dioxide) for angiography to neurosurgical units elsewhere following a warning in 1939which I based on a discussion in the Pathological Society for Great Britain and Ireland in November, 1938. Earlier application of this compound in a number of cases naturally turned attention at Filadelfia to liver cancer. Furthermore, since patients at Filadelfia developing cancer would be referred for treatment to other hospitals, there is no reason to suppose that reporting of cancer would be less efficient for them than average. With regard to the fraction known from death certificates, up to the introduction of international certificates a cancer present at death would in Denmark invariably be classified as the primary cause of death. As appears from table i,l consequently, cancers other than those with significant deviations from the expected values showed no reduction in frequency for patients treated less than ten years. Schneiderman agrees that the deficit in numbers for 1. 2. 3. 4. 5. 6.
Clemmesen, J., Frederiksen, V. F., Plum, C. M. Lancet, 1974, i, 705. Clemmesen, C. Acta psych. neurol. 1932, suppl. 3. Teglbjærg, H. P. S. ibid. 1936, suppl. 9. Faurbye, A. Blodets reaktion ved epilepsi. Copenhagen, 1942. Hendriksen, V. Spasmofili og epilepsi. Copenhagen, 1923. Munch-Petersen, C. J. Spinalvæskens sukkerindhold. Copenhagen, 1929.
Yde, A. Nyrefunktionen ved epilepsi. Copenhagen, 1938. 8. Clemmesen, J. Ugeskr. læg. 1939, 664; Selbie, F. Lancet, 1936, ii, 7.
847.
cervical uterine
compared with expected values is reduced sexual activity among epilepsy explainable by He at Filadelfia. adds that in a population with patients a low cervical-cancer rate one usually finds high breastcancer rates, suggesting that the low rates found at Filadelfia may be due to under-reporting, and thus disregarding long-established observations. In Denmark urban/rural comparison shows parallel occurrence of cervical and mammary carcinomas,9 and in Copenhagen the social trend for cervical carcinoma has no reverse counterpart for breast cancer, the latter showing no unambiguous social trend.10° Furthermore, age-standardised morbidity rates for Denmark, 1943-67, known to Schneiderman in proof, show parallel rising secular trends for the two sites in all urban and rural categories.ll No final explanation of this parallelism is yet available, but it may be noted that the age-distribution of cervical carcinoma in Denmark differs from that of many other countries. It is true that the total for other sites fail to reach the expected values for patients treated for more than ten years, with the exception of carcinoma of the liver. However, once having accepted cancers of different sites as of different causation, and thus forming a non-homogenous group, it seems somewhat illogical that Schneiderman attempts an estimate of liver cancer in proportion to their total (exclusive of brain tumours). Employing in this way the methods also used by Clemmesen et al., Schneiderman underlines that one more case of liver cancer would mean statistical significance-thus arriving at what may be termed hypothetical significancean evaluation we would hesitate to use in view of its consequences (for example, in estimating results in cancer cancer
therapy). It should be strongly emphasised that Clemmesen et al., among their cases of liver carcinoma, included a male patient, treated for less than ten years for epilepsy, and known to have received a dose of thorotrast equivalent to 440 rad in 1946-a dose that would have justified exclusion from the material because of its oncogenic effect. Since, nevertheless, Schneiderman seems to attach significance to the small excess of liver cancer, which, even including all cases, does not reach the level of statistical significance, we feel we should give further details of this and other cases for which the accurate dose of thorotrast is not known, together with cases not having received the compound: Males 28364: Born Oct. 13, 1903. Epilepsy diagnosed, 1936. Thorotrast 440 rad. 1946. Died Nov. 23, 1964. Cholangiocarcinoma. Cirrhosis hepatis. 11002: Born Oct. 10, 1915. Epilepsy diagnosed about 1926. Thorotrast 1938. Died April 7, 1965. Hepatocarcinoma. 17123: Born Sept. 14, 1930. Epilepsy diagnosed 1942. Thorotrast Nov. 30, 1942. Died July 17, 1967. Cholangiocarcinoma. 7783: Born Oct. 15, 1905. Epilepsy diagnosed 1947. Died April 18, 1967. Adenocarcinoma hepatis, probably cholangio-
carcinoma. Female 23198: Born March 3, 1899. Epilepsy diagnosed 1946. Died July 7, 1964. Necropsy: primary liver cancer (no histology).
Since the latest symposium on the toxicity of thorotrast 12 failed to determine the oncogenic dose of this compound, and with expected values for liver cancer of 1-1 for males and 0-7 for females treated with anticonvulsants for more than ten years, we trust that Dr Schneiderman will consider our statistics conservative, stating as we did that we found no evidence that phenobarbitone is 9. 10. 11. 12.
Clemmesen, J. J. natn. Cancer Inst. 1951, 12, 1. Clemmesen, J. Acta path. microbiol. scand. 1965, suppl. 174; ibid. 1969, suppl. 209. Clemmesen, J. ibid. 1974, suppl. 247. Proceedings of III International Meeting on Toxicity of Thorotrast, 1973. Danish Atomic Energy Commission Riso Rep. 294. Roskilde, Denmark.
38 to epileptics in high doses for more than a decade. He is right in saying, however, that we did not claim to have disproved that phenobarbitone is oncogenic, since we did not extrapolate to mice, guineapigs, rats, rabbits, and monkeys.
oncogenic when given
Cancer Registry, Danish Cancer Society, Finsen Institute,
Strandboulevard 49, Denmark.
Copenhagen 2100,
resistant. coaln1lase-DOsitive. Stabh.
JOHANNES CLEMMESEN.
VENTRICULAR FIBRILLATION IN HYPOTHERMIA SiR,—Dr Lloyd and Mr Mitchell (Nov. 30, p. 1294) may well be right in their hypothesis that ventricular fibrillation in hypothermia is due to a relatively greater degree of cooling of the conducting tissue which lies just under the endocardium.
However, they use the terms " nervous tissue " or neuromuscular " to describe the conducting tissue. The conducting system in mammalian myocardium consists of modified heart-muscle cells: nerve cells are not directly involved. "
Wellcome Medical Research Institute, Department of Medicine, University of Otago Medical School, Dunedin, New Zealand.
F. O. SIMPSON.
INTRAVENOUS CEPHRADINE IN SERIOUS PÆDIATRIC INFECTIONS SIR,—This is a follow-up letter to our reporton intravenous cephradine. To date, in an open clinical trial, we have treated 11 children with intravenous cephradine, doses ranging from 85 to 300 mg. per kg. body-weight per day. In 5, coagulase-positive Staphylococcus aureus In 2 was obtained from a variety of clinical specimens. patients, pneumococcal bacteraemia occurred simultaneously with lobar pneumonia (see accompanying table). 1 child had group-A oc-streptococcus bactersemia, in the presence of extensive cellulitis of the right lower extremity 1.
Macias,
E. G.
(case 8). No phlebitis or pain arose at the site of intravenous administration in any patients and Coombs-positive ansEmia or nephrotoxicity were not observed. The time of clinical improvement was closely parallel to the return to. negative culture-on average, 5-6 days after starting of intravenous cephradine. We believe that cephradine is an effective antibiotic in the treatment of serious peediatrit infections, particularly those produced by penicillin-
Lancet, 1973, ii, 683.
Department of Pediatrics, Section of Infectious Diseases, University of Texas Health Science Center at San Antonio, Texas 78284, U.S.A.
ENRIQUE G. MACIAS JERRY J. ELLER.
BODY NITROGEN AFTER TRAUMA
SIR,—The article by Dr O’Keefe and others (Nov. 2, p. 1035) on catabolic nitrogen loss will, we hope, be the first in a seriesexploring by isotopic techniques the flux of body nitrogen after trauma. They show that urinary urea nitrogen was little altered by operation in their 4 subjects but that protein breakdown was enhanced less than was the inhibition of protein synthesis. Thirty years ago we postulated an approximately linear
relationship between the extent of injury (measured by totality of tissue damage, blood loss, supervening infection, &c.) and the totality of metabolic response (e.g., catabolic nitrogen loss, water-salt conservation). In the past decade it has become clear that such linear relationships do not obtain for all the response parameters. Although minor degrees of injury (e.g., loss of 500 ml. of blood) are strong stimuli to salt and water conservation, they are but minor stimuli to the other components of the endocrine and metabolic responses. By contrast, severe injury with a maintained low-flow state and maximal catecholamine discharge (particularly if accompanied by infection) appears to constitute a near maximum stimulus to muscle catabolism. It is therefore our concern that the 4 patients studied by O’Keefe et al. were not representative of severe injury, and that conclusions from these findings should not be extended to the truly major injuries of military or civilian life. Evidence that protein nitrogen is lost from muscle after
TREATMENT OF INFECTIONS WITH INTRAVENOUS CEPHRADINE I
I
aureus.
I
* Incision and drainage performed. + Resistant to penicillin.