I'ordre de 85%). Lorsque cette fraction est inf6rieure . 0.30, avant de refuser la chirurgie ii faut proc.der, selon ce groupe de chercheurs, . une exploration
compl6mentaire incluant une ventriculographie biplan, une ventriculographie apr.s nitrog1yc.rine ou .pin.phrine, ou apr.s une extrasystole provoqu.e ainsi
qu'. des etudes isotopiques pouvant d& celer Ia pr6sence de fibres myocardiques viables dans les zones hypokin.tiques ou akin6tiques des parois ventriculaires.
New view offered of cause of postoperative sepsis Metabolic defects resulting in excessive catabolism of body protein to supply energy appear to be the basic disturbance leading to death in patients with severe sepsis. Treatment should therefore consist of providing energy substrates and altering hormonal patterns to favour anabolism. Dr. Richard J. Finley, the 1976 royal college medalist in surgery, has concluded from his research into severe postoperative sepsis in man that the commonly accepted sequence of poor capillary blood flow, tissue hypoxia, lacticacidosis and death does not apply to all patients dying from septic shock, and that treatment aimed solely at increasing blood flow and blood pressure is therefore inadequate, if not inappropriate. In his study, patients with severe sepsis, compared with controls, had significantly increased capillary blood flow
in skeletal muscle (as did fasting healthy subjects), the flow varying directly with the cardiac index. He reasoned, therefore, that the hyperdynamic circulation characteristic of severe sepsis is not likely due to peripheral arteriovenous shunts. Instead, he suggested that the sympathetic nervous system has a central role and that plasma catecholamines, which he found in significantly increased concentration in the patients with sepsis, cause many of the hemodynamic and metabolic changes, both directly and indirectly. He detected abnormal blood values for several other hormones and for energy substrates in these patients: compared with controls, they had a significant increase in concentration of insulin, glucagon, cortisol and phenylalanine, a substantial increase in concentration of lactate and a significant decrease in concentration of thyroxine, albumin and branched-chain amino
acids. The mean insulin: glucagon molar ratio, although not significantly different in the two groups, was much lower than values reported by others for normal subjects. He suggested that the hormonal state of patients with sepsis favours catabolism of body protein, and that the increased capillary blood flow in skeletal muscle is a response both to the mobilization of amino acids and to direct sympathetic stimulation. Because results from routine liver function tests in patients with severe sepsis have usually not been greatly altered from normal, liver function in these patients has been assumed to be adequate. However, Dr. Finley cited the abnormal concentrations of albumin, phenylalanine and lactate (especially in the absence of underperfusion of tissue in most of the patients) as strong evidence of impaired liver function.
Bone marrow transplantation: a survey The 25-year-long transplantation era has been dominated by work on kidney and heart transplants, but much other work has been done that is less well known. One such area is that of marrow transplantation, the topic of this year's Canadian Red Cross Society lecture, given by Dr. E. Donnall Thomas, professor of medicine at the University of Washington at Seattle. In a quiet, soft-spoken description of the work of a world-renowned centre, Dr. Thomas outlined the remarkable work he and his colleagues have done in two fields, aplastic anemia and acute leukemia; he modestly set the stage for a portrayal of how hopelessly-sick patients have been treated, at times with remarkable results. The story of the Seattle centre has been told before a television program in Canada depicted the human dimensions a year or so ago - but Dr. Thomas's low-key scientific approach had equal merit. Particularly well did he demonstrate the integration of research and patient care. Marrow transfusion first appeared to be potentially successful about 20 years ago, when it was used in the management of patients with anemia induced by irradiation or bone marrow disease.
It was, however, successful in a few patients only, primarily those who had a twin, and violent graft-v.-host (GVH) reactions put an end to the use of this form of therapy. Only a few individuals, Dr. Thomas among them, persisted in what he now sees as phase 1 of the marrow transplantation story. But persistence was rewarded: going back to the drawing board of canine research led to the important finding that tissue typing enabled the researchers to select transfusion-compatible litter mates. Phase 2 of the story began with the recognition in the late 1960s of the value of human tissue typing. Dr. Thomas and his colleagues then set up a clinical team to bring to patients the results of years of research and also the contributions of a well coordinated interdisciplinary team, to whom Dr. Thomas paid gracious tribute. Especially with the knowledge gained from an understanding of histocompatibility complexes, it became clear that there were human equivalents of the canine litter mates - siblings who could be reliably matched by serologic typing. And now two diseases, aplastic anemia and acute leukemia, could be treated in human patients, even though the pa-
tients had to have siblings as the source of the marrow, and despite previous failure with other methods of treatment. Dr. Thomas illustrated the methods of treatment and the results by reference to several interesting cases of remission. One was a case of aplastic anemia in a 12-year-old boy who had had hepatitis; he was seriously ill as a result of a lack of granulocytes and subsequent septicemia. He first received cyclophosphamide to depress his immune system. Next he received a transfusion of marrow from his sister, and then he was given methotrexat.x He made an excellent recovery - as have several others with aplastic anemia treated in this manner. Among patients aged 2 to 17 years Dr. Thomas noted a 4-year survival of greater than 65 % and among those in the 18- to 67-yearold group, more than 25%. Another case of Dr. Thomas's illustrated the results sometimes obtained in patients with acute leukemia. One was a girl, now in college, who has survived for 3½ years. She received cyclophosphamide first, then a course of radiation therapy and then a marrow transfusion from her brother; this was followed by a course of methotrexate.
CMA JOURNAL/FEBRUARY 7, 1976/VOL. 114 247
'.Miniquon It reflects a woman's natural cycle. COMPOSITION: Each package contains 11 blue tablets: mestranol 0.1 mg. 10 pink tablets: mestranal, 0.1 mg. and ethynodiol diacetate, 0.5 mg. CONTRAINDICATIONS: MINIQUEN should not be used in women with suspected ar avert liver disease, dysfunctian ar jaundice. MINIQUEN should nat be given to the patient during lactation due to the possibility of the secretian of estrogen and progestin or their metabolites in the milk. MINIQUEN should be withheld in the presence of preexisting genital or breast carcinoma; from patients with a history of thrombophiebitis or thromboembolic disease; in the presence of undiagnosed vaginal bleeding, a history of cerebral vascular accident, or the presence of unexplained loss of vision, defects in the visual field, diplopia, proptosis, migraine or the presence of neurovascular lesions of the eye; from any patient experiencing a sudden onset of severe headache, blurred vision, migraine or any neuro-ophthalmic condition that had not previously occurred, or if retinal hemorrhage or papilledema occur. In the presence of two consecutive missed menstrual periods, pregnancy should be ruled out, and if such should be the case, the drug discontinued. PRECAUTIONS, The possibility of non-functional causes should be considered in the presence of persistent break-through bleeding. The use of MINIQUEN in patients with a history of psychic depression should be carefully followed and the drug discontinued if recurrence of this condition appears imminent. The possible effect of estrogens on the metabolism of calcium and phosphorus should be borne in mind in patients with diseases affecting the metabolism of these substances. The insulin requirement of the diabetic patient occasionally changes when she is taking estrogen. This should be considered when MINIQUEN is prescribed for these patients. MINIQUEN should be used with caution in patients with cardiac or renal disease, hypertension, epilepsy or asthma. The pretreatment physical examination should include special reference to breast and pelvic organs, as well as a Papanicolaou smear. Endocrine and possibly liver function tests may be affected by treatment with MINIQUEN. Therefore, if such tests are abnormal in a patient taking MINIQUEN, it is recommended that they be repeated after the drug has been withdrawn for two months. Under the influence of estrogen-progestogen preparations, pre-existing fibroids may increase in size. DOSAGE AND ADMINISTRATION: Oral contraception with MINIQUEN should be started on the fifth day of the menstrual cycle counting the first day of flow as Day Onel. Noting the starting day, one tablet of MINIQUEN is taken daily for three weeks. This is followed by one week without medication when withdrawal bleeding may be expected. When a course of 21 tablets is finished and medication has bees stopped for seven days, the next course of 21 tablets should be started. Treatment is continued in this way, three weeks on tablets and one week off.
.,;
Soarle Pharmaceuticals Oakville, Ontario
She was also treated with antithymocyte globulin, which sometimes is valuable in treating GVH disease. This young woman is fortunate; she is one of the 25 to 50% of patients in this group who have survived for at least 1 year. Dr. Thomas emphasized one of the fascinating features of these patients who have had a poor prognosis, have received standard therapy already and are fortunate enough to have siblings on whom they can lean for therapeutic support. Successful treatment is marked by the engraftment of marrow cells that can be demonstrated to have originated in the sibling - in the 12-yearold boy the marrow contained XX
rather than XY cells, and in the college girl the marrow was found to contain XY rather than XX cells. Dr. Thomas ended this enlightening presentation by saying that certain problems remain with marrow transplantation, particularly cytomegalovirus pneumonia and immunologic difficulties. Yet, certainly, significant results are being achieved. Bone marrow transplantation is obviously not the ideal form of therapy for patients with aplastic anemia or acute leukemia, but in a very few patients it does succeed. For these patients there is hope - hope because of careful and dedicated work by men such as Thomas of Seattle.
Carcinogens are not that common The view that every chemical is a potential carcinogen must be dispelled, said Dr. E. Farber (who is the new chairman of the University of Toronto's department of pathology) during the symposium on oncogenesis sponsored jointly by the Canadian Society for Clinical Investigation and the royal college. Of the thousands tested, only about 75 chemicals have been identified as carcinogenic for humans. Most of these chemicals are not themselves carcinogens but are converted to carcinogenic derivatives by either microsomal enzymes in the liver or bacterial enzymes in the intestine. The conversion system is not yet well understood, but involves two pathways, activation and inactivation, either of which could be interrupted. Because the enzymes can be activated or inhibited, the process of carcinogenesis can be modulated; the therapeutic possibilities are obvious. Unfortunately, Dr. Farber noted, another group of chemicals, pesticides, can act as modulating agents: they can activate enzymes and thus increase the host's response to a potentially carcinogenic chemical to which he may be exposed. Hepatitis B virus is thought to have a similar effect, by activating liver enzymes, in the production of liver cancer. Today we are all exposed to some extent to two groups of such chemicals - polycyclic aromatic hydrocarbons, and nitrosamines and nitrosamides and Dr. Farber wondered to what degree these substances can be implicated in the genesis of all "naturally occurring" cancers. The geographic differences in incidence of certain cancers may be partly explained by the geographic differences in exposure to chemicals, Dr. Farber said, and he cited a striking example: women living on the southern coast of
the Caspian Sea have a high incidence of esophageal cancer, a tumour that, in other areas of the world, occurs mostly in men. This high incidence appears to be directly related to the repeated use among these women of a remedy for morning sickness consisting of fermented peppercorns and raisins, a concoction that has a high concentration of a nitrosamine. Cancer chemotherapeutic agents as a group are active carcinogens in animals, Dr. Farber pointed out, and there may be an increasing incidence of cancer associated with their increasing use. He therefore considers that chemotherapy is not the ideal treatment for young cancer patients. Chemical carcinogenesis has four stages: initiation, development, malignant neoplasia and progression. Only during the first stage is exposure to the chemical necessary, and this can be extremely brief - hours to weeks. The carcinogen has by then induced irreversible changes in the macromolecules of the cells. How it does this is not known, but Dr. Farber suggested that clues may come from studying the antigens of cancer cells, which are unique to each cancer even when induced by the same chemical. Some common antigens have been identified in various premalignant lesions. It is also not known why there is a latent period, perhaps many years, before the cancer becomes evident. The challenge, in Dr. Farber's view, is to determine how the host can suppress the evolution of altered cells. Four major types At the same symposium, Dr. A.B. Miller, of the National Cancer Institute of Canada, discussed the problems epidemiologists are looking at in regard tQ four major types of cancer - lung,
CMA JOURNALkFEBRUARY 7, 1976/VOL. 114 249
compl6mentaire incluant une ventriculographie biplan, une ventriculographie apr.s nitrog1yc.rine ou .pin.phrine, ou apr.s une extrasystole provoqu.e ainsi
qu'. des etudes isotopiques pouvant d& celer Ia pr6sence de fibres myocardiques viables dans les zones hypokin.tiques ou akin6tiques des parois ventriculaires.
New view offered of cause of postoperative sepsis Metabolic defects resulting in excessive catabolism of body protein to supply energy appear to be the basic disturbance leading to death in patients with severe sepsis. Treatment should therefore consist of providing energy substrates and altering hormonal patterns to favour anabolism. Dr. Richard J. Finley, the 1976 royal college medalist in surgery, has concluded from his research into severe postoperative sepsis in man that the commonly accepted sequence of poor capillary blood flow, tissue hypoxia, lacticacidosis and death does not apply to all patients dying from septic shock, and that treatment aimed solely at increasing blood flow and blood pressure is therefore inadequate, if not inappropriate. In his study, patients with severe sepsis, compared with controls, had significantly increased capillary blood flow
in skeletal muscle (as did fasting healthy subjects), the flow varying directly with the cardiac index. He reasoned, therefore, that the hyperdynamic circulation characteristic of severe sepsis is not likely due to peripheral arteriovenous shunts. Instead, he suggested that the sympathetic nervous system has a central role and that plasma catecholamines, which he found in significantly increased concentration in the patients with sepsis, cause many of the hemodynamic and metabolic changes, both directly and indirectly. He detected abnormal blood values for several other hormones and for energy substrates in these patients: compared with controls, they had a significant increase in concentration of insulin, glucagon, cortisol and phenylalanine, a substantial increase in concentration of lactate and a significant decrease in concentration of thyroxine, albumin and branched-chain amino
acids. The mean insulin: glucagon molar ratio, although not significantly different in the two groups, was much lower than values reported by others for normal subjects. He suggested that the hormonal state of patients with sepsis favours catabolism of body protein, and that the increased capillary blood flow in skeletal muscle is a response both to the mobilization of amino acids and to direct sympathetic stimulation. Because results from routine liver function tests in patients with severe sepsis have usually not been greatly altered from normal, liver function in these patients has been assumed to be adequate. However, Dr. Finley cited the abnormal concentrations of albumin, phenylalanine and lactate (especially in the absence of underperfusion of tissue in most of the patients) as strong evidence of impaired liver function.
Bone marrow transplantation: a survey The 25-year-long transplantation era has been dominated by work on kidney and heart transplants, but much other work has been done that is less well known. One such area is that of marrow transplantation, the topic of this year's Canadian Red Cross Society lecture, given by Dr. E. Donnall Thomas, professor of medicine at the University of Washington at Seattle. In a quiet, soft-spoken description of the work of a world-renowned centre, Dr. Thomas outlined the remarkable work he and his colleagues have done in two fields, aplastic anemia and acute leukemia; he modestly set the stage for a portrayal of how hopelessly-sick patients have been treated, at times with remarkable results. The story of the Seattle centre has been told before a television program in Canada depicted the human dimensions a year or so ago - but Dr. Thomas's low-key scientific approach had equal merit. Particularly well did he demonstrate the integration of research and patient care. Marrow transfusion first appeared to be potentially successful about 20 years ago, when it was used in the management of patients with anemia induced by irradiation or bone marrow disease.
It was, however, successful in a few patients only, primarily those who had a twin, and violent graft-v.-host (GVH) reactions put an end to the use of this form of therapy. Only a few individuals, Dr. Thomas among them, persisted in what he now sees as phase 1 of the marrow transplantation story. But persistence was rewarded: going back to the drawing board of canine research led to the important finding that tissue typing enabled the researchers to select transfusion-compatible litter mates. Phase 2 of the story began with the recognition in the late 1960s of the value of human tissue typing. Dr. Thomas and his colleagues then set up a clinical team to bring to patients the results of years of research and also the contributions of a well coordinated interdisciplinary team, to whom Dr. Thomas paid gracious tribute. Especially with the knowledge gained from an understanding of histocompatibility complexes, it became clear that there were human equivalents of the canine litter mates - siblings who could be reliably matched by serologic typing. And now two diseases, aplastic anemia and acute leukemia, could be treated in human patients, even though the pa-
tients had to have siblings as the source of the marrow, and despite previous failure with other methods of treatment. Dr. Thomas illustrated the methods of treatment and the results by reference to several interesting cases of remission. One was a case of aplastic anemia in a 12-year-old boy who had had hepatitis; he was seriously ill as a result of a lack of granulocytes and subsequent septicemia. He first received cyclophosphamide to depress his immune system. Next he received a transfusion of marrow from his sister, and then he was given methotrexat.x He made an excellent recovery - as have several others with aplastic anemia treated in this manner. Among patients aged 2 to 17 years Dr. Thomas noted a 4-year survival of greater than 65 % and among those in the 18- to 67-yearold group, more than 25%. Another case of Dr. Thomas's illustrated the results sometimes obtained in patients with acute leukemia. One was a girl, now in college, who has survived for 3½ years. She received cyclophosphamide first, then a course of radiation therapy and then a marrow transfusion from her brother; this was followed by a course of methotrexate.
CMA JOURNAL/FEBRUARY 7, 1976/VOL. 114 247
'.Miniquon It reflects a woman's natural cycle. COMPOSITION: Each package contains 11 blue tablets: mestranol 0.1 mg. 10 pink tablets: mestranal, 0.1 mg. and ethynodiol diacetate, 0.5 mg. CONTRAINDICATIONS: MINIQUEN should not be used in women with suspected ar avert liver disease, dysfunctian ar jaundice. MINIQUEN should nat be given to the patient during lactation due to the possibility of the secretian of estrogen and progestin or their metabolites in the milk. MINIQUEN should be withheld in the presence of preexisting genital or breast carcinoma; from patients with a history of thrombophiebitis or thromboembolic disease; in the presence of undiagnosed vaginal bleeding, a history of cerebral vascular accident, or the presence of unexplained loss of vision, defects in the visual field, diplopia, proptosis, migraine or the presence of neurovascular lesions of the eye; from any patient experiencing a sudden onset of severe headache, blurred vision, migraine or any neuro-ophthalmic condition that had not previously occurred, or if retinal hemorrhage or papilledema occur. In the presence of two consecutive missed menstrual periods, pregnancy should be ruled out, and if such should be the case, the drug discontinued. PRECAUTIONS, The possibility of non-functional causes should be considered in the presence of persistent break-through bleeding. The use of MINIQUEN in patients with a history of psychic depression should be carefully followed and the drug discontinued if recurrence of this condition appears imminent. The possible effect of estrogens on the metabolism of calcium and phosphorus should be borne in mind in patients with diseases affecting the metabolism of these substances. The insulin requirement of the diabetic patient occasionally changes when she is taking estrogen. This should be considered when MINIQUEN is prescribed for these patients. MINIQUEN should be used with caution in patients with cardiac or renal disease, hypertension, epilepsy or asthma. The pretreatment physical examination should include special reference to breast and pelvic organs, as well as a Papanicolaou smear. Endocrine and possibly liver function tests may be affected by treatment with MINIQUEN. Therefore, if such tests are abnormal in a patient taking MINIQUEN, it is recommended that they be repeated after the drug has been withdrawn for two months. Under the influence of estrogen-progestogen preparations, pre-existing fibroids may increase in size. DOSAGE AND ADMINISTRATION: Oral contraception with MINIQUEN should be started on the fifth day of the menstrual cycle counting the first day of flow as Day Onel. Noting the starting day, one tablet of MINIQUEN is taken daily for three weeks. This is followed by one week without medication when withdrawal bleeding may be expected. When a course of 21 tablets is finished and medication has bees stopped for seven days, the next course of 21 tablets should be started. Treatment is continued in this way, three weeks on tablets and one week off.
.,;
Soarle Pharmaceuticals Oakville, Ontario
She was also treated with antithymocyte globulin, which sometimes is valuable in treating GVH disease. This young woman is fortunate; she is one of the 25 to 50% of patients in this group who have survived for at least 1 year. Dr. Thomas emphasized one of the fascinating features of these patients who have had a poor prognosis, have received standard therapy already and are fortunate enough to have siblings on whom they can lean for therapeutic support. Successful treatment is marked by the engraftment of marrow cells that can be demonstrated to have originated in the sibling - in the 12-yearold boy the marrow contained XX
rather than XY cells, and in the college girl the marrow was found to contain XY rather than XX cells. Dr. Thomas ended this enlightening presentation by saying that certain problems remain with marrow transplantation, particularly cytomegalovirus pneumonia and immunologic difficulties. Yet, certainly, significant results are being achieved. Bone marrow transplantation is obviously not the ideal form of therapy for patients with aplastic anemia or acute leukemia, but in a very few patients it does succeed. For these patients there is hope - hope because of careful and dedicated work by men such as Thomas of Seattle.
Carcinogens are not that common The view that every chemical is a potential carcinogen must be dispelled, said Dr. E. Farber (who is the new chairman of the University of Toronto's department of pathology) during the symposium on oncogenesis sponsored jointly by the Canadian Society for Clinical Investigation and the royal college. Of the thousands tested, only about 75 chemicals have been identified as carcinogenic for humans. Most of these chemicals are not themselves carcinogens but are converted to carcinogenic derivatives by either microsomal enzymes in the liver or bacterial enzymes in the intestine. The conversion system is not yet well understood, but involves two pathways, activation and inactivation, either of which could be interrupted. Because the enzymes can be activated or inhibited, the process of carcinogenesis can be modulated; the therapeutic possibilities are obvious. Unfortunately, Dr. Farber noted, another group of chemicals, pesticides, can act as modulating agents: they can activate enzymes and thus increase the host's response to a potentially carcinogenic chemical to which he may be exposed. Hepatitis B virus is thought to have a similar effect, by activating liver enzymes, in the production of liver cancer. Today we are all exposed to some extent to two groups of such chemicals - polycyclic aromatic hydrocarbons, and nitrosamines and nitrosamides and Dr. Farber wondered to what degree these substances can be implicated in the genesis of all "naturally occurring" cancers. The geographic differences in incidence of certain cancers may be partly explained by the geographic differences in exposure to chemicals, Dr. Farber said, and he cited a striking example: women living on the southern coast of
the Caspian Sea have a high incidence of esophageal cancer, a tumour that, in other areas of the world, occurs mostly in men. This high incidence appears to be directly related to the repeated use among these women of a remedy for morning sickness consisting of fermented peppercorns and raisins, a concoction that has a high concentration of a nitrosamine. Cancer chemotherapeutic agents as a group are active carcinogens in animals, Dr. Farber pointed out, and there may be an increasing incidence of cancer associated with their increasing use. He therefore considers that chemotherapy is not the ideal treatment for young cancer patients. Chemical carcinogenesis has four stages: initiation, development, malignant neoplasia and progression. Only during the first stage is exposure to the chemical necessary, and this can be extremely brief - hours to weeks. The carcinogen has by then induced irreversible changes in the macromolecules of the cells. How it does this is not known, but Dr. Farber suggested that clues may come from studying the antigens of cancer cells, which are unique to each cancer even when induced by the same chemical. Some common antigens have been identified in various premalignant lesions. It is also not known why there is a latent period, perhaps many years, before the cancer becomes evident. The challenge, in Dr. Farber's view, is to determine how the host can suppress the evolution of altered cells. Four major types At the same symposium, Dr. A.B. Miller, of the National Cancer Institute of Canada, discussed the problems epidemiologists are looking at in regard tQ four major types of cancer - lung,
CMA JOURNALkFEBRUARY 7, 1976/VOL. 114 249
